Immunopathology Flashcards
1
Q
What are the steps of neutrophils getting into the interstitium and initiating phagocytosis?
A
- Margination (blood stasis)
- Rolling (via selectins on endothelium / sialyl-lewis receptors on leukocytes)
- Adhesion (integrins on leukocytes / ICAM/VCAM on endothelium)
- Transmigration (PECAM-1/CD-31 and collagenases)
- Activation and attachment - via TLRs and receptors for cytokines / opsonins
- Phagocytosis
2
Q
What cells in the tissue release inflammatory cytokines initiating the innate immune response?
A
Mast cells and dendritic cells (note that DCs make IL-1 / TNF)
3
Q
What can be seen in the cytoplasm of natural killer cells, and what two types of killing to they participate in?
A
Large granules - contain perforin / granzymes
- More activating receptors than inhibitory receptors activated (inhibitory receptors activated by MHC Class 1 binding typically, indicating a normal, healthy cell). These theoretically scoop up virally infected cells which CD8+ T cells cannot recognize
- Antibody-dependent cell-mediated cytotoxicity
4
Q
Do NK cells secrete cytokines?
A
Yes - They also secrete IFN-y (stimualte macrophages, which stimulate them by IL-12) and TNF like DCs
5
Q
What are the two arms of the adaptive immune system, and what are they typically directed towards?
A
Cell-mediated - effective against intracellular pathogens (i.e. viruses, intracellular bacteria, fungi, etc)
Humoral / antibody-mediated - targeted against extracellular microbes
6
Q
How does the adaptive system help the innate immune system?
A
While the innate system already has complement and C-reactive protein for opsonization, the antibodies produced by humoral immunity are also effective opsonins for macrophage / PMN phagocytosis. Furthermore, signalling via cytokines from innate immunity also helps increase phagocyte activation.
7
Q
Are T or B cells more mobile? How does the more mobile one get to lymph nodes?
A
T cells - since they must directly interact with cells to have a function (2/3 of all circulating lymphocytes)
Chemokines attract T cells to lymph nodes from the blood stream, and they are naive since they haven’t encountered antigen.
They undergo the normal process of margination / adhesion, etc, and enter through the high endothelial venules in the paracortex region, where they will sit in the paracortex.
8
Q
Where does T cell development occur? What is associated with the receptor?
A
Occurs in the thymus (also they are produced by lymphoid line in the bone marrow)
Associated with TCR is two CD3 receptors, as well as two zeta or two eta chains.
9
Q
Why do CD8 cells require a professional APC for activation if MHC Class 1 is constitutively expressed on all nucleated cells?
A
Professional APC will use its B7 to bind the CD28 co-receptor on T cells to provide the second activation signal, thus activating that CD8 T cell into a T-memory or T-effector cell which can go kill all nucleated cells expressing that ligand on MHC Class 1.
10
Q
What type of MHC do CD4+ T cells bind, and what important cytokines do they secrete / ligands to they express for maturation of the immune response (humoral immunity)? What will result if this ligand is not expressed?
A
Bind MHC Class 2, since 2x4 = 1x8
Secrete IL-2 for clonal expansion of T cells, as well as other cytokines to direct the exact immune response
Important ligand: CD40L -> binds CD40 on B cells to activate a specific class switching, in a specific cytokine environment.
If CD40L or CD40 is deficient -> Hyper-IgM syndrome, with decreased IgA/IgG/IgE because of defective class switching
11
Q
What cytokines does the Th1 subset secrete and what does this do? What causes formation of this subset?
A
Secretes IFN-y -> activates macrophages, induces class switching to IgG, suppresses Th2 response
Induced by macrophages secreting IL-12, IFN-y
12
Q
What cytokines does the Th2 subset secrete and what does this do? What causes formation of this subset?
A
Secretes IL-4, IL-5, and IL-13
IL-4 - Class switching to IgE, inhibits Th1
IL-5 - Eosinophil chemotactic agent
Induced by IL-4, IL-2 from APCs
13
Q
What cytokines does the Th17 subset secrete and what does this do? What causes formation of this subset?
A
Secretes IL-17 -> recruits inflammatory response via neutrophils and monocytes
Induced by TGF-beta in combination with IL-6
14
Q
What are the two types of Treg cells and what cytokines do they release? What causes formation of these subsets?
A
All secrete IL-10 / TGF-beta, which suppress the immune response
Natural T-regs = CD4+,CD25+, FoxP3+ T cells which were developed in thymus, suppress autoreactive T cells
Adaptive regulatory T cells = Originally CD4+ cells which are induced to express CD25 marker in the periphery, typically involved in mucosal immunity (i.e. MALT)
15
Q
What are the two CD8+ killing mechanisms?
A
- Perforin / granzyme pathway of direct killing, also induces apoptosis
- Induction of apoptosis via FasL binding Fas receptors on cell
16
Q
Where do B cells live, and what is a primary vs secondary lymph follicle?
A
They make up less than 1/3 of circulating lymphocytes, living primarily in the cortex of lymph nodes
Primary follicles - small, naive B cells
Secondary - Contain a germinal center with pale area representing replicating B cells which have encountered antigen, undergoing class-switching and affinity maturation
17
Q
What is the sequence of events which results in B and T-cell dependent antigens co-activating these two cell lines.
A
A B cell binds an extracellular antigen via its B cell receptor (immunoglobulin), then internalizes and processes this antigen. It will present a portion of the antigen on its MHC Class 2 (acts as a professional APC).
CD4+ T cell will bind MHC Class 2 if it can recognize the same antigen as that B cell. The B7 of the B cell will bind CD28 on T cell, signalling its activation.
For further maturation of the immune response, CD40L of the T cell binds CD40 receptor on B cells, activating it / inducing class switching.
18
Q
How does Thymic Independent (TI) activation of B cells work, and why is it not always preferable to T cell activation?
A
Certain large peptides like LPS or the pneumococcal capsule sugars can activate B cells in the absence of T cell recognition.
