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19. Mechanisms of Disease Exam 2 > 1. Diseases of the Immune System (Ch 6) > Flashcards

1. Diseases of the Immune System (Ch 6) Flashcards

1
Q

What is protection from infectious pathogens and the normal immune reponse?

A

immunity

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2
Q

Innate immunity are mechanisms that are ready to react to infections before they occur. Adaptive immunity are mechanisms that are stimulated by microbes. What term referes to adaptive immunity?

A

immune response

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3
Q

Innate immunity is always present and ready to provide defense against microbes/ to eliminate damage cells. What are the major components of innate immunity? 5

A 
epithelial barriers
neutrophils
dendritic cells
Natural killer cells
Complement
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4
Q

What cells are specialized cell population in the epithelia that capture protein antigens and displat peptides for recognition by T cells? Also initiate innate immune responses

A

Dendritic Cells

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5
Q

Natural killer cells are early protection against viruses and intracellular bacteria. What protein in the plasma plays an important role?

A

Complement system

mannose binding lectin and C reactive protein coat microbes to make them tasty- opsins

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6
Q

Innate immunity can recognize PAMPs and DAMPs which collectively are recognized by patterna reconition receptors PRRs. Where are PRRs located mainly?

A

cellular compartments where microbes may be present: plasma membran receptors detect extracellular microbes, endosomal receptors detect ingested microbes and cytosolic receptors detect mircobes in the cytoplasm

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7
Q

What are the three major classes of innate immune receptors?

A

TLRs
NOD like receptors
C-type lectin receptors

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8
Q

TLRs recognize microbial products which activate 2 transcription factors in a common pathway once bound, known as?

A

NF-kB which stimulates synthesis and secretion of cytokines and adhesion molecules **for recruitment of leukocytes
Interferon regulatory factors (IRFs) which stimulate production of antiviral cytokines (type 1 IFN)

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9
Q

NOD-like receptors NLRs, are cytosolic receptors which recognize necrotic cell product like uric acid and ATP. NLRs signal the inflammosome which does what?

A

activates caspase1 which cleaves precursor form of IL1 into its biologicall active form.
(GOF mutation can cause auntoinflammatory syndrome)

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10
Q

What are some examples of endogenous product that bind NLRs and cause inflammation? 3

A

Gout, lipids, cholesterol crystals

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11
Q

What is the following pathway?

  1. NLR creates inflammosome which activates caspase 1
  2. Inflammasome = NLRP3 sensory protein, adaptor protein — activated caspase 1
  3. Caspase 1 cleaves proIL1B into IL1B
A

Inflammasome pathway

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12
Q

What type of receptors are expressed on the plasma embrane of Mø and dendritic cells and detect fungal glycans and elicit inflammatory reactions to fungi?

A

C-type Lectin receptors CLRs

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13
Q

What are the two main reactions that the innate immune system provides host defense?

A

Inflammation
Antiviral defense via IFN1 (antiviral state)
*also stimulates adaptive response

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14
Q

The adaptive immune system consists of lymphocytes and their products including antibodies. What is the difference between humoral immunity and cell mediated immunity?

A

Humoral: protects against extracellular microbes and their toxins (B cells and Ab mediated)
Cell mediated/ cellular: responsible for defense against intracellular microbes (T cell mediated)

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15
Q

Match the lymphocyte with its corresponding function….
B, T helper, Cytotoxic T, T Reg, NK
-Neutralization of microbe, phagocytosis and complement activation
-killing of infected cell
-activation of macrophages, inflammation, activation of T and B cells
- Killing of infected cell
-suppression of immune response

A

B Cell/Abs-Neutralization of microbe, phagocytosis and complement activation
CTL -killing of infected cell
T helper-activation of macrophages, inflammation, activation of T and B cells
Natural Killer- Killing of infected cell
T regulatory cell-suppression of immune response

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16
Q

Lymphocytes specific for a large number of antigens exist before exposure to antigen and when an antigens enteres, it selectively activates the antigen specific cell. This is known as?

A

clonal selection

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17
Q

What is generated by somatic recombination of the genes that encode the receptor proteins?

A

antigen receptor diversity

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18
Q

Gene segments recombine randomly as mediated by RAG1 and RAG2, there are no mature lymphocytets if RAG is mutated. What receptor will be generated for T/B cells?

A

T cell is the TCR
B cell is the BCR
*Occurs in thymus

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19
Q

Because each T or B cell and its clonal progeny have a unique DNA rearrangement (and hence a unique antigen receptor), it is possible to distinguish polyclonal (non-neoplastic) lymphocyte proliferations from monoclonal (neoplastic) lymphoid tumors. Thus, analysis of antigen receptor gene rearrangements is?

A

a valuable assay for detecting tumors derived from lymphocytes (lymphoma) PCR!

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20
Q

What stimulates B lymphocytes to make antibodies and activate other leukocytes to destroy microbes?

A

Helper T cells

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21
Q

T cells mature in the thymus and are found in the blood constituting 60-70% of blood lymphocytes. The TCR of T cells consist of a disulfide linked heterodimer made up of an alpha and beta polypeptide chaine which variable regions. What does the AB TCR recognize?

A

antigens presented by major histocompatilbility MHC molescules on professional APCs

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22
Q

By limiting specificity of T cells for peptides displayed by cell surgace MHC molecules,- MHC restriction ensures what?

A

T cells see only cell-associated antigens

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23
Q

Each TCR has CD3 and Zeta chain that are invariable, involved in signal transduction. A small population of mature T cells express gama sigma polypeptide chains, which recognize?

A

peptides, lipids, and small molecules without assistance from MHC proteins @ epithelial surfaces

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24
Q

What type of T cell does the following? Cytokine-secreting helper cells that assist macrophages and B lymphocytes.Bind to class II MHC molecules (coreceptor) .

A

CD4+

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25
Q

What type of T cell does the following? T cells - cytotoxic (killer) T lymphocytes (CTLs) that destroy host cells harboring microbes. Bind to class I MHC molecules (coreceptor).

A

CD8+

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26
Q

What is the T cell coactivator location on the T cell which interacts with CD80/86 (B7.1/7.2) to provide furth signals for T cell activation?

A

CD28

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27
Q

B cells are 10-20% circulating lymphocytes found in LN, spleen and MALT. They recognize natigens via B cell receptor antigen complex which are IgM or IgD. Once activated B cells turn into plasma cells. What are the co-receptors?

A

IgA and IgB which are essential for signal transduction through the antigen receptor

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28
Q

T cells activate B cells which is relevant with regard to Hyper IgM syndrome. B cells also have a type 2 complement receptor known as CR2 or CD21 which is useful for?

A

recognizing complement proteins and CR2 is used by EBV to infect B cells - signaling

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29
Q

What cells are the most important antigen presenting cells for initiating T cell response against protein antigens?

A

Dendritic Cells (interdigiting dendritic cells)

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30
Q

DCs are commonly seen in the epithelia, immature DCs wihtin the epidermis are called langerhans cells. Why is this location great for immune defense?

A

this is the most common area where microbes and foreign antigens enter

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31
Q

What type of cell is present in germinal centers of lymphoid follicles in the spleen and LNs, which bear Fc receptors for IgG and C3b receptors to trap antigen bound to Abs or complement proteins?

A

Follicular dendritic cells (presents Ags to B cell to improve quality of Abs)

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32
Q

What are mononuclear phagocytes which process antigens from microbes and proteins to present to T cells, which can inhance the cells response. They phagocytose cells that are opsonized by IGg or C3b?

A

Macrophages

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33
Q

What cells function to destroy irreversibly stressed and abnormal cells such as virus infected and tumor cells? They contain azurophilic granules and can kill without prior exposure to microbes. have CD16 = Fc receptor for IgG and lyse IgG coated target cells called antibody-dependent cell-mediated cytotoxicity

A

Natural Killer cells

CD16!!

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34
Q

NK cell function is regulated by a balance between signals from activating and inhibitory. What activating receptors are best characterized and recognize surgace molecules that are induced by various kinds of stress?

A

NKG2D

NK inhibitory cells recognized MHC1 molecules on all healthy cells

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35
Q

What occurs when the healthy inhibitor receptors on a healthy cell is no longer presented to the NK cells?

A

The NK cell will no longer receive inhibitory signals and will signal to kill due to inhibition of MHC 1, killing infected cell

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36
Q

IL2 and IL15 stimulate proliferation of NK cells which release IL12 which produces Th1 which does what?

A

Releases IFNY to macrophages for activation

IL12 more for killing and secretion of IFNY

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37
Q

What cells lack TCRs but produce cytokines similar to T cells, producing IFNY, IL5, IL17, IL22, and functions in early defense against infections, recognize and eliminate stressed cells, and provide cytokines that influence the differentiation of T cells?

A

Innate Lymphoid Cells ILCs

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38
Q

Immune system tissues consist of generative or primary/central lymphoid organs and peripheral or secondary lymphoid organs. What are examples of each and what the produce?

A

Generative
Thymus : Tcells develop/mature
Bone Marrow: Blood cells and B cells
Peripheral
LNs: lymphocytes interact with APCs/Ags in circulating lymph
Spleen: lymphocytes can interact w blood borne antigens
MALT: (tonsils/adenoids/peyerspatches)- lymphocytes and plasma cells to be in vicinity of antigens within the mouth and intestinal tract

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39
Q

What are organized to concentrate antigens, antigen presenting cells and lymphocytes and the development of adaptive immune reponses?

A

Peripheral lymphoid organs

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40
Q

Within the peripheral lymphoid organs, T and B cells are segregated into separate areas. Where are they located?

A

B cells in follicles around the periphery and/or within the cortex
T cells located in the paracortex region, in the middle of the B cell follicles

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41
Q

Lymphocyte recirculation is important for T cells because naive T cells remaiin in the peripheral lymphoid organs while effector T cells travel to the site of damage. What about B cells?

A

Plasma cells remain in lymphoid organs and noe marrow and do not need to migrate to sites of infection because they secrete antibodies that are carried to distant tissues

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42
Q

What is the primary site of hematopoesis, and origin of stem lymphocytes and B cell maturation?

A

Bone marrow (generative organ)

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43
Q

Immature T cells arrive from bone marrow and as they mature they migrate from the peripheral cortex to the central medulla of what? The medulla contains mature T cells, dentritic APCs w high levels of MHC I and II and Hassall corpuscles which are?

