Chapter 6

Question 1

The normal immune response has two types of immunities

1) ___ immunity is when the body is ready to react to infections even before they occur and has evolved to specifically recognize and combat microbes

^** First it recognizes microbes or damaged cells, then it activates various mechanisms, and finally it eliminates the unwanted substances

It provides host defense by two mechanisms, inflammation and antiviral defense via Type __ interferons that creates an anti-viral state

2) ___ immunity is stimulated by microbes and is capable of recognizing microbial and nonmicrobial substances

^** Immune response usually refers to adaptive immunity

Answer 1

1) Innate

Type 1 Interferons

2) Adaptive

Question 2

The major components of innate immunity (0-12 hours after infection) includes

1) ___ to block entry of microbes from the external environemnt (as seen in the skin and GI tract)

^** Epithelial cells produce various antimicrobial molecules including defensins and lymphocytes to kill the microbes before they can fully penetrate the cells

2) Phagocytotic cells including ___ and ____

^** Remember, hemopoietic stem cells from the bone marrow can differentiate into monocytes and then be recruited to the site of infection where they turn into macrophages (but this process normally occurs when there is an injury or during inflammation Since these blood monocytes only have a half life of about 1 day)

However, the fetal yolk sac and liver also produces progenitor cells during early development, which differentiate into ____ which populate the tissues and stay for long periods in the steady state (can survive for several months or years) and are replenished via proliferation of resident cells

3) ___ cells are present in the epithelia, lymphoid organs, and most tissues and they display antigens and peptides for recognition by T lymphocytes along with secreting cytokines and therefore play a role in initiation of innate immunity, but don’t destroy the microbes
4) ___ cells provide early protection against viruses and intracellular bacteria
5) ___ cells also play a large role in inflammation via releasing heparin and histamine to reduce blood viscosity and cause vasodilation
6) ___ cells which have the appearance of lymphocytes (T cells, B cells, NK cell) but features of innate immune response cells

^** NK cells are considered the first defined ILCs and have a role in early defense against infections, recognition and elimination of stressed cells, and shaping the later adaptive immune responses via cytokines

7) The ___ system are plasma proteins activated by microbes

^** However, realize that in INNATE immunity, the complement system can be activated via the ___ pathway or ___ pathway, whereas in ADAPTIVE immunity the ___ pathway can be activated

8) Mannose binding lectin and C reactive proteins are two other circulating proteins that coat microbes for phagocytosis and Lung surfactant is also considered a component of innate immunity

Answer 2

1) Epithelial barriers (epithelia)
2) Neutrophils and macrophages (from monocytes)

Resident tissue macrophages

3) Dendritic cells
4) NK cells
5) Mast cells
6) Innate lymphoid cells (ILCs)
7) Complement

Alternative (activated via Gram- or Gram+ bacteria) and Lectin (activated via microbes containing mannose), Classical (activated via antibodies)

Question 3

In innate immunity if cells become injured or necrose, they release products called ___, which are recognized by leukocytes of the innate immune response via binding to ____

These PRRs can also bind to ___ which are the products associated with microbes when they invade the tissue

^** So in other words, depending on the type of injury (infection, necrosis, foreign body, cell injury, etc…) PAMPs or DAMPs are released that bind to leukocytes in the tissue via PRRs

These PRRs are located in ALL tissues where microbes could be present and different receptors bind to different microbes/products based on their location so for example,

1) ___ receptors bind to extracellular microbes
2) ___ receptors bind to ingested microbes
3) ___ receptors bind to cytoplasmic microbes

Answer 3

DAMPs (Damage-associated molecular patterns), PRRs (Pattern recognition receptors)

PAMPs (Pathogen associated molecular patterns)

1) Plasma membrane
2) Endosomal
3) Cytosolic

Question 4

Toll-like receptors TLRs are the best known PRRs

They exist in the ___ (where they detect extracellular microbes) and the ___ (where they detect the nucleic acid of ingested microbes) and even though there are 10 different kinds that bind to different sets of microbes, they all signal the same way

The signaling occurs via activation of ___, which stimulates the synthesis and secretion of cytokines and adhesion molecules needed for the recruitment and activation of leukocytes

And ___, which stimulates the production of antiviral cytokines, aka Type __

^** Germline ___ of function mutations that affect TLRs and the signaling results in immunodeficiency syndromes (talked about later)

Answer 4

Plasma membrane and endosomal membrane

NF-KappaBeta

IRFs (Interferon regulatory factors), Type 1 Interferons (IFN-alpha and IFN-beta are the most common)

Loss

Question 5

Along with TLRs that has a role in innate immunity, NOD-like receptors (NLRs) are found in the ___ and recognizes a wide variety of substances including products of ___ cells (uric acid and released ATP aka bacterial peptidoglycans which are products of damaged cells), ___ disturbances (like the loss of K+), and some microbial products

The way NLRs signal is through a cytosolic multi-protein complex called an ___

This inflammasome is made up of a sensor called ___, and adapter, and a inactive caspase-___

What happens in bacterial products, crystals, K+ efflux, necrotic cells leading to ROS, etc… (Aka products of dead cells and some microbes) become recognized by the inflammasome once bound to the NOD-like receptor and then the inactive caspase-1 becomes activated, which cleaves a precursor form of the cytokine ___ into active IL-1Beta and the active IL-1Beta is a mediator of acute inflammation that recruits leukocytes and induces fever

___ of function mutations in one of the NLRs leads to periodic fever syndromes called ___ syndromes, which can simply be treated with an IL-1 antagonist

^**These receptors can be responsible for the inflammation seen in gout due to binding of urate crystals, or obesity-associated type 2 diabetes via binding to lipids, or atherosclerosis due to binding of lipids

Answer 5

Cytosol, Necrotic, Ion

Inflammasome

NLRP-3, Caspase-1

Pro-IL-1Beta

Gain, Autoinflammatory

Question 6

Other receptors for microbial products include CLRs (C-type lectin receptors) which are expressed on the ___ of macrophages and dendritic cells which detect ___ glycans and elicit inflammatory reactions to fungi (via binding to microbial polysaccharides)

RIG-like receptors (RLRs) are also receptors for microbial products and is located in the ___ of most cell types to detect nucleic acids of ___ that replicate in the cytoplasm of infected cells via stimulating the production of antiviral cytokines

____ recognize short bacterial peptides that contain N-formylmethionyl residues (which is not normally found in normal mammalian proteins) and stimulates chemotactic responses of the cells

___ receptors recognize microbial sugars (such as those with terminal mannose residues) and induce phagocytosis of the microbes

Answer 6

Plasma Membrane, fungal.

Cytoplasm, viruses

GPCRs

Mannose receptors

Question 7

There are two types of adaptive immunity, ___ immunity which protects against extracellular microbes and their toxins and mediated via __ lymphocytes, and ___ immunity which protects against intracellular microbes and mediated via ___ lymphocytes

Mature lymphocytes that have not encountered an antigen to activate them are called ___ cells, however once activated they differentiate into memory cells, effector cells, and regulatory cells

Answer 7

Humoral, B, Cell mediated, T

Naive

Question 8

DO NOT confuse NK cells Natural killer cells) vs CTL (Cytotoxic T lymphocytes aka Killer T cells)

NK cells have a role in ___ immunity since they do not need to recognize an antigen and CTL cells have a role in ___ immunity since they recognize an antigen

___ is the idea that stem cells produce immature lymphocytes with many different antigen receptors and those that bind to bodies own antigens become destroyed (negative selection) and those that don’t mature… Now, when an antigen binds to its receptor on the inactive mature lymphocyte, the lymphocyte produces many clones of itself (realize most antigen receptors never meet their antigen)

^** This antigen receptor diversity occurs via ____ of genes that encode for the receptor proteins (TCR in T cells and Ig in B cells) due to the enzyme ___ and therefore if RAG is defective, mature lymphocytes can not be generated

Since each T and B cell along with their clonal progeny have unique DNA rearrangements and therefore unique antigen receptors, this can be used to determine if a tumor derived from lymphocytes is polyclonal aka derived from many different lymphocytes (___plastic) vs monoclonal derived from a single lineage of lymphocytes (___plastic) lymphoid tumors

Answer 8

Innate, adaptive

Clonal selection

Somatic recombination, RAG (RAG-1 and RAG-2 aka recombination activating genes)

Nonneoplastic, neoplastic

Question 9

There are 3 types of T lymphocytes

1) ___ cells stimulate B lymphocytes to make antibodies and activates other leukocytes to destroy microbes
2) ___ cells kill infected cells
3) ___ cells limit the immune response and prevents reactions against self antigens

T cells are produced in the bone marrow from hematopoietic stem cells and travel to the ___ where they mature and then found in the blood and T-cell zones of peripheral lymphoid organs

Answer 9

1) T-helper cells
2) CTL (Cytotoxic T Lymphocytes)
3) Regulatory T cells

Thymus

Question 10

T-cell recognize antigens via ___ receptors

The TCR has alpha and beta polypeptide chains, and variable and constant regions with the ___ region being the one to bind the antigen that is being displayed via MHCs (major histocompatibility complexes) on the surface of APCs (antigen presenting cells)

^** The immune system makes sure that T cells see only cell-associated antigens via limiting the specificity of T cells for peptides displayed by the cell surface MHC molecules, called MHC restriction

Along with the alpha and beta chains, there is the ___ (which is composed of two co-receptors with both having a epsilon subunit and one having a gamma subunit and the other a delta subunit) and __ chain that all together forms the TCR complex

^** The CD3 and Zeta proteins are involved in signal transduction

Side note, there is two other small populations of T cells including DeltaGamma TCRs that don’t need a MHC presenting cell to become activated and are present in the epithelium like the skin/mucosa/GI tract etc… And the other small subset is NK-T cells that recognizes Gylcolipids displayed by MHC like molecule - CD1

Answer 10

TCRs (T cell receptors)

Variable

CD3, Zeta

Question 11

Along with the TCR complex, T-cells also express CD4 and CD8 (coreceptors), CD28 (a costimulator than binds to B7 on APCs), and integrins (promote the attachment of T-cells to APCs) on their surface

CD4+ binds to Class ___ MHC molecules and therefore functions as T-helper cells to secrete cytokines and assist/activate macrophages and B lymphocytes

CD8+ binds to Class ___ MHC molecules and therefore mostly function as CTLs

Answer 11

2

1

Question 12

Immature B cells develop from precursor stem cells in the bone marrow and leave the bone marrow and circulates through the blood and lymphoid tissues where they are called naive B cells (aka virgin B cells) that display ___ or ___ as the membrane receptors that bind to antigens

Once stimulated (which we will talk about more in depth later) they turn into ___ cells where they can now secreted lots of antibodies

^** Antibody secreting cells detected in human peripheral blood is called plasmablasts

The B cell antigen receptor complex consists of Ig membrane receptors (IgD or IgM), along with ___ and ___ which are used for signal transduction (similar to the CD3 and Zeta chain for signal transduction in T cells)

The B cells also express ___ (which recognizes complement products generated during innate immune responses to microbes) and ___ which receives signals from helper T cells

^** Side note, the Epstein-Barr virus (EBV) uses the ___ receptor to enter the B cells and infect them

Answer 12

IgD or IgM

Plasma

Ig-Alpha (CD79a) and Ig-Beta (CD79b)

CD21 (aka CR2 aka Type 2 complement receptor), CD40

CD21 (aka CR2)

Question 13

___ cells are the most important antigen presenting cells for initiating T cell responses against protein antigens

These cells are located under the epithelia and in the interstitia of all tissues (where antigens can be produced) and immature dendritic cells in the epidermis are called ___ cells

Dendritic cells also express lots of TLR and Lectin receptors to respond to microbes, along with lots of MHCs to present the antigens of the microbes…also when they respond they are recruited to T-cell zones of lymphoid organs to present the antigens to T cells

___ cells are present in the germinal centers of lymphoid follicles located in the spleen and lymph nodes where they display Fc receptors for IgG and receptors for C3b to trap antigens bound to antibodies or complement proteins and these cells are important for humoral immunity via presenting antigens to B cells and selecting B cells with the highest affinity for the antigen

Answer 13

Dendritic

Langerhans cells

Follicular dendritic cells

Question 14

Macrophages have a role in both innate and adaptive immunity

In adaptive immunity, macrophages act as APCs, they are effector cells in certain cell-mediated immune responses where they eliminate ____ microbes, and they also are effector cells in humoral immunity where they phagocytose and destroy ___ microbes coated by IgG or C3b

CD56 and CD16 (an Fc receptor for IgG) are cell surface molecules used to identify ___ cells that destroy virus-infected and tumor cells as an early line of defense against these problems

^** The destruction of IgG coated target cells via NK cells is called antibody-dependent cell-mediated cytotoxicity (ADCC)

NK cells are regulated via activating and inhibiting receptors

Normally, NK cells recognize ___ molecules which are expressed on all healthy cells and act as inhibitor receptors and therefore no actions are taken

However, when a virus or tumor infects the cell, the infected cell’s MHC class 1 expression decreases and the infected cell’s ligands for activating receptors like ___ found on NK cells is increased leading to the infected or tumor cell being killed

^**NK cells secrete IFN-Gamme to activate macrophages to destroy ingested microbes as well and therefore provide early defense agaisnt intracellular microbial infections and NK cells proliferate via IL-2 and IL-15 and activate killing via IL-12

Answer 14

Intracellular, opsonized

NK cells (Natural killer cells)

Self class 1 MHC molecules

NKG2D

Question 15

The tissues of the immune system consist of ___ lymphoid organs where T and B lymphocytes mature and become competent to respond to antigens and include the thymus (T cells mature) and bone marrow (B cells mature)