The response will be IgM only (no class-switching is available without T cell help), will generate no memory, and are generally poorly immunogenic. This is why we conjugate the pneumococcal vaccine with an immunogenic protein, so T cell help will activate memory and a sustained immune response.
19
Q
Where do dendritic cells exist and what is their primary function?
A
Widespread in epithelial surfaces and interstitium of tissues, can be recruited to paracortex of lymph nodes via chemokines
-> function to present antigen primarily to CD4 T cells.
20
Q
Where are follicular dendritic cells present and what is their function?
A
Exist in germinal centers of lymphoid follicles, function to hold onto antigens for long periods of time and present these to B lymphocytes, promoting their activation. They sit there and accept antigens from them and hold onto them while they mutate and adapt.
21
Q
What are the 6 HLA / MHC loci and what chromosome do they exist on?
A
Like their number, chromosome 6!
1 letter for MHC Class 1: HLA-A, HLA-B, HLA-C
2 letters for MHC Class 2: HLA-DP, HLA-DQ, HLA-DR
22
Q
What is the function of MHC Class 1?
A
Expresses cytoplasmic proteins (proteins made within the cell). These are degraded on proteasome, transported into the ER via TAP-1/TAP-2, and put into MHC Class 1 molecules on all nucleated cells + PLATELETS.
They present these peptides on the surface of the cell to CD8+ T cells.
23
Q
What cells have MHC Class 2 and what can increase their expression?
A
Located on B cells, dendritic cells, and macrophages, but only constitutively expressed in dendritic cells. Upregulated via IFN-y.
24
Q
What is the function of MHC Class 2?
A
Expresses exogenous antigens which were cleaved in intracelullar vesicles, presenting peptides to CD4+ T cells.
25
How do NK cells activate antibody-dependent cell-mediated cytotoxicity?
Their Fc receptors bind an immunoglobulin which has bound a cell (part of adaptive immune response), and they release perforin / granzymes into the target cell. Can also use FasL death receptor.
26
What is Type 1 Hypersensitivity and what antigen-presenting cells are involved in the sensitization phase? How does this occur?
Immediate Hypersensitivity Reaction
2 APCs involved
1. Dendritic cells - present allergen via MHC Class II, while secreting IL-4 -> turn naive T-cells into allergen-specific Th2 cells, with clonal expansion
2. B cells - bind allergen via their BCR's, internalize, and present via MHC Class II. This further activates Th2 cells
27
Once sensitized Th2 cells are made, how does the sensitization phase of Type 1 hypersensitivity complete?
Allergen-specific active Th2 cells use their CD40L to stimulate class-switching of antigen-specific B cells (via CD40) in the presence of IL-4 stimulation. This creates IgE-secreting plasma cells.
IgE will attach to Fc receptors on basophils and mast cells, ready for next immune challenge.
28
What generally occurs in subsequent exposures of allergen in Type 1 hypersensitivity (following sensitization)?
1. Eosinophil development, recruitment, and activation (via IL-3, IL-5, and GM-CSF)
2. Cross-linking of IgE on mast cells / basophils, with activation and degranulation
29
What mediates the immediate reaction in Type 1 Hypersensitivity?
1. Biogenic amines -> histamine
2. Chemotactic factors for eosinophils
3. Enzymes (i.e. proteases)
4. Proteoglycans, which account for the metachromatic staining of basophils / mast cells
30
What two processes mediate the late phase reaction of Type 1 hypersensitivity?
1. Activation of phospholipase A2.
From arachidonic acid: make leukotrienes B4,C4, and D4 and PGD2 from cell membrane
From phospholipids: makes platelet-activating factor.
2. Secretion of cytokines/chemokines: i.e. IL-4, IL-5, TNF, and IL-1 -> proinflammatory and pro-TH2.
31
What are the major histopathologic findings of someone with chronic Type 1 hypersensitivity reactions?
As in asthma:
1. Bronchial smooth muscle contraction leading to hyperplasia
2. Increased respiratory glandular secretions (PSCC -> goblet cells via mucinous metaplasia)
3. Infiltration of chronic inflammatory cells, especially eosinophils
4. Exudative edema due to increased vascular permeability / vasodilation
32
What are the clinical features that can result from increased vasodilation, increased edema, bronchoconstriction, and increased glandular / mucinous secretions?
Vasodilation -> localized erythema which may cause shock
Edema -> hives on skin, or nasal / laryngeal edema
Bronchoconstriction -> wheezing / airway constriction following bronchospasm
Glandular / mucinous secretions -> rhinorrhea and even mucous plugs
33
What must antibodies be reacting to to constitute a Type II hypersensitivity reaction?
Antibodies bind to a fixed cell surface or tissue antigen.
The tissue antigen can be native to the tissue, or adsorbed onto the tissue (i.e. a microbial product or a drug like penicillin)
34
What are the ways in which a cell can be phagocytosed in Type II hypersensitivity?
Both are facilitated an antibody binding a cell antigen (definition of type 2 hypersensitivity)
1. Fixation of complement following the cascade, via C3b receptors
2. Direct target phagocytosis using immunoglobulin Fc as receptors.
35
Other than opsonization, give two other ways complement can cause tissue damage in T2 hypersensitivity?
1. Cell lysis -> formation of MAC
| 2. Acute inflammation leading to tissue injury -> via C3a / C5a anaphylatoxins
36
Name those two Type II hypersensitivity diseases.
1. Antibodies to epidermal desmosomes
2. Antibodies direct against glomerular and pulmonary basement membranes
1. Pemphigus vulgaris
| 2. Goodpasture syndrome
37
Other than complement mechanisms, give to other broad categories of Type II hypersensitivity mechanisms.
1. Antibody-dependent cell-mediated cytotoxicity (ADCC)
| 2. Antibody-mediated cellular dysfunction
38
How does ADCC work? Give one example.
Antibody binds target cell, facilitates killing of the cell via natural killer perforin/granzymes pathway.