A

Thymus- T cell maturation

Hassall corpuscles are squamous cell nests

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44
Q

What region does the following occur? APCs interact with lymphocytes, T and B cell clonal expansion, B cell differentiation into plasma cells, and migration oF T cells and plasma cells out of them into circulation… (T cells in paracortex and B cells in germinal centers in cortex)

A

Lymph Nodes

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45
Q

The main role of MHC (major histocompatibility complex) is to display peptide fragments of protein antigens for recognition by antigen specific T cells. What are the two types of MHCS?

A

MHC I
MHC II

Note MHC=HLA in human

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46
Q

What is the following characteristic of?
All nucleated cells
Typically recognize intracellular Ags (virus/tumor)
Ags are processed into peptides by proteasomes
Peptides transport to ER, load into groove of MHC and entire complex migrates to surface
Presentation of entire complex to CD8+ T cell

A

MHC Class I

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47
Q

What is the following characteristic of?
Antigen presenting cells (mø, B cells, DCs)
Typically recognize extracellular Ags (microbes/allergens)
Antigens are processed into peptides by endolysosomal enzymes
Vesicles form with processed peptides and MHC complex
Presentation of entire complex to CD4+ Helper T cells

A

MHC Class II

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48
Q

What are the differences between the MHC I and MHC II subregions?

A

MHCI: HLA-A/B/C
MHCII: HLA-DP/DQ/DR

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49
Q

The combination of HLA alleles in each individual is called the HLA haplotype. You receive one HLA from mom and one from dad resulting in?

A

Polymorphism that means that no two individuals besides identical twins express the same MHC molecules.

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50
Q

Since every has different HLA haplotypes, that means there is extensive heterogeneity leading to differences in fighting off illness and in allergic sensitivities. What is the clinical importance?

A

transplated organs -HLAs need to match

associated autoimmune diseases

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51
Q

What chromosome encodes the HLA molecular structure for a given individual?

A

Chr 6

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52
Q

What is the difference between MHC and HLA?

A

HLA are the MHC molecules present in humans

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53
Q

Cytokines are messenger molecules of the immune system and mediate many cellular interactions and functions of leukocytes. In innate immune responses, what produces cytokines, which ones, and what do they do?

A

Mø, DCs, NK cells
TNF, IL1, IL2, Type 1/2 IFN and chemokines
Induce inflammation and inhibit virus replication

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54
Q

In adaptive immune responses, what produces the cytokines, which cytokines and what is the main function?

A

CD4+ T cells
IL2, IL4, IL5, IL17, IFNY
Promotes lymphocyte proliferation and differentiation & to activate effector cells

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55
Q

Cytokines that stimulate hematopoiesis are called colony stimulating factors. What is their function, what cells produce them, and what are some cytokines?

A

Produced by marrow stromal cells, T cells, Mø
Function to increase leukocyte numbers
GM-CSF and IL7

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56
Q

In the case of immunization with a protein antigen, microbial mimics called ______, are given with the antigen and these stimulate the innate immune response.

A

Adjuvants

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57
Q

What are the three main steps of adaptive immune reponse?

A

Antigen recognition/display
Cell-mediated immune reponse
Humoral immune response

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58
Q

In cell mediate immunity, APCs bring back intracellular pathogens while expressing MHC-associated peptide antigens, leading to?

A

Recognition by T cells— proliferation, differentiation, migration and killing

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59
Q

When an antigen is presented to a lymphoid organ, CD4+ helper T cells secrete IL2 and express high affinity IL2 receptors. IL2 is a growth factor that acts on these T lymphocytes and stimulates their proliferation, leading to?

A

an increase in the number of antigen specific lymphocytes.

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60
Q

CD4+ T helper cells have CD40Ligand, CD40L which is expressed when B cells or macrophages present recognizable antigens. Leading to?

A

CD40L binding CD40 on the B cell or Mø, activating the cells

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61
Q

Some CD4+ cells differentiate into effector cells that secretes different cytokines. What are the 3 major types of T cells?

A

Th1 IFN Y
Th2 IL4 IL5 IL13
Th17 - IL17

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62
Q

Upon activation, B cells proliferate and differentiate into plasma cells that secrete different classes of antibodies. What are the two types of B cell activation?

A

T dependent*** and independent activation

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63
Q

In T cell dependent humoral immunity, B cells ingest protein antigens, digest and display them via MHCII to CD4+ Helper cells. What happens next?

A

T cell is activated and expressed CD40L (**important for isotype switching and affinity maturation) which stimulate B cell

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64
Q

Many polysaccharide and lipid antigens cannot be recognized by T cells but have multiple identical antigenic determinants (epitopes) that are able to engage many antigen receptor molecules on each B cell and initiate process of B cell activation, this process is known as?

A

T independent humoral immunity (nonprotein antigens)

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65
Q

What is require for immunoglobulin isotype switching and affinity maturation, so this does not occur in T independent B cell activation?

A

NEED T cells — so T independent is mainly IgM Ab

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66
Q

T dependent activation allows B cells to make IgA, IgG, and IgE. Isotype switching is induced by what two things?

A

IFN-Y and IL4

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67
Q

Helper T cells stimulate the production of Abs with high affinites for the antigen, known as _________, improves the quality of the humoral immune response.

A

affinity matuartion

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68
Q

What are the major sites of isotype switching and affinity maturation in which B cells are directed to via follicular helper T cells?

A

migrate to follicles and form germinal centers

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69
Q

Match the antibody with its function and features…. IgA/E/M/G

  • mucosal epithelia defense, present in high levels in colostrum
  • transported across the placenta and provides immunity for newborn, longest 1/2 life**
  • against parasites, shortest half life, highest affinity binding to FC receptor on mast cells and eosinophils
  • First Ig produced, pentamer = really big
A

IgA-mucosal epithelia defense, present in high levels in colostrum
IgG-transported across the placenta and provides immunity for newborn, longest 1/2 life**
IgE-against parasites, shortest half life, highest affinity binding to FC receptor on mast cells and eosinophils
IgM-First Ig produced, pentamer = really big

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70
Q

Injurious immune reactions called hypersensitivity, are the basis of the pathology associated with immunologic disease. What does it mean to be sensitized to something?

A

Meaning individuals that have been previously exposed to that antigen react upon second encounter.

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71
Q

Hypersensitivity reactions can be elicited by exogenous environmental antigens or endogenous self antigens, they usually result from an imbalance between effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses. What are two other important general features?

A
  1. The development of hypersensitivity diseases is often associated with inheritance of particular susceptibility genes
  2. The mechanisms of tissue injury in hypersensitivity are the same as the effector mechanisms of defense against infectious pathogens
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72
Q

Match the type of hypersensitivity with the thing that causes injury…

  • Th2 cells, IgE antibodies and mast cells
  • IgG and IgM antibodies bind antigens usually in the circulation and the antigen-ab complexes deposit in tissues and induce inflam
  • secreted IgG and IgM abs injure cells by promoting their phagocytosis or lysis and injure tissues via inflammation
  • sensitized T lymphocytes cause injury
A

Type 1-Th2 cells, IgE antibodies and mast cells
Type 3-IgG and IgM antibodies bind antigens usually in the circulation and the antigen-ab complexes deposit in tissues and induce inflam
Type 2- secreted IgG and IgM abs injure cells by promoting their phagocytosis or lysis and injure tissues via inflammation
Type 4- sensitized T lymphocytes cause injury

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73
Q

Type 1 hypersensitivity is a rapid immunologic reaction occurring in a previously sensitized individual that is triggered by the binding of an antigen to IgE ab on the surface of mast cells. What are the two well defined phases?

A

immediate reaction and late phase reaction

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74
Q

The immediate reaction of type 1 HS occurs minutes after exposure and subsides in a few hours, epinephrine is used to treat anaphylaxis. What are the 3 characteristics of the immediate reaction?

A

vasodilation
congestion
edema

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75
Q

the late phase reaction of type 1 HS occurs 2-24 hours later without additional exposure to the antigen and may last for several days. What are the main characteristics of late phase?

A

infiltration of tissues with EOSINOPHILS (N,B,Monocytes) and CD4+ T cells with concomitant tissue destructions in the form o mucosal epithelial cell damage

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76
Q

Most immediate hypersensitivity (HS) disorders are caused by excessive Th2 responses and these cells play a central role by stimulating?

A

IgE production and promoting inflammation

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77
Q

When an allergen is presented via APC to a CD4+ cell, making a Th2 T cell. The Th2 T cell will release cytokines such as IL4 IL5 and IL13, which do what?

A

IL4: class switch to IgE = more Th2
IL5: develop/activate eosinophils
IL13: enhances IgE production and stimulates mucus secretion

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78
Q

Mast cells are tissue cells while basophils are the circulating counterpart. Mast cells are mainly activated by what three things? Also can be triggered by chemokines, drugs, adenosine, etc.

A

activated by crosslinking of high affinity IgE FceR1 receptors
along with C3a and C5a

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79
Q

Mast and basophils have FceRI receptor for the Fc portion of IgE antibodies. IgE coated mast cells are said to be?

A

sensitized, because they contain the antibodie and once the allergen binds again, a reaction (type I HS) will occur (via crosslinking of antigen to IgE = mast cell degranulation)

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80
Q

mast cell activation leads to degranulation, releasing primary mediators, what are the 3 preformed mediators and their actions?

A

Histamine- vasoactive amine causing SM contraction, increased vasc permeability
Enzymes- neutral proteases chymase /tryptase lead to tissue damage and kinin production/ complement activation
Proteoglycans- package and store amines in granules (heparin)

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81
Q

Lipid mediators are also released from mast cells upon activation and degranulation, which are derived from arachidonic acids via phospholipase A2. What are the three main lipid mediators and what do they do?

A

Leukotrienes- C4/D4 vasoactive and spasmogenic agents known
Prostaglandin D2- intense bronchospasm and increase mucus secretion
Platele-activating factor PAF- platelet aggregation, histamine release, bronchospasm

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82
Q

Mast cells also release cytokines upon degraulation, including TNF/IL1 for leukocyte recruitment, IL4 for Th2 response amplification. In all, what mediatiors are responsible for the manifestation of immediate hypersensitivity reactions?

A

Preformed mediators
Lipid mediators (LKT/PGD2/PAF)
Cytokines-TNF, IL1, IL4, Chemokines

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83
Q

Cytokines are the main mediators that set the stage for what, by recruiting additional leukocytes?

A

late phase response.

