Chapter 5, Diseases of the immune system Flashcards
innate immunity definiton
(natural, or native immunity) mediated by cells and proteins that are always present, poised to react against infectious pathogens.
these cells are the 1st line of defense and the 1st to react.
they also have mechanisms to clear dead cell debris.
define hypersensitivity disorders?
the immune system causing tissue injury and disease
define adaptive, specific, acquired immunity
an immunity that is normally silent but responds to infectious agents. Since many pathogens have evolved to resist innate immunity and thus protection from the requires the specialized and powerful adaptive immunity/acquired or specific immunity.
what are recognized by the innate immunity?
phagocytes, dendritic cells and many other cells, such as epithelial cells, express receptors that sense the presence of infectious agents and substances released from dead cells.
these are called PAMP (pathogen-associataed molecular patterns)
what are the components of the innate immunity called that are responsible for pathogen recognition?
- pathogen-associated molecular patterns (shared among microbes of the same type)
- damage-associated molecular patterns (released from injured and necrotic cells.
- pattern recognition receptors (cellular receptors that recognize these molecules) 100 different receptors are used to recognize 1000 molecular patterns.
where are receptors of the innate immunity located?
everywhere; in the cell membrane for extracellular recognition, in endosoms for ingested substance detection and cytoplasm.
types of innate immunity receptors? best known receptors?
-toll-like receptors (these activate transcripton factors that stimulate the production of several membrane proteins to mediate inflammation, anti-viral cytokines (interferons). proteins promote lymphocyte activation, even more potent adaptive immune response.) TLR recognize, LPS (lipopolysaccharide) endosomal TLRs recognize viral and bacterial RNA and DNA
NOD-like receptors and inflammasome. activation of which form the cytokine interleukin-1 (IL-1) which recruits leukocytes and induces fever.
NODS recognize: uric acid and ATP and ion distrubances (K concentration)
-C-type lectin receptors (CLRs) in macrophages membrane
-RIG-I recognize RNA
-DNA sensors recognizes DNA
They (NOD) signal via a protein complex called the “inflammasome” which activates Caspase-1 which cleaves interleukine-1 to generate IL-1 which causes acute inflammation when secreted.
what are the 2 mechanisms by which the innate immunity provides defense.
- inflammation: complement activation trigger components of inflammation.
- anti-viral defense: type I interferons produced in response to viruses act on infected and infected cells and act to prevent replication and digest viral nucleis acids. They also serve to activate he more powerful adaptive immune response.
name the 2 type of adaptive immunity?
-humoral immunity: antibodies made by B-lymphocytes
-cell-mediated (cellular) immunity mediated by T-lymphoctes.
Antibodies protect from extracellular pathogens in blood and mucosal surfaces.
T-cells directly kill via cytotoxic T-cells or activate phagocytes.
where do T and B lymphocytes mature from?
-T lymphocytes mature in thymus
-B lymphocytes mature in bone marrow
each T or B cell expresses only one type of receptor
what are the receptors on B and T cells called?
B-cell (antibody)
T-cell (T-cell receptors)
there is massive diversity in the structure of these receptors.
define Clonal selection?
a process proposed to explain how a single B or T cell that recognizes an antigen that enters the body. The antigen is selected from the pre-existing cell pool of differing antigen specificities and then reproduced to generate a clonal cell population that eliminates the antigen. (the cell that recognizes it is replicated)
phases of lymphocytes?
- naive lymphocytes (antigen receptors expression but no function)
- effector lymphocytes (eliminate microbes)
- memory lymphocytes (rapid response upon subsequent encounter with antigen)
function of T lymphocytes.
they help B-cells make anibodies for foreign antigens.
they recognize protein fragments on MHC displayed by cells via the TCR (T-cell receptor)
what is the TCR (T cell receptor) made of?
heterodimer of disulfide linked a- and b- chains that have a variable and constant region.
CD3 and ζ-chain do not bind antigen but initiate intracellular mechanisms upon antigen recognition.
what does CD4 and CD8 on T-cells bind to?
class II MHC = CH4 CD4+ cells help B cells produce antibodies by secrete soluble cytokines. help macrophages destroy what they ingested. class I MHC = CH8 (called cytotoxic T lymphocytes (CTLs) because they kill infected cells, and tumor cells.)
function of T-cells with CD28?
function as receptors for molecules called costimulators. control the migration of the T cells to different tissues.
what suppresses immune response.
regulatory T lymphocytes
what is MHC restriction?