Example is killing of tumor cells in cancer
39
What is the difference between ADCC and antibody-mediated cellular dysfunction? Give two examples of the latter.
Antibody-mediated cellular dysfunction does not cause cell death, just impairs the function of the cell.
1. Myasthenia gravis - antibodies to Ach receptors in motor end plate
2. Graves disease - antibodies which stimulate TSH receptors on thyroid follicular cells
40
What is the definition of Type III hypersensitivity?
Immune complexes form and deposit in tissues, or the immune complexes form when antigens get lodged in tissues.
These immune complexes cause activation of complement once deposited, which mediates the tissue injury via influx of acute inflammatory cells.
41
What is the main difference between Type II and Type III hypersensitivity?
Type III hypersensitivity is forming immune complexes to a SOLUBLE antigen, which may be circulating or planted
Complement will ALWAYS be involved in tissue damage.
42
What are some examples of exogenous antigens which can cause Type III hypersensitivity?
Microbial antigens
Drugs
Animal serum (serum sickness)
43
What types of "self" antigens can generate type III hypersensitivity?
Things that are soluble -> i.e. nuclear antigens in lupus.
Will fix complement and mediate cellular damage.
Also cancer cells, if mechanism is not ADCC (which would be a type II hypersensitivity), but rather complement
44
What is an example of a local Type III hypersensitivity and how does it work?
Arthus reaction -> antigen is injected, circulating antibody neutralizes it and forms immune complexes directly in the area where the antigen was injected. Complement is fixed in tissues and a skin rash is formed.
45
How can an exogenous antigen cause systemic immune complex disease? What factors control the rate of deposition
Example: serum sickness
Controlled by factors of 1. the immune complex: how large, the charge, the structure, as well as 2. host factors (how well are phagocytes clearing these immune complexes)
46
Where in the body do immune complexes tend to deposit and why?
Areas where the complexes are present or being filtered
i.e.
Small / medium sized vessels -> complexes lodged from blood stream
Renal glomeruli -> where complexes are filtered out and get lodged in basement membrane
Joints -> synovial fluid made as an ultrafiltrate of plasma
Skin
47
What initiates the tissue damage in Type III hypersensitivity?
Everything initiated by complement, including vasodilation, increased vascular permeability, opsonization, chemotaxis of inflammatory cells, and cell lysis by MAC
48
What causes secondary damage following complement in Type III hypersensitivity?
Degranulation and ROS via PMNs and macrophages, with resultant endothelial damage and activation of primary / secondary hemostasis and coagulation cascade.
49
What histologically characterizes Type III hypersensitivity?
Typically fibrinoid necrosis of small to medium-sized blood vessels from chronic activation of the clotting cascade -> deposition of fibrin in vessels
This will be accompanied by acute inflammatory cells, edema / hemorrhage, and possible thrombosis of vascular lumen
50
How can Type III hypersensitivity lead to ischemic necrosis?
Lodging of immune complexes in blood vessels with formation of vascular luminal thromboses cause clotting which reduces blood supply to a tissue.
-> ischemic / coagulative necrosis results
51
What laboratory visualizing techniques are commonly utilized to assess presence of antibody complexes in tissues?
1. Most common - Direct immuno-fluorescence (anti-Ig or anti-complement)
- > antibodies are tagged with fluorescent marker
2. More rarely -> electron-dense deposits on electron microscopy
52
Give two examples of type III hypersensitivity disease.
1. Acute poststreptococcal glomerulonephritis
| 2. Systemic lupus erythematosus (SLE)
53
What are the two types of Type IV hypersensitivity? Give two examples of each.
1. Delayed-type hypersensitivity
- > contact dermatitis due to poison ivy (atopic dermatitis is Type 1)
- > tuberculosis skin testing
2. Cytotoxic T-cell mediated hypersensitivity.
- > Graft-versus-host disease
- > Hashimoto's thyroiditis
54
What are the two phases of delayed-type hypersensitivity, and what happens in the first phase?
1. Sensitization phase -> APC presents peptide via MHC Class II to response CD4+ T cell, becomes Th1 cells via stimulation via IL-12. This takes 1-2 weeks.
2. Effector phase - happens after 1-2 days following secondary exposure
55
How does the sensitization phase of Type IV hypersensitivity differ from Type I hypersensitivity?
Type I hypersensitivity - IL-4 stimulates CD4 differentiation into Th2 cells, which facilitate B cells to make IgE
Type IV hypersensitivity - IL-12 stimulates CD4 differentiation into Th1 cells, which facilitate secretion of IFN-y
56
What occurs in the effector phase of Type IV hypersensitivity?
1. Activation and proliferation memory Th1 cells
- > secrete IFN-y, IL-2, TNF, and chemokines to recruit monocytes
2. Monocytes are activated to M1 macrophages via IFN-y, and stimulate further Th1 proliferation via their IL-12. More TNF, IL-1, and chemomkines are made.
57
What are the initial and late histopathological findings of Type 4 hypersensitivity effector phase?
1. Initial -> diffuse infiltrate of Th1 cells
2. Later -> collections of activated macrophages, surrounded by Th1 lymphocytes. This is the granulomatous inflammation we know and love.
58
What is the pathogenesis of the cytotoxic T cell-mediated hypersensitivity (a subset of Type 4)?
APC like macrophage or dendritic cell presents via MHC Class 1 a cytoplasmic peptide of a cell class you don't want killed.
CD8 T cells begin killing good cells via perforin / granzymes or Fas/FasL pathway (i.e. Type 1 diabetes, Hashimotos, Graft-vs-host)
59
What is the direct pathway of graft recognition?
Usage of donor's APCs to stimulate host CD4 or CD8 T cells via the proper MHCs to result in activation
1. CD8 cells are activated by cytoplasmic peptides of the graft APCs being presented on MHC Class I, which are recognized as foreign by the receipient's T cells.
2. CD4 T cells are activated by APCs presenting any extracellular peptides on MHC Class II, thus allowing recognition of donor MHC.