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84
Q

Late phase response is when leukocytes- mainly eosinophils are recruited which amplify and sustain the inflammatory response without doing what?

A

additional exposure to the triggering antigen

***eosinophils have major basic protein that cause tissue damage (IL5 recruits)

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85
Q

An increase in propensity to develop immediate HS reactions is called atopy. Atpoic individuals have higher serum IgE levels and more IL4 producing Th2 cells than general population. What is found in 50% of atopic individuals?

A

50% have a positive family history for allergies

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86
Q

What is an idea that early childhood and even prenatal exposure to microbial antigens educates the immune system in such a way that subsequent pathologic responses against environmental allergens are prevented?

A

Hygeine Hypothesis

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87
Q

Systemic anaphylaxis occurs within minutes after exposure: itching, hives, and skin erythema appear followed by a striking contraction of respiratoru bronchioles and respiratory distress. What are the 3 things it is characterized by?

A

vascular shock
widespread edema
difficulty in breathing

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88
Q

What is a food antigen-driven disease of childhood that causes recurrent dysphagia and weight loss because the patient is not able to swallow effectively and because it hurts?

A

Eosinophilic Esophagitis

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89
Q

Antibodies that react with antigens present on cell surfaces or in the extracellular matrix causes disease by destroying these cells, triggereing inflammation or interfering with normal functions in what HS reaction?

A

Antibody mediated type II HS (IgG/IgM)

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90
Q

IgG and IgM antibodies injure cells by promoting phagocytosis and injure tissues by inducing inflammation. What is the main way they do this?

A

IgG/M activate the classical complement pathway, activating complement, allowing lysis and inflammation

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91
Q

Cells coated with IgG antibodies are killed by a variety of effort cells, mainly NK cells and mø and cell lysis occurs without phagocytosis in what pathway?

A

antibody-dependent cellular cytotoxicity (ADCC)

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92
Q

In ADCC, MOA- When antibody is directed at a parasitic infection, there if Fc receptor-mediated inflammation and phagocytosis, characteristic of ADCC. IgG and IgE antibodies bearing Fc receptors coat the parasite. Macrophages, natural killer cells, and neutrophils can then recognize the Fc receptor and destroy the antibody-coated target cells. What is the contribution to HS reactions?

A

Unknown

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93
Q

Transfusion reactions, hemolytic disease of the newborn, autoimmune hemolyic anemia and drug reactions such as drugs that act as haptens are all examples of what?

A

antibody mediated cell destruction in disease

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94
Q

When antibodies are deposited in fixed tissue, injury is due to inflammation. The depositive Abs activate complement which leads to C3a/5a. What are 2 things that can happen due to this?

A

glomerulonephritis

vascular rejection in organ grafts

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95
Q

Sometimes, antibodies directed against cell surface receptors impair or dysregulation function without causing cell injury or inflammation, occuring in what two dieseases?

A

Myasthenia gravis: abs antagonize NM transmission = muscle weakness
Graves: abs against TSH receptor acts as agonist and stimulates cells (anti-receptor)

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96
Q

Type II hypersensitivity reactions are where antibodies directly react with antigens present on the cel surface/extracellular matrix, including what two things?

A

autoantibodies

exogenous antigens that are bound to cell surfaces

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97
Q

One mechanism of Type II HS is opsonization leading to phagocytosis or direct lysis in the case of antibody-dependent cellular cytotoxicity. What two diseases use this?

A

anemia
thrombocytopenia
(basic mech is no cells)

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98
Q

the second mechanism of Type II HS is complement and Fc receptor mediated inflammation on damaged tissues such as basement membrane proteins or streptococcal proteins that cross react with myocardium. What are three examples where this mechanism is used?

A

Vasculitis
Goodpasture syndrome
Acute rheumatic fever

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99
Q

The third mechanism of Type II HS is antibody mediated cellular dysfunction with a basic mechanism of dysfunction due to receptor blockade. What are three examples of this?

A

Myasthenia gravis (ab blocks binding at receptor)
Graves (ab activates binding at receptor)
Insulin resistant diabetes (ab inhibits insulin binding at receptor)

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100
Q

Type III HS occurs when antigen-ab complexes deposit in tissue and cause damage by eliciting inflammation at the sites of deposition. What is the most common area where this occurs?

A

In the vessel walls - circulation

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101
Q

Antigens in type III HS can be exogenous or endogenous. besides for the blood vessels (vasculitis) what are the other two regions of the body typically involved?

A

kidney- glomerulonephritis

joints- arthritis

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102
Q

What is the prototype of a systemic immune complex disease, which was once sequela to the administration of large amount of foreign serum?

A

acute serum sickness

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103
Q

What are the 3 phases of pathogenensis of type IIIHS?

A

formation of immmune complexes (1 week)
deposition of immune complexes (chose areas of high filtration of blood)
inflammation and tissue injury (10 days post antigen)

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104
Q

In what disease is there repeated or prolonged exposure to antigen- called chronic serum sickness, associated with persistent antibody reponses to autoantigens?

A

Systemic lupus Erythematosus SLE - lupus

***Fibrinoid necrosis & bumpy lumps upon immunofluorescence

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105
Q

What is a local immune complex disease where a localized area of tissue necrosis forms resulting from acute immune complex vasculitis in the skin? As antigen diffuses into the vascular wall, it binds preformed antibody and LARGE immune complexes are formed locally.

A

Arthus reaction

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106
Q

When performing immunofluorescence on kidney biopsies, how are you able to tell the difference between a type II and type III HS reaction?

A

Type II: will have smooth linear lines and will look clear- uniformly attached
TypeIII: will have grainy/granular lines because there are deposited complexes, which do not line the tissue perfectly like type 2 HS

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107
Q

Are the following type 2 or 3 HS reactions?

  1. in the kidney, post-streptococcal cross-reactive antibodies are forming immune complexes that deposit in the glomeruli
  2. In the heart, post-streptococcal cross reactive antibodies directly act on the myocardium
A
  1. Type 3

2. Type 2

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108
Q

Type IV HS reaction causes inflammation by either cytokines released from CD4+ T cells or by killing done by CD8+ T cells. The cytokines released may be chronic and destructive. The prototype of T cell mediated inflammation is ______, a tissue reaction to antigens given to immune individuals.

A

delayed type hypersensitivity DTH

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109
Q

Activation of the T cell occurs when Naive T cells recognize antigens displayed APCs. Whether the T cell becomes Th1 or Th17 T cell depends on the cytokines the APC releases, which are?

A

APC releases IL12 = Th1 = IFNy = more Th1

APC releases IL6, IL23, IL1 = Th17

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110
Q

IFN-Y secreted by Th1 cells are mainly responsible for many of the manifestations of DTH. IFN-Y classically activates M1 macrophages leading to what outcome?

A
  • Enhanced ability to phagocytose and kill microorganisms
  • Express more class II MHC molecules on the surface
  • Secrete pro-inflammatory TNF, IL-1, and chemokines
  • Produce more IL-12 which causes an amplified TH1 response

*Activated macrophages eliminate the offending antigen, but if activation is sustained, continued inflammation leads to tissue injury

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111
Q

What is tissue injury from DTH reactions, which is thought to occur by environmental chemical agents bind to and structurally modify self proteins and peptides and elicit a CD4+T cell response to the ‘foreign’ antigens? This same process is thought to occur in drug reactions.

A

Contact dermatitis - poison ivy

also rheumatoid arthiritis, MS and IBD are CD4+ mediated

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112
Q

CD8+ T cell mediated cytotoxicity- CTLs kill antigen expressing target cells leading to tissue damage. What are two good examples of this?

A

Type I DM

Graft rejection after organ transplantation

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113
Q

CD8+T cells produce IFNY and are involved in inflammatory reactions resembling DTH, especially following what infections?

A

Virus infections or exposure to some contact senitizing agent

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114
Q

What is the one hallmark histologically of some type IV reactions?

A

Granulomas with macrophages, epithelioid cells, giant langhan cells, and CD4+T cells

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115
Q

What are the following?

  1. presence of an immune reaction that is specific for some selft antigen or self tissue
  2. The reaction is not secondary to tissue damage, but rather it is the thing that is causing the tissue damage
  3. absence of another well-defined cause of disease
A

Three requires that pathologic autoimmune disease must meet to be confirmed as an autoimmune dz

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116
Q

Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen. What is self tolerance?

A

refers to lack of responsiveness to an individuals OWN antigens - which is monitored by central and peripheral tolerance

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117
Q

Central tolerance is learned prior to release from generative lymphoid organs while peripheral tolerance is?

A

ongoing regulation in peripheral tissues

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118
Q

In T cell development, random somatic gene rearrangements generate diverse TCRs. When self reactive T cells come in contact with self ags, they are set to die via apoptosis in the thymus. This process is known as?

A

negative selection or deletion

*some may become Tregs

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119
Q

What protein stimulates expression of some peripheral tissue restricted self antigens in the thymus and is thus critical for deletion of immature T cells specific for these antigens?

A

AIRE -autoimmune regulator

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120
Q

When B cells are developing in the bone marrow, if they strongly recognized self ags, many of the cells reactivate the machinery of antigen receptor gene rearrangment and begin to express new antigen receptors, not specific for those antigens. What is this process called?

A

receptor editing

*if the editing does not help, the B cell undergoes apoptosis

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121
Q

What are the two main mechanisms focused on for peripheral tolerance?

A

anergy

suppression by Tred cells

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122
Q

In peripheral tolerance lymphocyte that recognize self antigens may be rendered unresponsive- anergy. Anergy may occur when both signals (MHC and costim) are not availible. What is the costimulation needed?

A

CD28 on T cell binds B7.1/7.2 on APC

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123
Q

When T cells are self reactive in the periphery, they receive inhibitory signals from structures that are homologous to CD28. What are the two?

A

CTLA4 and PD1

when tested in mice without these, mice had autoimmune diseases

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124
Q

Tumors and viruses actually use PD1 and CTLA4 to inhibit T cell death, leading to tumor/virus growth. This has lead to what?

A

antibodies against CTLA4/PD1 have been made for tumor immunotherapy by removing the breaks on the immune reponse

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125
Q

Treg cells (induced by TGFB) also prevent immune reactions against self antigens. The best Treg cells are CD4+ that express CD25, the alpha chain of the IL2 receptor and a transcription factor known as?

A

FOXP3 (required for development and maintence of Treg cells)

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126
Q

When there are mutations in FOXP3, it results in severe autoimmune diseases known as?

