Diseases Of The Immune System Flashcards
(124 cards)
1
Q
What are the six major components of the innate immune system?
A
- Epithelia
- Monocytes and neutrophils
- Dendritic cells
- Innate lymphoid cells
- Other cell types e.g. mast cells
- Plasma proteins e.g. complement proteins
2
Q
Mammals have 10 Toll-like receptors, each recognising a different set of microbial molecules. They are found in the plasma membrane and endosomal vesicles. What is the result of the common pathway they signal by?
A
- Activation of transcription factor NF-kB which stimulates synthesis and secretion of cytokines and the expression of adhesion molecules
- Activation of interferon regulatory factors which stimulate the production of the antiviral cytokines, type I interferons
3
Q
Several NOD-like receptors (found in cytosol) signal via a multiprotein complex, the inflammasome, which activates caspase-1 which in turn activates IL-1. What can trigger this pathway?
A
- Products released from damaged/necrotic cells e.g. uric acid, ATP
- Loss of intracellular K+
- Some microbial products
4
Q
For the following receptors relating to innate immunity, identify their cellular location, and the type of substances they respond to:
1. C-type lectin receptors
2. RIG-like receptors
3. Receptors that activate the STING pathway (leading to production of interferon-a)
4. G-protein coupled receptors
5. Mannose receptors
A
- Plasma membrane of macrophages and dendritic cells. Fungal glycans
- Cytosol of most cell types. Viral nucleic acids
- Cytosol. Microbial DNA (often viruses)
- Plasma membranes of neutrophils, macrophages and most lymphocytes. N-formylmethionine (all bacterial proteins initiated by this)
- Plasma membranes of phagocytes. Microbial sugars (which often contain terminal mannose residues)
5
Q
What is the role of natural killer cells?
A
To recognise and destroy severely stressed or abnormal cells.
note also secrete cytokines like interferon-y, activating macrophages to destroy ingested microbes
6
Q
The binding of CD16 on NK cells with IgG Fc tails is what ultimately confers the ability to lyse the target cell (antibody-dependent cellular cytotoxicity). This is regulated by activating and inhibitory receptors also, what expressed molecules could affect these?
A
Surface molecules induced by stress (activating), self class I MHC molecules, expressed on all healthy cells (inhibitory)
7
Q
What reactions of the innate immune system allow it to provide host defence?
A
Inflammation, antiviral defence, stimulate the adaptive immune response.
8
Q
What are the two types of adaptive immunity and the cell types that mediate them?
A
Humoral immunity - B lymphocytes
Cellular immunity - T lymphocytes
9
Q
What is the enzyme responsible for recombining antigen receptor genes in B and T cells?
A
RAG proteins (products of RAG-1 and RAG-2)
10
Q
What are the three major populations of T cells and their basic function?
A
- Helper T lymphocytes - stimulate B lymphocytes to make antibodies and activate other leukocytes to destroy microbes
- Cytotoxic T lymphocytes - kill infected cells
- Regulatory T lymphocytes - limit immune responses and prevent reactions against self antigens
11
Q
alpha/beta T cell receptors can recognise antigens under what circumstance?
(gamma/delta TCRs do not need this, found on a small population of lymphocytes)
A
When they are presented on major histocompatibility (MHC) molecules on antigen presenting cells.
12
Q
What proteins form the TCR complex?
A
The alpha and beta polypeptide chains of the TCR, six noncovalently linked chains comprising the CD3 complex and (greek)s chain dimer
13
Q
CD4 and CD8 both act as coreceptors in T cell activation. What are the differences between them?
A
CD4 - binds only to class II MHC molecules and found on T helper cells
CD8 - binds only to class I MHC molecules and found on cytotoxic T cells
14
Q
After stimulation of the B cell receptor complex B cells develop into plasma cells and memory B cells. what is the B cell receptor complex made of?
A
An IgM or IgD antibody and a heterodimer of Iga (CD79a) and Igb (CD79b)
15
Q
On B cells where do CR2(CD21) and CD40 receptors get signals from respectively?
A
Complement products and helper T cells
16
Q
What are four features of dendritic cells that account for their key role in antigen presentation?
A
- Location (under epithelia and in the interstitia of all tissues)
- Expression of many receptors for capturing and responding to microbes (and other antigens), including TLRs and lectins
- In response to microbes they are recruited to the T cell zones of lymphoid organs to present antigens to naïve T cells
- Express high levels of MHC and other molecules needed for antigen presentation and T cell activation
17
Q
What are the secondary lymphoid organs?
A
Lymph nodes, spleen, mucosal and cutaneous lymphoid tissues
18
Q
What is the general structure of lymph nodes as an example of the segregation of naïve B and T lymphocytes?
A
B cells are concentrated in discrete follicles around the periphery, along with FDCs. These may have a germinal centre if B cells within one have recently responded to an antigen.