T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.
Class I MHC
expressed on all cells surfaces that are nucleated expressed in 3 closely linked loci; HLA-A, HLA-B, HLA-C
has a conserved region for CD8+ binding.
has polymorphic a-chain noncovalently associated with invariable B2- microglobulin polypeptide.
binds moslty intracellular elements.
Class II MHC
encoded by HLA-D. class 2 are heterodimers with a- and b-chains. expression restricted to APC's (antigen presenting cells) dendritic cells, macrophages and B-cells binds extracellular elements. (has domain for CD4+)
How to B-lymphocytes recognize antigens?
via membrane bound antibody of the immunoglobulin M (IgM) class, expressed on the surface together with signaling molecules to form the B-cell receptor (BCR) complex.
IgM has large diversity due to rearrangement and assembly of a multitude of immunoglobulin gene segments.
what can B-cells respond to?
unlike T-cells that respond to MHC only, B-cells can respond to more chemical structure; soluble or cell-associated proteins, lipids, polysaccharides, nucleic acids, without the requirement of MHC.
when B cells are activated they secrete what?
they turn into plasma cells to secrete immunoglobulins: (5 classes)
IgG, IgM, IgA, which make up 95% of circulating antibodies
IgA: (mucosal secretions)
IgE, IgD.
what receptors do natural killer cells express?
2 types of receptors:
Inhibitory, which recognize self/MHC 1 which is on all cells
Activating receptors which are on infected and stressed cells (stressed cells have fewer MHC I, thus NK cells are activated via their activating receptors and kill the stressed cells.
what do natural killer cells secrete upon activation?
cytokines: interferon-y (gamma) which activates macrophages.
Function of ILC’s (innate lymphoid cells)
these cells lack TCR (T-cell receptors), but produce cytokines similar to those made by T-cells.
these cells mostly reside withing tissues, so they provide early defense before T-cell activation.
which cells function as antigen presenting cells?
macrophages also engulf and present proteins
dendritic cells that display protein antigens to naive T-cells. (they have spines branching off of them, hence the name)
Dendritic cells properties?
1: they are located right under the skin (called langerhans cells)
2: they display many receptors for capturing microbes (TCR’s and C-type).
3: they go to T-cells zones upon activation to present antigen
4: express high levels of MHC.
name the lymphoid tissues?
generative/primary/central lymphoid organs: T and B-cells mature here to become competent to respond to antigens (thymus, bone marrow)
Peripheral/secondary lymphoid organs: in which adaptive immune responses to microbes are initiated.
where are the peripheral lymphoid organs located?
- lymph nodes:
- spleen
- cutaneous and mucosal lymph systems: under epithelia and GI tract. (peyers patches, tonsils)
location of B and T cells in lymphoid organs (lymph)?
B-cell = follicle
T-cell = parafollicle cortex
activated B cells from germinal center. FDC (follicle dendritic cells) which present antigens
location of B and T cells in the spleen?
T = around periarteriolar lymphoid, and B cells inside follicles.
cytokines of the innate immune system function?
induce inflammation and inhibit virus replication; TNF, IL-1, IL-12, type I IFNs, IFN-y
made by macrophages, DC, ILC, and NK cells
cytokines of the adaptive immune system function?
made by CD4+ T-cells activated by antigen and other signals to promote lymphocyte proliferation and differentiation, and activate effector cells.
TGF-b and IL-10 limit immune response to prevent damage.
function of colony stimulating factors?
they function to produce more WBC from bone marrow in response to infection. Examples: GM-CSF and IL-7.
Adapative immune system steps?
- antigen recognition
- activation
- proliferation
- differentiation (into effector and memory cells)
- elimination of antigen and decline of response
what do APCs secrete during innate immune responses to antigens?
APCs express molecules called costimulators and secrete cytokines that stimulate the proliferation and differentiation of T lymphocytes. principle costimulators of T-cells are CD80 and CD86 (b7 proteins) expressed on APC’s and recognized by CD28 on T-cells.
what happens to T-cells activated by antigen and costimulators?