A

IPEX

immune dysregulation, polyendocrinopathy, enteropathy, Xlinked

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127
Q

Treg cells supress the immune system due to secretion of IL10 and TGFB, and they also express what, which may bind to B7 molecules on APCs and reduce their ability to activate T cells via CD28?

A

CTLA4

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128
Q

What are two other mechanisms in which T cells and B cells in the periphery are deleted if they are self reactive?

A

Via Bim - proapopotic signal and via Fas-Fas death receptor pathway

APOPTOSIS

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129
Q

What arises from a combinations of the inheritance of susceptibility genes which may contribute to the breakdown of selftolerance and environmental triggers such as infections and tissue damage which promote the activation of self-reactive lymphocytes?

A

Autoimmunity

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130
Q

HLA genes have the greatest contribution to autoimmunity. Ankylosing spondylitis is typically hereditary inflammatory coniditon of the joints, particularly the spine. Inflammation leads to degeneration and then fusion of the vertebrae. What HLA gene is this disease strongly associated with?

A

HLA-B27- individuals with this class 1 HLA gene have 100-200 fold greater chance of developing the disease as compared to people without it.

**Male, young, severe back pain presentation

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131
Q

There are some autoimmune disease that are associated with non-MHC/HLA genes such as PTPN22 and NOD2. Mutations in PTPN22 which encodes protein tyrosine phosphatase, can lead to what diseases?

A

rheumatoid arthritis, type 1 DM, and more

***PTPN22 most frequenctly implicated in autoimmunity

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132
Q

Polymorhpisms in which gene renders paneth cells in intestinal epithelium ineffective at microbial killing? Defective killing and clearance allows accumulation of bacteria and an exaggerated immune response.

A

NOD2 gene polymorphism causing crohn disease

No NOD-like receptor = dysbiosis d/t increase gut flora

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133
Q

Autoimmune disorders may be triggered by infections, because they upregulate the expression of costimulators on APCs and they also may express antigens that have same AA sequence as self antigens. This leads to immune response against microbial antigens resulting in the activation of self reactive lymphocytes called?

A

molecular mimicry - seen in rheumatic heart disease in which antibodies against streptococcal proteins cross react with myocardial proteins and cause myocarditis

134
Q

autoimmune diseases tend to be chronic sometimes with relapses and remissions, and the damage is often progressive. What is a cause of this, in which an immune response against one self antigen causes tissue damage, releasing other antigens and resulting in activation of lymphocytes by these newly encountered epitopes?

A

epitope spreading

135
Q

What is a good example of epitope spreading?

A

Initial T cell response leads to kertotic lesions in oral and conjunctival mucosa (oral lichen planus) causing membrane disruption which exposes antigenic proteins, leading to a secondary B cell response of blistering in secondary pemphigoid

136
Q

Match the autoantibodies with their disease:
1. anti-basement membrane, anti- type IV collagen
2. anticardiolipin, anti-β2-glycoprotein “lupus anticoagulant”
3. anti-dsDNA, anti-Sm
4. anti-histone antibodies
5 anti-SS-A, anti-SS-B
6 anti-U1-ribonucleoprotein
7 anti-Jo-1
8 anticentromeric antibody ==
9 anti-DNA topoisomerase

A
  1. Goodpasture Syndrome ==
  2. Antiphospholipid Syndrome, SLE ==
  3. SLE ==
  4. drug-induced SLE ==
  5. Sjogren Syndrome ==
  6. Mixed Connective Tissue Disease (MCTD)
  7. polymyositis/dermatomyositis ==
  8. limited scleroderma (CREST syndrome)
  9. diffuse systemic scleroderma
137
Q

ANA is a sensitive test for multiple autoimmune diseases. Its presence can prompt more specific testing to confirm the diagnosis. Other tests are more SPECIFIC, such as what for SLE?

A 
Anti DS DNA 
Anti Smith (Sm)

Use more sensitive first becuase if it is negative then we know it is not autoimmune dz

138
Q

What are the four different staining patterns for antinuclear antibodies ANA?

A

homgenous (Lupus-abs to chromatin/histones/ DS DNA)
speckled (most common least sepcific, abs to non-nuclear DNA- sjogren)
Nucleolar (systemic sclerosis)
Centromere (systemic sclerosis with abs specific for centromeres)

139
Q

What is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies - ANA in which injury is caused by deposition of immune complexes and binding of antibodies to various cells and tissues?

A

Systemic lupus erythematosus

140
Q

SLE is as high as 1 in 2500, affecting mainly women, 2-3 fold increase in prevalence in blacks and hispanics than in whites. What is the hallmark of SLE?

A

production of autoantibodies *****ab to DS-DNA and Smith (Sm) are diagnostic

141
Q

What is following a classic picture of?
erythematous malar facial skin rash and renal failure with proteinuria and hematuria from immune complex deposition in glomeruli.

A

SLE Lupus

142
Q

ANA are directed against nuclear antigens and can be grouped into four categories; abs to DNA, abs, to histones, abs to non-histone proteins bound to RNA, and abs to?

A

nucleolar antigens (systemic sclerosis)

143
Q

The defect in SLE is failure of mechanisms that maintain self tolerance - genetic and environmental causes. Family genetic patterns including which HLA gene?

A

HLA DQ (produce the autoabs)
Female Bias: Xchromosome
UV light

144
Q

Some other SLE genetics could be the inherited deficiency of complement proteins leading to failure to clear immune complexes. Deficiency in which complement protein can lead to defective phagocytic clearance of apoptotic cells?

A

C1q

145
Q

There are many immunologic factors that result in self reactive lymphocytes such as failure of self toelrance in B cells and CD4+ T cells. How do TLR engagement by nuclear DNA and RNA and Type 1 interferons contribute?

A

TLR engagement provides second signal for B cell activation = increase autoabs
Type 1 IFN: activates lymphocytes in SLE

146
Q

What are the main environmental factors that can lead to SLE?

A

exposure to UV light
gender bias - X chromosome
Drugs like hydralazine and procainamide

147
Q

Most of the tissue injury/systemic lesions are cuased by immune complexes mediated inflammation, also known as?

A

Type III HS

148
Q 
There are 11 criterion that someone with SLE may or may not have. 
ANA
Immunologic DOs
Hematologic DO
Neurologic DO
Renal DO
Serositis
Arthritis
and what other 4 things?
A

Malar rash
discoid rash (scarring/hypopigment)
photosensitivity
oral ulcers

149
Q

All of the following listed are when you start to expect lupus, which is the most important / common in SLE?

Arthritis
Skin rashes
Fever
Fatigue
Hemolytic anemia
Edema
A

Hemolytic Anemia is seen in 100% of lupus patients!!

150
Q

Autoantibodies specific for red, white cells and platelets opsonize these cells and promote their phagocytosis and lysis. In tissues nuclei of damaged cells react with ANAs and lose their chromatin pattern, become homogenous known as?

A

LE bodies or hematoxylin bodies

**LE cell is a phagocytic leukocyte (Neutro) which has engulfed the denature nucleus of an injured cell

151
Q

There are 6 patterns/classes of glomerular disease seen in SLE. What is the first and last stage and what occurs as the end-stage process?

A

1st stage is minimal mesangial nephritis

last stage is Advanced sclerosing lupus nephritis with fibrosis as end stage process

152
Q

The most common and severe form of lupus is the 4th (IV) stage - diffuse lupus nephritis. Half or more of the glomeruli is affected. Why is this considered to be the most common?

A

Becuase this is when people start showing symptoms of lupus! Including proteinuria and hematuria

153
Q

In Diffuse lupus nephritis, the glomeruli show increased cellularity due to proliferation of endothelial, mesangial and epithleial cells with EM showing deposits in the subendothelium. What will immunoflueorescence show?

A

granular pattern of IgG antibody contain complexes

154
Q

What can be seen in skin with people with SLE? 2

A

basal layer degeneration of the epidermis (vacuolated spaces between degen skin - white)
Positive immunoflueorescence for complement and Ig deposition along dermal - epidermal jxn
**fibrinoid necrosis may affect vessels present

155
Q

Cardiovascular complications are also seen in SLE. Before steroids were used, Libman-Sacks (valvular) endocarditis was more common. This nonbacterial verucous endocarditis takes the form of single or multple verrucous - warty deposits, as well as what other things?

A

The warts are comprised of fibrin and not infective but can embolize (rarely)

***Coronary artery disease increases due to many factors, but may also have contributions from immune complexes and antiphospholipid abs = endo damage and atherosclerosis

156
Q

What is a a neutrophil or macrophage that ingests the nucleus of a damaged cell? This is not used for dianosis anymore but may be seen in blood or body fluids…

A

L-E Cell (hemotoxylin)

157
Q

What are the most common causes of death due to lupus?

A

renal failure and intercurrent infections and CAD

158
Q

Chronic discoid lupus erythematosus DLE is a disease in which skin looks like SLE but there are no other systemic manifestations. What are the three things seen with DLE?

A

discoid rash
positive ANA
positive immunoflueorescence

159
Q

Discoid lupus is characterized by the presence of skin plaques showing varying degrees of edema, redness, scaliness and skin atrophy. Commonly located on the face and scalp above the neck. They have positive ANA but? Progression?

A

negative Anti-DS DNA

Progression is possible to systemic organ involvment but only in 5-10% poeple

160
Q 
What type of lupus presents with the following? 
Athralgia
fever
positive ANA
 Discoid rash
hematologic disease
positive immunofluorescence
A

Drug induced lupus erythematosus

no renal involvement, no etiology known, no positive DS-DNA

161
Q

Medicine induce breakdown of self tolerance has been seen in medications like hydralazine and procainamide. Instead of the positive DS-DNA abs, what is seen which is specific to drug induced lupus?

A

Positive Anti-Histone Abs

arthralgia/fever= positive ANA

162
Q

Hydralazine confers high risk for DIL (drug induced lupus) in people with ______ HLA
Procainamide confers high risk for DIL in people with the _______ allele?

A 
Hydralazine = HLA-DR4 allele
Procainamide= HLA-DR6 allele

take away drug = lupus goes away

163
Q

What syndrome is a chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of the lacrimal and salivary glands?

A

Sjogren Syndrome

164
Q

The decrease of tears and saliva in sjogren syndrome is from lymphocytic infiltration and fibrosis of the lcarimal and salivary glands. The infiltrate is predominantly made of what?