T lymphocytes are concentrated in the paracortex, adjacent to the follicles with DCs.
19
Q
Where can T lymphocytes and B lymphocytes be found in the spleen respectively?
A
- Periarteriolar lymphoid sheaths
- Follicles in areas known as the splenic white pulp
20
Q
MHC molecules class I and II, also called HLA in humans are encoded by what genes from what chromosome?
A
From the MHC locus on chromosome 6
MHC class I alpha chain by HLA-A, HLA-B and HLA-C
MHC class II from the HLA-D region by HLA-DP, HLA-DQ and HLA-DR
21
Q
Both class I and II MHC molecules are noncovalently linked heterodimers with highly variable alleles in the population affecting affinity of binding to different peptides.
Compare their structures.
A
- Class I - Polymorphic alpha or heavy chain with three domains - a3 is nonpolymorphic and is the site of CD8 binding. Once bound to a cytoplasmic peptide (between a1 and a2) will associate with B2-microglobulin chain to form the stable complex then transported to the cell surface.
- Class II more equally sized alpha and beta chains, both polymorphic. Peptides (antigens derived from extracellular microbes or proteins) bind at the interaction face of a1 and B1. B2 binds CD4
22
Q
What leads to the largely unique HLA haplotype in an individual?
A
Inheritance of one set of HLA genes from each parent. Then expression of different molecules for each gene locus. This plus the significant polymorphism of HLA genes leads to two unrelated individuals expressing the same HLA halotype being extremely unlikely. For siblings it is 1 in 4.
23
Q
What are two different types of immune response, and two other immune requirements cytokines contribute to?
A
Innate (TNF, IL-1, IL-12 type I IFNs, IFN-y), adaptive (IL-2, IL-4, IL-5, IL-17, IFN-y), termination (TGF-B, IL-10) and stimulation of hematopoiesis to increase leukocyte production (CSFs and IL-3)
24
Q
What is the overall function of cytokines in the innate and adaptive immune responses respectively?
A
- To induce inflammation and inhibit virus replication
- Promote lymphocyte proliferation and differentiation as well as to activate effector cells.
25
Costimulation of the adaptive immune response is important to ensure it is not directed at harmless antigens. What are the principal costimulators for T cells, and the receptor they act on?
B7 proteins (CD80 and CD86) on antigen presenting cells recognised by CD28 on naïve T cells
26
What is one of the earliest responses of a CD4+ helper T cells once activated?
Secretion of IL-2 and expression of high affinity receptors for IL-2 creating an autocrine loop where IL-2 acts as a growth factor stimulating T-cell proliferation.
27
Some CD4+ T cells differentiate into effector cells which secrete distinct sets of cytokines. For Th1, Th2 and Th17 what are these and what is their function?
- Th1 - IFN-y, potent ‘classical’ macrophage activator along with CD40L
- Th2 - IL-4, stimulates B cell differentiation into IgE plasma cells, and T cells to Th2. IL-5, stimulates eosinophil production and activates them at immune response sites. IL- 13 enhances IgE production and stimulates epithelial mucus secretion. Also induce ‘alternative’ macrophage activation.
- Th17 - IL-17, recruits neutrophils and monocytes
28
What are the two pathways by which antibody responses to antigens are triggered?
- T-dependent - B cells endocytose antigens recognised by Ig receptors and display degraded peptides from these on MHC class II molecules, activating helper T cells which recognise these, causing them to express CD40L and cytokines, in turn stimulating B cells.
- T-independent - When polysaccharide and lipid antigens that can’t bind to MHC molecules engage antigen receptor molecules on B cells, activating them. This tends to be a relatively simple response, stimulating secretion of mainly IgM antibody.
29
What is the function of T follicular helper cells?
Stimulate activated B cell affinity maturation and isotype switching as well as proliferation within germinal centres in follicles.
30
As well as binding microbes preventing them from infecting cells, which antibodies;
1. Opsonise, targeting for phagocytosis?
2. Activate the complement system by the classical pathway?
3. Cooperate with eosinophils to kill parasites?
4. Is secreted by mucosal epithelia?
5. Is actively transported across the placenta?
1. IgG
2. IgG and IgM
3. IgE
4. IgA
5. IgG
31
What is the half life of most IgG antibodies?
3 weeks
32
Where can plasma cells actively (continuing antibody production) reside for months to years?
Bone marrow
33
Characterise the two phases of a local type I hypersensitivity reaction
- Initially vasodilation, vascular leakage and depending on the tissue smooth muscle spasm or glandular secretions.
- 2-24 hours later (late phase), infiltration with eosinophils, neutrophils, basophils, monocytes and CD4+ T cells with tissue destruction, typically mucosal epithelial damage
34
What are the four types of hypersensitivity reactions?
