Immunodeficiency disorders

Question 1

For DiGeorge Syndrome, what is this due to? What are some presentations?

Answer 1

1. developmental failure of the third and fourth pharyngeal pouches (22q11 microdeletion)
2. T-cell deficiency (lack of thymus), hypocalcemia (lack of parathyroids), abnormalities of heart, great vessels, face

Question 2

Severe combined immunodeficiency (SCID): what is it, etiologies, characterized by, treatment

Answer 2

1. defective cell-mediated and humoral immunity
2. cytokine receptor defects (need cytokine signaling for mature B and T cell proliferation),
   ADA deficiency (needed to deaminate adenosine and deoxyadenosine for excretion as waste products; buildup is toxic to lymphocytes),
   MHC class II deficiency
3. susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines
4. sterile isolation (‘bubble baby’) and stem cell transplantation

We didn’t know this but the inside linebacker, number 7, had some CRazy defect, and it ended up affecting our Backs and Tackles. Later, our assistant dean of admissions took ill with something also. Then, my head coach just fell apart. As it turned out, I should have learned they should not Fuck Very Big Pussy, or we get prone to opportunistic infections and live vaccines. Now these kids are as bad as that kid in a bubble and might need a transplant.

Question 3

X-linked agammaglobulinemia: what does it involve, cause, presentation, what to avoid?

Answer 3

1. complete lack of immunoglobulin due to disordered B-CELL MATURATION (pre- and pro-B cells can’t mature)
2. mutated Bruton tyrosine kinase; X-linked
3. presents after 6 months of life with recurrent bacterial, enterovirus (e.g. polio and coksackievirus), and Giardia lamblia infections; maternal Abs present during first 6 months of life are protective
4. AVOID LIVE VACCINES

Question 4

Common variable immunodeficiency (CVID): involves what, risk for what?

Answer 4

1. low immunoglobulin due to B-cell or helper T-cell defects
2. Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood; also for autoimmune disease and lymphoma

Question 5

IgA deficiency: what is this and what are you at increased risk for?

Answer 5

1. low serum and mucosal IgA; most common immunoglobulin deficiency
2. increased risk for mucosal infection, especially viral; however, most patients are asymptomatic!!

Question 6

Hyper-IgM syndrome: characterized by, due to what? misc

Answer 6

1. Elevated IgM
2. mutated CD40L (on helper T cells) or CD40 receptor (on B cells): no second signal delivery to helper T cells during B-cell activation and the cytokines necessarily for Ig class switch NOT PRODUCED!!
3. Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor opsonization), especially at the mucosal sites

Question 7

Wiskott-Aldrich Syndrome characterized by? due to?

Answer 7

1. thrombocytopenia, eczema, recurrent infections (defective humoral and cellular immunity); bleeding a major cause of death
2. mutation in WASP gene; X-linked

Question 8

Complement deficiencies

Answer 8

C5-C9: increased risk for Neisseria infection;

C1 inhibitor: hereditary angioedema, characterized by edema of the skin (especially periorbital) and mucosal surfaces

Question 9

For autoimmune disorders, what are they characterized by? involves what? who? Cause?

Answer 9

1. immune-mediated damage of tissues (1% prev in US)
2. loss of self-tolerance (self-reactive lymphocytes regularly generated but UNDERGO APOPTOSIS with negative selection in thymus or bone marrow OR become anergic (recognition of antigen in peripheral lymphoid tissues with no second signal)
3. More common in women; classically women of childbearing age
4. likely an environmental trigger in genetically suscpetible individuals (increased incidence in twins and certain HLA subtypes)

Question 10

SLE: what is it; clinical features; characterizations? Other associations?