A

activated CD4+ T cells and some B cells w plasma cells

165
Q

Sjogren 75% people have rheumatoid factor, 50-80% have positive ANAs. But the most important antibodies associated with the syndrome are?

A

two ribonucleoprotein antigens
SS-A(Ro) and SS-B(La) in 90% patients

ppl with SSA will have early onset and longer disease duration

166
Q

Trigger of sjogren may be viral infection of the salivary glands which causes local cell death and release of self ags. T and B cells in the area attack resulting in?

A

inflammation, tissue damage, and fibrosis eventually

167
Q

Along with lcarimal and salivary glands as targets, exocrine glands sucha as lining the respiratory and GI tracts and vagina are affected as well. What is the first histologic finding?

A

periductal and perivascular lymphatic infilitration

168
Q

What are the three most common clinical presentation of someone with sjogren syndrome?

A 
dry eyes (due to decreased lacrim secretions evaulated with schirmers test), dry mouth- smooth tongue (papillary atrophy) with superimposed candida yeast infection due to dry mouth
Root caries/cavities due to dry mouth - difficulty swallowing
169
Q

What is essential for the diagnosis of sjogren syndrome?

A

biopsy of the lip to examine the minor salivary glands

170
Q

there are some complications with sjogren syndrome including extraglandular disease such as pulmonary fibrosis. Over time there is persistent lymphocytic inflammation that switches over to mainly B cells due to somatic rearragment. In about 5% of patients this B cell inflammation leads to?

A

Lymphoid proliferation becoming clonal leading to marignal zone LYMPHOMA (Bcell malignancy due to chronic lymphocytic inflammation)

171
Q

What disease is characterized by 1- chronic inflammation thought to be the result of autoimmunity 2- widespread damage to small blood vessels 3- progressive interstitial and perivascular fibrosis in the skin and multiple organs?

A

Systemic Sclerosis (scleroderma old name but didnt encompass the totality of the disease)

172
Q

There are two categories of systemic sclerosis known as diffuse and limited, what are the differences?

A

Diffuse scleroderm is characterized by widespread skin involvement at onset with rapid progression and early visceral involvement
Limited scleroderma: skin involvement is often confined to fingers, forearms, and face

173
Q

Systemic sclerosis is fibrosis throughout the body including skin, GI tract, kidneys, heart, lungs or can occur in a limited form. The cause is unknown but the disease likely results from three interrelated processes known as?

A

autoimmune responses, vascular drainage, collagen deposition

174
Q

Clinical features of systemic sclerosis has a female to male ratio of 3:1 with peak incidence around 50-60 years. Upon histological slides, you can see dense collagenous deposition consisten with?

A

subcutaneous fibrosis + inflammation

**vascular hyalinization

175
Q

Distinctive features of systemic sclerosis are striking cutaneous changes, especially skin thickening. What is episodic vasconstriction of the arteries and arterioles of the extremities seen in virtually all patients and preceds other symptoms in 70% of the cases?

A

Raynaud phenomenon

176
Q

What in systemic sclerosis is attributable to esophageal fibrosis and its resultant hypomobility in 50% of people with the disease?

A

Dysphagia

177
Q

Sclerosis tends to be more severe in black women with pulmonary and sometimes renal disease causing the majority of deaths. What are the two ANAs strongly associated with systemic sclerosis?

A

***DNA topoisomerase I (anti-scl70) abs (highly specific)

Anticentromere Abs in 20-30% of people who tend to have CREST

178
Q

Renal disease with sclerosis is mild, with mild proteinuria but rarely severe enough to cause nephrotic syndrome. However when there is malignant hypertension, is can cause?

A

fatal renal failure

179
Q

Sclerodactyly can progress to raynauds disease, causing enough blood block to cause necrosis and ?

A

distal phalangeal bone undergoes ischemic resoprtion

180
Q

Additional manifestations of system sclerosis includes GI tract - GI reflux and esophageal ulceration (d/t no blood/ischemia), renal vascular disease, pulmonary hypertension and?

A

pulmonary fibrosis d/t sclerosis

181
Q

Upon immunoflueorescence anti scl-70 (anti DNA topoisomerase) representative of systemic sclerosis can be seen as what pattern?
Anticentromere antibody which is indicative of CREST syndrome can be seen immunoflueorescently as what pattern?

A

Anti Scl-70 : Speckled

Anticentromere Ab: Centromere

182
Q

What is a unique form of limited sclerosis with a better prognosis than diffuse sclerosis because it involves less of the body/organs?

A

CREST syndrome

183
Q 
Describe each of the following clinical presentations of limited sclerosis - CREST syndrome...
Calcinosis
Raynaud's phenomenon
Esophageal dysfunction
Sclerdactyly
Telangiectasis
A

Calcinosis: calcium deposits in the skin
Raynaud’s phenomenon: spasm of blood vessels in response to cold/stress
Esophageal dysfunction: dysphagia d/t abnormal esophageal contraction
Sclerodactyly: thickening and tightening of skin on fingers and hands
Telangiectasis: dilation capillaries causing red marks on surface of skin

184
Q

What leads to the fibrosis in scleroderma?

A

fibrosis may be the result of activation of fibroblasts by cytokines produced by T-cells and alternatively activated macrophages

185
Q

What are the three hallmarks of scleroderma?

A

chronic inflammation, widespread damage to small blood vessels, progressive interstitial and perivascular fibrosis

186
Q

What is a disease with clinical features that are a mixture of the features of SLE, systemic sclerosis and polymyositis?

A

mixed connective tissue disease MCTD

187
Q

In MCTD, it is characterized by serologically high titers of antibodies to ribonucleoprotein particle containing-? What is most common present feature?

A

U1 ribonucleoprotein
(anti-ribonucleoprotein RNP)

Raynaud Phenomenon

188
Q

What disease is a newly recognized constellation of DOs characterized by tissue infiltrates dominated by IgG4 antibody producing plasma cells and lymphocytes, particularly T cells, storiform fibrosis, obliterative phlebitis and usually increase serum IgG4?

A

IgG4 related disease

189
Q

IgG4 disease commonly affects middle aged and older men, pathogenesis is not understood although IgG4 production in lesions is a?

A

hallmark of the disease

190
Q

Autoimmune pancreatitis, Riedel thyroiditis, Mikulicz syndrome (sjogren), idiopathic retroperitoneal fibrosis and what other two diseases are now known to be caused by IgG4 related disease?

A

inflammatory pseudotumors and inflammatory aortitis

191
Q

What is uniting pathophysiology? IgG4-producing plasma cells, T lymphocytes, and fibrosis. Eventual fibrotic scarring and?

A

irreversible damage to involved areas

192
Q

Rejection is a process in which T lymphocytes and antibodies produced against graft antigens react and destroy tissue grafts. The major antigenic differences between a donor and recipient that result in rejection of transplants are?

A

differences in HLA alleles.

193
Q

Grafts between the same species are called allografts, between different species is xenograft. There are two pathways for recognition of organ grafts including?

A

Direct- use APCs from the donor

Indirect- use recipients APCs to activate B and T cell response

194
Q

In direct allorecognition, Dentritic cells from donor meet T cells at the grafted organ or travel to lymph node near by. The donor DC via class I and II MHC will do what?

A

Activate CTLCD8 and CD4+ T helper cells causing tissue damage, inflammation, and killing graft cells

195
Q

In the indirect pathway of allorecognition, the recipients APC presents the antigen to the CD4 cell which can then activate macorphages or B cells which then leads to?

A

plasma cells to attack the blood vessels + inflammation from macrophages

** No CTL because these CTLs recognize graft antigens present by host APCs and cannot recognize graft cells directly.

196
Q 
Which of the following is B cell or T cell mediated?
Hyperacute rejection
Acute rejection
Acute Antibody mediated rejection
Chronic Rejection
Chronic Antibody mediated rejection
A 
B- Hyperacute rejection
T- Acute rejection
B- Acute Antibody mediated rejection
T- Chronic Rejection
B- Chronic Antibody mediated rejection
197
Q

Acute cellular rejection within the initial months after transplantation presents with signs of organ failure. Cytokines secreted by activated CD4+ T cells – inflammation results in increased vascular permeability and local accumulation of mononuclear cells leading to?

A

graft injury caused by activated macrophages

198
Q

Hyperacute rejection occurs when preformed antidonor antibodies are present in the circulation of the recipient. Possibly present due to previous transplant, prior blood transfusions. Rejection occurs within minutes to hours. What is seen morphologically in kidneys?

A

Ig/complement deposited in vessel wall causing endothelial injury and thrombi to form

*marked inflammation, thrombotic microvasculopathy and fibrinoid necrosis

199
Q

Acute antibody-mediated rejection is caused by antidonor abs produced after transplantation. The abs formed by the recipient may cause injury via?

A

complement activation, inflammation and antibody dependent cell mediated cytotoxicity.

200
Q

What type of rejection usually develops insidiously without preceding acute rejection and primary affects vascular componenets? Abs are detected in the circulation but are not readily identified within the graft.

A

Chronic antibody mediated rejection

201
Q

Acute rejection occurs within days of tranplantation, months or years after immunosuppression is tapered. What are the two histological patterns seen with acute cellular (T cell mediated) rejection?

A
  1. tubulointerstitial pattern - interstitial inflammation of tubules w CD4/8 T cells
  2. Vascular pattern- vessel inflammation, swollen endothelial cells *endotheliitis
202
Q

Acute antibody mediated rejection is manifested mainly by damage to glomeruli and small blood vessels. Typically the lesions consist of inflammation of glomeruli and peritubular capillaries with deposition of?

A

complement breakdown product Cd4- produced during activation of complement system by ab-dependent classical pathway

**Note C4d stain will be positive = acute ab - mediated rejection

203
Q

Chronic antibody mediated rejection is becoming increasingly frequent. It is dominated by vascular changes including thickening with inflammation, glomerulopathy, and what main thing?

A

fibrosis with primary effect on the vessels

204
Q

There are many methods to improve graft survival such as HLA matching between donor and recipient for kidney transplants to match HLA-A-B-DR, but it is not matched for other transplants. What is a practical necessity in all other donor-recipient combinations?

A

Immunosuppressive drugs/therapy

205
Q

Immunosuppressive drugs in current use includ steroids (reduce inflammation), mycophenolate mofetil (inhibits lymphocyte proliferation) and tacrolimus (FK506) which does what?