CD4+ helper T-cells is secretion of the cytokine IL-2 and expression of IL-2 receptors. This stimulates the growth of T-cells with a specific antigen.
their actions is mediated by CD40 (activate macrophages).
what do CD4+ T-cells of the TH1 subset secrete?
IFN-y (gamma) along with CD40 they activate macrophages
what do CD4+ T-cells of the TH2 subset secrete?
IL-4 sitmulates B cels differentiation into IgE-secreting plasma cells
IL-5 = activates eosinophils
IL-13 activates mucosal epithelial cells to secrete mucus + “alternative pathway” macrophage activation for tissue repair.
what do CD4+ T-cells of the TH17 cells do?
IL-17 is the signature cytokine to recruit neurophils and monocytes to destroy some extracellular bacteria and fungi.
what happens of activated B-cells?
CD8+ T-lymphocytes differentiate into CTL’s (cytotoxic T-lymphocytes) which kill infected cells via the perforin and granzymes (perforin makes a hole in membrane, granzymes activate cellular caspases to induce apoptosis.
how are T-cells regulated?
by a balance of costimulatory (CH28 recognizing B7 ligands on APCs)
and inhibitory receptors (CTLA-4 and PD-1, which block signals from the TCR and from CD28).
2 pathways of B-cell activation?
- T-cell independent: long polysaccarides have long sequences that may bind to IGD and IGM receptors, the clustering of the receptors creates a strong signal.
- T-cell dependent: B-cell cleaves up protein and presents them on MHC II which if T cells recognize will activate B-cells via CD40 secretion.
what do B-cells do upon activation?
expanded B-cell clones differentiate into antibody-secreting plasma cells which secrete antibodies with the same specificity as the cell surface antibodies that recognized the antigen. polysaccarides = IgM.
define affinity maturation?
Helper T cells stimulate the production of antibodies with higher affinity for the antigen.
define follicular helper T cells (Tfh)?
helper T cells that stimulate these processes in B lymphocytes also migrate to and reside in the germinal centers along with B-cells.
the follicles are a major sites of isotype switching and affinity maturation.
humoral immune response function?
- antibodies bind to microbes to prevent them infecting cells
- IgG antibodies (opsonize) microbes for neutrophils and macrophages
- IgG and IgM activate the complement system via classic path
- IgA secreted in mucosal tissues and neutralizes microbes in respiratory and GI tract.
- passive immunity for newborn as IgG goes across placenta
- IgE coats helminthic parasites (eosinophils kill them)
Autoimmunity reactions against self antigens description?
the “self tolerance” of the immune system fails
immune mechanisms of type I (immediate hypersensitivity) also called allergy
Th2 cells, and production of IgE antibody causing: immediate release of vasoactive amines and other mediators from mast cells; later recruitment of inflammatory cells
IL-4 (stimulated B cell to class switch to IgE
IL-5 activates eosinophils that are recruited to the reaction
IL-13 acts on epithelial cells and stimulated mucus secretion
histopathologic lesions of type I (immediate hypersensitivity) also called allergy
vascular dilation, edema, smooth muscle contraction, mucus production, tissue injury, inflammation
(1st 4 are caused by the release of histamine)
prototypical disorders of type I (immediate hypersensitivity) also called allergy
anaphylaxis; allergies; bronchial asthma (atopic forms)
Immune mechanisms of type II (antibody mediate hypersensitivity)
Production of IgG, IgM - binds to antigen on target cell or tissue - phagocytosis or lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes
histopathologic lesions of type II (antibody mediate hypersensitivity)
phagocytosis and lysis of cells; inflammation; in some diseases, functional derangement without cell or tissue injury
prototypical disorders of type II (antibody mediate hypersensitivity)
autoimmune hemolytic anemia; goodpasture syndrome
Immune mechanisms of type III (immune complex-mediated hypersensitivity)
deposition of antigen, antibody complexes - complement activation - recruitment of leukocytes by complement products and Fc receptors - release of enzymes and other toxic molecules.
histopathologic lesions of type III (immune complex-mediated hypersensitivity)
inflammation, necrotizing vasculitis (fibrinoid necrosis)
prototypical disorders of type III (immune complex-mediated hypersensitivity)
systemic lupus erythematosus: some forms of glomerulonephritis; serum sickness; arthus reaction
joints (arthritis)
immune complexes are deposited in areas where the blood is filtered (synovial fluid, urine).
immune mechanisms of type IV (cell-mediated hypersensitivity)
activated T lymphocytes - 1. release of cytokines, inflammation and macrophage activation; 2. T cell-mediated cytotoxicity.
histopathologic lesions of type IV (cell-mediated hypersensitivity)
perivascular cellular infiltrates; edema; granuloma formation; cell destruction.
prototypical disorders of type IV (cell-mediated hypersensitivity)
contact dermatitis; multiple sclerosis type 1 diabetes; tuberculosis.