60
What is the effect of the direct pathway in terms of graft rejection?
Results in acute rejection (cell-mediated)
CD8 T cells directly kill graft cells
CD4 T cells activate macrophages via IL-2 and IFN-y and amplify the inflammatory response, leading to graft damage
61
What seems paradoxical about the direct pathway of graft rejection?
Our T cells should not be able to be activated by another person's MHC -> there must be some molecular mimicry going on where foreign MHC + foreign peptide looks somewhat like self MHC.
62
What is the indirect pathway of graft recognition important for, and which type of T cell participates? Why?
Important for development of chronic rejection
CD4+ T cell participates, but not CD8 T cell since the indirect pathway relies on host APCs presenting to T cells. Host APCs will not be able to present graft material as intracellular / cytoplasmic foreign material, only extracellular (CD4 pathway only).
63
What type of hypersensitivity are the indirect and direct pathways of graft rejection?
All type-4, cellmediated hypersensitivities.
Only the direct path contains CD8+ T cells which participate in Cytotoxic T-cell mediated hypersensitivity, the rest are CD4+ delayed-type hypersensitivities.
64
What causes hyperacute rejection, and what provides the prior sensitization stimulus?
When the recipient has preformed antibodies towards donor antigens
-> can be due to previous transplant, blood transfusions (contain WBCs), or pregnancies
65
How does acute humoral rejection differ from hyperacute?
Acute humoral rejection involves newly-formed antibodies in the recipient directed against the graft, overtime. Requires T cell help for the most part, and normally days to weeks later weeks to manifest.
66
What type of hypersensitivity is hyperacute graft rejection, and what does it look like?
It is a type 2 hypersensitivity (tissue antigen, insoluble), looks like type 3 because of high levels of complement deposition in tissues, but it's the donor's tissues.
- > edema
- > acute inflammatory infiltrate
- > endothelial cell damage, fibrinoid necrosis, hemorrhage, and thrombosis
- > tissue infarct
67
What are the symptoms of acute rejection of kidney transplant?
Increased serum creatinine, decreased urine output, and development of renal failure days to weeks after transplantation / reduction in immunosuppression
68
What are the two primary mechanisms of acute rejection, and which is more easily treatable?
1. Cell-mediated - due to T-cell overactivity (from direct pathway)
- > easily treated by increasing immunosuppression (most immunosuppressives effective against T-cell proliferation)
2. Humoral - due to antibodies formed after transplantation. More difficult to treat.
69
How does acute, cell-mediated rejection appear histologically?
Interstitial inflammatory infiltrate with T cells and macrophages, injuring tubules (tubulitis) and vascular endothelium (endothelitis and edema)
70
How does acute, humoral rejection appear histologically? There are really two presentations here, and one is more common.
Since it is due to antibodies, it usually appears exactly like hyperacute rejection (just later).
1. Most common - A type 2 hypersensitivity which looks like type 3 w/ associated vasculitis and fibrinoid necrosis.
2. Alternatively, can present with vascular intimal thickening via foamy macrophages which are recruited by antibodies which cannot fix complement (low avidity). Fibroblasts and SMCs will proliferate due to cytokine production and lead to tissue atrophy. Not associated with vasculitis, more vessel stenosis by thick intima.
71
What is the timescale of chronic rejection and what lab values are associated with it?
Typically years after transplantation, may follow acute rejection which did not resolve, multiple resolved acute rejections, or indolent course without any past history of rejection.
Associated with: slowly increasing serum creatinine
72
What immunologic mechanism is behind chronic rejection?
Indirect pathway of CD4+ T cell activation
-> activated macrophages and APCs present alloantigens from broken down graft / areas of ischemia, which leads to further T cell activation and subsequent inflammation & breakdown of graft for more antigen presentation.
73
What are some non-immunologic mechanisms of graft rejection?
1. Insufficient nephron mass (small kidney in bring person leading to glomerular hyperfiltration)
2. Reperfusion injury at engraftment
3. Infections due to immunosuppressive therapy
4. Immunosuppressive drug toxicity
5. Increasing age of recipient with atherosclerosis / hypertension
74
What are atubular glomeruli?
A mechanism of graft breakdown whereby autoimmune destruction of the tubules will lead to loss of glomeruli which supply them
75
What is the dominant pathologic feature of chronic graft rejection?
Scarring -> vascular fibrosis with intimal thickening, interstitial fibrosis, tubular atrophy, and chronic inflammatory infiltrate.
-> fibroblasts and interstitial fibrosis aplenty
76
What is the most important thing to prevent hyperacute rejection?
ABO blood group compatibility
| -> check this to make sure graft won't be instantly rejected due to blood in it when you first put it in
77
Other than ABO compatibility, what three things are done to prevent solid organ transplant rejection?
1. HLA matching (especially in renal transplants)
2. Immunosuppressant therapy
3. Induction of immune tolerance by using agents which selectively block co-stimulatory molecules, inducing anergy
78
Can antibodies play a role in chronic rejection?
Yes, if Th1 cells stimulate the proliferation of B cells.
79
What mediates transplant rejection in allogeneic hematopoeitic stem cell transplant?
Recipient's surviving T cells and NK cells (immune system is supposed to be ablated prior to transplantation)
80
Give two reasons why a little bit of graft versus host disease (GVHD) might be good?
1. Reduces chances of graft rejection -> remaining recipient T cells which were not ablated will be killed by the donor's immune system
2. Donor cells are often given in malignancy conditions, and if the graft immune system can recognize the host tumors, it can serve better anti-tumor properties
81
What are the common manifestations of GVHD in terms of which tissues are affected?
1. Skin -> often maculopapular rash acutely, with dermal fibrosis chronically
2. Liver - often jaundice due to injured bile ducts
3. Mucosal surfaces like GI tract, eyes, and mouth can be damaged leading to N/V, eye dryness
4. Lymphoid organs -> destruction of thymus and LN
82
What is central tolerance? What different processes do T / B cells undergo? What must occur if these mechanisms fail?