Answer 10

1. systemic autoimmune disease: Ab’s against host damage multiple tissues via type II (cytotoxic) and type III (antigen-antibody complex) hypersens;
2. fever, weight loss, BUTTERFLY RASH (sunlight), arthirits, pleuritis, pericarditis, CNS psychosis, renal damage (diffuse proliferative glomerulonephritis is most common injury), endocarditis (Libman-Sacks with small sterile deposits on both sides of mitral valve), myocarditis, pericarditis, TAL, renal failure and infection (death)
3. antinulear antibody (sens, not spec) and anti-dsDNA antibodies (highly specific);
   antihistone Ab = drug-induced SLE (caused by hydralazine, procainamide, isoniazid)
4. Antiphospholipid antibody syndrome associated with SLE: autoantibody against proteins bound to phospholipids, most effective being anticardiolipin and lupus anticoagulant (lead to false-pos syphilis test and falsely-elevated PTT respectively), arterial and venous thrombosis include DVT, hepatic vein thrombosis, placental thrombosis, stroke; requires LIFELONG ANTICOAG

Question 11

Sjogren syndrome: involves? presentation? Characterized by? associations? increaed risk for what?

Answer 11

1. autoimmune destruction of lacrimal and salivary glands (lymphocyte-mediated damage, or type IV hypersen, with fibrosis
2. dry eyes (keratoconjunctivitis), dry mouth (xerostomia), and recurrent dental caries in older woman (50-60 years): CAN’T CHEW A CRACKER, DIRT IN MY EYES
3. ANA, anti-ribonucleoprotein antibodies (anti-SS-A/Ro and anti-SS-B/La)
4. autoimmune diseases, especially rheumatoid
5. increased risk for B-cell (marginal zone) lymphoma, which presents as unilateral enlargement of parotid gland late in disease course

My mom, a 55 yo woman, noticed she couldn’t eat or really chew anything. This was the 4th time this has happened in her life; she finds it annoying when her eyes and mouth dry up, and her teeth are painful. Her name is Anna, and with her friends ROsie and LArry, they noticed she’s starting to get swan-like hands. Oh boy, is that something swelling up along her neck?

Question 12

Scleroderma is what? how is it divided?

Answer 12

Autoimmune disease characterized by activation of fibroblasts and deposition of collagen (fibrosis);
localized scleroderma and systemic sclerosis

Question 13

For localized scleroderma, what does this involve?

Answer 13

JUST SKIN: most common subtype is morphea, and highly associated with antibodies to DNA topo II

Question 14

For systemic sclerosis, what does that involve? How is this broken up?

Answer 14

1. skin and visceral organs
2. Limited type: limited areas of skin (mostly hands, face, and neck) with late visceral involvement and prototype is CREST syndrome (Calcinosis/anti-Centromere Ab’s, Raynaud phenomenon, Esophageal dysmotility, Scelrodactyly, and Telangiectasias of the skin);
   Diffuse type: involves skin and can involve any visceral organ; GI tract (GERD, dysphagia), lungs (interstitial fibrosis, pulmonary HTN) and kidneys (malignant HTN leading to renal failure) commonly involved

The assistant dean said I need to eat more fiber and that’ll get my colon working. Then I’ll have my choice of schools: if I go local, I’ll have to back up morphea, and have to look at Topo Jr’s abs. But if I go widely, I’ll just make sure that I consider playing multiple positions and not LIMIT my chances: I’ll brush my teeth with Crest if need be to impress the coach. If I stay diffuse and get playing time, I’ll have to watch out for problems down the line: GI, lungs, kidneys

Question 15

Mixed CT disease; involves what? characterized by what?

Answer 15

autoimmune-mediated tissue damage with mixed features of SLE, systemic sclerosis, and polymyositis;
serum Ab’s against U1 ribonucleoprotein

Question 16

Robbins: Major components of innate immunity? 5 things

Answer 16

1. Epithelial barriers to block microbe entry
2. Phagocytic cells like neutrophils and macrophages
3. Dendritic cells
4. NK cells
5. Plasma proteins like the complement system

Question 17

TLR’s will signal by a pathway that culminates in _____ of two sets of TF

Answer 17

activation;

1. NF-kB: stimulates synthesis and secretion of cytokines and expression of adhesion molecules to recruit WC’s
2. interferon reg factors: stimulates production of antiviral cytokines like type I interferons

Question 18

Mature lymphocytes that have not encountered antigen for which they are specific to? Differentiate into what?