- Type I - Immediate hypersensitivity
- Type II - Antibody-mediated hypersensitivity
- Type III - Immune complex-mediated hypersensitivity
- Type IV - Cell-mediated hypersensitivity
35
The excessive response of what cell type causes most immediate hypersensitivity disorders?
Th2
36
Mast cells can be activated by a number of triggers such as C5a, C3a, IL-8, codeine, morphine, adenosine, melittin and IgE. How does activation via IgE antibodies work?
FceRI is a high affinity receptor specific for Fc of IgE. A mast cell is sensitised when it is coated with IgE. Multivalent antigens bind and cross link IgE bringing Fce receptors together, triggering signal transduction pathways that lead to release mediators and production of others
37
Give examples of the mediators of immediate hypersensitivity that are released from mast cell granules under the categories of 1. Vasoactive amines, 2. Enzymes, 3. Proteoglycans
1. Histamine (smooth muscle contraction, increases vascular permeability, stimulates mucus secretion.
2. Neutral proteases (chymase, tryptase) and acid hydrolases. (Tissue damage, kinin generation and activation of complement)
3. Heparin and chondrotin sulfate
38
Other than those released by granules, what other mediators do mast cells release during a hypersensitivity reaction?
- Lipid mediators (Leukotrines, protoglandin D2, PAF)
- Cytokines (TNF, IL-1, chemokines, IL-4)
39
What is often an abundant leukocyte population in a late phase hypersensitivity reaction and what do they do?
Eosinophils - Liberate proteolytic enzymes and major basic protein and eosinophil catinoic protein, causing tissue damage. Sometime release Charcot-Leyden crystals (galectin-10) which promote inflammation and enhance Th2 response.
40
Name four examples of disorders caused by immediate hypersensitivity
Anaphylaxis, Bronchial asthma, allergic rhinitis, food allergies
41
What are the three mechanisims by which antibody-mediated hypersensitivity can cause disorder?
Opsonisation and phagocytosis (when affects cells), inflammation (when affects fixed tissues) and cellular disfunction
42
What are four examples of disorders caused by antibody-mediated hypersensitivity acting through opsonisation and phagocytosis?
- Transfusion reactions
- Haemolytic disease of the newborn
- Autoimmune haemolytic anaemia/agranulocytosis/thrombocytopenia
- Drug-induced destruction of blood cells
43
Type II hypersensitivity reactions caused through inflammation occur due to the antibodies activating the complement cascade in turn triggering the rest of the inflammatory mediators, damaging the affected tissues. What are some examples of disorders caused by this?
Some forms of glomerulonephritis and vascular rejection in organ grafts.
44
In some cases of type II hypersensitivity reactions antibodies directed against cell surface receptors can affect their function without causing cell injury or inflammation. What are two examples of this?
- Myasthenia Gravis - reactive with acetylcholine receptor in the motor end plates of skeletal muscles. block transmission therefore causing weakness
- Graves disease - against TSH receptors on thyroid epithelial cells. stimulating the cells, resulting in hyperthyroidism
45
What are the three phases of the pathogenesis of systemic immune complex-mediated hypersensitivity disorders?
1. Formation of immune complexes of antibodies and antigen (about 1 week after first exposure)
2. Deposition of immune complexes in vessels - organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where these complexes become concentrated and tend to deposit
3. Inflammation and tissue injury (about 10 days post exposure) (acute, antibody mediated with high complement and neutrophil involvement- can cause fibrinoid necrosis)
46
What are some examples of immune complex-mediated hypersensitivity diseases?
Serum sickness, SLE, reactive arthritis, poststreptococcal glomerulonephritis. Arthus reaction (experimental)
47
Initial differentiation of CD4+ T cells is driven by the cytokines produced by the APC at the time of T cell activation. Which will produce Th1 and Th17?
- Th1 IL-12 (then self amplified with IFN-y)
- Th17 IL-1, IL-6 and IL-23
48
What is the prototype of CD4+ T cell-mediated hypersensitivity inflammation?
Delayed type hypersensitivity, e.g. the tubercillin reaction, contact dermatitis
49
What is delayed-type hypersensitivity morphologically characterised by?
accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules producing perivascular “cuffing”. In fully developed lesions the venules show marked endothelial hypertrophy (reflecting cytokine mediated activation)
50
What is a T cell-medicated hypersensitivity disorder that may include the function of CD8+ T cells (as opposed to mainly just CD4+ T cells)?
Type 1 diabetes
51
Briefly explain the principal mechanism of T cell-mediated cell killing
CTLs recognise a target cell -> secrete a complex consisting of perforin, granzymes and other proteins that enters target by endocytosis -> perforin facilitates release of granzymes -> granzymes cleave caspases inducing apoptosis
52
Give some examples of T cell- mediated diseases (and the related antigens)
Multiple sclerosis (protein antigens in myelin), inflammatory bowel disease (enteric bacteria; self antigens?), type 1 diabetes (antigens of pancreatic islet B cells)
53
What three requirements should be met to categorise a disorder as being caused by autoimmunity?