Prevention of auto-reactivity of T-cells or B cells during the maturation process within the primary lymphoid organs.
T cells will be eliminated via apoptosis, with a small amount becoming Tregs
B cells will be eliminated via apoptosis in the bone marrow, undergo anergy, or may undergo receptor editing (via light chain editing)
If these mechanisms fail - need peripheral tolerance to prevent autoreactivity (backup systems in the periphery)
83
How does peripheral anergy of T cells occur?
T cell binds MHC + self antigen, and does not see a costimulatory signal, or its CD28 binds an inhibitory signal (CTLA4 rather than B7)
84
How does peripheral anergy of B cells occur?
Usually due to lack of self-reactive helper T cells.
85
How are T cells suppressed by Tregs?
T-regs recognize that self-antigen is being bound, and locally release regulatory cytokines, suppressing this autoreactivity (Remember that Tregs have intermediate self-antigen reactivity)
86
How does activation-induced cell death of T-cells occur?
Initially, T-cells are resistant to Fas-mediated apoptosis. However, as they become overactive, they will T cells will overexpress Fas / FasL, allowing for paracrine / autocrine deletion via apoptosis.
87
What are a few immune-privileged areas, and how do they deal with the immune system targeting self-antigens there?
Brain, testes (brain-testis barrier via sertoli cells), and eyes (prevent clouding of cornea)
Two main mechanisms
1. Hiding of self antigen
2. Expression of FasL on tissues to induce apoptosis in any cell that comes near.
88
What are genetic factors that can lead to loss of tolerance?
Usually, expression of problematic MHC molecules, or loss of a self-tolerance mechanism due to a single gene mutation
89
How can a microbial infection initiate an autoimmune reaction?
1. Increases expression of co-stimulatory molecules on APCs which are also presenting self antigen.
2. Creating an immunologic cross-reaction via molecular mimicry (amplification of autoreactive T cells), as in S. pyogenes infection
90
How can autoimmune conditions become progressively worse after initiation?
Via the process of epitope spreading -> antigens not normally seen without tissue damage will become expressed, further continuing lymphocyte activation vs self-antigens
91
Who is typically diagnosed with systemic lupus erythematosus?
African American Women in their early 20s.
92
What two auto-antibodies are very specific but not sensitive for SLE?
1. Anti-dsDNA
| 2. Anti-Smith antigen
93
How can inherited complement deficiencies predispose to SLE T3 hypersensitivity?
RBCs express C4 receptors. When in circulating, immune complexes can attract the early stages of complement cascade, and the C4 component can stick to these RBCs, clearing them out of circulation when they get to the spleen.
If you have complement deficiencies, these Ab complexes cannot be cleared as well -> worse autoimmune manifestions
94
What are some environmental triggers of SLE?
Certain medications (i.e. hydralazine, drug-induced lupus)
Exposure to UV radiation -> exposes nuclear antigens in the epidermis.
95
What is the general pathogenesis of SLE? Include the three major classes of antibodies which are formed.
Loss of self-tolerance and activation of auto-reactive CD4+ T cells -> activation of B cells specific to self antigens.
1. Anti-nuclear antibodies (ANAs)
2. Antibodies vs formed blood elements (RBCs, platelets, WBCs)
3. Antiphospholipid antibodies
96
What are the clinical manifestations of these three antibody types? What type of hypersensitivity are these, when relevant?
1. Anti-nuclear antibodies (ANAs) - immune complex formation in small blood vessels (i.e. glomeruli) - Type III hypersensitivity
2. Antibodies vs formed blood elements (RBCs, platelets, WBCs) - anemia, thrombocytopenia, or leukopenia (Type II hypersensitivity)
3. Antiphospholipid antibodies
- > delayed coagulation in vitro -> lupus anticoagulant antibodies
- > hypercoagulability in vivo -> antiphospholipid antibody syndrome
97
What does SLE do to your arteries?
Type 3 hypersensitivity -> Leads to fibrinoid necrosis & inflammation, with fibrous scarring in multiple organs
-> can even lead to non-inflammatory occlusions especially in kidneys and CNS (i.e. strokes) due to antiphospholipid antibodies predisposing to thrombus formation
98
What kidney condition does SLE cause and why?
Diffuse proliferative glomerulonephritis, due to Type 3 hypersensitivity, and resultant fibrinoid necrosis, acute inflammation, and thrombosis
99
What are "wire loops" of SLE?
Very thick glomerular capillaries seen in SLE due to extensive immune complex deposition
100
What is the most common type of skin involvement for lupus? Why?
Erythematous rash on the face (butterfly / malar rash) -> sun exposure areas receive UV radiation damage and expose the epidermal nuclear antigens
101
Where do antibodies tend to get stuck in the skin and what does this cause on a histological level?
Usually get stuck at the dermo-epidermal junction, especially affects basal cells - can be seen by direct immunofluorescence
-> this is often associated with some dermal vasculitis (T3 hypersensitivity)
102
How will direct immunofluorescence findings differ between systemic and local lupus syndromes?
Systemic -> immune complexes will be deposited at DE junctions even where there's no rash
Local -> complex deposition will only occur where there is active pathology
103
Other than skin, kidneys, and arteries, give a few other places where immune complexes are known to cause problems in lupus?
1. Joints -> ultrafiltrate of plasma, type 3 hypersensitivity
2. Serosal surfaces -> fibrinous inflammation of peritoneum and especially pericardium
3. Heart -> especially valves (vegetations) and pericardium (pericarditis)
104
How does lupus predispose to atherosclerosis, especially coronary arteries?
High levels of constant inflammation -> elevated C-reactive protein = risk factor for atherosclerosis
105
How are lymphoid organs affected by lupus?
Follicular hyperplasia in lymph nodes and spleen due to increased number of plasma cells
106
How is lab detection of anti-nuclear antibodies different than detection of antibody-complexes present within tissues normally? Is this test specific or sensitive?