Answer 18

Naive; effector and memory cells

Question 19

____ and ____ stimulate proliferation of NK cells; wheras ____ activates killing and secretion of IFN-gamma

Answer 19

IL2, IL15; IL12

Question 20

Class I MHC molecules are derived from what? What helps make the alpha chains?
Class II molecules are made of what?

Answer 20

1. Heterodimers with alpha chains linked to beta2-microglobulin; alpha chains encoded by HLA-A, HLA-B, HLA-C
2. Has alpha1, alpha2, beta1, beta2 and are encoded in region called HLA-D, with HLA-DP, HLA-DQ, HLA-DR

Question 21

List some facts about IgA, IgG, IgE?

Answer 21

IgA: secreted from mucosal epithelia and neutralizes microbes in lumens of respiratory and GI tract
IgG: actively transported across placenta and protects newborns; can opsonize microbes and target them for phagocytosis
IgE: with eosinophils can cooperate to kill parasites; TH2 stimulates their production

Question 22

Define type I, II, III, IV hypersensitivity

Answer 22

1. Immediate: injury caused by TH2 cells, IgE Abs, mast cells, and other leukocytes
2. Ab-mediated disorders: secreted IgG and IgM Ab’s injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation
3. Immune complex-mediated disorders: IgG and IgM Ab’s bind antigens usually in circulation, and antigen-Ab complexes deposit in tissues and induce inflammation
4. Cell-mediated immune disorders: sensitized T lymphocytes (TH1 and TH17 cells and CTLs) are cause of tissue injury

Question 23

Mediators of immediate hypersens:

Eosinophils do their work via what two things?

Answer 23

1. Preformed mediators: vasoactive amines, enzymes, proteoglycans
2. Lipid mediators: leukotrines, prostaglandin D2, platelet-activating factor
3. Cytokines: TNF, IL-1, chemokines, IL-4;
4. Major basic protein
5. Eosonophil cationic protein

Question 24

How do T cells undergo central tolerance? B cells?

Answer 24

Immature lymphocytes: if they encounter self-antigens in the thymus and bind too well –> negative selection or deletion (Need AIRE, an autoimmune regulator!!!)
Developing B cells: If they recognize self-antigen, can undergo receptor editing but if this antigen receptor gene rearrangement doesn’t occur, APOPTOSIS!!!

Question 25

In the periphery, how can T cells undergo tolerance?

Answer 25

1. Anergy (no costimulatory factor; CTLA-4 is an inhibitor ligand that can bind B7 with better affinity than CD28) 2. Reg T cells: they express CD25, FOXP3, and also CTLA-4 3. Induction of apoptosis: could be Bcl (pro-apoptotic) or engagement of Fas by FasL (if there is a muation in the FAS gene, you have autoimmune lymphoproliferative syndrome)

Question 26

List some genes that could be associated with autoimmunity:

Answer 26

1. HLA-B27 2. PTPN22 (RA, type 1 diabetes, other autoimmune disesae) 3. NOD2 (Crohn disease; this is a member of the Nod-like receptor family) 4. IL-2 receptor (CD25) and IL-7 receptor alpha chains: MS and other autoimmune diseases

Question 27

What is virtually diagnostic of SLE?

Answer 27

Ab's to dsDNA, and the Sm antigen

Question 28

What is a model for SLE pathogenesis?

Answer 28

Apoptosis of cells releases nuclear antigens and with B and T lymphocytes that are abnormal, you could have complexes of the antigens and antibodies made; just a cycle of antigen release and immune activation --> high-affinity autoantibodies

Question 29

For the kidney, what are the stages of nephritis in SLE?