- Presence of an immune reaction specific for some self antigen or tissue
- Evidence that such a reaction is not secondary to tissue damage but is of primary pathologic significance
- Absence of another well-defined cause of the disease
54
In the process of central tolerance what happens when, 1. an immature T cell reacts to a self-antigen? 2. an immature B cell reacts to a self antigen?
1. Negative selection/clonal deletion where the cell is killed by apoptosis. Some CD4+ T cells will instead develop into regulatory T cells
2. Receptor editing (antigen receptor gene is rearranged again). If this does not occur then cell death by apoptosis will
55
How is central tolerance developed in the thymus?
Thymic antigen-presenting cells present a wide variety of autologous proteins antigens on self MHC molecules to immature T cells. E.g. of how peripheral antigens are presented in the thymus is the protein called AIRE which stimulates expression of some peripheral tissue-restricted antigens and the absence of which can lead to autoimmune polyendocrine syndrome
56
Anergy is a mechanism of peripheral tolerance where lymphocytes that recognise self antigens become functionally unresponsive. Along with a lack of costimulators, there are inhibitory signals. What are two inhibitory receptors, and their ligands, found on T cells?
CTLA-4 binds B7 (Like CD28)
PD-1 binds PD-L1 and PD-L2
57
Suppression by regulatory T cells is a part of peripheral tolerance, and is believed to play an important role in maternal tolerance of the fetus in pregnancy. What are two factors required in the development and maintenance of these cells?
-IL-2, particularly its receptor CD25 (the alpha chain)
- FOXP3 (transcription factor, mutations are the cause of IPEX)
58
What are the three mechanisms of peripheral tolerance?
Angery, suppression by regulatory T cells, deletion by apoptosis
59
What are the four categories ANAs can be grouped into based on their specificities?
- DNA
- Histones
- Nonhistone proteins bound to RNA
- Nucleolar antigens
60
Which autoantibodies are virtually diagnostic for SLE?
Antibodies to double stranded DNA and the Smith [Sm] antigen
61
What antibodies do the following indirect immunofluorescence staining patterns for ANAs usually reflect?
1. Homogenous/diffuse nuclear staining
2. Rim/peripheral staining
3. Speckled pattern
4. Nucleolar pattern
5. Centromeric pattern
1. To chromatin, histones, and, occasionally, double stranded DNA, common in SLE
2. To double stranded DNA and sometimes nuclear envelope proteins
3. Least specific, most commonly seen. To non-DNA nuclear constituents like Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens
4. To RNA. most often in patients with systemic sclerosis
5. To centromeres. Often systemic sclerosis
62
Other than ANAs, what are some antibodies that can be present in SLE?
- Against blood cells (red cells, platelets, lymphocytes)
- Antiphospholipid antibodies (e.g. prothrombin, protein S, C, B2-glycoprotein I, annexin V)
63
Complete the steps for the hypothetical, synthesised model of SLE:
1. UV irradiation and other environmental insults lead to …
2. Inadequate clearance of the nuclei of these cells results in a large burden of nuclear antigens
3. The… that have remained functional due to underlying abnormalities responsible for… are stimulated by nuclear self antigens
4. Antibodies are produced against the antigens
5. Antigen-antibody complexes bind to… and may be internalised
6. The nucleic acid components engage TLRs and stimulate B cells to produce more autoantibodies
7. TLR stimuli also activate DCs to produce interferons and other cytokines, enhancing the immune response and causing more apoptosis.
The net result is…
1. UV irradiation and other environmental insults lead to the apoptosis of cells
2. Inadequate clearance of the nuclei of these cells results in a large burden of nuclear antigens
3. The self-reactive lymphocytes that have remained functional due to underlying abnormalities responsible for defective tolerance are stimulated by nuclear self antigens
4. Antibodies are produced against the antigens
5. Antigen-antibody complexes bind to Fc receptors on B cells and DCs and may be internalised
6. The nucleic acid components engage TLRs and stimulate B cells to produce more autoantibodies
7. TLR stimuli also activate DCs to produce interferons and other cytokines, enhancing the immune response and causing more apoptosis.
The net result is a cycle of antigen release and immune activation resulting in the production of high affinity autoantibodies.
64
What are four possible autoantibody related mechanisms of tissue injury in SLE?
- Type III hypersensitivity from ANA-ligand complexes.
- Type II hypersensitivity in the form of opsoninisation of red cells, white cells, and/or platelets
- Antiphospholipid antibody syndrome
- Neuropsychiatric manifestations from antibodies crossing the bbb and reacting with neurons or receptors for various neurotransmitters
65
What are LE bodies/hematoxylin bodies and what is their historical significance?