And ___ lymphoid organs in which adaptive immune responses to microbes are initiated and include the lymph nodes, spleen, and mucosal and cutaneous lymphoid tissues

1) Lymph nodes are aggregates of lymphoid tissues located along lymphatic channels throughout the body and APCs in the nodes sample antigens of microbes that entered through the epithelia, into the tissues, and then into the lymph channels

^** Dendritic cells also pick up antigens of microbes in the epithelia and tissues and bring them into the lymph channels via lymph vessels

In lymph nodes, B and T lymphocytes are segregated and the B cells are concentrated in ___ located around the ___ of each node and if the B cells in a follicle have responded to an antigen, they contain a central region called a ___ center… The follicles contain follicular dendritic cells involved in the activation of B cells

T cells are located in the ___ adjacent to the follicles and contain dendritic cells that present antigens to T lymphocytes

2) The spleen serves their role in detecting blood born antigens where blood-born antigens are trapped via dendritic cells and macrophages in spleen sinusoids
3) Cutaneous lymphoid systems are located under the epithelia of the skin and the mucosal lymphoid systems are located under the epithelia of the GI tract

^** Pharyngeal tonsils and Peyer’s patches of the intestine are two examples of mucosal lymphoid tissue

Note that lymphocytes constantly recirculate between tissues and home to particular sites and this is most important for naive T cells to see if they can find an antigen or effector cells to located and eliminate microbes, but not as much for B cells since they just secrete antibodies

Answer 15

Primary (aka generative aka central)

Secondary (aka peripheral)

1) Follicles, cortex (aka periphery aka outside), germinal center

paracortex

Question 16

Class 1 MHC molecules are coded by the 3 HLA genes HLA-___, ___, and ___ and consist of 3 __ subunits and 1 ___ subunit (with alpha 1 and alpha 2 binding 8-10 amino acids, alpha 3 containing a binding site for CD8, and Beta2M helps transport the peptide to the surface of the MHC molecule)

So the ___ chain binds to CD8+ T cells

MHC1 molecules display peptides from ___ proteins such as viral or tumor antigens and are recognized by CD8+ T cells

^** CD8+ T cells are said to be Class 1 MHC restricted

Class 2 MHC molecules is coded by 3 HLA genes called HLA-___, ___, and ___ and consists of 2 alpha and 2 beta subunits

^** ___ and ___ subunits bind the peptide and the ___ subunit binds CD4+ T cells (Therefore CD4+ T cells are said to be class 2 MHC restricted)

Class 2 MHC molecules present antigens that are internalized into vesicles and typically derived from ___ microbes and soluble proteins

Finally, MHC genes also code for some complement proteins (sometimes called Class 3 molecules) and some cytokines like TNF and LT (lymphotoxin)

Answer 16

HLA-A, B and C, alpha, Beta2m (microglobulin)

Alpha-3

Cytosolic

HLA-DP, DQ, and DR

Alpha1 and Beta1, Beta2

Extracellular

Question 17

Innate immune cytokines include commonly IL-1, TNF, IL-12, Type 1 IFNs, IFN-gamma, and chemokines

Adaptive immune cytokines include commonly IL-2, IL-4, IL-5, IL-17, and IFN-gamma

Cytokines that stimulate hematopoiesis are called ___ and include IL-7, GM-CSF, and others

Answer 17

colony stimulating factors (CSF)

Question 18

Microbes and their protein antigens are captured by dendritic cells that are resident in the epithelia and tissues, and these dendritic cells now become APCs that move to peripheral lymphoid organs (where lymphocytes circulate) in order to display their antigens to Naive T-cells

When these APCs bind the microbe’s protein antigen, as they travel to the peripheral lymphoid organs costimualtors are up-regulated such as ___ which is found on the dendritic APCs that binds to ___ on naive T cells

^** Therefore, there is 2 signals required for the adaptive immune response (TCR complex + Coreceptor AND CD28-B7 Costimulation) and this 2 signal requirement ensures that adaptive immune responses are induced by microbes and not harmful substances

For immunization via vaccines a patient is given a protein antigen that mimics the microbial protein antigen (which is called an ___) leading to stimulating of innate immune responses and the presentation of costimulators on APCs just like a real microbe acts

Once the APC travels to the peripheral lymphoid organs and activates the naive T cells to begin to proliferate, the T-cell up-regulate secretion of ___ and also they up-regulate the expression of high-affinity receptors for IL2 on themselves and therefore stimulate their own proliferation in an autocrine manner (cytokines act on the same cells that produce them)

Now that the T cells have proliferated in the peripheral lymphoid organs into effector (TH0) and memory T cells, the effector T cells enter into the blood stream and migrate towards the actual site were the rest of the antigens are present

Once the matured T cells get to the site of infection, they once again interact with APCs (that have the same antigens as the dendritic cells that activated them) in order to become even more active and make the macrophages (located at the site of injury) and B-lymphocytes (located in the lymphoid organs where in this case the some mature T cells stay) more potent

This occurs due to the up-regulation of ___ on the mature T cells that binds to ___ on the APCs at the site of injury along with increased cytokine secretion and continued up-regulation of B7 and CD28

Answer 18

B7 (CD80 + CD86), CD28

Adjuvant

IL-2

CD40L, CD40

Question 19

So at the site of injury, the CD4+ T cells can differentiate into 3 major effector Th cell

When a Th1 cell secreting ___ along with the CD40L and CD40 interaction and the MHC/TCR interaction occurs, macrophages are activated resulting in the classical macrophage activation pathway to destroy ingested microbes

^** TH1 cells also stimulate ___ antibody production

TH2 cells with the CD40L and CD40 interaction, MHC/BCR interaction, along with secretion of ___ stimulates B cells to differentiate into IgE-secreting plasma cells (which increases mast cells) and ___ activates eosinophils to destroy helminths (parasites)

^** TH2 also activates the classical macrophage pathway via IL-4 and IL-13

TH17 cells secrete IL17 to recruit neutrophils and monocytes some extracellular bacteria, and ___

**I would know PG 198 ***

Answer 19

IFN-gamma

IgG

IL-4, IL-5

Fungi

Question 20

Most antibody responses are T cell ___ which means B cells bind peptide microbes and ingest the protein antigens into vesicles, and degrade them and then display them via class __ MHC molecules for recognition by TH1 or TH2 helper T cells and then activation into plasma cells or memory cells

^** Also CD40/CD40L and cytokine interactions are needed for activation

There are some polysaccharides and lipid antigens than can not be recognized by T cells, and these non-peptide microbes bind to MANY different BCRs (epitopes) on the same B cell via cross linking and this itself initiates B cell activation into plasma cells and this entire response is called T cell ___

^** So realize T cell dependent can differentiate into memory cells but T cell independent cant

Answer 20

Dependent, 2

Independent

Question 21

Like we already talked about, when a Naive B cell becomes activated via a T-helper cell, it proliferates and becomes active as a plasma cell where it can now release antibodies

The antibodies that are released are based on the antigen that it bound to when it met with the T-helper cell, and since most polysaccharides and lipids that make up microbes stimulate the secretion of ___ antibodies, this is the antibody that is continued to be made if no cytokines are expressed

However, if when the Naive B cell and TH cells were bound and cytokines were released from the Th cell to the B cell’s cytokine receptor, then it can induce the B cell to undergo isotope switching and therefore change its secretion from IgM to IgG, IgA, or IgE

IL-4 from TH2 cells causes class switching to Ig___

IL-5 from TH2 cells cause class switching to Ig___ (to defend against extracellular pathogenic bacteria like in the gut)

IFN-Gamma from TH1 cells cause class switching to Ig__

Also realize that TH cells can cause stimulation and production of antibodies with the highest affinity for the antigen which is called ____ to improve the humoral immune response

^** Isotype switching and affinity maturation occur mainly in ___ centers (in secondary follicles to be exact) and the TH cells that aid in this process are called follicular helper T cells (TFH cells)

Answer 21

IgM

IgE

IgA

IgG

Affinity maturation

Germinal

Question 22

Antibodies can have various effects including

1) Binding to microbes to prevent them from infecting cells (neutralization)
2) Class switching to Ig___ which opsonizes microbes and targets them for phagocytosis (macrophages and neutrophils that express Fc tails for IgG), or Ig___ for mucosal immunity (GI tract and respiratory lumens) or Ig__ for mast cell and eosinophil activation for parasites)
3) ___ and ___ activate complement via the classical pathway to promote phagocytosis and microbe destruction (lysis) along with inflammation
4) ___ important for protecting the newborn via transportation across the placenta (passive immunity to neonates)
5) Antibody dependent cytotoxicity via activation of NK cells

Answer 22

2) IgG, IgA, IgE
3) IgG and IgM
4) IgG

Question 23

When the immune system reacts abnormally to a foreign substance, causing injury, it is called a ___ reaction

^** Can occur from both exogenous (environmental) antigens or endogenous self antigens which is called an ___ disease

Hypersensitivity reactions are often due to a failure of normal regulation from inheritance of a particular susceptibility gene

There are 4 types of hypersensitivity reactions, name them

1) Results in systemic lupus erythematosus (immune system attacks itself and leads to an inflammatory disease), some forms of glomerulonephritis, serum sickness (acute and chronic), reactive arthritis, and Arthus reaction (deposition of antibody-antigen complexes in the vascular wall leading to vasculitis) and this is due to Ig__ and Ig___ antibodies forming a complex with antigens (Ab-Antigen complex) and being deposited in tissues and inducing inflammation in those tissues leading to neutrophil and monocyte recruitment that causes tissue damage due to the release of lysosomes and ROS

2) Results in anaphylaxis, allergies, bronchial asthma (atopic forms) and is caused by Th___ cells, Ig____ antibodies, mast cells and some other leukocytes
^** These cells release vasoactive amines and other mediators from mast cells etc and later recruit inflammatory cells

3) Results in contact dermatitis (skin rash), multiple sclerosis (immune system destroying nerves), Type 1 diabetes, and tuberculosis and is caused by activated ___ lymphocytes including Th__, Th___, and ___s that release cytokines, causing inflammation, and cause T-cell mediated cytotoxicity
4) Results in autoimmune hemolytic anemia (Abs against a persons own RBCs cause them to burst), blood transfusion reactions, or Goodpasture syndrome and this anti-body mediated disorder is caused by excess Ig___ and Ig___ antibodies (aka cytotoxic Abs) that promote the phagocytosis and lysis of healthy cells along with inducing inflammation

Fibrinoid necrosis is an example of Type __ hypersensitivity

Granulomas are an example of type ___ hypersensitivity

** Just for some distinction, type 2 is associated with no major complexes being formed and phagocytosis and is tissue specific whereas type 2 has complexes formed and death via necrosis and is non tissue specific

Aka type 2 Ag is where it is suppose to be and type 3 Ag is not where it is suppose to be

Answer 23

Hypersensitivity

Autoimmune

1) Immune-complex Type 3, IgG and IgM
2) Immediate Type 1, Th2, IgE

3) Cell mediated Type 4, Th1/Th17/CTLs
^** Note TH2 cells are considered Type 1, not type 4

4) Antibody-mediated Type 2, IgG and IgM

Type 3

Type 4

Question 24

Immediate Type 1 hypersensitivity is a rapid immunologic reaction occurring in a previously sensitized individual that has IgE antibodies on the surface of ___ cells (due to sensitization)

These IgE antibodies are bound to the mast cell’s ___ (Fc receptor) and when the mast cell binds a subsequent allergen, cross-linking of the high affinity IgE FC receptors occurs and it causes the release of mediators from their cytoplasmic granules that is responsible for the reaction (**Note the granules also have acidic proteoglycans that bind to toludine blue)

^** C3a and C5a can also elicit this response and therefore are called anaphylatoxins, along with Il-8, bee venom, and some physical stimuli

Normally, Type 1 has two phases

1) The Immediate reaction becomes evident within a few minutes and can last a few hours and this causes vasodilation, vascular leakage, smooth muscle spasms and possibly glandular secretions (via mast cells releasing vasoactive amines and lipid mediators)
2) The Late-phase reaction occurs 2-24 hours after exposure and is characterized by leukocyte infiltration of tissues (eosinophils, neutrophils, basophils, monocytes, CD4+ T cells, etc) and cause tissue damage commonly in the form of mucosal epithelial cell damage (via mast cells releasing cytokines)… Also the leukocytes that are recruited amplify and sustain the inflammatory response without additional exposure to the triggering of antigen and one common and abundant leukocyte recruited for these types of reactions are called ___

^** These are both caused by excess ___ cells responses leading to IgE production via class switching (which occurs from IL-___ being releases) and promotion of inflammation

IL-__ enhances IgE production and acts on epithelial cell to stimulate mucus secretion

Also remember Th2 cells activate eosinophils via IL-___ to release major basic protein and eosinophil cationic protein (which damage tissues) and this occurs in the late-phase reaction

Last, realize that mast cell’s counterpart ___ also have IgE Fc receptors and cytoplasmic granules to be activated in allergic reactions, but these are different from mast cells due to the fact that they are not present and instead circulate in the blood where they can be called during inflammation

Answer 24

Mast

FCeRI

Eosinophils

Th2, IL-4

IL-13

IL-5

Basophils

Question 25

Once cross linking occurs and mast cells become activated,

1) Signals for degranulation occur first, which discharges ___ (primary) mediators

^** These preformed mediators can be divided into 3 categories including

A) Vasoactive amines such as ___ that causes smooth muscle contraction, increased vascular permeability, vasodilation, and mucus secretion by nasal, bronchial, and gastric glands

B) Release of ___ such as proteases (causes proteolysis aka protein catabolism that causes cytoskeletal damage) and hydrolases and these enzymes can also produce kinins and inflammatory components of complement (like C3a)