Uses indirect immunofluorescence -> use patient's serum on cells with exposed nuclei, then apply fluorescently tagged anti-immunoglobulins
Sensitive but not specific -> lupus almost always associated w/ positive ANA, just don't know which Ab
107
What are two common, nonspecific patterns of fluorescence via the ANA indirect immunofluorescence test?
1. Homogenous pattern -> antibodies to diverse nuclear complements including DNA
2. Speckled pattern -> antibodies to non-DNA nuclear components (i.e. Smith antigen)
108
What does a rim (peripheral) pattern mean via the ANA indirect immunofluorescence test?
Very specific pattern for SLE -> antibodies to dsDNA
109
What does a nucleolar pattern mean via the ANA indirect immunofluorescence test?
Seen in systemic sclerosis normally -> antibodies to nucleolar RNA
110
What does a centromere pattern (with glowing of the mitosis / division) mean via the ANA indirect immunofluorescence test?
Seen in limited system sclerosis (CREST syndrome)
111
When is specific ANA characterization done?
Following a positive IF-ANA test
| -> more expensive, can tell if anti-dsDNA or anti-Smith specifically
112
What lab value do antiphospholipid antibodies elevate, and what test will be interfered with due to their presence?
1. Prolonged aPTT (contact activator, intrinsic pathway)
2. Syphillis test - FTA-ABS -> will react with cardiolipin, seem as nonspecific antibodies generated in syphillis infection.
113
What are LE cells / hematoxylin bodies?
An old test for lupus -> can shake up patient's anticoagulated blood.
If you see neutrophils or macrophages which have eaten nuclei of injured cells from shaking (nuclei were opsonized by ANAs) -> they have lupus
LE cell = Lupus erythematosus cells
114
What are common general complaints / clinical findings in lupus? How is it treated?
Fever, malaise, malar rash, joint pain, hematuria / RBC casts, proteinuria
Treated with immunosuppressants
115
What is the highly local lupus variant, and what are its clinical manifestations? How do lesions appear grossly and microscopically?
Chronic discoid lupus erythematosus -> a scarring dermatosis
Involvement of sun-exposed skin on face and scalp, with no antibodies in non-lesional skin
116
How do lesions of chronic discoid lupus erythematosus appear grossly and microscopically?
Lesions will appear as scaly skin plaques with red border, and will form scars.
Microscopically, there will be epidermal atrophy, and chronic inflammation around the DE junction (involves basal cells)
117
How does subacute cutaneous lupus erythematosus differ from chronic discoid lupus erythematosus?
Different ANA antibodies cause it, and it results in a mild, non-scarring rash.
Importantly, it will also have some systemic manifestations (not totally local)
118
Does drug-induced lupus go away after the drug is removed? Will there be ANAs?
Yes - it goes in remission
And yes, there will be ANAs, although not anti-dsDNA or anti-Smith
119
What is Sjogren syndrome and its two forms? What is the secondary form commonly associated with?
Chronic autoimmune disorder of lacrimal and salivary glands, common in middle-aged women
Primary - sicca syndrome (dry eyes / mouth)
Secondary - associated with another immune disease -> especially rheumatoid arthritis
120
What are antibodies typically direct against in Sjogren syndrome?
Rheumatoid factor (in secondary) and ribonucleoproteins SS-A (Ro) and SS-B (La)
SS = Sjogren syndrome
121
What are the early and late manifestations of Sjogren syndrome in lacrimal / salivary glands?
Early - lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia
Late - Glandular fibrosis / atrophy
122
Other than lacrimal / salivary glands, what other surfaces can be affected in Sjogren's syndrome?
1. Mucosal surfaces like cornea, mouth, and nose
- > ulceration and inflammation secondary to drying (loss of lacrimal / salivary glands)
- keratoconjunctivitis sicca in eyes
- xerostomia of the mouth
2. Enlargement of parotid gland (secondary to lymphocyte buildup)
123
What condition do these autoimmune conditions like SS and SLE predispose you to because of stimulation of B cell proliferation?
B cell lymphomas
124
What characterizes systemic sclerosis (scleroderma) and what are the two broad types?
Excessive fibrosis, affecting middle-aged women
1. Diffuse systemic sclerosis
2. Limited systemic sclerosis
125
What is diffuse systemic sclerosis?
Rapidly progressing variant
| -> initial involvement of skin, followed by abnormalities in many visceral organs
126
What is limited systemic sclerosis?
Slowly progressing variant, confined to skin of face / distal upper extremities
-> does not extensively involve visceral organs
127
What is CREST syndrome?
A subset of limited systemic sclerosis, characterized by:
```
Calcinosis
Raynaud phenomenon
Esophageal dysmotility
Sclerodactyly
Telangectasia
```
128
What causes sclerodactyly?
Skin gets very tight due to scarring and contracture, which leads to warping of the hands
129
What ANAs are fairly specific for diffuse systemic sclerosis and CREST syndrome?
Diffuse systemic sclerosis - anti-Scl 70 (DNA topoisomerase I)
CREST syndrome - anticentromere antibody
130
How do T cells contribute to the pathogenesis of systemic sclerosis?
1. Stimulation of B cells for ANAs
2. Secretion of growth factors for fibroblasts -> excessive collagen production
3. Secretion of inflammatory cytokines which lead to persistent injury of microvascular endothelium
131
How does microvascular damage contribute to worsening of systemic sclerosis?
Increases platelet activation, release of growth factors for fibroblasts -> excessive collagen production
Over time, fibrinoid necrosis w/ vessel narrowing can result in tissue ischemia, resulting in more necrosis and scarring
132
Where is the skin affected first in systemic sclerosis, and what is the worse possible manifestation of this?
Affected first in distal upper extremities (then face and upper trunk)
-> worst manifestation is autoamputation due to extensive scarring and microvascular hyalinization -> ischemia
133
What does systemic sclerosis do the GI tract?
Collagenization of wall with muscular atrophy
Esophageal dysmotility results (especially in CREST), as well as GE reflux
Can also impair absorption.