Define Atopy
an increased propensity to develop immediate hypersensitivity reaction. Atopic people have higher serum IgE levels and more IL-4 producing Th2 cells.
4 conditions of antibody mediated cell destruction and phagocytosis?
- transfusion reactions from incompatible blood.
- hemolytic disease of the newborn due to IgG maternal RBC crossing placenta
- autoimmune hemolytic anemis agranulocytosis and thrombocytopenia, antibodies produced against own RBC.
- drugs bind to membrane proteins against which antibodies are produced to combat drug-protein complex.
immune complex-mediated disease (type III hypersensitivity)
antigen-antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation.
T cell-mediated diseases (type IV hypersensitivity).
Th1 effector cells secrete cytokines (IFN-y) activate macrophages, Th17 cells secrete cytokines that recruit neutrophils and monocytes in CD4+ T cell-mediated inflammation.
what are the 2 types of T cell-mediated diseases (type IV hypersensitivity)
- cytokine-mediated inflammation in which the cytokine are produced mainly by CD4+ T cells.
- Direct cell cytotoxicity, mediated by CD8+ T cells.
define immunologic tolerance?
a state of unresponsiveness to an antigen that is induced by exposure of specific lymphocyte to that antigen.
define self tolerance?
refers to lack of immune responsiveness to one’s own tissue antigens.
what are the 2 mechanisms by which the body eliminates immune reaction against the body’s own antigens.
- central tolerance
2. peripheral tolerance
define central tolerance?
the killing of cells that are self reactive while they are in the lymphoid organ during development. self reactive cells are deleted if they react/negative selection.
what type of cells are responsible for deleting self antigens?
AIRE (autoimmune regulator), mutation of which causes autoimmune polyendocrinopathy. some Cd4 T-cells survive to become regulatory T-cells
B-cells may undergo a 2nd round of rearrangement of antigens that are not self reactive.
methods of dealing with T-cells that escape central tolerance test, to prevent them from doing damage.
ANERGY.
-Anergy: self-reactive T-cells respond to APC (antigen presenting cells) with no co-stimulator B7 molecule meaning and inhibitory signal is triggered int he T-cell
methods of dealing with T-cells that escape central tolerance test, to prevent them from doing damage.
SUPPRESSION by REGULATORY T-CELLS.
these cells are CD4+ that express high levels of CD25, the alpha-chain of the IL-2 receptor, and a transcription factor of the forkhead family called FOXP3. IL-2 and FOXP3 are needed for regulatory CD4+ T-cells maintenance.
T cells suppress immune responses via cytokines such as IL-10 and TGF-b which inhibit lymphocyte activation and effector functions. They also express CTLA-4 which may bind to B7 molecules on APCs and reduce their ability to activate T cells via CD28.
methods of dealing with T-cells that escape central tolerance test, to prevent them from doing damage.
DELETION BY APOPTOSIS
T-cells that recognize self antigen will have their apoptotic pathway triggered via upregulation of Bcl-2.
another mechanism is the Fas death recepter. Mutation of Fas causes: autoimune lymphoproliferative syndrome (ALPS).
what are immune-privileged sites?
antigens in sites that tend to be shielded from the immune system. But these antigens may be released in the case of trauma such as post-traumatic orchitis and uveitis.
2 methods in which microbes trigger autoimmune reactions?
- microbial inflammation can stimulate expression of costimulatory molecules on APCs in the tissue, thus favoring a breakdown of T cell tolerance and subsequent T cell activation.
- molecular mimicry: microbial antigens may mimic self antigen and activate self-reactive lymphocytes as a cross-reaction.