A

inhibits T cell functions by inhibiting NFAT which stimulates transcription of cytookine genes (IL2)

206
Q

Another drug used to treat rejection include T cell and B cell depleting antibodies and?

A

pooled intravenous IgG (IVIG) which supresses inflammation

207
Q

Although immunsuppression prolongs graft survival it carries its own risks, for example there is an increased risk for infection and tumors. One of the most frequent infection is?

A

poyloma virus - common in the renal tubules, may cause graft rejection

208
Q

Immunosuprresion also leads to an increased chance in neoplasia/tumor growth. Viral induce tumors such as lymphomas, kaposi sarcoma, HPV, EBV as well as what on the skin?

A

squamous cell carcinomas

209
Q

Use of hematopoietic stem cells (HSC) transplants for hematologic malignancies, BM failure syndromes and disorders caused by inherited HSC defectis is increase in number each year. How are the retreived?

A

from the peripheral blood upon administration of hematopeitic GFs or from the umbilical cord blood of newborn infants.

210
Q

In most cases of BM transplant, the patients own BM is killed with high doses of chemotherapy to destroy the immune system to allow new stem cell transplant to be accepted by the body. What are the two main complications with this proceess?

A

graft versus host disease GVHD

immunodeficiencies

211
Q

What occurs when immunologically competent cells or their precurosors are transported into immunologically crippled recipients and the transffered cells recognize alloantigens in the host and attack host tissues?

A

Graft versus host disease

212
Q

GVHD is most commonly seen in HSC transplantation. Donor T cells recognize recipient HLA as foreign and react against them. To try to minimize GVHD, HSC transplants are done between donor and recipients that are?

A

HLA matched using precise DNA sequencing mehtods for molecular typing of HLA alleles

213
Q

Acute GVHD occurs within days to week after allogenic BM transplant. Any organ may be affected by most clinical presentations are of immune system and epithelia of the skin, liver and intestines. Involvement of the skin is manifested as? what other two manifestations are commonly seen

A

a generalized rash that may lead to desquamation in sever cases

  • also small bile duct destruction leads to jaundice, mucosal ulceration leads to bloody diarrhea
214
Q

Chronic GVHD may follow acute or occur insidiously. pt has extensive cutaneous injury with destruction of skin appendages and fibrosis of dermis, chronic liver disease presented as cholestatic jaundice. Damage to the GI tract which may cause? What other two things

A

esophageal strictures

  • involution of thymus/depletion of lymphocytes in LNs
  • life threatening infections
215
Q

GVHD is mediated by T lymphocytes contained in the transplanted donor cells, so depletion of donor T cells before transfusion virtually eliminates the disease. What does this lead to ?

A

recurrence of tumor in leukemic patients – graft versus leukemia effect

216
Q

Immunodeficiency is common complication of HSC transplantation as well. It may be due to a prior treatment, myeloablative preparationg for the graft, a delay in repopulation of the recipients immune system and/or?

A

attack on the hosts immune cells by grafted lymphocytes

217
Q

Affected individuals of immundeficiency due to HSC transplantation are easy prey to infections. Infection with what is important and why?

A

cytomegalovirus CMV because of CMV induce pneumonitis is fatal

218
Q

What is the morphology of rejection mediated by preformed antibodies?

A

hyperacute rejection– thrombosis, ischemic damage and rapid graft failure

219
Q

All of the following are?
• arteriosclerosis
• activated T-cells secrete cytokines that induce proliferation of vascular smooth muscle cells
• antibodies cause endothelial injury
• vascular lesions + T-cell reactions cause parenchymal fibrosis
• intimal thickening and luminal narrowing

A

They are hallmarks of chronic rejection

220
Q

Immunodeficiencies can be divided into primary (congenital) and secondary (acquired) which sometimes aris due to cancers, infections, malnutrition or side effects of immunosuppression, irradiation or?

A

chemotherapy for cancer and other diseases

221
Q

Most primary immunodeficiencies are detected in infancy between 6mo to 2 years of life with the tell tale signs being?

A

susceptibility to recurrent infections

222
Q

What disease is a primary innate immunodeficiency of leukocytes, which is autosomal recessive condition characterized by defective fusion of phagosomes and lysosomes, resulting in defective phagocyte function and susceptibility to infections?

A

Chediak Higashi Syndrome

223
Q

Chediak higashi occurs when there is failure of phagolysosomal fusion, which leads to no killing of the phagocytosed bacteria within the cell. What is seen upon blood smear as well as clinically?

A

Upon blood smear you can see luekocytes with giant granules

There are abnormalities in melanocytes (leading to albinism), cells of nervous system and platelets

224
Q

What is there an increased chance of infection with chediak higashi and why?

A

increase bacterial infection because neutrophils cannot kill bacteria

225
Q

What disease is an inherited defect of microbicidal activity , which is characterized by defects in bacterial killing and render patients susceptible to recurrent infection?

A

Chronic granulomatous Disease

226
Q

Chronic granulomatous Disease results from inherited defects of phagocyte oxidase (superoxide production), which leads to formation of granuloma which is?

A

accumulation of macrophages around the bacteria walls off the infection, forming center of necrosis with T cells and macrophages around the edge

227
Q

The terminal components of complement C5,6,7,8,9 are required for MAC lysis of organisms. When there is a deficiency in any of the ones listed, lysis of microbial membrane cant occur leading to what infection and disease?**

A

**Neisseria infections are extremely common which are gram negative bacteria and can lead to meningitis

228
Q

A deficiency of C1 inhibitor C1INH gives rise to hereditary angioedema. This is an AD DO more common than complement deficiency states. The C1 inhibitor’s targets are proteases, specifically?

A

C1r and C1s of complement, XII of coagulation, and killakrein system

229
Q

What are 3 common clinical presentations of someone with hereditary angioedema due to C1 inhibitor deficiency?

A

face swelling
hand mobility decreases + swelling
intestinal swelling

230
Q

What deficiency is the most common complement protein deficiency associated with increased bacterial or viral infections?

A

C2 deficiency

231
Q

In C2 complement deficiency, most patients have no clinical manifestations, however some have SLE like autoimmune disease… Why are there no clinical manifestations?

A

because the alternative complement pathway is adequate for the control of most infections (doesnt need C2)

232
Q

What ID represents a constellation of genetically distinct syndromes, all having in common defects in both humoral and cell mediated immune responses?

A

Severe combined Immunodeficiency SCID

233
Q

SCID people are extremely susceptible to recurrent severe infections by a wide range of pathogens including candida albicans, pneumocystis jiroveci and?

A

pseudomonas

**without HSC transplant death occurs in 1st year of life

234
Q

The most common form of SCID is the Xlinked, hence why SCID is more common in boys than girls, the mutation is in the common Y-chain (yc) subunit of?

A

cytokine receptors which is a signal tranducer for IL2,4,7,9,11,15,21

IL7 needed for T cell prolif, IL15 need for NK prolif

(T cells are deminshed and B cells are present but cannot produce Abs without T cellS)

235
Q

The remaining 40% of SCID cases is autosomal recessive DOs, the most common being a deficiency of the enzyme?

A

adenosine deaminase ADA

Lack of ADA leads to accum of deoxyadenosine which is toxic to immature lymphocytes (blocks T cells, some B cells availble but cant make Abs without T cells)

236
Q

SCID patients/infants present with prominent thrush (oral candidiasis)m extensive diaper rahs and?

A

failure to thrive , some with morbilliform rash (measels like) shortly after birth because maternal T cells are transffered across placenta and attack fetus

237
Q

What is characterized by the failure of B cell precursors (pro-B cells and pre-B cells) to develop into mature B cells?

A

X linked agammaglobulinemia (bruton)

238
Q

in X linked agammaglobulinemia B cells are absent or markedly decreased. There are CD19+ B cells in normal numbers but they dont express BCRs. it is caused by mutations in?

A

bruton tyrosine kinase BTK gene on X chromosome

239
Q

BTK protein tyrosine kinase is associated with Ig receptor complex of preB and mature B cells and is needed to transduce signals from the receptor. When it is mutated, the pre B cell receptor cannot?

A

deliver the signal, and B cell maturation stops.

240
Q

X linked agammaglobulinemia is mainly seen in males but sometimes in females. The disease usually does not present until about 6 months however, because?

A

maternal abs are provided via breast milk and IgG from placenta until they wane around 6 months, then start to show signs

241
Q

Recurrent bacterial infections of respiratory tract, sinusitis, otitis media, bronchitis and pneumonia call attention to the disease. Almost always due to what three organisms?

A

Haemophilus influenzae
streptococcus pneumoniae
staphylococcus aureus

242
Q

X linked agammaglobulinemia has issues with enteroviruses such as giardia lamblia an intesetinal protozoan which causes persistent infection. What are 3 other characteristics beside absent B cells seen with this dz?

A

germinal centers are underdeveloped
plasma cells are absent
T cell mediated reactions are NORMAL

*** treat with IVIG

243
Q

What is a T cell deficiency that results from failure of development of the third and fourth pharyngeal pouches? What do 3/4 give rise to?

A

DiGeorge Syndrome (thymix hypoplasia)

Gives rise to thymus, parathyroid, C cells of thyroid, and ultimobranchial body (heart/ great vessels malformed)

244
Q

Individuals with digeroge syndrome have no thymus, which means there is no maturation of T cells. This may be inherited in a sporadic or familial pattern, most involving what deletion?

A

22q11 deletions

245
Q

Digeorge also manifest with facial and palatal, cardiac abnormalities, T cell deficiency and humoral deficiency cause no CD4+ Helper cells. Why might there be tetany?

A

due to decrease or no calcium in the body cause of the hypoplastic parathyroid

246
Q

What disorder of a patient makes IgM antibodies but are deficient in their ability to produce IgG, IgA and IgE antibodies?

A

Hyper-IgM syndrome

247
Q

70% of people with Hyper-IgM syndrome have the X linked form, caused by mutations in the gene encoding CD40L. What occurs when there is a CD40L deficiency (on T cells) or lack there of?

A

When there is no CD40L on T cells to engage CD40 on B cells, there is no Ig class switching or affinity maturation of B cells

** Recurrent pyogenic infections

248
Q

Hyper-IgM syndrome again has problems with encapsulated bacterial (pyogenic) infection becuase of the lack of?

A

opsonizing antibodies (IgG)

249
Q

Hyper-IgM syndrome you will see increased IgM and decreases of all other classes. You can treat with either IVIg or?