134
What part of the kidney is affected in systemic sclerosis and what systemic effect can this cause?
Affects the afferent arterioles due to excessive fibroblast proliferation -> leads to stenosis of the intima
Decreased renal blood flow will lead to increased renin-angiotensin-aldosterone pathway
-> high blood pressure
135
Why does epidermal atrophy occur in the skin in systemic sclerosis?
Because involvement of the vessels with excess collagen production and fibroblast proliferation + fibrinoid necrosis, microvasculature will be injured and decrease blood flow.
Cells will atrophy in response to this.
136
What are the two most problematic manifestations of systemic sclerosis now?
1. Lungs - Pulmonary interstitial fibrosis -> pulmonary hypertension
2. Heart - myocardial fibrosis with possible pericarditis
137
What are the three primary clinical features of Mixed Connective Tissue Disease? What feature is notably not present?
1. SLE characteristics - fever, cytopenias
2. Systemic sclerosis characteristics - Hand swelling, Raynaud phenomenon, esophageal dysmotility, pulmonary interstitial fibrosis
3. Polymyositis - inflammation of muscles
Actually minimal kidney involvement as well despite SLE / Scleroderma manifestations
138
What antibody is associated with Mixed Connective Tissue Disease, and what is the treatment?
anti-U1 RNP (a ribonucleoprotein)
Treatment: Corticosteroids -> responds quite well.
139
What types of infections B cell deficiencies predispose you to?
B cell - infections with pyogenic bacteria which are often encapsulated, certain viruses (i.e. enteroviruses, hepatitis, polio), and intestinal parasites like Giardia
140
What types of infections do T cell deficiencies predispose you to?
T cell - viruses, fungi, intracellular bacteria, and protozoa
141
What is typically the cause of impaired humoral immunity in SCID?
Secondary to abnormal T-cell functioning (abnormal differentiation or activation)
->however, may be a bone marrow stem cell defect
142
What is the most common cause of SCID? Its pattern of inheritance?
X-linked
- > due to a defect in IL-2 receptor gamma-chain.
- > deficient T cell proliferation
143
What is the second most common cause of SCID? Its pattern of inheritance?
Autosomal recessive
- > Adenosine deaminase (ADA) deficiency
- > involved in metabolism of purines, leads to accumulation of metabolites which inhibit DNA synthesis and are toxic to developing T cells (5' nucleotidase deficiency)
144
How is ADA deficiency treated?
With gene therapy -> harvest patient's bone marrow, use a retroviral vector to "transfect" stem cells with normal ADA gene, expand infected cell line it in vitro, and infuse back into the patient
145
What are the anatomic features of SCID?
Systemic lymphoid tissue is absent or hypoplastic
Thymus is underdeveloped and lacking lymphoid cells. Lacks thymic (Hassel's) corpuscles.
146
Does SCID always present with severe lymphopenia?
No, depending on the defect there will occasionally be normal lymphocyte counts but they are dysfunctional
147
Why will patients with SCID often have scant amounts of IgG in their blood when diagnosed?
Diagnosed as infants -> will have some IgG transferred from their mother passively across the placenta
148
Give two ways in which SCID patients can develop graft-versus-host disease?
1. Transplacental transfer of maternal T cells -> no immune system to fight it
2. Blood transfusion -> make sure to inactivate T cells by first irradiating blood products
149
What is the treatment for SCID, and how to we prevent GVHD?
Early allogeneic stem cell transplant (before 1 year)
- > prevent via depletion of mature T cells in donor sample (will be active against recipient HLA)
- > all new T cells will develop properly in the patient's thymus
150
What will be absent in the immune defect of DiGeorge Syndrome?
Since it affects the development of the 3rd and 4th pharyngeal pouches
- > Thymus will be affected (will be absent or very small)
- > little T cell maturation can occur
- > B cells will be unaffected
151
What anatomical defects are present in DiGeorge syndrome (22q11)? Include non-immunologic things
1. Hypoplastic or absent thymus
2. Absent or rudimentary parathyroid glands -> tetanus due to hypocalcemia secondary to increased neuronal excitability
3. Congenital defects of heart
4. Facial deformities (small mouth / chin)
152
What infections is a DiGeorge patient susceptible to?
All infections requiring cytotoxic or delayed hypersensitivity
->viral, fungal, and TB infections
(serum Ig levels, and antibody response to most bacteria is normal assuming there's any T function at all)
153
What is the treatment for DiGeorge?
Transplantation of fetal thymus or thymic epithelium, but this is often not needed since there is enough thymus remaining to seed the remaining gland
154
What causes Bruton's Agammaglobulinemia and what is the mode of inheritance?
X-linked -> seen mostly in males
Caused by BTK mutations (B-cell tyrosine kinase) which is required for maturation from pre-B cells to B cells.
155
What will be the anatomical consequences of Bruton's agammaglobulinemia (XLA)?
Absent B cells in blood / lymphoid tissues (but normal pre-B cells in bone marrow)
Germinal centers absent, tonsils poorly developed
Lack of plasma cells!
Virtual absence of serum Igs with normal T cell function
156
What are the pyogenic bacterial infections that Ig deficiency will lead you to?
S. aureus, S. pneumoniae, H. influenzae
157
What is the treatment for XLA?
Periodic gamma globulin infusions
158
What disorders are associated with XLA and why?
Arthritis and autoimmune diseases like lupus-like disorders (the few autoreactive B cells that make it into the periphery may become active due to defective BTK signalling (required for destroying sell-reactive B-cells))
159
What causes Hyper IgM syndrome and what lab values will be associated? What is the mode of inheritence?
```
X-linked
Defect in CD40L required for class switching
```
Associated with normal or high IgM, and low IgA, IgG, and IgE (AGE)
160
What is the most common primary immunodeficiency? How do you get it?
Selective IgA deficiency
Can be congenital or acquired (toxoplasmosis, viral infections, drug exposures)
161
What is one important consideration when treating someone with selective IgA deficiency?