C) ___ like heparin (an anti-coagulant) and chondroitin sulfate and these proteoglycans are important to package and store the amines in the granules

2) Signals for de novo synthesis and release of secondary mediators occurs

^** These secondary mediators include lipids and cytokines

A) Lipids mediators are produced due to the fact the Phospholipase A2 becomes activated and cleaves AA and therefore the production of PGs and LT

^** The Leukotrienes that are formed are mainly LT__ (highly chemotactic for neutrophils, eosinophils, and monocytes), along with LT__ and LT ___ which are extremely potent (much more so than histamine) in causing ___ vascular permeability and C4 and D4 also cause ___ and vaso___ (Realize that even though these cause vasoconstriction, the vasodilation is much more active and therefore vasodilation predominates)

The main PG produced is PG__2 that leads to some increase vasodilation, increased vascular permeability, intense bronchospasms, and increased mucus secretion

Also some ___ is produced as a lipid mediator and has a role in platelet aggregation, histamine release, vasodilation, increased vascular permeability, and bronchospasms

B) Cytokines are also released including TNF, IL-1, chemokines, etc for leukocyte recruitment and also some IL-4 for TH2 amplification, etc… And all of these are responsible for the ___ reaction

***** So just to recap, histamine and leukotrienes, and some other mediators aid in the immediate response leading to vasodilation, vascular leakage, smooth muscle spasms, edema, mucous secretion, etc… And cytokines and chemokines aid in the late-phase reaction that recruits additional leukocytes, causes epithelial damage, bronchospams, etc

Answer 25

1) Preformed

A) Histamine

B) Enzymes

C) Proteoglycans

A) LTB4, LTC4 and LTD4, Increased, bronchospasms, vasoconstriction

PAF (platelet activating factor)

B) Late phase

Question 26

An increased propensity to develop immediate hypersensitivity reactions is called ___ and susceptibility to immediate hypersensitivity reactions is genetically determined and environmental factors also play a role

Nonatopic allergies do not involve Th2 or IgE since they are triggered by non-antigenic stimuli like temp changes or exercise

___ is characterized by vascular shock, widespread edema, and difficulty breathing

Answer 26

Atopy (atopic)

Systemic anaphylaxis

Question 27

Antibody mediated type 2 hypersensitivity is caused by antibodies reacting with antigens present on cell surfaces or the ECM (can be autoantibodies or reactions with exogenous antigens on cell surfaces/tissue matrix), leading to inflammation and destroying these cells

When cells are coated (opsonized) with antibodies (specifically IgG), they become recognized by the Fc receptor of a phagocyte leading to their digestion and destruction

If cells are opsonized by IgG or IgM, the complement system can also be activated via the ___ pathway which leads to the formation of MAC to destroy the cells (this only can occur in cell that have thin walls like Neisseria bacteria), or the formation of byproducts (C3b and C4b) which deposits back onto the cell surfaces and once again allows phagocytes to recognize them and digest and destroy the cells

Along with phagocytosis via bound antibodies or phagocytosis via complement opsonization or straight up death from complement activation (MACs), cells can also be destroyed via ___, which occurs when these cells are coated with IgG and recognized by NK cells, macrophages, and some other effector cells leading to their death

Common diseases associated with type 2 antibody mediated hypersensitivity include

1) Transfusion reactions
2) Erythroblastosis fetalis (aka hemolytic disease of the newborn where the mothers IgG antibodies pass to the fetus and destroys its cells)
3) Autoimmune hemolytic anemia (destruction of RBCs), agranulocytosis, and thrombocytopenia (destruction of platelets)
4) Certain drug reactions that act as a “hapten”
5) Goodpasture syndrome (caused by Fc receptor and complement mediated inflammation)
6) Pernicious anemia (body cant absorb enough b12 since intrinsic factor is neutralized via antibodies)

Answer 27

Classical

ADCC (antibody-dependent cellular cytotoxicity)

Question 28

When antibodies deposit in fixed tissues during Type 2 hypersensitivity, it leads to inflammation and tissue injury (due to ROS and proteases destroying the cytoskeleton) since complement activation causes C3a and C5a byproducts to be produced and leukocytes activated via binding of their Fc and C3b receptors

^** Antibody-mediated inflammation is the mechanism responsible for some forms of glomerulonephritis and vascular rejection of organ grafts

Along with opsonization/phagocytosis destroying cells or inflammation leading to tissue injury, sometimes the circulating antibodies do NOT cause cell injury of inflammation and simply lead to cellular dysfunction like that seen in ___ (a neuromuscular disease leading to fluctuating muscle weakness and disease)

^** Here, antibodies instead react with Ach receptors in motor end plates of skeletal muscle and therefore block the NT binding to its receptor leading to muscle weakness

___ disease is another disease caused by cellular dysfunction from circulating antibodies, but instead of the antibodies inhibiting transmission like those in MG, these antibodies actually stimulate TSH receptors on thyroid epithelial cells leading to hyperthyroidism

Answer 28

Myasthenia Gravis

Graves disease

Question 29

Immune complex-mediated Type 3 hypersensitivity occurs when Ag-Ab complexes are deposited in tissues leading to complement activation and inflammation

^** Realize this is different from type 2 since the antigens are not associated with being present on the cell surface or ECM and instead, they get deposited in vessel walls and tissues

Immune complex mediated diseases tend to be systemic (although they can occur in the kidney, joints, small blood vessels, etc)

____ is an example of this type of systemic disease often due to the administration of large amounts of foreign serum and this disease has taught us that systemic immune-complex diseases occur in 3 phases

1) First, the immune complexes must form and this occurs when an antigen protein is administered to a patient, causing their body to trigger an immune response and the adaptive immune response eventually (about a week later) produces antibodies that get secreted into the blood…

The antibodies in the blood pair up with their antigens (the original injected protein antigen) in the blood circulation and therefore form the antigen-antibody complex

2) Next, the complexes are deposited in various tissues and vessels (with medium sized complexes and slight antigen excess being the most pathogenic) and often affect glomeruli and joints
3) Finally, inflammation and tissue injury occurs due to the complement activation and initiation of an ___ inflammatory reaction (about 10 days after injection) (***lots of neutrophils are recruited) where clinical features such as fever, urticaria (skin rash), joint paint (arthralgias),lymph node enlargement and proteinura appear and the resultant inflammatory lesion is called ___ if it occurs in blood vessels, ___ if it occurs in renal glomeruli, ___ if it occurs in the joints, etc…

**** The principle morphologic manifestation of immune-complex injuries is acute ___, associated with necrosis of the vessel wall and intense ___ infiltration and these areas of necrotic tissue and deposits of immune-complexes/complement/plasma proteins/etc… Is called ___ necrosis

^** When deposited in the kidney, granular lumpy deposits of Ig and complement are seen and electron dense deposits along the glomerular basement membranes

Acute serum sickness is when a single large exposure to an antigen occurs, however, sometimes there can be repeated or prolonged exposure to an antigen which results in chronic serum sickness and various diseases like SLE (Systemic lupus erythematosus)

___ reaction is a localized area of tissue necrosis due to an acute immune-complex vasculitis usually found in the skin leading to fibrinoid necrosis and superimposed thrombosis

Answer 29

Acute serum sickness

3) Acute, Vasculitis, glomerulonephritis, arthritis

vasculitis, neutrophilic, Fibrinoid

Arthurs

Question 30

T-cell mediated type 4 hypersensitivity is due to cytokine production by CD4+ T cells causing inflammation and killing via CD8+ T cells

^** This is the major type of hypersensitivity found in most autoimmune diseases

Type 4 T-cell mediated hypersensitivity is often also called ___ due to the fact that a reaction often takes a few days to occur when a patient with a previous immunity is administered an antigen

TH1 inflammation is characterized by activated macrophages and TH17 is characterized by activated neutrophils

Remember, if APCs release ___ to CD4+ T cells they differentiate into TH1 cells and if the APCs release IL-1, IL-6, IL-23, TGF-Beta they turn into ___ cells

The TH1 cells secrete their own cytokines mainly ___ which is responsible for many of the manifestations seen in DTH like the activation of phagocytes (like macrophages), up-regulation of Class 2 MHCs, TNF/IL-1/chemokine secretion to promote inflammation, and increased IL-12 to continue autocrine proliferation and this inflammatory response results in tissue injury

Th17 cells secrete IL-17, IL-22, and some chemokines to also induce inflammation via recruitment of lots of ___ and monocytes and Th17 cells also can increase their own proliferation through an autocrine manner by producing IL-21

Answer 30

DTH (Delayed-type hypersensitivity)

IL-12, TH17

IFN-Gamma

Neutrophils

Question 31

The classic example of DTH is the ___ reaction where injection of PPD (aka tuberculin aka Purified Protein Derivative) occurs (PPD is a protein containing antigen of the tubercle bacillus)

The patient will show signs of redness around 8-12 hours after injection and full peak symptoms 24-72 hours after, finally subsidizing

The patient will show accumulations of mononuclear cells (mainly CD4+ T cells and macrophages) around the veins (venules) which are said to produce perivascular ___ and if the lesion is fully developed, the venules will show signs of endothelial hypertrophy

If the antigen does not go away in 2 to 3 weeks (such as if the tubercle bacillus colonize in the lungs), the prolonged macrophage infiltration will turn into ___ cells and remember, this results in a ___ (called granulomatous inflammation) seen in ___ necrosis and is associated with strong Th1 activation and IFN-gamma secretion

^** Can also be caused via foreign bodies that activate macrophages but do not cause an immune response

So to recap, 24-72 hours after injection, perivascular accumulation aka cuffing will be seen, and if the antigens stay around for 2-3 weeks then granulomatous inflammation will be seen

Other DTH reactions involve contact dermatitis (resulting in a rash), psoriasis, rheumatoid arthritis and multiple sclerosis (which are systemic auto-immune diseases) and inflammatory bowel disease

^** All characterized via inflammation mediated by Th1, Th17, or both

Answer 31

Tuberculin

Cuffing

Epithelioid, granuloma, caseous necrosis

Question 32

While CD4+ T cell mediated Type 4 hypersensitivity is the most common (tissue injury due to inflammation), there is also CD8+ T cell mediated Type 4 hypersensitivity where CTLs kill antigen expressing target cells (tissue injury from killed cells) and ___ is a good example of this

CTLs also have a role in graft rejection and viruses and while they help kill infected cells, they can sometimes cause tissue damage

CTLs kill via ___ and ___ that activate caspases inside the infected cells leading to apoptosis, and they also contain ___ which can bind to FAS expressed on target cells and trigger apoptosis as well

^** CD8+ T cells also secret IFN-gamma, especially after viral infections, and therefore have a small role in inflammation (which can also injure tissues)

Answer 32

Type 1 diabetes

Granzymes and Perforins, FasL

Question 33

For autoimmunity, there must be three requirements including

1) The presence of an immune reaction specific for some self antigen or self tissue
2) Evidence that the reaction is not secondary to tissue damage, but instead due to primary pathogenic significance
3) The absence of another well-defined cause of the disease

Immune mediated inflammatory diseases is a group of diseases characterized via chronic inflammation

Autoimmune disorders can be extremely variable, some immune responses are directed against a single organ (organ-specific disease) like in ___ that has auto reactive T cells and antibodies specific for Beta cells in the pancreatic islets or ___ where autoreactive T cells react against the CNS’s myelin

Or, there can be an immune response to a widespread antigen resulting in systemic or generalized disease, with the best example of a systemic disease being ___ where a diverse set of antibodies is directed against DNA, platelets, RBCs, protein-phospholipid complexes, etc that results in widespread lesions throughout the body

Goodpastures syndrome is a hybrind between the two (it effects two organs the lungs and kindeys) due to antibodies in the basement membranes that causes lesions in these organs

Answer 33

Type 1 diabetes, multiple sclerosis

SLE (Systemic Lupus Erythematosus)

Question 34

Autoimmunity results from the loss of self-tolerance (the lack of responsiveness to an individuals own antigens)

Since antigen receptors on lymphocytes that recognize antigens resulting in a response are generated via somatic recombination, genes are made that cause cells to react to our good antigens (self)… Therefore, these must be eliminated so we don’t have reactions to normal antigens

There are two types if self-tolerance

1) Central tolerance is the deletion of lymphocytes that recognize self antigens present in the primary organs (like the thymus for T cells and bone marrow for B cells)

Deletion of T cells (aka negative selection) occurs when a Thymic APC presents a self antigen (via self MHC molecules) to a TCR on a T cell that leads to apoptosis

^** Also note that some cells that bind to their self antigen do not undergo apoptosis, but instead become ___ cells

A protein called ___ is needed for the expression of some self antigens in the thymus and therefore, if AIRE is decreased, then the self antigens can not be displayed to immature T cells, and the immature T cells never bind the self antigen and never undergo negative selection

^** Often the self antigens that AIRE stimulate the expression of are referred to as “peripheral tissue-restricted” and therefore only exist in the primary tissue which is why it’s important because if the T cells make it past the primary tissue, there is not way to kill them in the peripheral tissue

B cells also undergo deletion (aka negative selection) in the bone marrow when a B cell recognizes a self antigen… HOWEVER, B cells ALSO undergo ___ when the B cell strongly recognizes a self antigen via reactivating its antigen receptor gene rearrangement process and therefore the B cell instead of dying, simply makes a new antigen that will no longer bind to the self antigen and therefore no immune reaction will occur for the self antigen

Answer 34

T-regulatory

AIRE (Autoimmune regulator)

Receptor editing

Question 35

2) Peripheral tolerance is needed for when T or B cells “slip” past negative selection and move out into the peripheral tissues and therefore peripheral tolerance is needed to prevent the activation/expansion of auto-reactive T cells