Form when nuclei of damaged cells react with ANAs, loose their chromatin pattern and become homogeneous. LE cells are phagocytic leukocytes that have phagocytosed these and demonstrating these in vitro was a test for SLE
66
What are the seven main forms of renal involvement in SLE?
- Tubulointerstitial lesions
- Six patterns of glomerular disease (in order of class I to class VI)
- Minimal mesangial lupus nephritis
- Mesangial proliferative lupus nephritis
- Focal lupus nephritis
- Diffuse lupus nephritis (most common and severe)
- Membranous lupus nephritis
- Advanced sclerosing lupus nephritis
67
Other than effects on the kidney, what are a few other common possible features of SLE?
- Acute necrotising vasculitis (with fibrinoid necrosis)
- Malar rash and sun sensitivity
- Non-erosive synovitis with little deformity
- Pleuritis - often with effusions, often becomes fibrous
68
Sjögren syndrome is a chronic autoimmune disease. When in isolation it is called sicca syndrome, but more commonly it is associated with other autoimmune diseases. What is it characterised by, and which is the most commonly associated autoimmune disease?
- dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) (destruction of the lacrimal and salivary glands)
- Rheumatoid arthritis
69
What antibodies are considered serologic markers of Sjögren syndrome, however, can also be found in some cases of SLE?
Anti SS-A (Ro) and anti SS-B (La)
(ribonucleoprotein antigens)
70
While the pathogenesis of Sjögren syndrome remains obscure what is the decrease in tears and saliva (and sometimes other exocrine glands) the ultimate result of?
Lymphocytic infiltration (predominantly active CD4+ T helper and B cells) and fibrosis of the lacrimal and salivary glands
71
What three things is systemic sclerosis (scleroderma) characterised by?
- Chronic inflammation thought to be the result of autoimmunity
- Widespread damage to small blood vessels
- Progressive interstitial and perivascular fibrosis in the skin and multiple organs
72
What is the CREST syndrome that limited systemic sclerosis can manifest as?
Calcinosis, Raynaud phenomenon, oEsophageal dysmotility, Sclerodactyly, Telangiectasia
73
Briefly outline the autoimmunity, vascular damage and fibrosis in systemic sclerosis. (Note that triggers remain unknown)
Autoimmunity- Sparse inflammatory infiltrates. Activated CD4+ T cells (Th2), stimulate collagen and ECM protein transcription in fibroblasts and chronic inflammation. ANAs present but role unclear.
Vascular damage - Intimal proliferation in digital arteries. Capillary dilatation with leaking, destruction. Nailfold capillary loops distorted early. Endothelial activation and injury. Eventually widespread narrowing of microvasculature leads to ischemic injury and scarring.
Fibrosis - may be cumulation of multiple abnormalities including accumulation of alternately activated macrophages, actions of fibrogenic cytokines, scarring following ischemic damage and possibly intrinsic abnormalities of the fibroblasts
74
Which ANA has a strong association with diffuse systemic sclerosis and limited systemic sclerosis respectively?
- anti-Scl 70 (against DNA topoisomerase I)
- an anticentromere antibody (tend to have CREST syndrome)
75
What are three examples of complications from systemic sclerosis?
Oesophageal hypomotiliy, pulmonary hypertension, biliary cirrhosis
76
Mixed connective tissue disease has clinical features that overlap with SLE, systemic sclerosis and polymyositis. It typically presents with synovitis of the fingers, Raynaud phenomenon, myositis and modest renal involvement that responds well to corticosteroids. How is it serologically characterised?
High titres of antibodies to U1 ribonucleoprotein
77
What is IgG4-Related disease, which can affect many organs mainly in middle aged to older males, characterised by?
Tissue infiltrates dominated by IgG4 antibody producing plasma cells and lymphocytes, fibrosis (storiform), obliterative phlebitis and usually increased serum IgG4.
78
Briefly describe hyperacute graft rejection
Occurs as soon as blood flow is restored. Pre-existing antibodies (blood group antigens or from prior MHC exposure from pregnancy, transfusions or other transplants) bind to graft vascular endothelium and activate complement leading to endothelial injury, thrombosis and ischemic necrosis of the graft
79
Both the direct and indirect pathways of recognising alloantigens lead to the activation of CD8+ and CD4+ T cells. What are these pathways?
Direct - Graft antigens are presented to T cells by graft APCs (thought to be most important for CTL-mediated acute rejection)
Indirect - Graft antigens are picked up by host APCs, processed, and presented to host T cells (thought to play a greater role in chronic rejection)
80
The frequency of T cells that can recognise foreign antigens in a graft is much higher than those specific for any microbe meaning immune responses to allografts are stronger than responses to pathogens. Where do the major antigenic differences that result in rejection lie?