A

stem cell transplantation

250
Q

In addition to pyogenic infections, people with Hyper-IgM syndrome are also susceptible to pneumonia cuased by the intracellular organism _______ because CD40L mediated macrophage activation ( a key reaction of cell mediated immunity) is also defective.

A

pneumocytis jiroveci

** will have normal amount of B and T cells

251
Q

What ID is a realtively frequent but poorly defined entity which encompasses a heterogeneous group of disorders in which the common feature is hypogammaglobulinemia, generally affecting all the antibody classes but sometimes only IgG?

A

Common variable immunideficiency CVID

252
Q

The diagnose of CVID is based on the exclusion of other causes of decreased antibody production. It is the most common significant primary immunodeficiency, however as opposed to x-linked aggamaglobulinemia…?

A

there is normal or near normal numbers of B cells, But these B cells do not differentiate into plasma cells

253
Q

The patient with CVID typically presents with recurrent sinus and pulmonary infections (pyogenic bacteria, d/t no IgA). patient are prone to development of persistent diarrhea via giardia lamblia. In contrast to agammaglob, CVID affects male and females?

A

equally and the onset of symptoms is later in childhood or adolescence

254
Q

With CVID there is also granuloma formation and autoimmune disease such as? 2

A

anemia and thrombocytopenia ( attacks self)

255
Q

Isolated IgA deficiency occurs in 1 in 600 eastern european, affected individuals have low levels of both serum and secretory IgA. This can occur in familial and acquired forms, loss of IgA means less defense against inhaled and ingested pathogens leading to what 3 things?

A

sinus and respiratory infections
urinary bladder infections
gastrointestinal infections
(high frequency of autoimmune diseases and allergies)

256
Q

Most times people dont know they have isolated IgA deficieny until what occurs?

A

transfusion related anaphylaxis - red cells induce anaphylaxis = IgA deficiency
*red cell washing can prevent these reactions to rid IgA

257
Q

What disease is characterized by an inability to eliminate epstein-Barr virus (EBV) and eventually lead to fulminant infectious mononucleosis and the development of B cell tumors?

A

X linked lymphoproliferatuve syndrome

258
Q

in X linked lymphoproliferatuve syndrome, what is the defect which causes attenuated NK and T cell activation resulting in increased susceptibility to viral infections?

A

SLAM-associated protein SAP is deficient which is involved in the activation of NK, T and B cells

259
Q

What syndrome is an X linked disease characterized by thrombocytopenia, eczema, and a marked vulnerability to reccurent infection resulting in early death?

A

Wiskott Aldrich Syndrome

260
Q

in Wiskott Aldrich Syndrome, the thymus is normal wiht loss of T cells in the blood and T cell zones of LNs.IgM levels are low but IgG are normal, IgA and IgE are elevated. What is the deficient gene and how can this be treated?

A

WASP gene mutation which is thought to be involved in linking membrane receptors to cytoskeletal elements

  • treat with stem cell transplant HSC
261
Q

What is an autosomal recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectases), nuerologic deficits, increased incidence of tumors and immunodeficiency?

A

Ataxia telangiectasia

262
Q

in Ataxia telangiectasia, there is a mutated gene known as the ATM gene, which causes defective DNA repair. What is the first presentation of the dz, and what can be seen due to being immmune deficient in IgA and IgG?

A

First presentation is neurodegenerative disease with ataxia, first vascular malformation is excessive BV around eye in sclera

  • respiratory infections, autoimmune dz, cancer via lymhpomas
263
Q

Secondary or acquired immunodeficiencies may be encounterd in idividuals with cancer, diabetes, malnutrition, chronic infection, and in persons receiving chemotherapy/radiation for cancer or immunsuppressive drugs to prevent graft rejection. What is the most common?

A

Acquire immunodeficiency syndrome (AIDS)

264
Q

What is a disease caused by retrovirus human immunodeficiency virus (HIV) and characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms and neurologic manifestations?

A

AIDS

265
Q

What is the main difference between HIV and AIDS?

A

AIDS is the manifestation of what occurs when HIV affects the body to a degree where immune dysfunction results in infections, neoplasms, and neurologic manifestations

266
Q

The highest groups at risk for HIV/AIDS are homosexuals or bisexual men 60%, intravenous drug abusers 20%, hemophiliacs 0.5%, recipients of blood and blood components 1%, heterosexual contacts, HIV infection of newborn. What are the three major routes of transmission?

A

sexual contact
parenteral inoculation
passage of virus from infected mothers to newborns

267
Q

Sexual transmission of HIV constitutes about 75% of the cases- virus within semen and enters recipients body through?

A

abrasions in rectal or oral mucosa

1- direct inoculation into blood vessels
2-infection of DC or CD4+ in mucosa

268
Q

Parenteral transmission of HIV occurs in IV drug users**, hemophiliacs and recipients of blood transfusions. How can mother to infacnt transmission of AIDS occur? 3

A

in utero by transplacental spread
during delivery through infected birth canal
after birth by ingestion of milk

269
Q

Does this risk of transmission of HIV/AIDs increase or decrease when you have STDs such as chlamydia and syphillis?

A

There is an increase rate of transmission

270
Q

Health care works have the risk of seroconversion (contracting a disease from a patient) after a needlestick accident varies with the type of infection. What is the chance of contracting HIV from needlesitck as compared to HepC?

A

HIV- o.3% chance

HEPC- 30%

271
Q

HIV is a nontransforming human retrovirus belonging to the lentivirus family. there is HIV1 and HIV2, what is the most common type of US/Europe and which is the most common in west africa/india?

A

Africa india is HIV 2

US is HIV1

272
Q

HIV1 retrovirus is spherical with cone shaped core derived from host cell membrane, the virus core contains nucleocapside protein P7/p9, two copies of viral genomic RNA, three viral enzymes and?

A

major capsid protein p24 *** most relevant cause we can test for p24 antigen to determine if infected

273
Q

Most important structures of HIV are p24 capsid protein, viral enzymes such as protease, reverse trancriptase, and integrase, HIV-1 RNA genome containing gag pol and env genes which are typical of retroviruses and what glycoproteins? What are they good for?

A

gp120 and gp41 - which stud the outside of the spherial virus

important for attachment and also good drug/vaccine targets

274
Q

The two major targets of HIV are the immune system and central nervous system. Immune deficiency affect cell mediated immunity is hallmark of AIDS**. This results chiefly from infection and loss of?

A

CD4+ T cells as well as impairment in the function of surviving helper T cells.

Virus becomes established in lymphoid tissue where it may be latent for a while

275
Q

The life cycle of HIV consists of infection of cells, integration of the provirus into the host cell genome, activation of viral replication and?

A

production and release of infectious virus

276
Q

HIV-1 high yield genome regions to know… Match function with genome region
LTR, gag, env, pol
-Encodes for the surface glycoproteins
- encodes for the protein inside the virus
-initiates trasncription, binds transcription factors
-encodes viral enzymes

A

env-Encodes for the surface glycoproteins
gag- encodes for the protein inside the virus
LTR-initiates trasncription, binds transcription factors
pol-encodes viral enzymes (-ases)

277
Q

HIV infects cells using CD4 molecules as receptor various chemokine receptors as coreceptors. What are the chemokine coreceptors?

A

CCR5 and CXCR4

**bind of virus gp120 to CD4 is not enough for infection, needs gp120 to also bind to CCR5 and CXCR4

278
Q

Once virus gp120 binds to CD4 and to CCR5 (if R5 strain) or CXCR4 (if X4 strain) after conformational change, leads to another conformational change in gp41 resulting in exposure of the fusion peptide of GP41. This does what?

A

uses fusion peptide to drill into the host target cell membrane, and inserts the viral genome

279
Q

Note- if there is high chemokines in the area of HIV infection, they take up their receptors, which could possibly lead to?

A

lack of receptors for HIV to bind to leading less viral infection

280
Q

Once the viral genome is internalized into the T cell, the RNA genome of the virus undergoes reverse transcription. How?

A

reverse transcriptase synthesizes proviral DS DNA from the original RNA genome

281
Q

Once reverse transcriptase is complete, integrase inserts the proviral DNA sequence into the host genome. lastly, host cell activation via cyotkines occur, leading to?

A

triggering of LTR to initiate transcription of HIV viral RNA

282
Q

HIV effects memory and activated T cells but is inefficient at infecting Naive T cells because it contains an enzyme that introduces mutations in the HIV genome which inhibit further DNA replication. What is thh enzyme?

A

APOBEC3G

283
Q

Completion of viral life cycle occurs only after cell activation, most CD4T cells virus activation results in cell lysis. When an antigen stimulation occurs- it activates the CD4 cell which releases NF-kB which normally upregulates the T cell response. What does it do when the cell is infected w HIV?

A

NFkB activates the transcription of HIV proviral DNA through LTR (cause has NFkB binding sites)

*NFkB is bound to inhibitor IkB until activated via cytokines/microbes

284
Q

Loss of CD4T cells with HIV is mainly due to infection of the cells and direct cytopathic effects of the replicating virus. In infected individuals, 100 billion viral particles are produced each day and 1-2 billion CD4 T cells die. What are 2 possible mechanisms for CD4T cell death?

A

increased plasma membrane permeability d/t budding of virus particles from infected cells and virus replication interfering with protein synthesis

(direct killing/cytopathic effect)

285
Q

Non-cytopathic HIV infection activates the inflammasome pathway and leads to a form of cell death known as? In which inflammatory cytokines and cellular contents are released - increasing chance of infecting new cells

A

Pyroptosis

286
Q

Note: as time goes on, the body is no longer able to keep up with the decline in CD4+ T cells, so acute infection compared to AIDS 10 years later shows?

A

A huge decline in the number of CD4T cells

287
Q

There are many immune abnormalities seen due to the decrease/lack of T cells in a person with AIDS, including, decreased T cell function in vivo, altered T cell function in vitro, polyclonal B cell activation, altered monocyte/macrophage function and?

A

lymphopenia

288
Q

In addition to loss of CD4+ T cells, infection of macrophages and dendritic cells is also important in the pahtogenesis of HIV. Like T cells the number of affect macrophages is high in tissues but low in?

A

blood (monocytes low)

289
Q

HIV1 can infect and multiply in terminally differentiated macrophages because of the vpr gene. Mø have some budding of the virus but the majority is stored within. Unlike CD4T cells, mø are resistant to?