^** Also, sometimes self antigens just aren’t even present in the generative (primary) tissues and therefore it isn’t until the peripheral tissues that the T or B cells meet their self antigen leading to apoptosis

This tolerance is best characterized by looking at T cells (so we will ignore B cells for now, but just know they also have similar outcomes)

So what happens, is the now mature auto-reactive T cells have made it into the peripheral tissues… Now one would think that these cells start binding to self antigens displayed via APCs of healthy tissue and causing an immune response… However in normal tissue, ACPs that are not stimulated via any immune reaction are simply referred to as resting APCS (often just called resting dendritic cells)… These resting dendritic cells have no reason to be on a red alert for an infection or injury and therefore these resting dendritic cells display low levels of ___

Remember, a T cell can only become active when it binds to an APC that has BOTH the MHC antigen AND a costimulator (like CD28 on the T cell binding to B7 on the APC)

So now when the T cells that are reactive to self antigens bind to the Class 1 or 2 MHC presented via a APC, instead of becoming stimulated (only occurs via B7 and CD28 binding) and causing an immune response, NONE (or very little) ___ is expressed on the resting dendritic cells and therefore the T cell does not have both signals to become active and this results in the cell being rendered functionally unresponsive, which is called ___

^** Like we just said, if no B7 is expressed in resting dendritic cells, then no T-cell CD28 costimulators can bind to the APC’s B7… However, sometimes low levels of B7 is still expressed in resting APCs, and in this case, ___ which has a higher affinity for B7 than does CD28, actually binds to the B7 causing inhibition of the needed B7-CD28 costimulation signal and once again anergy occurs

^** Now realize if an immune reaction was needed due to entry of a microbe, the APCs up-regulate B7 expression

___ is another example of something that binds to two ligands expressed on various cells that inhibit the costimulatory signal needed for auto-reactive T cell activation and instead leads to anergy

^** So if there is a CTLA4 or PD1 defect, an autoimmune disease will develop due to the fact that auto-reactive T cells will bind both signals needed to activate them

Answer 35

Costimualtors

B7, Anergy

CTLA4

PD-1

Question 36

CD4+ T reg cell develop in the thymus but can also regulate tolerance out in the peripheral tissues

T reg cells require IL- ___ for their production and maintenance (which binds to ___ on the T-reg cell aka the alpha chain of their IL-2 receptor) and a transcription factor ___ (which can be used as a marker for T-reg cells),

If FOXP3 is mutated, it can lead to a systemic autoimmune disease called ___

If CD25 is mutated, it can lead to various autoimmune diseases like multiple sclerosis

In order to prevent the activation of autoimmune reactive T cells, T reg cells ___ CD80/CD86 (B7) expression on APCs via the T-reg cells themselves binding to B7 via CTLA-4, Increase ___ and ___ production to inhibit inflammation, and ___ CD40 levels on the APCs

** These T-reg cells are also important in acceptance of a fetus (prevent immune reactions in the mother against fetal antigens)

Answer 36

IL-2, CD25, FOXP3

IPEX (Immune dysregulation, Polyendocrinopathy, enteropathy, X-linked)

Decreased, IL10 and TGF-Beta, decrease

Question 37

As we already talked about, negative selection (aka deletion) leads to apoptosis in central tolerance and in peripheral tolerance (if anergy does not occur)

For deletion to occur once a self-antigen is recognized, pro-apoptotic ____ is expressed and the absence of anti-apoptotic BCl-2 and BCL-X occurs and therefore the intrinsic (mitochondrial) pathway for apoptosis occurs

Another way apoptosis can occur is via ___-___ binding

^** Remember, FASL is expressed on the T cells a FAS is on the APC or B cell

If the FAS gene is mutated, an autoimmune disease called ___ occurs

Also, some antigens are straight up hidden from the immune system like those in the eyes, brain, and testis because they don’t interact with the blood anyway, but if trauma were to cause them to be released into the blood, prolonged tissue inflammation and injury could occur (like orchitis aka inflamed testicles or uveitis aka inflamed eye)

Answer 37

BIM

FAS-FASL

^** FAS = CD95

ALPS (Autoimmune Lymphoproliferative syndrome)

Question 38

Autoimmunity is due to the failure of tolerance either via 1) inheritance of susceptibility genes OR 2) environmental infections and tissue damage that cause activation of self-reactive lymphocytes

^** Both of these problems can lead to defective tolerance or regulation, abnormal expression of self antigens, or inflammation/innate immune response that can activate autoimmune diseases

1) As we mentioned above, the role of susceptibility genes has an important role in development of an autoimmune disorder

___ genes are the most common defective genes leading to these problems and a great example of this is ___ (which is an inflammatory autoimmune disease that causes arthritis in the spine and large joints) and this is due to the inheritance of a Class 1 HLA allele called ___

Note that Rheymatoid arthritis, T1D, Multiple Sclerosis, and SLE are due to the DRB1 protein

Along with HLA genes, there are some non-MHC genes that have a role in autoimmunity as well including

A) ___ defects are is seen in Rheumatoid arthritis, T1Ds, and others, which encodes a protein tyrosine phosphatase that when defective can no longer control the activity of a tyrosine kinase and therefore excessive lymphocyte proliferation occurs

^**Gene involved in immune regulation

B) ___ defects are seen in Crohns disease (a form of inflammatory bowel disease) due to not being able to sense microbes in the intestinal epithelia resulting in entry and chronic inflammatory

^**Gene involved in immune responses to microbes

C) Defects in IL-2 receptors (CD25) Via the IL2RA gene and IL-7 causing T-reg cells to be defective can result in multiple sclerosis and other autoimmune diseases

^**Genes involved in immune regulation

Answer 38

HLA, Ankylosing Spondylitis, HLA-B27

A) PTPN22

B) NOD2

Question 39

2) As mentioned in the previous notecard, environmental infections and tissue damage that cause activation of self-reactive lymphocytes

A) Infections can possibly lead to the ___ regulation of costimulators on APCs (like B7) leading to a decreased anergy and instead increased activation of self reactive T cells

B) ____ can occur which is when microbes present antigens with the same amino acid sequence as self-antigens and therefore an immune response to these microbes also initiates the response of self reactive T cells such as in Rheumatic heart disease

HIV and EBV can actually induce polyclonal B cell activation due to changing the self antigens released from tissues after damage to make them no longer recognized as harmless and therefore elicit a response

Answer 39

A) Increased (up-regulation)

B) Molecular mimicry

Question 40

Autoimmune diseases are ___ (acute or chronic?) and progressive due to the fact that amplification of an immune response due to self antigens prolongs and exacerbates tissue injury, and ___ which is the idea that self antigen immune responses damage tissues, which release other antigens causing further lymphocyte activation and inflammation

Answer 40

Chronic

Epitope spreading

Question 41

Remember, autoimmune disease can be either organ-specific or systemic depending on how many organs are affected

___ autoimmune diseases are often also called collagen vascular diseases (aka connective tissue diseases) since they involve blood vessels and connective tissues

1) Systemic Lupus Erythematosus (SLE) is classified as an autoimmune disease, mediated by ___, specifically, ___s that are deposited as immune-complexes (Type ___ hypersensitivity) and binding of antibodies to various cells and tissues

Often, the autoantibodies found in SLE mediate glomerulonephritis (so SLE and glomerulonephritis are strongly found together in the same disease)

Answer 41

Systemic

1) Autoantibodies, ANAs (Antinuclear antibodies), Type 3

Question 42

The ANAs found in SLE are directed against ____ antigens that can be grouped into 4 categories including

1) Abs to DNA
2) Abs to histones
3) Abs to non histone proteins bound to RNA
4) Abs to nucleolar antigens

Immunofluorescence is the most common way to detect the ANAs and looking at the pattern helps determine the antibody present

There are 4 basic patterns including

1) Homogeneous aka diffuse nuclear staining reflects Abs to ___ and histones, and sometimes ___ (double stranded)
2) Rim aka peripheral staining reflects Abs to ___ and sometimes nuclear envelope proteins
3) Speckled pattern is the most common observed pattern and therefore very unspecific, however it can show ___ antigens, along with ribonuleoproteins, and SS-A and SS-B reactive antigens
4) Nucleolar pattern reflects Abs to ___ and is therefore often seen in patients with ___ (an autoimmune disease of connective tissue)
5) Centromeric pattern reflects Abs for centromeres and is also seen in patients with systemic sclerosis

****ABs to ___ and the ___ are the diagnostic to determine SLE

*** If you see nucleolar and centromeric patterns upon staining, think systemic sclerosis

If you see homogeneous/peripheral (aka rim)/speckled staining think SLE

Answer 42

Nuclear

1) Chromatin and histones, dsDNA
2) dsDNAs
3) Sm (smith)
4) RNA, Systemic sclerosis

ssDNA (Aka anti-ssDNA), Sm antigens (Smith) (Aka anti-Sm)

Question 43

Along with ANAs found in SLE, ___ antibodies are also seen in this disease (where the immune response attacks normal proteins in the blood and is called ____ antiphospholipid antibody syndrome) that can destroy RBCs, platelets, lymphocytes, etc and sometimes one can present with a false positive test for syphilis

^** Note that the antiphospholipid antibody syndrome is called “secondary” because it is involved with SLE… If patients exhibit ONLY the manifestations of a hypercoagulable state and no evidence of other autoimmune disease, they are said to have primary antiphospholipid Ab syndrome

Sometimes these antiphospholipid Abs interfere with vitro clotting tests and are therefore they can also be called ___

No matter what you call them, the antiphospholipid Abs lead to patients at risk for a ____coagulable state and therefore they expose patients to developing venous and arterial thromboses

Answer 43

anti-phospholipid, secondary

lupus anticoagulants
^** So realize this is the same thing as antiphispholipid Abs

Hyper

Question 44

Now we know that SLE is due to ANAs (like anti-ssDNA or anti-Sm) and some other autoantibodies (like antiphospholipids)

However, the mechanism that leads to this situation is due to failure to maintain self tolerance (like all autoimmune diseases)

Genetically, a few factors can lead to SLE

1) Alleles of the HLA-___ locus have been linked to the production of autoAbs in SLE
2) Some patients can inherit defects in the __ system (like C2, C4 or C1q) leading to failure of apoptotic cell clearance or loss of B-cell tolerance
3) Defects in genetic loci involved in lymphocyte signaling and interferon responses

Immunologic factors can also lead to SLE development including

A) Failure of self-tolerance for B cells allows B cells to exist and make Abs against healthy tissue

B) CD4+ T cells that escape self-tolerance and instead are specific for nucleosomal Ags and therefore activate B cells to produce Abs for those nucleosome Ags

C) TLRs are activated by binding to the immune complexes nuclear DNA and RNA causing activation of B lymphocytes that can produce autoAbs

D) Self nucleic acids mimic their microbial counterpart and activate APS via their TLRs to secrete ____ which via various ways can lead to increased autoAB production

E) Increased ___ (a member of the TNF family) causes the survival of B cells

Environmental factors seem to be more important however for developing SLE and include

I) Exposure to ___ light can cause apoptosis in cells, alter the DNA to make it immunogenic, and stimulate keratinocytes to produce IL-1

II) SLE predominantly affects women, and possibly this is due to actions of sex hormones and genes on the X chromosome

III) Drugs

***To sum this all up lets start from the beginning

First, UV radiation or some other environmental damage causes apoptosis of the cells which produces apoptotic bodies… Now various other mechanisms like complement defects can lead to failure of apoptotic cell clearance and therefore a buildup of nuclear antigens… At the same time, if a patient has susceptibility genes or some other underlying abnormality that causes B and T lymphocytes to make it past the tolerance stage, these self-reactive lymphocytes can become stimulated via nuclear self antigens and produce antibodies against the increased amount of nuclear antigens building up…. Now the antibodies bind to the nuclear antigens and these complexes bind to Fc receptors on B cells and dendritic cells, get internalized, engage TLRs and cause more autoantibodies to be produced via the B cells along with cytokines produced via the dendritic cells (like Type 1 IFNs) that furthers stimulates B cell production of autoAbs… The net result is a shit load of autoAbs circulating in the blood and therefore SLE occurs

Answer 44

1) HLA-DQ
2) Complement

D) Type 1-IFNs

E) BAFF

I) UV

Question 45

For the ANAs found is SLE (involved in the immune complex formation), dsDNA and other DNA-anti-DNA complexes are often detected in the glomeruli of the kidneys which is why glomerulonephrtitis (inflammation of the kidney) is typically associated with this disease… Granular deposits of complement are and Igs are also found in the glomeruli

Also commonly seen in SLE are ___ cells which are phagocytes that have engulfed the denatured nucleus of an injured cell due to the ANS binding to them

^** This technique is not often used anymore

Answer 45

LE cells

Question 46

Morphologic changes in SLE are extremely variable, but the most characteristic lesions result from immune complex deposition in the

1) Blood

^** In the blood, acute necrotic vasculitis (inflammation of blood vessels) can occur in any tissue and necrotic tissue and deposits of immune-complexes/complement/plasma proteins/etc… is called ___ necrosis and as it becomes chronic, vessels undergo fibrous thickening and luminal narrowing

2) Kidneys

^** There are 6 possible classes of glomerular disease seen in SLE and these are discussed on the next notecard… Just note that class ___ is the least common and class ___ is the most common

Realize that most cases involve the glomeruli, however, changes in the interstitium and tubules are often present as well and RARELY, ____ lesions are actually the predominant abnormality (with immune complexes in the tubular basement membranes)

^** Not very important

3) LE, or hematoxylin, bodies in the bone marrow or other organs
4) Skin

^** The ___ rash is often seen in patients with SLE on the nose and cheeks and sometimes extremities and trunk