Answer 29

1. Minimal mesangial lupus nephritis (class I) 2. Mesangial proliferative lupus nephritis (class II) 3. Focal lupus nephritis (class III): proliferation of endothelial and mesangial cells 4. Diffuse lupus nephritis (class IV): proliferation of endothelial, mesangial, and epi cells; hematuria and proteinuria, as well as HTN 5. Membranous lupus nephritis (class V): diffuse thickening of capillary because of deposition of subepi immune complexes; see severe proteinuria or nephrotic syndrome and production of BM-like material 6. Advanced sclerosing lupus nephritis (class VI): end-stage renal disease

Question 30

In Sjogren syndrome, about 75% of patients have what? What could be the initiating trigger? What is essential to diagnose this?

Answer 30

Rheumatoid factor; initiating trigger may be a viral infection of the salivary glands, with CD4 T cells and B cells specific to self antigens; biopsy of the lip (to examine minor salivary glands)

Question 31

Potential causes of systemic sclerosis (scleroderma)?

Answer 31

1. Autoimmunity: CD4 T cells respond to antigen and release cytokines to activate inflamm cells and fibroblasts, and TGF-beta and IL-13 produced to stim transcription of genes that encode collagen and other ECM proteins in fibroblasts; ultimately, inflamm cells and fibroblasts are activated 2. Vascular damage: microvascular disease could be the initial lesion; repeated cycles of endothelial injury followed by platelet aggregation lead to release of PDGF and TGF-beta to trigger perivascular fibrosis 3. Fibrosis: infiltrating leukocytes with fibrogenic cytokines, hyperresponsiveness of fibroblasts to cytokines, scarring eventually

Question 32

What type of reactions can occur in the presence of a graft?

Answer 32

1. T Cell-mediated reactions: acute (CD8 and CD4) and chronic 2. Antibody-mediated reactions: acute (exposure to class I and class II HLA antigens) and chronic antibody-mediated rejection

Question 33

For grafts and limiting reactions, what can you give?

Answer 33

1. Immunosuppressive drugs (streoids, mycophenolate mofetil to inhibit lymphocyte proliferation, tracolimus to inhibit phosphatase calcineurin which would activate NFAT) 2. T cell- and B cell-depleting Ab's 3. Pooled IVIG 4. Plasmapheresis

Question 34

Defects in Innate Immunity:

Answer 34

1. Inherited defects in leukocyte adhesion (leukocyte adhesion deficiency type 1 and 2 2. Inherited defects in phagolysosome function (autosomal recessive condition characterized by defective fusion of phagosomes and lysosomes, or Chediak-Higashi) 3. Inherited defects in microbicidal activity (chronic granulomatous disease) 4. Defects in TLR signaling

Question 35

In X-linked agammaglobulinemia, what characteristics are included?

Answer 35

1. B cells absent or markedly decreased in circulation, and all serum Ig levels decreased; pre-B cells, which have CD19 but NOT Ig, found in normal numbers in the marrow 2. Germinal centers of lymph nodes, Peyer's patches, appendix, and tonsils underdeveloped 3. Plasma cells absent 4. T cell-mediated reactions NORMAL!!!

Question 36

Besides defects in CD40 or CD40 L, what could be an issue in hyper-IgM?

Answer 36

Defect in AID (activation-induced cytidine deaminase)

Question 37

In X-linked lymphoproliferative syndrome, what is this characterized by and what is the mutation usually?

Answer 37

Inability to eliminate EBV, leading to fulminant infectious mono and development of B-cell tumors; SLAM-associated protein (SAP)

Question 38

Primary amyloidosis associated with ______, and secondary amyloidosis when...

Answer 38

plasma cell disorder; complication of an underlying chronic inflammatory or tissue-destructive process

Question 39

In primary amyloidosis, what can be found in the serum/urine?

Answer 39

Monoclonal Ig's or free light chains, or both!!