A

cytopathic effects of HIV so they are RESIVOIRS of infection

290
Q

In addition to Mø, 2 types of DCs are important targets for HIV- mucosal and follicular DCs. What is though of both of these DCs?

A

Mucosal DCs: are infected by the virus and transport it to lymph nodes
Follicular DCs: are in the germinal centers of LNs and are reservoirs of HIV

291
Q

There are B cell abnormalities associated with AIDS as well, such as polyclonal acitvation of B cells resulting in B cell hyperplasia. This may be from EBV, due to lymphoma, nonspecific HYPERgammaglobulinemia, but have impaired humoral immmunity— why?

A

because there are CD4T cells to allow isotype switching so there is a reduction in Ab production leading to inc. infection by encapsulated bacteria - pneumoniae and influenzae (need IgG for opsinization)

292
Q

The nervous system is a major target for HIV, predominantly infected cells of CNS are microglia and mø. HIV is carried into the brain by infected monocytes -> microglia. Neurologic symptoms are caused indirectly by?

A

viral products and soluble factors produced by infected microglia

293
Q

What is characterized by infection of memory CD4T cells (w CCR5) in mucosal lymphoid tissues and death of many infected cells?

A

acute/early HIV infection

294
Q

T cell’s largest reservoir of memory cells is in the mucosal tissues, acute infection causes large depletion of lymphocytes. After mucosal injury and entry of the virus, what follows?

A

dissemination of the virus and development of host immune response

*transported via DCs to LNs, where they present virus to CD4T cells, viral replication occurs in LNs

295
Q

The replication in the LNs lead to viremia (2-3 weeks) = high numbers of HIV particles are present in the patients blood. As HIV spreads the individual mounts what at about 3-7 weeks?

A

Individual mounts antiviral humoral and cell mediated immune response to stop viral replication (virus specific CD8CTLs which partially control infection - see drop in viremia by 12 weeks)
**seroconversion where go from Ab negative to Ab positive

296
Q

What is the clinical presentation of the intial spread of HIV virus and host response. Occurs 3-6 weeks after infection, with flu like symptoms occuring in 40-90% of people. Symptoms include sore throat, myalgia, fever, weight loss, fatigue, rash, cervical adenopathy, diarrhea, vomiting

A

Acute retroviral syndrome

297
Q

The extent of viremia, measured as ______ levels in the blood, is a useful surrogate marker of HIV disease progression and is of clinical value in the management of people with HIV.

A

HIV-1 RNA

298
Q

Note: blood CD4+ counts are the most reliable short-term indicator of disease progression , instead of?

A

Viral load

299
Q

The first detectable substance of HIV is viral RNA (10days) via nucleic acid test NAT. What are the second and third substances detectable?

A

2nd is the protein antigen p24 (15 days)

3rd is the antibody to HIV (25 days)

300
Q

Why is the window period important in regards to HIV and showing positive in blood?

A

Donated blood! entails a 7-14 days window period from exposure to positive results and is tested via NAT for HIV

301
Q

The viral set point is at the end of initial viremic spike and may predict CD4 cell loss. What is clinical latency (chronic infection)?

A

period of silent massecre of CD4 cells which may last years without symptoms, which replicatoin and destruction occurs in the LNs and spleen

302
Q

HIV escapes immune control via many mechanisms including antigenic variation, down modulation of Class I MHC (avoids CD8), evolves and switches to using both CCR5 and CXCR4 which leads to a more rapid?

A

decline in CD4T cells because of the greater infection of the T cells

303
Q

In what phase of HIV infection are patients asymptomatic or develop opportunistic infections such as oral candidiasis (trush), vaginal candidiasis, herpes zoster and possibly MTb?

A

Chronic phase of infection

304
Q

The final phase of progression to AIDs is characterized by breakdown of host defense, increase in plasma virus, and severe life threatening clinical disease. Pt presents with long lasting fever, fatigue, weight loss and diarrhea. After a variable period what else may occur? 3

A

opportunistic infections, secondary neoplasms, clinical neurologic disease

305
Q

In the united states, the typical adult patient with AIDS present with fever, weight loss, diarrhea and what else? 4

A

lymphadenopathy
multiple opportunistic infections**
neurologic disease
secondary neoplasms

306
Q

Opportunistic infections account for the majority of deaths in untreated patients with AIDS, frequency of these infections have decreased due to?

A

highly active antiretroviral therapy HAART which relies on combination of three-four drugs that block differe steps of HIV life cycle

307
Q

A patient presents with mulptiple lesions upon brain mri and one is biopsied. It is not cancer but shows CNS toxoplasmosis… What is your dx?

A

AIDS! metastatic

308
Q

15-30% of untreated HIV infected people develop pneumonia at some time during the course of disease with what type of fungus? This used to be in 20% of AIDS patients but has dropped since HAART

A

Pneumocytis jiroveci fungus (via reactivation of a prior latent infection*)

**AIDS defining illness

309
Q

What is the most common fungal infection in AIDS patients with common clinical manifestations being infection of oral cavity, vagina and esophagus? Note: oral infection is sign of immuno decompensation and heralds transition to AIDS. Invasive infection is infrequent usually due to drug-induced neutropenia/ catheters

A

Candidiasis (fungus)

310
Q

What virus more commonly affects the eye and GI tract. Chorioretinitis is seen in 25% of patients before HAART? This occurs exclusively in patients with CD4+ T cell counts less than 50/microliter

A

Cytomegalovirus (virus)

311
Q

What is a protozoa lead to 400,000 people in milwaukee being infected, which was traced back to the city’s water supply. Deaths due to excessive diarrhea where more likely in HIVand elderly populations

A

Cyptosporidium (enteritis)

312
Q

AIDS patients have a high incidence of tumors including Kaposi sarcoma KS, B cell lymphoma, cervical cancer, and anal cancer. What are these caused by?

A

oncogenic DNA viruses specifically kaposi sarcoma herpesvirus, EBV, HPV

313
Q

What is a vascular tumor that are rare in the US besides AIDS patients, which it is the most common type? Which is characterized by proliferation of spindle shaped cells that express markers of bothe endothelial and smooth muscle cells?

A

Kaposi Sarcoma KS

314
Q

Kaposi Sarcoma KS is believed to be caused by what? Which establishes latent infection during which several proteins are produced with potential roles in stimulating spindle cell proliferation and preventing apoptosis.

A

Human Herpesvirus 8 or KS herpesvirus

315
Q

KSHV is not only restricted to endothelial cells but is also seen in rare B cell lymphomas (primary effusion lymphoma) and also in?

A

castleman’s disease (a B cell proliferative DO)

316
Q

Lymphomas are AIDS defining condition - partially explained by T cell deficiency, there are two mechanisms that underlie the increased risk of B cell tumors in HIV, which are?

A
  1. unchecked proliferation of B cells infected with oncogenic herpesviruses in the setting of profound T cell depletion (AIDS)
  2. Germinal center B cell hyperplasia in the setting of early HIV infection
317
Q

Without T cells, control of B cell proliferation infected with EBV/KSHV is lost, leading to the formation of B cell lymphomas composed of tumor cells infected by (EBV). EBV is latent in memory B cells and when activated without T cell presence what occurs?

A

EBV mutates and causes EBV+ B cell lymphomas since T cells are not availble to kill the virus

318
Q

In early HIV infection, germinal center B cell hyperplasia occurs. Mutations occur during class switching and somatic hypermutation leading to B cell lymphomas with translocations where? 2

A 
Burkitt lymphoma (MYC)
Large B cell lymphoma (BCL6)
319
Q

Patients with AIDS have an increased occurence of carcinoma of the uterine cervix and anal cancer. This is due to the reactivation of latent HPV infection. 10 times more common in HIV patients, what is seen clinically? 3

A

squamous cell carinoma of cervix, cervical dysplasia and carcinoma in situ (precursor to cancer)

320
Q

Involvement of the NS is a common manifestation of AIDS, 90% upon autopsy demonstrate neurologic involvement. Including meningoencephalitis, aseptic meningitis, vacuolar myelopathy, peripheral neuropathy, and most commonly what?

A

progressive encephalopathy designated clincally as HIV associated neurocognitive disorder :)

321
Q

What is the most common neoplasms seen in association with AIDS?

A

B cell non-hodgkin lymphomas

322
Q

What is a condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise?

A

Amyloidosis

323
Q

In amyloidosis abnormal fibrils are produced by aggregation of misfolded proteins- insoluble B pleated sheets are formed and accumulate. Amyloid may be systemic or localized, what are the subclassifications of systemic?

A

systemic/generalized is primary amylodsis- associated with plasma cell disorder
secondary amyloidosis occurs when complication of underlying chronic inflammatory or tissue destructive process.

324
Q

In systemic amyloidosis the difference between primary and secondary amyloidosis, is that primary has plasma cell proliferations and secondary is due to chronic inflammatory conditions. What is the difference in major fibril protein?

A

Primary is AL - light chain disease

Secondary is AA - amyloid associated

325
Q

If amyloidosis is systemic, you can also try to dianose it in an abdominal fat pad biopsy. Otherwise, what are the common areas to be manifested by amyloid? 4

A

kidney
brain
liver
heart

326
Q

Histologically, amyloid deposition is always extracellular and begins between cells - close to basement memebranes. What is the most common organ for amyloidosis?

A

Kidney

327
Q

Kidneys may be normal sized grossly, histologically the amyloid is deposited primarily in the glomeruli, first appearing as subtle thickening. What can this lead to?

A

proteinuria and edema, often the initial presentation

328
Q

Amyloidosis of the heart is major organ effected in senile systemic A. Heart is enlarged and firm with deposits as focal subendocardial accumulations within the myocardium between muscle fibers. This disruption of the myocardium may result in?

A

dysrhythmias - often the initial presntation

329
Q

What causes vascular fragility that may lead to bleeding, sometimes massive that can occur spontaneuously or following seemingly trivial trauma?

A

Vascular amyloidosis

330
Q

What is the best stain for diagnosis of amyloidosis, in which the protein aggregates will turn red and then look apple green on flueoresence?

A

congo red stain for amyloid

331
Q

What is the difference between seeing bubble gum pink and apple green colors when congo red stain is introduced?

A

Bubble gum pink deposits that means there are presence of amyloid with congo red stain
Apple green is seen as amyloid under polarized light

19. Mechanisms of Disease Exam 2 (5 decks)

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