Urticaria, Bullae, Maculopapular lesions, and Ulcerations are also common

Also, involved areas show ___ of the basal layer of the epidermis and in the dermis there is edema and perivascular inflammation

Also some deposition of Igs and complement along the dermoepidermal junction can be seen, but this is also observed in other diseases

5) Serosal cavities can be involved like those seen in pericarditis (inflammation of the sack surrounding the heart aka pericardium) due to fibrinous inflammation which is an exudate that contains lots of fibrinogen that thickens into a fibrin coat
6) Cardiovascular system can also be involved and one example is valvular endocarditis (the inner lining of the heart) aka ___ which is deposits (vegitations) on any heart valve on either surface of the leaflets

^** Coronary artery disease due to coronary atherosclerosis is also common

7) Splenomegaly, capsular thickening, follicular hyperplasia, and penicillar arteorioles can show concentric intimal and smooth muscle hyperplasia resulting in Onion-skin lesions
8) Pleuritis (lung inflammation) and pleural effusions (fluid between tissues that line lungs and chest) are also common

The clinical features for SLE is very diverse, however, commonly it includes a young woman with a butterfly rash over the face, fever, joint pain but no deformity, pleuritic chest pain (inflammation of lung’s tissue layers), photosensitivity, Generic ANAs (100% of patients but non-specific), renal involvement, some hematologic derangement (or anemia or thrombocytopenia), mental aberrations, coronary artery diseases, and prone to infection

Often occurs as flare-ups and remissions over years or decades and increased immune-complex activation causes patients to have hypocomplementemia (low complement levels since it is all being used up via the increased immune-complexes formed)

Answer 46

1) Fibrinoid
2) 1, 4(IV)

Tubulointerstitial

3)

4) Butterfly rash

Vacuolar degeneration (aka hydropic changes aka lipid vacuoles)

6) Libman-Sacks

Question 47

Name the 6 different classes of lupus nephritis (kidney inflammation due to SLE)

1) When less than 50% of the glomeruli are involved and can be either segmental (a single portion affected) or global (multiple portions affected)… These glomeruli are swollen and endothelial cells have proliferated due to increased WBCs, also capillaries have necrosed and hyalin thrombi are present… Also mild hematuria is common (blood in urine)

^** Note that extracapillary proliferation is associated with ___ necrosis and ___ formation

2) The MOST common and severe form of nephritis and lesions are similar to those of class 3, but here ___ than 50% of the glomeruli is affected…Like class 3, it can be classified as segmental (IV-S) or global (IV-G).. Patients show hematuria, proteinuria, mild to severe renal insufficiency, etc…

Since this is a more severe response, glomeruli show increased proliferation and endothelial, mesangial, and epithelial cells (so more cells in histology slide compared to Class 3), which can also produce cellular crescents

Most importantly, ___ immune complex deposits create a circumferential thickening of the capillary wall called a ___ which can be seen on light microscopy, electron microscopy, and immunofluorescence

3) Mesangial cell proliferation leading to accumulation of the mesangial matrix… Along with granular mesangial deposits of Ig and complement without involvement of the glomeruli capillaries
4) Sclerosis (stiffening of a structure) of more than 90% of the glomeruli and represents end stage renal disease
5) VERY uncommon with immune complex (Ag-Ab complex) in the mesangium (a structure in the kidney associated with the capillaries)
6) Thickening of the capillary walls due to deposition of subepithelial immune complexes along with increased production of basement membrane like material

^** Do NOT confuse subEPIthelium seen here, with the subENDOthelial depositions seen in Class 4

Answer 47

1) Class 3 (Focal lupus nephritis)

Focal necrosis, crescent

2) Class 4 (Diffuse lupus nephritis), more

Subendothelial, Wire loop

3) Class 2 (Mesangial proliferation lupus nephritis)
4) Class 6 (Advanced sclerosing lupus nephritis)
5) Class 1 (Minimal mesangial Lupus nephritis)
6) Class 5 (Membranous lupus nephritis)

Question 48

Some other types of lupus include

1) Chronic Discoid Lupus Erythematosus is a disease the mimics SLE’s ___ manifestations, but not the ___ manifestations

It is characterized by skin plaques surrounded by an elevated erythematous border and occurs from Igs and C3 deposited at dermoepidermal junctions (similar to SLE)

This chronic scaring skin rash disease is different from SLE because most of the time it does not contain anti-___

^** In other words, this disease is localized mainly to just the skin and commonly face and scalp

2) Subacute cutaneous lupus erythematosus is a disease that seems to define an intermediate between SLE and discoid lupus

Here, the skin is once again predominantly involved, but some systemic symptoms also occur

The skin rash in this disease is widespread, superficial, and ___ (does or does not?) scar unlike in discoid lupus where its rash does scar

There is also a strong association with ___ antigen and the HLA-___ genotype

Often occurs from a reaction to light that causes a rash

3) Drug induced lupus erythematosus is often associated with the development of ANAs and while many of the normal SLE clinical symptoms are present including arthralgias (joint pain), fever, or serositis (inflammation of a serous membrane like the peritoneum, pericardium, etc), often CNS and renal involvement are not common

Here, Anti-___ is also rare (like in discoid lupus), but there is an EXTREMELY high frequency for Abs specific for ___ and if one has the HLA-DR4 or HLA-DR6 allele they are at increased risk for this to occur

Answer 48

1) Skin, systemic

dsDNA

2) Does not scar

SS-A, HLA-D3

3) dsDNA, Histones

Question 49

Another autoimmune disease resulting in chronic inflammation is ___ and this affects primarily the joints and remember, the gene defect most commonly associated with this disease is ___ and anti-CPCs are found in most patients

Answer 49

Rheumatoid Arthritis, PTPN22

Question 50

Sjogren syndrome is another autoimmune disease characterized by ___ (keratoconjunctivitis sicca) and dry mouth called ___ due to immunologically mediated destruction of the ___ and ___ glands due to lymphocyte infiltration and fibrosis

^** This disease can occur on its own as a primary form (aka ___ syndrome), or it can be associated with other autoimmune diseases and therefore called a secondary form (most commonly associated with Rheumatoid Arthritis)

Antibodies against two ribonucleoprotein antigens ___ and ___ are seen in 90% of patients and thus considered serological markers for the disease, but they are not diagnostic since remember, SS-A is also found in SLE

Inheritance of certain class 2 molecules predisposes the patient for the development of particular autoAbs

Lots of T and B cells are activated against self-antigens and commonly it begins when the salivary glands are infected with a virus, which causes local cell death and release of tissue self antigens or it can simply occur from an autoimmune T -cell reaction against an unknown self antigen expressed in the glands

Major morphological features are lacrimal and salivary glands affects (like we already mentioned), along with histological findings of periductal and perivascular ____ infiltration in both the major and minor salivary glands and eventually lymphoid follicles with germinal centers may be seen

The ductal epithelial cells can also undergo ___, which obstructs the ducts and eventually atrophy of the acini, fibrosis, and hyalinization occurs

If lymphoid infiltrate becomes to large, it can look like a lymphoma and these patients are at high risk for developing ___-cell lymphomas

Extraglandular disease is developed in 1/3 of patients including synovitis (inflammation of synovial membrane aka synovial joints), diffuse pulmonary fibrosis, and peripheral neuropathy

Unlike SLE, which has its kidney problems as mainly glomerular lesions and very rarely tubulointerstitial lesions, here, tubulointerstitial nephritis is common

Lacrimal and salivary gland inflammation is called ____ syndrome

^** Don’t confuse this with Sicca syndrome, which is a decrease in tears and saliva production

Also note one MUST biopsy the ___ to examine minor salivary glands in order to make the diagnosis of Sjogren syndrome

Answer 50

Dry eyes, Xerostomia, Lacrimal and salivary

Sicca syndrome (aka decrease in tears and saliva)

SS-A(Ro) and SS-B(La)

Lymphocyte

Hyperplasia, B-cell

Mikulicz syndrome

Lip

Question 51

___ (also called Scleroderma) is a systemic autoimmune disease characterized by chronic inflammation, damage to small blood vessels, and hardening of the skin due to interstitial and perivascular fibrosis in the skin (and some other organs)

^** So excessive fibrosis throughout the body = Systemic sclerosis

There are two types of this disease

1) ___ scleroderma has progressive widespread skin involvement and one or more internal organs (early visceral involvement)

^** The ANAs found in this type of scleroderma include ___ aka anti-__

2) ___ scleroderma has skin involvement limited to the fingers, forearms, and face and visceral organ involvement occurs LATE and therefore clinical course is benign (not harmful)

^** The ANAs found in this type of scleroderma include ____

^** Another name for limited scleroderma is ___ syndrome since it involved Calcinosis (deposition of calcium in skin), Raynaud’s phenomenon (vasoconstriction in hands), Esophageal dysfunction (difficulty swallowing), Sclerodactyly (skin thickens on fingers), and Telangiectasias (dilated capillaries on face, hands, and mucous membranes)

^** Note that the vasoconstriction of the arteries and arterioles of the extremities, called ____, are actually seen in ALL patients with either form of scleroderma

Also, dysphagia aka difficulty swallowing is seen in 50% of patients and due to ___ fibrosis

Answer 51

Systemic sclerosis

1) Diffuse

DNA topoisomerase I (anti-Scl 70)

2) Limited

Anticentromere antibody (also called CENPs aka Centromeric proteins)

CREST

Raynaud phenomenon

Esophageal

Question 52

Systemic Sclerosis occurs from three interrelated processes

1) Autoimmune response

^** CD4+ T cells, specifically Th2 cells are found in the skin and remember, these cells can release cytokines like TGF-Beta, IL-13, and PDGF to stimulate gene transcription for collagen and ECM proteins to be deposited by fibroblasts (fibrosis)

Also so evidence for humoral immunity activation

2) Vascular damage

^** An initiating event or chronic inflammation causes the destruction of endothelial cells to occur (Signs include increased vWF, increase platelet aggregation, etc)… leading to intimal proliferative and obliterative vasculopathy (Aka occlusions of arterioles and small arteries with fibro-proliferative change)

The constant cycles of endothelial injury and therefore platelet aggregation, leads to the release of lots of platelet and endothelial factors that end up leading to perivascular fibrosis

3) Collagen deposition (aka fibrosis)

^** If the vascular lesions persist, it can cause ischemia which leads to fibrosis and scaring.

There may also be a defect in the fibroblasts that cause excess collagen to be made

** Ok so lets recap…. Systemic sclerosis occurs due to an initial vascular injury (from autoimmunity or an environmental factor) which ends up causing structural alterations (like loss of small blood vessels or proliferative obliterative vasculopathy aka occlusion of arterioles and small arteries with fibro-proliferative change) and functional defects in the vasculature; and this results in activation of fibroblasts in various organs leading to perivascular ___ (which remember, is the deposition of mainly ____ aka connective tissue)

Answer 52

fibrosis, collagen

Question 53

Most comonly seen in black women, the morphology of Systemic Sclerosis includes

** Note that intima is just short for tunica intima which is the inner most layer of an artery or vein

1) Skin

^** Diffuse, sclerotic atrophy of the skin and fingers can take on a tapered, claw like appearance with limited joint motion

Edema, perivascular infiltrates (mainly CD4+ T cells), swelling, and degeneration of collagen fibers occurs…. Also, capillary and small artery thickening of the basal lamina, endothelial cell damage, and partial occlusion occurs and the loss of blood supply can lead to cutaneous ulcerations or atrophic changes in the terminal phalanges

Increased fibrosis of the dermis, increased compact collagen in the dermis, and hyaline thickening of the walls of the dermal arterioles and capillaries occur

In patients with CREST, diffuse subcutaneous calcifications may also develop

So once again, realize that histologically you will see extensive deposition of dense ___ in the dermis and also absence of appendages and a foci of inflammation

2) Alimentary tract (aka digestive tract)

^** Atrophy and collagenous fibrous replacement of the muscularis (thin layer of the GI tract) can occur at any level, but is most common and severe in the ___, which develops a “rubber-hose-like” inflexibility

Also since the esophagus is messed up, the lower esophageal sphincter can be defective giving rise to reflux and therefore Barrett’s metaplasia and strictures

Malabsorption can also occur due to loss of villi and microvilli in small bowel

3) MSK system

Early on inflammation of the synovium along with hypertrophy and hyperplasia of the synovial soft tissues can occur with fibrosis later ensuing

4) Kidneys

^** Most kidney involvement is due to vascular lesions like in the interlobular arteries that show intimal thickening from collagen deposits and also concentric proliferation of intimal cells (but these changes are restricted to vessels 150-500 um in size)

Hypertension also occurs in some patients and if it does, vascular alterations can be associated with fibrinoid necrosis and accounts for 50% of deaths for people with this disease due to the development of malignant hypertension and therefore renal failure

5) Lungs

^**Pulmonary hypertension (with pulmonary vasospasms) and interstitial fibrosis

6) Heart

^** Pericarditis with effusion, myocardial fibrosis, and thickening of intramyocardial arterioles occur

Answer 53

1) Collagen

2) Esophagus

Question 54

Some other autoimmune diseases include

1) 3 distinct disorders that are characterized by inflammation and injury to the skeletal muscles, and is immunologically mediated are called inflammatory ___ (Talked about in Chapter 27)

^** myositis = inflammation and degeneration of muscle tissue

2) ___ disease is used to describe a disease that has mixed clinical features of SLE, systemic sclerosis, and polymyositis

^** Characterized by high titers of antibodies to ___ aka Anti-U1 RNP antibodies and presents with synovitis of the fingers, Raynaud phenomenon and mild myositis; also renal involvement is modest

3) Polyarteritis Nodosa is due to necrotizing inflammation of the walls of blood vessels in small or medium sized muscular arteries
4) IgG4-related diseases are disorders characterized by tissue infiltrates dominated by IgG4 Ab-producing plasma cells and lymphocytes (mainly T cels) and Mikulicz syndrome aka Sjogren syndrome is an example