HLA allelles
81
What are the two patterns present in acute rejection of a graft?
Acute cellular rejection and acute antibody-mediated rejection
82
What is the typical morphology of acute antibody-mediated rejection in kidney transplants?
Damage to glomeruli and small blood vessels. Inflammation of glomeruli and peritubular capillaries, associated with deposition of complement products. Small vessels may also show focal thrombosis.
83
In acute cellular rejection CD8+ and CD4+ T cells are activated causing cell death and inflammation (with subsequent damage) respectively. Describe the morphology of the two patterns of injury in the kidney:
1. Tubulointerstitial (Type I)
2. Vascular (Type II and III)
1. Extensive interstitial and tubular inflammation associated with focal tubular injury. Inflammatory infiltrates contain activated CD4+ and CD8+ T lymphocytes.
2. Inflammation of vessels (II), sometimes necrosis of vessel walls (III). Endotheliitis/intimal arteritis - swollen endothelial cells and lymphocytes between the endothelium and the vessel wall
84
Chronic rejection of a graft is refractory to most therapies and manifests as interstitial fibrosis and gradual narrowing of graft blood vessels. What is believed to be the cause of this?
T cells responding to alloantigens and secreting cytokines stimulating activities and proliferation of fibroblasts and vascular smooth muscle. Alloantibodies also involved.
85
Describe the morphology of chronic graft rejection in the kidney
- Vascular changes, often intimal thickening and vascular occlusion.
- Glomerulopathy with duplication of the basement membrane and peritubular capillaritis with mulitlayering of peritubular capillary basement membranes.
- Interstitial fibrosis and tubular atrophy with loss of renal parenchyma
- Typically sparse interstitial mononuclear cell infiltrates
86
What is primary immunodeficiency?
Genetically determined defects in innate or adaptive immunity
87
Primary defects in innate immunity tend to affect leukocyte functions or the complement system. Name four patterns of inherited leukocyte dysfunction, and provide an example for one.
- Defects in leukocyte adhesion
- Defects in phagolysosome function e.g. Chédiak-Higashi syndrome, autosomal recessive, defective fusion of phagosomes and lysosomes. Gene coding LYST protein dysfunctional, believed to regulate lysosomal trafficking.
- Defects in microbicidal activity
- Defects in TLR signalling
88
What is the most common complement protein deficiency and what presentation is it associated with?
C2
C2 and C4 deficiencies are associated with increased bacterial or viral infections. At the same time, many have no clinical manifestations, presumably because the alternative pathway is adequate for most infections.
89
Deficiency of what is associated with increased susceptibility to recurrent Neisseria (gonococcal and meningococcal)?
Terminal complement components - C5, 6, 7, 8 and 9 (as they are required for assembly of the membrane attack complex)
90
What do immunodeficiencies from defects in adaptive immunity result from?
Abnormalities in lymphocyte maturation or activation
91
In Severe Combined ImmunoDeficiency (SCID) death occurs in the first year of life without HSC transplantation. How does it present?
Prominent thrush, extensive diaper rash and failure to thrive. Some develop morbilliform rash shortly after birth as maternal T cells are transferred across the placenta and attack the foetus. Extremely susceptible to recurrent, severe infections.
92
X-linked SCID is the most common form, accounting for 50-60% of cases.
ADA (adenosine deaminase) deficiency is the most common autosomal recessive form of SCID.
Briefly outline the pathogenesis for both of these forms of SCID
- X-linked - defect in the y-chain subunit of cytokine receptors. (IL-2, 4, 7, 9, 11, 15, 21). IL-7 is required for survival and proliferation of lymphoid progenitors, particularly T cell -> greatly reduced T cells. IL-15 is important for maturation and proliferation of NK cells -> often have NK deficiency.
- ADA deficiency - not clear but thought that leads to accumulation of deoxyadenosine and its derivatives which are toxic to rapidly dividing immature lymphocytes, particularly T cells
93
Briefly explain the basis of the cause of the following examples of disorders affecting the adaptive immune response:
1. X-linked agammaglubulinemia
2. Common variable immunodeficiency
3. Selective IgA deficiency
4. X-linked hyper-IgM syndrome
5. X-linked lymphoproliferative disease
1. Failure of B cell maturation, absence of antibodies; mutation in BTK gene, kinase required for maturation signals from the pre-BCRs and BCRs
2. Defects in antibody production; cause unknown in most cases
3. Failure of IgA production; cause unknown
4. Failure to produce isotope switched high affinity antibodies (IgG, IgA, IgE); mutation in gene encoding CD40L
5. Defect in a signalling molecule causing defective responses to EBV and lymphoproliferation
94
Acquired Immunodeficiency Syndrome (AIDS) is caused by the retrovirus human immunodeficiency virus (HIV). What is it characterised by?