Epitope spreading definition?
autoimmune response may itself promote further autoimmune attack. tissue injury may lead to exposure of self antigen epitopes that were previously concealed but are now presented to T-cells in an immunogenic form.
describe (SLE) systemic lupus erythematosus
it is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues. (it affects all organs)
what is the hallmark of SLE (systemic lupus erythematosus)
the production of autoantibodies. which recognize nuclear and cytoplasmic components while others are directed against cell surface antigens of blood cells.
name the 4 types of anti-nuclear antibodies?
- antibodies to DNA
- antibodies to histones
- antibodies to nonhistone proteins bound to RNA
- antibodies to nucleolar antigens.
ANAs are detected with indirect immunofluorescence.
describe how T and B cells are tested for autoreactivity during maturation in the thymus and bone marrow?
T-cells (negative selections) are killed if they autoreact, but not all of them are killed, some leave the cells and become regulatory cells.
B-cells that recognize a self-antigen can be reorganized (receptor editing).
what is the pathogenesis of SLE (systemic lupus erythermatosus).
a failure of the mechanisms that maintain self-tolerance what causes this is unknown but both genetic and environmental factors play a role.
what factors play a role for SLE (systemic lupus erythermatosus) environmental and genetic?
-Familial association:
-HLA association: people with HLA-DR2 or HLA-DR3 have higher risk.
ENVIRONMENTAL: UV light damaging DNA
-gender bias attributable to sex chromosomes. related to X-chromosome, independent of hormone effects.
Pathogenesis of SLE? (systemic lupus erythermatosus)
UV radiation and other environmental insults lead to the apoptosis of cells.
Inadequate clearance of the nuclei of these cells results in a large burden of antigens.
The self-reactive lymphocytes are THAT SURVIVED and ESCAPED the bone marrow may be activated by the nuclear antigens. and produce antibodies against them
antibodies bind to Fc receptors on B-cells and dendritic cells and may be internalized. Nucleic acid components engage TLRs and stimulate B cells to produce more autoantibodies. TLR (toll like receptors) also activate dendritic cells to produce interferons and other cytokines which further enhance immune response and cause more apoptosis
The net result is a cycle of apoptosis and antigen release and immune activation.
tissue damage mechanisims of SLE (systemic lupus erythermatosus)
- immune complex (type 3 hypersensitivity reaction) deposited in the kidney).
- Autoantibodies also contribute to the pathology and clinical manifestations of SLE (type 2 hypersensitivity). The antibodies can opsonize RBC, WBC, platelets.
- Anti-phospholipid antibody syndrome: anti-phospholipid antibodies, the patient may develop venous thrombosis which is associated with miscarriages and focal cerebral or ocular ischemia.
- Some antibodies can cross the BBB and react with the neural cells (cognitive dysfunction).
Morphology of (systemic lupus erythermatosus)?
- Blood vessels: vasculitis and firbinoid necrosis of the vessel walls, in chronic stages fibrinoid thickening and luminal narrowing.
- Kidney: the kidney is almost always affected by this disease as immune complexes are deposited.
what are the wire loop structure seen in kidneys with SLE?
they are dubendothelial immune complex depositis that may create a circumferential thickneing of the capillary wall. patient show hematuria (blood in urine) and proteinuria
butterfly rash on the face is also seen.
cardiovascular effects of SLE? (systemic lupus erythermatosus)
Valvular endocarditis (libman sacks) deposits on either surface of the heart valve. Vegetations in contrast are larger while those in rheumatic heart disease are smaller and confined to the lines of closure of the valve leaflets.
how does SLE (systemic lupus erythermatosus) affect the lungs and spleen?
splenomegaly capsular thickening, follicular hyperplasia.
Central penicilliary arteries may show concentric intimal and smooth muscle cell hyperplasia, producing so called onion-skin lesions.
LUNGS: pleuritis and pleural effusions there are some cases of chronic interstitial fibrosis and secondary pulmonary hypertension.
Describe Rheumatoid arthritis?
an autoimmune disease that affects primarily the joints but also may involve extraarticular tissues such as the skin, blood vessels, lungs and heart.
Describe Sjogren syndrome?
a chronic disease characterized by dry eyes (keratoconjunctivitis sicca), and dry mouth (xerostomia) resulting from immunological mediated destruction of the lacrimal and salivary glands.
- has primary form: isolated disorder
- has a secondary form: associated with another disease.