Answer 54

1) Myopathies
2) Mixed connective tissue disease

U1 RNP complex (ribonucleoprotein)

Question 55

A major barrier to transplantation is the process of rejection, in which the recipients immune system recognizes the graft as being foreign and attacks it

The major antigenic differences between a donor and recipient that results in rejection of transplants are differences in ___ alleles

^** Grafts from one person to another are called allografts and the antigens from the donor are therefore called alloantigens

When a patient receives a graft from the donor, the patients recognize alloantigens from the donor by two pathways

1) ___ pathway of allorecognition

^** In the direct pathway, T cells of the patient recognize alloAgs on APCs (most commonly, dendritic APCs) from the donor and this donor APC - patient T cell recognition occurs in either the grafted organ OR in the draining lymph nodes

The T cells activate and proliferate into
CTLs or TH1 cells (some TH17) and cause tissue damage due to local inflammation and killing of the graft cells

2) ___ pathway of allorecognition

^** In the indirect pathway, patients T lymphocytes recognize alloAgs that are presented on the recipient’s own APCs and this this pathway is similar to the physiologic processing and presentation of other foreign antigens

^** This type of graft rejection results in ____ of inflammatory reaction via activation of CD4+ T cells and B lymphocytes to produce Abs

Also, if there are CTLs that become activated in the indirect pathway, they can NOT kill graft cell since they only recognize graft Ags presented by the patients own APCs and therefore, the main mechanism of cellular rejection and destruction is due to T-cell cytokine production and inflammation

*** So to recap, ___ recognition would be associated with an acute rejection since the T cell recognizes unprocessed allogenic MHC molecules on graft APCs and Acute T-cell mediated rejection occurs from activation of CTLs killing the graft cells, along with CD4+ T cells initiating an inflammatory reaction via secretion of cytokines which leads to increased vascular permeability and accumulation of lymphocytes and macrophages… Also note acute antibody mediated rejection can occur as well in which antibodies are produced after transplantation towards the donors cells and can cause complement cytotoxicity, inflammation, or antibody dependent cell mediated cytotoxicity and all of these affect the graft’s ____

___ recognition would be chronic rejection since the presentation of processed peptides of allogenic MHC molecules bound to self MHC molecules causes the rejection and chronic T-cell mediated rejection causes T-cells to secrete cytokines leading to local inflammation and chronic antibody mediated rejection also occurs and develops slowly (insidiously) and also primarily affects vascular components and causes endothelial injury

^** Also note there is a rejection called ___ rejection which occurs when patients have PREFORMED antidonor antibodies in their circulation and commonly due to a previous transplant, prior blood transfusions, or multiparous women (had more than one child)

Answer 55

HLA

1) Direct
2) Indirect

DTH (Delayed type hypersensitivity)

Direct, vasculature

Indirect

Hyperacute

Question 56

Rejection reactions are classified as hyperacute, acute, or chronic

1) Hyperacute

^** Occurs in minutes to hours and Igs and complement are deposited in the vessel wall causing endothelial injury and ___-___ thrombi. ___ also accumulate very quickly in the arterioles, glomeruli, and peritubular capillaries and as changes become more diffuse (widespread) and intense, it leads to thrombotic occlusions and ___ necrosis in the arterial walls

Finally, the kidney necrosis (infractions) and must be removed

2) Acute

^** Occurs within a few days, however it can also occur months or possibly years after immunosuppression is terminated

Remember, acute immunity can be from either T-cell mediated rejection or antibody-mediated rejection

A) Acute cellular (T-cell mediated) rejection is seen as either a _____ pattern sometimes called type ___ and in this type of rejection there is extensive interstitial inflammation and infiltration of the tubules (tubulitis) between epithelial cells

Or it can be seen as the ___ pattern which shows inflammation of the vessels (where inflamamtory cells are attacking and undermining the endothelium) called ____ aka type ___ and sometimes the vascular wall can necrosis (type 3)

^** In the absence of an accompanying antibody-mediated rejection, patients respond well to immunosuppressive therapy

B) Acute Antibody-mediated rejection is manifested mainly by damage to the ___ and ___ (like the peritubular capillaries) and deposition of ___ (produced in the antibody dependent classical pathway) occurs

^** Inflammation of peritubular capillaries is called capillaritis

3) Chronic

^** This type of transplant rejection is associated with increased serum ___ levels over a period of 4 to 6 months

Chronic rejections are dominated by vascular changes (arteriosclerosis) and these changes include thickening of the tunica intima layer due to inflammation, duplication of the ___ (due to secondary chronic endothelial injury), and peritubular capillaritis with multilayering of the peritubular capillary basement membranes

^** Transplant glomerulopathy (a set of diseases affecting the glomeruli) is a characteristic manifestation of chronic ___-mediated rejection

Interstitial fibrosis and tubular atrophy with loss of renal parenchyma may also occur secondary to the vascular lesions and also NK cells and plasma cells will be present

Answer 56

1) Fibrin-platelet, neutrophils, fibrinoid

A) Tubulointerstitial, 1

Vascular, endotheliitis, 2

B) Glomeruli and small blood vessels, Cd4

3) Creatine

Basement membrane

Antibody (since remember most chronic rejections are due to Abs)

Question 57

In order to increase graft survival chances, HLA matching would be the most beneficial… However sometimes this can’t be done like in liver, heart, or lung transplants and therefore another important way to decrease chances of an organ rejection is ____ therapy which includes ___ to reduce inflammation, Mycophenolate Mofetil to inhibit lymphocyte proliferation, and Tacrolimus (FK506) to inhibit ___ cell function via inhibiting NFAT needed for their activation

Once could also prevent host T cells from receiving costimulatory signals from dendritic cells during the initial phase of sensitization

Opportunistic infections can occur when one has a lowered immune system and one of the most frequent infections due to the induced immunosuppression aimed at prolonging graft survival is ___ and this latent virus in the lower GI tract becomes reactivated during immunosuppression and causes infection of renal tubules and graft rejection

^** Other latent viral infections that can become reactivated during immunosuppression include EBV-induced lymphomas, HPV induced squamous cell carcinomas, and Kaposi sarcoma

Answer 57

Immunosuppressive, steroids, T-cell

Polyoma virus

Question 58

Patients that have hematologic malignancies (cancer that begins in the cells of blood forming tissues), bone marrow failure syndromes (like aplastic anemia), or inherited stem cell defects (sickle cell, thalassemia, or immunodeficiency states) can all benefit from ____ transplants

For this to work, the patient has their immune system destroyed via chemotherapy so that when the HSCs are transplanted, they don’t get destroyed

However, two major problems can occur with this type of transplantation

1) ___ is when immunologically competent cells or their precursors are transplanted into immunologically crippled recipients and therefore the transferred T-cells recognize alloAgs in the host cell and therefore attack the host cell’s tissues

^** So in other words, donors T-cells are able to respond to Ags and when transferred to the recipient, the donor HSCs recognize the recipient’s antigens as foreign and attack it

HLA matching is critical for this to now happen

^** Also realize since this disease is due to donor T cells recognizing recipients Ags, if you eliminated donor T cells you can eliminate GVHD, but instead now you get graft-versus-leukemia effects since these donor T cells were important in controlling leukemia cells and suppressing EBV related B-cell lymphomas

GVHD can be acute of chronic

A) Acute GVHD occurs days to weeks after allogenic bone marrow transplantation and has its major clinical manifestations involving the immune system and epithelia of the ___, ___, and ____

^** Skin involvement manifests with a ___, liver involvement causes small bile duct destruction and therefore ___, and mucosal ulcerations in the gut cause bloody diarrhea

B) Chronic GVHD can occur after acute syndrome or by itself and includes extensive cutaneous injury (destruction of skin appendages and fibrosis of the dermis), chronic liver disease, GI tract damage leading to esophageal strictures (narrowing of esophagus), involution of thymus (shrinking), decreased lymphocyte count in the lymph nodes, and some may develop autoimmunity

2) ____ is the other problem that occurs after HCS transplantation (aka bone marrow transplantation aka BMT) and commonly due to prior treatment, myeloablative preparation of the graft, delayed repopulation of the recipients immune system, or attack on the host’s immune cells by grafted lymphocytes….

^** Either way, now the recipient has a decreased immune system and commonly ___ can infect the patient and cause death

Answer 58

HSC (Hematopoietic stem cell)

1) GVHD (Graft vs host disease)

A) Skin, liver, and intestines

Rash, jaundice

2) Immunodeficiency

CMV (Cytomegalovirus)

Question 59

Immunodeficiencies can be divided into ___ (aka congenital) disorders which are genetically determined or ___ (aka acquired) that can arise from complications of cancers, infections, malnutrition, or side effects from irradiation/chemotherapy/etc.

1) Primary immunodeficiencies can affect both innate and adaptive immunity

^** Usually detected at a ___ age (between 6 months and 2 years) due to susceptibility of recurrent infections

A) Primary defects associated with innate immunity

^** Innate immunity defects are usually due to defective leukocyte function or complement system defects (talked about on the next few notecards)

B) Primary defects associated with adaptive immunity

^** Adaptive immunity defects are usually due to defective lymphocyte maturation or activation (talked about after primary defect notecards)

2) Secondary immunodeficiencies can occur from defective lymphocyte maturation (such as from destroying the bone marrow during chemotherapy or tumors), inadequate Ig synthesis (like in malnutrition), or lymphocyte depletion (like from drugs or severe infections)

Answer 59

Primary, Secondary

1) Young

Question 60

Name the primary defects associated with innate immunity for leukocyte function defects

1) Leukocyte adhesion deficiency type 1 has a defect in the ___ chain of ___ or ___ (both are integrins needed for leukocyte adhesion) also called CD__/CD___
2) Leukocyte adhesion deficiency type 2 has a defect in the fucosyl transferase enzyme, which causes no sialyl-Lewis X to be produced which is the ligand (on the leukocytes) for P and E ___ found on the endothelial cells

^** Both type 1 and 2 result in recurrent bacterial infections since granulocytes can function properly since they cant migrate

3) Chediak-Higashi syndrome is due to a ___ defect (aka failure of phagosomes to fuse with lysosomes) from the cytosolic protein called LYST (needed to regulate lysosomal trafficking) and this causes defective phagocyte function

^** Leads to neutropenia (decreased neutrophils), defective degranulation, and delayed microbial killings and in blood smears leukocytes are seen containing giant granules

4) ___ is a defect in the microbicidal activity (aka compounds that are suppose to reduct the infections of microbes) due to inherited defects in the genes encoding ____ which is needed for the production of an oxidative burst in the phagocytes (a rapid release of ROS to degrade and kill bacteria)

^** It can be either X-linked where the enzyme is defective in the ___ components or autosomal recessive where it is defective in the ____ components

The disease is called chronic granulomatous disease since a macrophage-rich chronic inflammatory reaction tries to control the infection when the initial neutrophil defense is not working and leads to granulomas

5) MPO (Myeloperoxidase) deficiency can also occur leading to decreased microbial killing due to defective MPO-H2O2 system
6) TLRs can also be defective like TLR3 defect associated with viral RNA (recurrent herpes simplex encephalitis) or MyD88 associated with bacterial pneumonias

Answer 60

1) B2 chain, LFA-1 integrin or MAC-1 integrin, CD11/CD18
2) selectin
3) Phagolysosome
4) Chronic granulomatous disease, phagocyte oxidase

Membrane, Cytoplasmic

Question 61

Name the primary defects associated with innate immunity for complement system defects

1) A deficiency in the classical pathway due to defects in ___ or ___ and this leads to reduced resistance to bacterial or viral infections and reduced clearance of immune complexes leading to SLE-like autoimmune disease manifestations
2) ___ defects lead to problems with all complement functions since both the classical and alternative pathway need it and can lead to increased recurrent pyogenic infections (pus formations normally from pyogenic bacteria)

^** Increased incidence of immune complex mediated glomerulonephritis occurs

3) If C5, C6, C7, or C8 are defective the MAC can not form and recurrent risk towards Neisseria bacteria occurs (gonococcal and meningococcal infections)
4) Deficiency of complement regulator proteins such as ___ which can give rise to ____ (rapid swelling of the dermis, subcutaneous tissue, mucosa, and submucosal tissues) since it can not regulate the complement system and therefore excess complement activation occurs causing up-regulation of vasoactive peptides like bradykinin

Answer 61

1) C2 or C4
2) C3
4) C1 INH (C1 inhibitor), hereditary angioedema

Question 62

There are various primary defects associated with adaptive immunity and include (these will be divided up over the next few notecards)

** Note, these are defects in adaptive immunity due to lymphocyte maturation defects **

1) In ____, infants present with oral candidiasis (aka prominent thrush aka accumulation of fungus in the mouth), a diaper rash (rash on butt), and the failure to thrive… Some infants can develop GVHD rash and all SCID infants are susceptible to various bacteria and without HSC transplantation, death occurs

^**SCID can occur from defects in both humoral and cell mediated adaptive immunity, and depending on the defect allows one to classify what type of SCID it is

A) X-linked SCID is the most common (50-60%) form and due to a mutation in the common ___ subunit of cytokine receptors and with no receptors, the proliferation of lymphoid progenitors (particularly t cell precursors in the thymus) does not occur and T-cells can not develop

^** IL-___ is the most important for Pro-T cells to turn into Immature T cells and IL-___ is the most important for NK cell maturation

Since T cells do not develop, there is also a decreased amount of antibody synthesis since T-cell help can not activate the B cells

^** Histologically, lobules of undifferentiated epithelial cells resembling fetal thymus is found