Profound immunosuppression that leads to opportunistic infections, secondary neoplasms and neurologic manifestations
95
Complete the following description of the structure of the HIV-1 virion from inside to outside :
- A cone shaped viral core containing the major capsid protein … , nucleocapsid protein p7/p9, two copies of viral genomic RNA and the three viral enzymes protease, … and integrase
- Core surrounded by …
- … (lipid bilayer derived from host cell membrane)
- Studded with two viral glycoproteins …
- A cone shaped viral core containing the major capsid protein p24, nucleocapsid protein p7/p9, two copies of viral genomic RNA and the three viral enzymes protease, reverse transcriptase and integrase
- Core surrounded by a matrix protein p17
- Viral envelope (lipid bilayer derived from host cell membrane)
- Studded with two viral glycoproteins, gp120 and gp41
96
Once HIV enters the body through mucosal tissues and blood, which cells are first infected?
T cells, DCs and macrophages
97
Explain the differences between the R5, X4 and R5X4 strains of HIV
R5 strains use chemokine receptor CCR5 as a coreceptor and preferentially infect monocyte/macrophage linage cells (and memory T cells). (M-tropic, more prevalent early in course)
X4 strains use CXCR4 and preferentially infect T cells (T-tropic)
R5X4 can use both chemokine receptors as costimulators
98
How does HIV infect a cell?
gp120 binds to CD4 -> conformational change producing a coreceptor recognition site on gp120 which binds to CCR5 or CXCR4 -> conformational change in gp41 exposing the hydrophobic ‘fusion peptide’ at the tip of gp41 -> this inserts into the cell membrane leading to fusion of the virus and host cell membranes, releasing the core into the cell
99
Once converted to cDNA by reverse transcriptase what state does the T cell need to be in for the HIV genes to circularise, enter the nucleus and integrate into the host genome?
Active in the cell cycle (dividing)
100
What makes HIV inefficient at productively infecting naïve T cells?
They contain an active form of an enzyme (APOBEC3G) that introduces mutations in the HIV genome. Once the cell is activated, this becomes inactive.
101
Why can completion of the HIV viral life cycle (with viral replication and shedding which in most CD4+ cells results in lysis) in latently infected cells only occur after cell activation?
The long-terminal-repeat sequences that flank the HIV genome contain binding sites for the transcription factor NF-kB, which is held inactive in the cytoplasm until the cell is activated.
(NF-kB is used to drive the expression of the viral RNA)
102
What viral gene allows HIV-1 to gain nuclear entry in terminally differentiated non-dividing macrophages?
vpr gene. The protein allows nuclear targeting of the HIV pre-integration complex through the nuclear pore
103
Early in the HIV disease course there is polyclonal activation of B cells, resulting in germinal centre B cell hyperplasia, sometimes accompanied by autoimmune phenomena like immune thrombocytopenic purpura. What are three possible causes of this?
- Reactivation or reinfection with EBV (is a polyclonal B cell activator)
- Viral gp41 which can promote B cell growth and differentiation
- Increased production of IL-6 by infected macrophages which stimulates proliferation of B cells
104
Microglia are the prominent cell type in the brain infected by HIV. The mechanism of HIV damage to the brain is obscure but one theory is that it is caused by viral products and soluble factors produced by infected microglia. What is the clinical syndrome of CNS abnormalities called (a progressive encephalopathy)?
HIV-associated neurocognitive disorder (HAND)
105
What are the three phases of HIV infection?
1. An acute retroviral syndrome
2. A chronic phase in which most individuals are asymptomatic
3. Clinical AIDS
106
What is the primary clinical measurement used to determine when to start antiretroviral therapy with HIV infection?
CD4+ T cell count (most reliable short term indicator of disease progression)
107
The viral set point in HIV is a predictor for the rate of decline of CD4+ T cells (and so the progression of disease). What measurement is this?
The viral load (level of HIV-1 RNA in the blood) at the end of the acute phase, which remains fairly stable for several years. (It reflects the equilibrium reached between virus and host response)
108
What is occurring during the chronic phase of HIV infection that usually lasts 7-10 years?
HIV replication and cell destruction in the spleen and lymph nodes with rapid (but not enough) replacement. Most T cells circulating in the blood do not harbour the virus
109
In the process of progression to AIDS how does the typical patient present before the serious opportunistic infections, secondary neoplasms or clinical neurologic disease, which once emerged lead to the patient being said to have developed AIDS?
Long-lasting fever (>1 month), fatigue, weight loss, diarrhoea and generalised lymph node enlargement
110
Name one example from each category of AIDS-defining opportunistic infections in patients with HIV infection:
1. Protozoal and Helminthic
2. Fungal
3. Bacterial
4. Viral
1. Cryptosporidium (enteritis)
2. Cryptococcus (CNS infection)
3. Mycobacterium (atypical - disseminated or extrapulmonary; TB pulmonary or extrapulmonary
4. Cytomegalovirus (pulmonary, intestinal, retinitis or CNS)
111
What is the common feature of the neoplasms that patients with AIDS have a higher incidence of?