Describe the pathogenesis?
it remains obscure as to what causes the disease but it seems to be linked to auto reactive cell activation.
what age group does the sjogren syndrome affect the most? what are the affects of the dry eyes and mouth?
50-60 years of age.
-keratoconjunctivitis (dry eyes): blurred vision, burning and itching and thick secretions that accumulate in the conjunctival sac
-Xerostomia: difficulty swallowing solid foods. decrease in taste, cracks and fissures in the mouth and dryness of the buccal mucosa.
parotid enlargement is seen.
Describe systemic sclerosis (Scleroderma)?
Systemic sclerosis is an immunologic disorder characterized by excessive fibrosis in multiple tissues, obliterative vascular disease, and evidence of autoimmunity, mainly the production of multiple autoantibodies.
Its affects on the GI tract lungs and kidneys heart and skeletal muscles are what causes death.
what characterizes the systemic sclerosis (scleroderma)?
CREST syndrome:
- Raynaud phenomenon
- Esophageal dysmotility,
- sclerodactyly
- telangiectasia (widening of the veins)
pathogenesis of systemic sclerosis (scleroderma)?
Not known
likely results from 3 interrelated processes-autoimmune responses, vascular damage, and collagen deposition.
-It is caused by CD4+ T cells responding to a yet unidentified antigen that accumualte in the skin and release cytokines that activate inflammatory cells and fibroblasts.
CD4+ Th2 cells secrete IL-13 and macrophages secres TGF-B which stimulate synthesis of collagen and ECM proteins.
The cause of vascular damage is unknown. It could be due to chronic inflammation with mediators released by inflammatory cells inflicting vascular damage. Repeated cycles of endothelial injury followed by platelets aggregation lead to release of platelet and endothelial factors that trigger endothelial proliferation and intimal and perivascular fibrosis eventually widespread narrowing of the microvasculature leads to ischemic injury and scarring. excessive collagen production by cells causes fibrosis.
how does recognition and rejection of allografts occur?
T lymphocytes and antibodies produced against graft antigens react against and destroy the graft. The major antigenic differences between a donor and recipient that result in rejection of transplants are differences in HLA alleles. Graft exchanged between individuals of the same species are called allografts because HLA genes are highly polymorphic there is always some differences between individuals (except identical twins).
how are antigens of transplanted grafts presented?
either taken up by host APCs or by the grafts own APCs present them to the host T-cells.
what are the grades of rejection?
- hyperacute: (preformed anitbodies, IGM) These bind to endothelium and activate clotting. This is avoided by blood matching the graft and recipient. The IGM may be specific for blood groups antigens or may be antibodies speciific for allogeneic MHC molecules as a result of prior explore to said MHC molecules. (blood transfusion, pregnancy, organ transplant)
- acute: 2 types: #1: acute cellular rejection: CD8+ CTLs may directly destroy graft CD4+ secrete cytokine and induce inflammation. #2: Antibody-mediated (vascular or humeral) rejection, with antibodies binding to endothelial cells.
- chronic: manifests as interstitial fibrosis and gradual narrowing of graft blood vessels (graft arteriosclerosis) T cells are believed to react against graft alloantigens and secrete cytokines which stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells in the graft.
grades are based on the basis of clinical and pathological features.
what are some of the methods used to increase the survival of transplanted grafts?
HLA matching is important. Survival improves with increasing number of loci matched. With advancements in drugs for immunosuppression HLA matching is no longer done on vital organs that need quick transplant: lung heart.
what is the most optimal way of immunosupression during organs transplant?
prevent host T cells from receivign costimulatory signals from donor DC during the initial phase of sensitization. This is done by blcoking the interaction of the B7 molecules on the DC of the graft and the CD28 receptors on host T cells this induces either T-cell apoptosis or anergy.
Describe Graft-vs-host disease (GVHD) as a result of transplantation of hematopoietic stem cells.
Transplanted bone marrow stem cells recognize the host cells as foreign and act against them. Careful DNA sequencing-based methods are used to match the donor and recipient. there are 2 types:
-Acute GVHD: (days-weeks) epithelial cell necrosis in 3 principal target organs: liver, skin and gut. Destruction of bile ducts causes jaundice, mucosal ulceration of the gut results in bloody diarrhea. Rashes develop on the neck, ears and palms of hands and soles of feet, then they become generalized.