B) Autosomal recessive SCIDs are the remaining forms of SCIDs and the most common autosomal recessive SCID is due to a defect in the enzyme ___ and this causes a buildup of toxic substances towards immature lymphocytes (mainly the T cell lineage)

^** Histologically, remnants of Hassall’s corpuscles are found

Other less common autosomal recessive SCIDs include mutations in RAG (Recombinase-activating genes) leading to no somatic gene rearrangement (which is needed for T-cell receptors and Ig genes to be produced) or Jak3 mutations causing GammaC chan to not be able to induce a signal and same effects as above ^

2) X-linked Agammaglobulinemia aka Bruton Agammaglobulinemia

^** In this disease, B-cell precursors (Pro-B and Pre-B cells) do not develop into mature B cells due to a defective ___ gene (a cytoplasmic tyrosine kinase) which is associated with the Ig receptor complex that is needed to transduce signals from the receptor and since this is mutated, no maturation occurs

^** It does not occur until maternal Igs are depleted 6 months after birth and often recurrent bacterial infections of the ___ tract (pharyngitis, sinusitis, otitis media, bronchitis, pneumonia, etc…) call attention to this disease and are due to Haemophilus influenzae, Streptococcus Pneumoniae, or Staphylococcus aureus

Also viral infections are common in the bloodstream or mucoasl secretions due to enterovirsus including echovirus, poliovirus, or coxsackievirus and finally, an intestinal protozoan called Giardia lamblia sometimes causes infections

Characteristics for this disease include absent B cells and serum Igs of all types, Pre-B cells with CD19 but no Ig expression, Germinal centers/Peyers pathces/appendix/tonsils all underdeveloped, Absence of plasma cells in body, T-cell mediated reactions normal

^** Some patients also develop autoimmune diseases like arthritis and dermatomyositis) and treatment is replacement with Igs

Answer 62

1) SCID (Sever combined immunodeficiency)

A) Gamma-chain (GammC)

IL-7, IL-15

B) ADA (Adenosine deaminase)

2) Btk (Bruton tyrosine kinase)

Respiratory

Question 63

There are various primary defects associated with adaptive immunity and include (these will be divided up over the next few notecards)

** Note, these are defects in adaptive immunity due to lymphocyte maturation defects **

3) DiGeorge syndrome (aka ___) occurs from a __-cell deficiency from the failure of the development of the third and fourth pharyngeal pouches and therefore immature T cells can not mature

^** Since these fail to develop, the patient presents with loss of T-cell mediated immunity and poor defense against fungal and viral infections, ___ due to no development of the parathyroid glands resulting in hypocalcemia, and congenital defects of the heart and great vessels due to no development of the ultimobranchial body

Remember, this is due to a 22q11 deletion syndrome on the TBX1 gene

4) Bare lymphocyte syndrome is due to a defect in transcription factors needed for ___ gene expression leading to no activation of CD4+ T cells

Answer 63

3) Thymic hypoplasia, T

Tetany

4) Class 2 MHC

Question 64

There are various primary defects associated with adaptive immunity and include (these will be divided up over the next few notecards)

** Note, these are defects in adaptive immunity due to lymphocyte activation and function defects **

1) Hyper-IgM syndrome is when the patients Abs can make IgM, but not IgG, IgA, or IgE

^** The defect causes not T-helper cells to be able to activate B cells and macrophages and in 70% of the cases this is an X-linked disease that causes a mutation in the gene encoding the ____ in the T-helper cells (remember, the CD40L-CD40 interaction is needed for class switching, affinity maturation, AND stimulation of microbicidal functions of macrophages and since it is important for macrophage function in cell-mediated immunity, patients with the CD40L mutations are susceptible to ____ infections leading to pneumonia )

The other 30% have a loss-of-function mutation causing a defect in CD40 or AID (activation-undiced cytidine deaminase) which is an enzyme required for Ig class switching and affinity maturation

Serum has normal or high IgM levels, no IgA, no IgE, low or no IgG, and normal B and T cell numbers (just realize the B cells can’t be converted to plasma cells other than IgM)

2) CVID (Common variable Immunodeficiency) is a group of disorders characterized by hypogammaglobulinemia and unlike X-linked agammaglobulinemia, there are ___ amounts of B cells however NO plasma cells since they cant differentiate into them

^** This disease is due to defects in both B-cells themselves and Helper-T cell mediated activation of the B cells… and can be from a defective receptor for the cytokine BAFF or a defect in the molecule ICOS, etc…

Although the clinical presentation is similar to X-linked agammaglobulinemia, CVID occurs in both sexes equally and the onset is later (in childhood of adolescence) compared to 6 months in for X-linked agammaglobulinemia

Also, B-cell areas of lymphoid tissue are hyperplastic since they can become activated and proliferate in response to an antigen, but they cant produce Abs so therefore they are incompletely activated

3) Isolated IgA deficiency has patients with low levels of serum IgA and secretory IgA due to a defect in the IgA differentiation of naive B lymphocytes to IgA producing plasma cells

^** Most are asymptomatic, but because IgA is the major antibody in external secretions, mucosal defenses are weakened and infection occurs in the respiratory, Gi, and urogenital tract

Patients also present with sinopulmonary infections and diarrhea and high risk for autoimmune diseases like SLE and rheumatoid arthritis]

4) X-linked lymphoproliferative (XLP) disease is characterized by the inability to eliminate ___ and therefore eventual fulminant (aka severe) infectious mononucleosis and the development of B-cell tumors

^**This is due to a mutation in the gene that codes for an adaptor molecule called ___ which is needed to activate Nk, T, and B lymphocytes along with the development of follicular helper T cells causing no germinal centers or high affinity antobiodies to be produced

Answer 64

1) CD40L, P. Jiroveci
2) Normal (or near normal)
4) EBV, SAP (SLAM-associated protein)

Question 65

There are also primary immunodeficiencies associated with systemic diseases and the two major ones include

1) Wiskott-Aldrich syndrome

^** This disease has ___ inheritance and characterized by thrombocytopenia, eczema (inflammation of the skin), and recurrent infection leading to early death

The disease is caused from a defect in the ___ gene which is needed for membrane receptors (like antigen receptors) to be linked to cytoskeletal elements

2) Ataxia telangiectasia

^** This disease has ___ inheritance characterized by ataxia (abnormal gait), vascular malformations aka dilated capillaries (telangiectases), neurological deficits, increased incidence of tumors, and immunodeficiency

The disease is due to a defect in the ___ gene, which codes for a protein kinase that acts as a DNA damage sensor by activating ____ via phosphorylation and therefore activation of cell cycle checkpoints and apoptosis with cells that have damaged DNA so if this is defective, DNA repair can not occur and the generation of antigen receptors can be abnormal… This gene also has a role in somatic recombination so a defect can cause problems with isotype switching

Answer 65

1) X-linked

WASP (Wiskott-Aldrich syndrome protein)

2) Autosomal recessive

ATM (Ataxia telangiectasia mutated), p53

Question 66

AIDS is caused by the retrovirus HIV (Human immunodeficiency virus) as is characterized by immunosuppression leading to increased opportunistic infections, secondary neoplasms, and neurological manifestations

The main routs of transmission include sexual contact (mainly man to man), parenteral inoculation (intravenous drug abusers, hemophiliacs, or recipients of blood transfusions), and transmission from mother to newborns (during intrapartum from an infected birth canal or peripartum from ingestion of breast milk are the most common)

^** Viral transmission occurs via either

1) Direct inoculation into the blood vessels breached by trauma
2) Infection of dendritic cells or CD4+ cells within the mucosa

Also note that HIV is ___ via coexisting STDs (especially those associated with genital ulcerations)

^** Include Treponema pallidum, herpes simplex virus, Chlamydia trachomatis, and Neisseria gonorrhoeae

Answer 66

Enhanced

Question 67

HIV is a nontransforming human retrovirus that belongs to the ____ family

There are two forms (HIV-1 and HIV-2) with HIV-1 being the most common

The HIV structure contains a viral core consisting of the major capsid (virus shell) protein ___, a nucleocapsid protein p7/p9, ___ copies of single stranded viral genomic ___NA, and 3 viral enzymes including ___, ___, and ___

The viral core ^ (What we just talked about above) is surrounded by a matrix protein called ___, which is under the virion envelope that has two glycoproteins called ___ and ___ studded into the viral envelope

The HIV-1 RNA genome has Long terminal repeats (LTRs), gag, pol, and env genes which are typical of retroviruses

Answer 67

Lentivirus

P24, 2 copies, RNA, protease and reverse transcriptase and integrase

P17, gp120 and gp41

Question 68

HIV can infect many tissues but the two major tissues are the immune system and CNS

Profound immune deficiency, primariliy effecting ___-mediated immunity is the hallmark of AIDS and the main mechanism for the HIV infection is from a ___ amount of ____ cells (with moncytes/macrophages and dendritic cells also being targets of the HIV infection since they also contain the CD4 receptor)

As an overview, HIV enters through the mucosal tissues and blood and first infects T cells, along with dendritic cells and macrophages, and then it becomes established in the lymphoid tissues where it can remain latent

The HIV life cycle occurs in multiple steps including

1) Infection of the cells

^** This occurs from the ___ and ___ binding first, followed by a conformational change and then ____ co-receptors ___ or ___ binding to the CD4-gp120 complex

^** Note that CCR5 chemokine co-receptor is a R5 strain of the HIV and is called ___-tropic since it preferentially Infects cells of the monocyte/macrophage lineage

CXCR4 is an X4 strain of HIV and called ___-tropic because it preferentially infects T cells

^** R5 strain dominates in acute infection but overtime X4 accumulates and then becomes dominant

Once the gp120-CD4-Chemokine complex is formed, another conformation change occurs in ___ which exposes a fusion peptide which inserts into the cell membrane of the target cells (monocytes/macrophages or T cells) leading to fusion of the virus with the host cell

Answer 68

Cell-mediated, decreased, CD4+ T helper cells

CD4 and gp120, chemokine CCR5 or CXCR4

M-tropic

T-tropic

Gp41

Question 69

The HIV life cycle occurs in multiple steps including

1) Infection of the cells (talked about on last notecard)
2) Integration of the provirus into the host cell genome

^** After fusion, the virus core containing the HIV genome enters the cytoplasm of the cell and the HIV RNA genome undergoes ____ leading to synthesis of cDNA aka proviral DNA (double stranded complementary DNA) and in dividing T cells the cDNA circularizes, enters the nucleus, and then integrated into the host genome

HIV is able to infect memory and activated T cells, but has a hard time infecting ___ cells because naive T cells have the enzyme APOBEC3G that causes mutations in the HIV genome once it undergoes reverse transcription… However, once the naive T cells become activated, they lose the enzyme and this is why activated or memory T cells can be infected

3) Activation of viral replication

Now remember, the viral life cycle can only be completed after cell activation, so if a cell was already actively replicating, then it just continues along its path…. However most of the time after the provirus is integrated into the host cell’s genome, it stays there in a latent phase where it is silent for months or years

So in this case above ^ once the cell become activated in most CD4+ T cells, the virus activation results in cell ___

Remember, when a T cell is activated by antigens or cytokines it phosphorylates IKB in the cytoplasm, releasing the inhibition it had on NF-KB and therefore NF-KB is up-regulated and translocates to the nucleus where it sends signals for increased transcription of IL-2 and its receptor occur so that the T cells can proliferate and differentiate…. HOWEVER, when the HIV has infected the nucleus and the infected cell becomes activated by an antigen or cytokine (either from the HIV itself or some other infecting microbe), the NF-KB up regulates and translocates to the nucleus but instead of binding on normal promoter regions in the nucleus, it actually binds to the HIV genome that has NF-KB binding sites (the HIV LTR sticky regions) and this causes the ___ of HIV proviral DNA (HIV DNA provirus -> HIV RNA provirus moves to cytoplasm) and leads to the production of ___ and lysis of the cell

^** So in other words, if you have HIV you are at an increased risk for recurrent infections -> recurrent infections cause increased lymphocyte activation and production of pro-inflammatory cytokines -> More cytokines and antigens from microbes stimulates more HIV production from the mechanism we explained above ^ -> More CD4+ T cells undergo lysis and die -> More infection since less T cells -> never ending cycle

4) Production and release of infectious agents

Answer 69

2) Reverse transcription

Naive T cells

3) Lysis

transcription, virons

Question 70

Like we’ve already talked about, T cell depletion occurs mainly from direct cytopathic effects (lysis) of the replicating virus however some other mechanisms can also cause the loss of T cells including

1) Activation induced cell death where chronic activation of uninfected cells responding to HIV itself or an associated infection that cause the cells to undergo apoptosis
2) Pyroptosis
3) Destruction of lymphoid tissues
4) Loss of immature CD4+ T cells
5) Loss of TH1 responses

Since CD4+ T cells are important for both adaptive and humoral immunity, loss of this effects almost every component of the immune system including lymphopenia (low WBCs), decreased T cell function, altered T cell function, polyclonal B cell activation, and altered monocyte and macrophage functions

We’ve mainly talked about infection of T cells by HIV, but remember macrophages and dendritic cells are also infected

1) Macrophages infected by HIV occurs mainly in the tissues

^** Remember, cell division is needed for nuclear entry and replication for most retroviruses, but HIV can infect and multiply in terminally differentiated non-dividing macrophages due to the viral ___ gene

Also unlike CD4+ T cells, macrophages are resistant to the cytopathic effects of HIV and therefore they can harbor the infection since they don’t lyse like T-cells do and are important for the late stages of HIV infection

2) Dendritic cells (Mucosal and follicular)

^** The ___ dendritic cells become infected by the virus and transport it to the regional lymph nodes where it can then be transferred to CD4+ T cells

____ dendritic cells in the germinal centers of the lymph nodes are potential reservoirs of HIV where they trap the HIV virions due to the dendritic cells FC receptor binding to anti-HIV Abs coated around the virions

Answer 70

1) vpr
2) Mucosal

Follicular

Question 71

Even though we have been focusing mainly on cell-mediated defects from HIV, B cells also undergo changes….