~40% will have serum antibodies to IgA
- Most are IgG and would just cause serum sickness, but some have IgE which can cause anaphylaxis
162
What types of infections are those with secretory IgA deficiences susceptible to?
Sinopulmonary infections (mucosal immunity) and diarrhea (GI - mucosal immunity to Giardia, enteroviruses)
163
What disorders are associated with selective IgA deficiency?
Increased respiratory allergies, autoimmune diseases like RA / SLE, and Celiac disease
164
What is common variable immunodeficiency (CVID)? How does it differ from the other similar condition?
The common variable is "hypogammaglobulinemia"
- > group of heterogeneous disorders which decrease Ig's sometimes only IgG
- > differs from Bruton's because it is autosomal recessive and not X-linked
(seen in girls now)
-> also tends to be diagnosed much later than Bruton's, in teenage years
165
For common variable immunodeficiency, is a B-cell deficit always present? What is it normally? How could it not be present?
Normally a defect to differentiate into plasma cells to produce antibody
B cell deficit does NOT need to be present -> can just be T-cell disorder with excessive immunosuppression or failure to help develop Abs.
166
What finding is common in lymphoid tissue in the duodenum due to CVID?
Nodular lymphoid hyperplasia -> persistent antigen stimulation of B cells, but plasma cells are absent
167
Why are non-caseating granulomas present in CVID?
Pyogenic bacteria which cannot be neutralized via antibodies must be surrounded by T-cells and macrophages
168
What disorders are associated with CVID, and what is the treatment?
Autoimmune disorders like RA, and B-cell lymphomas
-> treatment: periodic IV immunoglobulin (same as XLA)
169
What is the diagnostic triad of Wiskott-Aldroch syndrome?
```
WATER
Wiskott
Aldroch
1. Thrombocytopenia
2. Eczema
3. Recurrent infections (immunodeficiency)
```
170
What causes Wiskott-Aldroch Syndrome?
Mutation in WASp, which functions in reorganizing cytoskeletal actin.
This is required for B cell, T cell, and platelet function
171
Early on, what type of infection are Wiskott-Aldroch patients susceptible to? What poses their greatest risk of death?
Susceptible to encapsulated pyogenic bacterial infection (poor polysaccharide antibody response, peptide is okay)
-> Bleeding risk due to low, small platelet count risks death
172
What happens in WA patients as time goes on?
Progressive depletion of lymphocytes in blood and T-cells as well -> loss of cellular immunity (was present before)
173
What is the treatment and associated disorders with WA?
Treatment - stem cell transplant
Associated - Lymphoma
174
What causes Ataxia-Telangectasia?
Autosomal recessive defect in ATM gene
| -> unable to repair double-strand DNA breaks
175
What is the diagnostic quad of ataxia-telangectasia?
4 A's
Cerebellar Ataxia
spider Angiomas (telangectasia)
IgA deficiency -> sinopulmonary infections
elevated Alpha-fetoprotein (impaired organ development)
176
Why is there variable immunodeficiency in ataxia-telangectasia?
DNA breaks are required for antigen-receptor splicing in immune cells
177
What causes LAD-1?
CD18 defect, an integrin required for phagocyte adhesion, migration, and chemotaxis
Autosomal recessive
178
What are the clinical manifestations of Leukocyte Adhesion Deficiency (LAD-1)?
Recurrent skin / mucosal bacterial / fungal infections, lack of pus formation (neutrophils cannot migrate out), leukocytosis from high neutrophils in the blood, impaired wound healing, and periodontal disease
179
What are bare lymphocyte syndrome types II and III a subset of, and what causes them?
Subset of autosomal recessive SCID
-> caused by a deficiency in Class II MHC molecules, and markedly impaired cellular and humoral immunity, predisposing to all infections.
180
What causes Chronic Granulomatous Disease (CGD)? How is it inherited?
Defect in NADPH oxidase to generate superoxide anion for respiratory burst
- > need to make HOCl from H2O2 and MPO
- > Mostly X-linked recessive, but 1/3 autosomal recessive
181
How are lesions in chronic granulomatous disease histologically unique?
Central core of neutrophils surrounded by a T-cell / macrophage lymphoma
-> can't kill the bacteria via ROS, but can surround and contain the infection in granulomas of subcutaneous tissue
182
What organisms are most dangerous for CGD?
Catalase-positive bacteria
183
What are two tests for diagnosis of CGD?
1. Dihydrorhodamine (DHR) flow cytometry test -> CGD neutrophils can't oxidize DHR to fluoresce rhodamine
2. Nitroblue tetrazolium (NBT) -> CGD neutrophils can't turn yellow NBT to insoluble, black NBT
184
What is the treatment for CGD?
gamma-interferon (not well understood, probably makes neutrophils better at using non-oxidative pathway)
185
What causes Chediak-Higashi (CH) syndrome and what is the pattern of inheritance?
Autosomal recessive
Lysosomal trafficking regulator protein dysfunction
186
What happens to granular cells in CH?
They have giant granules due to fusion of cytoplasmic granules (defective lysosomes)
187
What happens to neutrophils in CH and why is this relevant ?
Enlarged lysosomes with impaired neutrophil function -> poor phagolysosome formation and bactericidal activity
-> recurrent pyogenic infections
188
What happens to the skin in CH?
Giant melanosomes in melanocytes -> partial albinism due to poor spreading of melanin
189
What happens to platelets in CH?
Abnormal dense bodies -> mild bleeding tendency
190
How is the nervous system affected in CH?
Progressive dysfunction and peripheral neuropath, not well understood (likely microtubule dysfunction)
191
What will C1, C2, and C4 deficiencies cause?
Poor clearing of immune complexes via C4 receptors on RBCs -> autoimmune or immune complex diseases (like SLE glomerulonephritis)
-> MBL and alternate pathway will still allow for MAC killing
192
What will C3 deficiency cause?
Frequent, serious pyogenic infections
193
What will C5-9 deficiencies cause?
Recurrent, disseminated Neisseria infections