-Chronic GVHD: skin lesion resembling those systemic sclerosis.
Some attempts have been made to deplete donor T-cells which has had mixed results in preventing this disease.
what are the 2 types of immunodeficiency?
Primary: congenital
Secondary: acquired immunodeficiency.
Describe primary (inherited) immunodeficiencies?
primary immunodeficiency diseases are inherited genetic disorders that impair mechanisms of innate immunity, (phagocytes, NK cells, or complement) or the humoral and/or cellular arms of adaptive immunity (mediated by B-lymphocytes and T-lymphocytes respectively. This is usually detected during infancy.
Describe Brutons disease (inherited, primary immunodeficiency)
X-linked agammaglobulinemia (XLA) or bruton disease, is characterized by the failure of pre-B cells to differentiate into mature B cells and as the name implies, a resultant absence of antibodies (gamma globulin) in the blood.
Normally in B-cells immunoglobulin (Ig) heavy chain genes are rearranged first followed by light chain genes. In XLA the maturation stops at the heavy chain gene rearrangement because of a tyrosine kinase that is associated with the pre-B-cell receptor and is involved in pre-B-cell signal transduction. This is called Bruton tyrosine kinase (BTK).
The disease usually does not become apparent until 6 months of age. recurrent bacterial infections to the lungs are symptoms. Streptococcus pneumonia is usually the cause.
Describe DiGeorge syndrome (thymic hypoplasia)
Digeorge syndrome is caused by a congenital defect in thymic development resulting in deficient T-cell maturation. The lack of T-cells in the lymph nodes, spleen, peripheral blood, making the patient vulnerable to viral, fungal, and protozoal infections.
the thymic tissue may be transplanted.
It is caused by deletion of affecting chromosomal region 22q11.
Describe ataxia telangiectasia?
an autosomal recessive disorder characterized by abnoraml gait (ataxia) vascular malformations (telangiectasia) neurologic deficits, increased incidence of tumor and immunodeficiency.
It is caused by defective production of isotype-switched antibodies, mainly IGA and IgG2. Its usually associated with ATM disorder, ATM is needed for apoptosis during DNA damage.
what are the forms of transmission of the HIV infection (aids)
its a retrovirus that is transmitted via:
- Sexual transmission: virus in the semen enters via abrasions in the anal or oral cavity. It can be transmitted in 2 ways: via DC or CD4 in the mucosa or directly inoculation into the blood vessels.
- Parenteral transmission: IV drug users
- mother-to-infant transmission: via: transplacental, breast milk, during birth.
Describe the structure of the HIV?
the virus core contains: major capsid protein p24, nucelocapsid protein, 2 copies of viral genomic RNA and 3 viral enzymes (protease, reverse transcriptase, integratse).
p24 is the most abundant viral antigen and is detected by an assay widely used to diagnose HIV infection. The core is surrounded by matrix protein called p17. 2 viral glycoproteins gp120, and gp41 which are critical for HIV infection of cells.
HIV affects the CNS and immune system.
Process of HIV infection?
- HIC uses CD4 as a receptor. HIV gp120 binds CD4 is essential for infection and accounts for the tropism of the virus for CD4+ T cells and for CD4+ monocytes/macrophages and DCs. However the gp120 and CD4 binding is insufficient for infection so the coreceptors CCR5 and CXCR4 serve as coreceptors. Some strains of HIV have preference for certain coreceptors. Mutations to the CCR5 gene makes people resistant to certain strains of the virus but they can still be infected.
The HIV capsule contains a transmembrane protein gp41. The binding of gp120 to CD4 creates new conformational change on gp120 for the co-receptors CCR5 or CXCR4. coreceptor binding induces conformational change in gp41 that exposes a hydrophobic region called the fusion pepetide which inserts into the membrane of the target cells leading to fusion of the virus with the host cell.
The virus will remain laiden for a while until the cell is activated by some environmental signal and NF-kB starts to transcribe genes including the virus itself. Eventually the transcription of the virus leads to the cells death.
what is responsible for the poor recall of previous infections of HIV infected individuals?
The HIV virus kills CD4 cells which prevents the formation of memory T cells. This results in poor response to previous infections. The HIV can remain latent in T-cells and memory T-cells which are long lived and these are important reservoirs for the virus.