There is polyclonal ___ (Inhibition or activation?) of B cells leading to B-cell hyperplasia in the germinal centers, hypergammaglobulinemia, bone marrow plasmacytosis, and formation of circulating immune complexes

^** But even though there are a lot of activated B cells, patients with AIDS still cant mount an Ab response to new antigens due to the fact that T-helper cells are decreased and can’t help them become activated, and some other factors…

Along with the immune system, remember we said that the CNS is also affected and here the HIV infects macrophages and microglial cells (M-tropic lineage)

Answer 71

Activation

Question 72

Once the virus enters through the mucosal epithelia (where it normally comes through), a few subsequent phases occur including

1) ___ syndrome is the clinical presentation of the initial spread of the virus and host response and occurs 3-6 weeks after infection and resolves spontaneously after 2-4 weeks

Symptoms are fever like (soar throat, fever, weight loss, fatigue, possible rash, possible diarrhea, possible vomiting)

^** The primary infection occurs when ___ cells with the CCR-5 chemokine in the mucosal lymphoid tissue becomes infected and large amounts of T cells die

At the same time, dissemination (spreading) of the virus occurs via mucosal dendritic cells taking in the virus and bringing them to the lymph nodes and passing them on the CD4+ T cells via direct contact

^** Here, the HIV undergoes viral replication leading to ___ (viruses in the blood that is measured as ____ levels aka viral load) where it continues its dissemination to the peripheral lymphoid tissues infecting macrophages mainly at first, along with dendritic cells and Helper-T cells

As dissemination occurs, development of host immune responses also happens (anti-viral humoral and cell-mediated along with CD8+ CTLs) and evident by 3-7 weeks after the infection

^** The appearance of CTLs are responsible for the initial containment of the HIV infection

After initial viremia, infected people reach a stead state called the ____ and this can be used as a predictor for the rate of decline of CD4+ T cells and therefore progression of the HIV disease

^** Therefore CD4+ Cell counts and not viral load are the primary clinical measurement used to determine when to start antiretroviral therapy

Answer 72

1) ) Acute retroviral syndrom

Memory CD4+ T cells

Viremia, HIV-1 RNA levels

Viral set point

Question 73

Once the virus enters through the mucosal epithelia (where it normally comes through), a few subsequent phases occur including

2) Middle, Chronic phase (most patients are asymptomatic)

^** Here, the virus is now concentrated in ____ (mainly the lymph nodes and spleen) where continues HIV replication and cell destruction occurs

** Remember, this replication and destruction is occurring in the tissues, not the peripheral blood at the moment, however since CD4 T cells in the tissue are declining, there is less and less going out into the peripheral blood**

Along with a slow decline in the number of CD4+ T cells in both the lymphoid organs (from being destroyed) and the blood (from not enough T cells able to get into circulation), the immune defense system starts to decline as well and therefore the number of HIV infected cells begins to increase

^** The immune system declining is due to the HIV beginning to evade the immune detection via destroying CD4+ T cells, antigenic variation, down-regulating class ___ MHCs on infected cells (so that the viral antigens are not recognized by CTLs), and switch from CCR5 to some other chemokine

Since not clinical manifestations of HIV occur during this period, it is called the ____ period

Even though most patients are asymptomatic, candidiasis (thrush), herpes zoster, mycobacterial tuberculosis, and some other small opportunistic infections might occur

Answer 73

2) lymphoid tissues

Clinical latency

Class 1

Question 74

Once the virus enters through the mucosal epithelia (where it normally comes through), a few subsequent phases occur including

3) Clinical AIDS

Typically occurs in about 7-10 years and clinical features include long lasting fever (over a month) and weight loss, diarrhea, generalized lymphadenopathy

Also, AIDS indicator diseases including

1) Neurologic diseases,
2) Multiple opportunistic infections
3) Secondary neoplasms

Opportunistic infections account for the majority of deaths in untreated patients with AIDS

Infections include

A) 15-30% of patients develop pneumonia via ___, which is a ___ infection and presents with cough and hypoxia

B) A patient with an infection in the oral cavity (oral THRUSH), esophagus, or vagina has ____ which is a ___ infection

C) ____ affects the eyes (chorioretinitis and blindness) and GI tract (Intestinal)

D) Bacterial infections including Mycobacterium avium-intracellulare (part of MAC) which is an atypical mycobacteria occurs ___ in the infection (commonly a cause of Fever of Unknown Origin with a count of less than 50 CD4 cells/mm3) and in contrast to that, M. Tuberculosis occurs ___ in the course of AIDS

E) Meningitis is due to ___, which is a __ infection of the CNS (note sometimes AIDS patients don’t exhibit meningeal inflammation even though they have meningitis) and encephalitis (brain inflammation) is due to ____ which causes MASS lesions in the brain aka CNS and is a protozoal/helminthic infection

F) Profressive multifocal leukoencephalopathy (brain white matter diseases and therefore affects the CNS) is caused by ___

G) Mucocutaneous ulcerations in the mouth, esophagus, genitalia, etc. is due to ____

H) Presistent diarrhea is commonly due to ____ (a protozoan infection) or isospora belli or Microsporidia

I) Epstein Barr virus can cause ____ characterized by white hair-like projections from the tongue (different from an oral thrush seen in Candida albicans since it does NOT scrape off with a tongue blade)

Answer 74

A) P. Jiroveci, fungal

B) Candida albicans , fungal

C) Cytomegalovirus

D) later, early

E) Cryptococcus neoformans, fungal, Toxoplasma gondii

F) JC virus

G) Herpes simplex virus

H) Cryptosporidium

I) OHL (Oral hairy leukoplakia)

Question 75

Neoplasms due to AIDS are also common and caused by oncogenic DNA viruses mainly….

****A) ____ is a vascular tumor and the most common neoplasm associated with AIDS

^** It is characterized by spindle shaped cells that express markers for both endothelial cells (vascular or lymphatic) and smooth muscle cells; along with chronic inflammatory cell infiltrates

KS is caused by ___ and establishes a latent infection during which spindle cell proliferation and activation, along with prevention of apoptosis occurs… And the activated spindle cells produce proinflammatory and angiogenic factors that recruit inflammatory and neovascular components that lead to the tumor

B) Primary B-cell lymphomas (commonly occur in the CNS) are caused by tumor cells infected with oncogenic viruses, most commonly ____

^** Unchecked proliferation of B cells infected with oncogenic herpesviruses in the setting of profound T cell depletion can lead to lymphomas such as EBV+ large cell lymphomas or EBV+ Hodgkin lymphomas (associated with a large tissue inflammatory response and Reed-Sternberg cells) or KSHV+ primary effusion lymphoma

^**In a patient with AIDS, they obviously have low T cell counts… Since T cell immunity is required to restrain to proliferation of B cells infected with oncogenic viruses like EBV (or KSHV), since it is low, this control is lost

THERE IS A SECOND mechanism that can cause B-cell lymphomas not related to EBV and this can occur in patients who might be receiving HAART and therefore have preserved CD4 T cell counts… This mechanism is due to germinal center B-cell hyperplasia in the setting of early HIV infection due to defective AID enzyme can occur

C) Invasive cancer of the uterine cervix, which can be caused by ___

^** This can also be caused by ___ cancer

Answer 75

A) Kaposi sarcoma (KS), HHV8 (aka Human Herpes virus 8 aka KSHV aka KS herpesvirus….ALL THE SAME THING)

B) EBV

C) HPV

Anal

Question 76

So if one sees hyperplasia of B cell follicles, it is the ___ stages of HIV infection due to polyclonal B-cell activation and hypergammaglobulinemia seen in HIV patients

As the disease progresses, B-cell proliferation subsides and gives way to severe lymphoid involution (inactivation/shrinkage)… The lymph nodes become atrophic and small and can carry opportunistic infections and eventually the spleen and thymus also become involuted

Answer 76

Early

Question 77

___ is a combination of 3-4 drugs that block different steps of the HIV life cycle and alter the course of HIV and incidence of opportunistic infections (like P. Jiroveci) and tumors (like Kaposi sarcoma)

Some downsides to this therapy include Immune reconstitution Inflammatory Syndrome, where patients in an advanced state of the disease actually get worse even though CD4+ T cells are increasing and viral load decreasing

Answer 77

Highly Active Antiretroviral Therapy (HAART)

Question 78

Amyloidosis is various conditions (inherited and inflammatory) in which there are extracellular deposits of ___ proteins leading to tissue damage and functional compromise

Abnormal fibrils (which remember are fine fibers like a myofibril or neurofibril) are produced by the aggregation of ____ proteins, which are normally soluble in their folded conformations

These deposits bind ___ like heparan sulfate and dermatan sulfate, along with plasma proteins like ____

These deposits in the extracellular space appear amphorus, eosinophilic, hyaline, extracellular substance with progressive accumulation causing it to encroach on and produce pressure atrophy of adjacent cells

A diagnosis is made via a ___ biopsy

Answer 78

Fibrillar

Misfolded

Proteoglycans/GAGS, SAP (Serum amyloid P component)

Tissue

Question 79

One of the best ways to tell amyloid from other hyaline materials like collage or fibrin, is a ___ stain that shows the presence of ___ upon polarizing microscopy which is a DIAGNOSTIC feature for ALL amyloids

A cross Beta plated sheet conformation is also a characteristic

Answer 79

Congo red stain, Green birefringence

Question 80

Rather than a single disease, amyloidosis is a group of diseases having in common the deposition of similar appearing proteins (95% proteins and 5% SAP aka P component and other glycoproteins)

1) The ___ protein is made up of either complete Ig light chains, the amino-terminal fragments of light chains, or both

The AL protein is produced from free Ig light chains (mainly lambda) secreted by a monoclonal population of ___ cells from an acquired mutation and therefore associated with certain forms of plasm cell tumors

2) The ___ protein is derived from proteolysis of a unique non-Ig protein made by the liver called ___, which circulates bound to HDLs

^** Since the SAA protein is increased in inflammatory states such as during the ___, this is associated with ___ inflammation and also called ____ amyloidosis

Chronic inflammation causes the activation of macrophages, which secrete IL-1 and IL-6 such as in the acute phase response to the liver cells, which increase their SAA production and therefore proteolysis causes AA protein to be formed

3) The ___ protein constitutes the core of cerebral plaques found in Alzheimers disease and is formed from proteolysis of a large transmembrane glycoprotein called the amyloid precursor protein

Other more rare causes of amyloidosis due to aggregation of normal serum proteins include

4) ATTR proteins (transthyretin) which binds and transports thryoxine and retinol and therefore disorders with this protein deposit due to a mutation are called familial amyloid polyneuropathies
5) ___ is the amyloid fibril subunit associated with hemodialysis and is a component of the MHC class 1 molecules and a normal serum protein

It comes from the precursor protein B2 microglobulin

Answer 80

1) AL (Amyloid light chain)

Plasma

2) AA (Amyloid-associated), SSA (Serum amyloid-associated)

Acute phase response, chronic, secondary

3) AlphaBeta
5) AB2m

Question 81

To classify the diseases, they are either systemic (generalized) amyloidosis aka involve several organ systems or localized amyloidosis

^** Systemic amyloidosis can be further broken down into primary (associated with a ___ cell disorder) or secondary (occurs as a complication of an underlying chronic inflammatory or tissue destructive process)

There is a 3rd category called hereditary (or familial) amyloidosis

1) Systemic, Primary (plasma cell disorder), amyloidosis

^**Aka Immunocyte dyscarasias with amyloidosis

This category is mainly of the ___ protein accumulation type due to clonal proliferation of plasma cells that synthesize an Ig that is prone to form amyloid due to its intrinsic physiochemical properties

The best example of this systemic amyloidosis is patients with ____ (a plasma cell tumor characterized by multiple osteolytic lesions aka bone loss throughout the skeletal system)

^** This is a primary amyloidosis because of ___ proteins which are free, unpaired kappa and lambda light chains secreted into the blood (also found in the urine and tissues) or monoclonal Igs are found in the serum

This is an immunocyte dyscrasias (blood disorder) with amyloidosis…

2) Systemic, secondary amyloidosis

This category is mainly of the ___ protein and is called secondary because it is secondary to a ____ condition

The most common condition associated with this is ___

This is a reactive systemic secondary amyloidosis

3) Hemodialysis associated amyloidosis can be associated with chronic ___ failure and result in ___ protein accumulation

Answer 81

Plasma

1) AL

Multiple myeloma

Bence-Jones protein

2) AA

Chronic inflammation

Rheumatoid arthritis

3) Renal, AB2m

Question 82

Like we said on the previous notecard, there is a 3rd category called hereditary (or familial) amyloidosis and includes

1) Familial Mediterranean fever due to excessive ___ production in response to an inflammatory stimuli from a gene called pyrin and ____ is the major fibril protein accumulated
2) Familial amyloidotic neuropathies or systemic senile amyloidosis are both due to mutant TTRs resulting in ATTR fibril accumulation with the precursor protein being Transthyretin

Answer 82

1) IL-1, AA

Question 83

In contrast with Systemic amyloidosis, the other category of Localized amyloidosis includes

1) Senile cerebral leading to Alzheimers disease is associated with ___ protein as the major fibril accumulation from a larger precursor protein called APP (amyloid precursor protein)
2) In patients with T2Ds, ___ amyloidosis can occur including medullary carcinoma of the thyroid or islets of Langerhans

Answer 83

1) AB

2) Endocrine