(Kapsoi sarcoma, B-cell lymphoma, cervical cancer in women and anal cancer in men)
Caused by oncogenic DNA viruses
112
How does AIDS related Kaposi Sarcoma (a vascular tumour characterised by proliferation of spindle shaped cells) differ from the sporadic form?
Usually widespread (affecting skin, mucus membranes, GI tract, lymph nodes and lungs), and tends to be more aggressive.
113
What two mechanisms are believed to underlie the increased risk of B-cell tumours in HIV infected individuals? (Which is reduced with ART but still more frequent than the general population)
- Unchecked proliferation of B cells infected with oncogenic herpesviruses in the setting of profound T cell depletion
- Germinal centre B-cell hyperplasia in the setting of early HIV infection (risk of introducing oncogenes when rearranging immunoglobulin genes)
114
What do all types of amyloid, regardless of clinical setting or chemical composition appear as in electron microscopy, x-ray crystallography and infrared spectroscopy, and with congo red staining respectively?
- Continuous nonbranching fibrils with a diameter of approx 7.5 to 10nm
- cross-B-pleated sheet conformation
- Apple-green birefringence under polarised light
115
What is amyloid?
Abnormal fibrils produced by the aggregation of misfolded proteins which bind to a wide variety of proteoglycans and glycosaminoglycans
116
More than 20 different proteins can aggregate to form amyloid. What are the three major biochemical forms, and how are they initiated?
- Amyloid light chain protein - from monoclonal plasma cells - associated with certain plasma tumours
- Amyloid-associated protein - from (? incomplete) proteolysis of serum amyloid associated protein synthesised in the liver, circulates on HDL. SAA increased as part of acute phase response so associated with chronic inflammation (secondary amyloidosis)
- B-amyloid protein - Derived from proteolysis of amyloid precursor protein. Is core of cerebral plaques in Alzheimer disease and deposited in cerebral blood vessel walls
117
Amyloidosis results from abnormal folding of proteins, which become insoluble, aggregate, and deposit as fibrils in extra cellular tissues. What two general categories can the proteins that form amyloid fit into?
- Normal proteins that have an inherent tendency to fold improperly, associate and form fibrils, and do so when they are produced in increased amounts
- Mutant proteins that are prone to misfolding and subsequent aggregation
118
How can amyloidosis be classified?
- Systemic
- Primary (plasma cell disorders)
- Secondary (reactive i.e. inflammatory)
- Hereditary
- Localised
119
What is an investigational clue, but does not guarantee, for AL/primary amyloidosis?
Unpaired kappa or lambda light chains (Bence-Jones protein) in the serum or urine. Note most patients with myeloma who have this finding do not develop amyloidosis ?to do with variance in light chain aa sequences.
120
What protein is associated with amyloid of aging and a number of heredofamilial amyloidoses?
Transthyretin (TTR) - normal function is binding and transport of thyroxine and retinol
121
How to amyloid deposits cause harm?
They do not evoke an inflammatory response. They cause tissue injury and impair normal function by causing pressure on cells and tissues
122
Describe clinical features that may be present in amyloidosis involving the following systems:
1. Renal
2. Cardiac
3. Gastrointestinal
4. Vascular
1. Proteinuria that may be severe enough to cause nephrotic syndrome. Progressive obliteration of glomeruli that ultimately leads to renal failure and uraemia
2. Insidious CHF. Conduction disturbances and arrhythmias. Occasionally masquerades as chronic constrictive pericarditis
3. Tongue may be sufficiently enlarged and inelastic to hamper speech and swallow. Stomach and intestine may lead to malabsorption and diarrhoea
4. Vascular fragility that can lead to major bleeding from minimal trauma. AL can also sometimes bind factor X, inactivating it.
123
The diagnosis of amyloidosis depends on the histologic demonstration of amyloid deposits in tissues. 1.What are common sites used to look for this and 2. What other tests can be performed?
1.Kidney, rectum, gingiva, abdominal fat aspirates
2. -For suspected AL, serum and urine protein electrophoresis and immunoelectrophoresis as well as bone marrow aspirates looking for monoclonal plasmacytosis.
- Scintigraphy with radiolabeled serum amyloid P component
124
ELISA testing is used to test for HIV and uses colour change from activated enzyme-bound antibodies to indicate results. What are the three types of ELISA tests?
- Indirect (tests for antibody against a known antigen)
- Sandwich (tests for a specific antigen)
- Competitive (gives an indication of the volume of antigen (lighter colour = more)