HIV can also infect Macrophages, and DC (dendritic cells).
what may be needed for retroviruses like HIV to be able to access the nuclear area of a host cell?
Cell division may be required for retroviruses to infect host DNA.
NOTE: macrophages allow viral replication, they are quite resistant to the cytopathic effects of HIV.
what happens when dendritic cells are infected by HIV?
-Mucosal DCs may be infected by the virus and transport it to regional lymph nodes, where the virus is transmitted to CD4+ T cells. Follicular DCs in the germinal centers of lymph nodes also are potential reservoirs of HIV. Although some follicular DCs may be susceptible to HIV infection, most ivrus particles are found on the surface of the dendritic processes.
Describe the neural damage done by HIV?
HIV is carried into the brain my infected monocytes. the Virus infects macrophages and microglia, which belong to the macrophage lineage located in the brain.
what are the stage of HIV?
- Acute phase: HIV infects CD4 T-cells in the mucosal lymphoid tissue and death of many of these cells occurs. In a few days HIV particles are present in the patients blood. 3-6 weeks the patient has acute HIV syndrome: fever, weight loss, fatigue, rash, diarrhea, vomiting.
- Chronic phase: lymph nodes and the spleen are sites of continuous HIV replication and cell destruction.
- AIDS: breakdown of host defense and dramatic increase in plasma virus and severe life-threatening clinical disease. Opportunistic infections emerge.
how to measure HIV progression?
measure HIV-1 RNA levels in the blood. The viral load at the end of the acute phase reflects the equilibrium reached between the virus and the host defense. This level of steady-state viremia called the viral set-point is a predictor of the rate of decline of CD4+ T cells and therefore progression of HIV disease.
what are the clinical symptoms of HIV?
fever, weight loss, diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurological disease and in many cases, secondary neoplasms.
what are the tumors that AIDS patients have a higher incidence of?
viruses establish latent infections that are kept in check in healthy individuals by a competent immune system.
-Kaposi sarcoma: vascular tumor that is characterized by a proliferation of spindle-shaped cells that express markers of both endothelial cells (vascular or lymphatic) and smooth muscle cells.
-B-cell lymphoma: The restrained proliferation of B cells control is lost and the infected B-cells undergo unchecked proliferation that predispose to mutations and the development of B-cell tumors.
cervical cancer (women):
Anal cancer (men):
what happens to lymph nodes with aids?
they slowly atrophy and become small and may harbor opportunistic pathogens. inflammatory response to infection both in the lymph nodes and at extranodal site may be sparse or atypical because CD4+ cells are deficient and the presence of these and other infectios agents may not be apparent without special stains. Later stages of AIDS the spleen and thymus also are converted to wastelands that are virtually devoid of lymphocytes.
Amyloidosis description?
a condition associated with a number of disorders in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise.
the deposits are called amyloid because the charged sugar groups give the deposits staining characteristics resemble starch (amylose). Though its unrelated to starch. over 30 proteins can form amyloid.
-AL (amyloid light chain) amyloid:
-AA (amyloid associated) amyloid (made in the liver)
-B-amyloid protein (Ab)
Structure of amyloid.
Amyloid forms from abnormal folding of proteins, which assume a B pleated sheet conformation, aggregate and deposit as fibrils in extracellular tissues. Normally intracellular misfolded proteins are degraded, which extracellular proteins are taken up by macrophages for degradation.
in amyloidosis these checks and balances are lost causing misfolding.
-aggregation my be local or systemic.
-on clinical ground it may be primary or secondary.
describe primary and secondary amyloidosis.
- Primary: plasma cell proliferation’s; clonal proliferation of plasma cells that synthesize abnormal Ig molecules
- Secondary: secondary to an associated inflammatory condition. It could occur during: tuberculosis, bronchiectasis, chronic osteomyelitis, it complicated rheumatoid arthritis. It can also occur in response to certain cancers: renal cell carcinoma, hodgkin lymphoma.
what is the excessive deposit of protein a result of?
- excessive production of proteins that are prone to aggregation
- mutations that produce proteins that cannot fold properly and tend to aggregate
- defective or incomplete proteolytic degradation of extracellular proteins.
Amyloidosis does not evoke normal inflammatory response but do cause tissue injury and impair normal function by causing pressure on cells and tissues.
