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USMLE: Immunology

Terms in this set (75)

Bruton's Agammaglobulinemia
Defect: Bruton's tyrosine kinase (BTK gene on X chr) -> blocks B cell differentiation and maturation (prevents Pre-B -> immature B transition)

Presentation: recurrent bacterial infections after 6 months (maternal IgG) -> opsonization defect. Especially H. influenzae and S. pneumoniae.

Labs: Normal Pro-B and Pre-B (CD10+ B Cells), decreased immature, mature, memory, et, decreased Igs (all classes)
Hyper IgM syndrome
Defect: Defective CD40L on helper T cells (Type 1) or defective AID (Type 2)(defective class switching)

Presentation: Severe pyogenic infections early in life

Labs: increased IgM, decreased Ig's of other classes
Selective Ig Deficiency (IgA most common -> IL-5 converts to IgA)
Defect: Defective isotype switching

Presentation: Sinus and lung infections, milk allergies, diarrhea, anaphylaxis on exposure to blood products with Specific Ig

Labs: decreased plasma cells, decreased secretory IgA
Common Variable Immunodeficiency (CVID)
Defect: Defect in B cell maturation (many causes)

Presentation: Acquired in 20-30s, increased risk of other autoimmune diseases, lymphoma, sinopulmonary infections

Labs: Normal B cells, decreased plasma cells, decreased Ig (all classes)
Thymic Aplasia (Di-George's Syndrome)
Defect: 22q11 deletion -> failure of development of 3rd and 4th pharyngeal pouches -> Thymus and parathyroids fail to develop (prevents Immature T cell -> CD4/CD8 T cells)

Presentation: Tetany (hypocalcemia), recurrent viral/fungal infections, T cell deficiency, congenital heart and great vessel defects

Labs: low T cells, low PTH, low Ca, absent thymic shadow
IL-12 Receptor deficiency
Defect: decreased Th1 response

Presentation: Disseminated mycobacterial infections

Labs: decreased IFN gamma
Hyper IgE syndrome (Job's Syndrome)
Defect: Th cells fail to produce IFN-gamma -> inability of neutrophils to respond to chemotactic stimuli

Presentation: FATED -> coarse Facies, cold staph Abscesses, retained primary Teeth, increased IgE, D*ermatologic problems (eczema)

Labs: increased IgE
Chronic Mucocutaneous Candidiasis
Defect: T cell dysfunction

Presentation: Candida albicans infections of skin and mucous membranes

Labs: branched and budding yeast with pseudohyphae at 20C, germ tube + at 37C
Severe Combined Immunodeficiency (SCID)
Defect: defective IL-2-R (most common, XR, prevents Pro-T -> immature T), ADA deficiency (XR, prevents lymphoid stem cell -> Pro-B/Pro-T) OR failure to synthesize MHC II antigens (prevents formation of CD4+ T cells)

Presentation: Recurrent viral, bacterial, fungal and protozoal infections -> treat with bone marrow transplant (no allograft rejection)

Labs: decreased IL-2R = decreased T cell activation
increased Adenine = toxic to B and T cells (decreased dNTPs = decreased DNA synthesis
Ataxia Telangiectasia
Defect: DNA repair enzyme defect

Presentation: classic triad = cerebellar defects, spider angiomas, IgA deficiency

Labs: decreased IgA
Wiskott-Aldrich Syndrome
Defect: XR defect -> progressive deletion of B and T cells

Presentation: Triad (TIE) = Thrombocytopenic purpura, Infections, Eczema

Labs: Increased IgE and IgA, decreased IgM
Leukocyte Adhesion Deficiency (type I)
Defect: Defect in LFA-1 integrin (CD18) protein on phagocytes

Presentation: Recurrent bacterial infections, absent pus formation, delayed separation of umbilicus

Labs: Neutrophilia (PMNs unable to leave blood vessels)
Chediak Higashi Syndrome
Defect: AR defect in microtubular function -> decreased phagocytosis

Presentation: Recurrent pyogenic infections (staph and strep), partial albinism, peripheral neuropathy
Chronic Granulomatous Disease
Defect: lack of NADPH oxidase (decreased ROS -> superoxide), absent respiratory burst in neutrophils

Presentation: increased susceptibility to catalase positive organisms (SPACE = S. aureus,Pseudomonas, Aspergillus, Candida, E. coli)

Labs: Negative Nitrotetrazolium Blue dye reduction test (negative = clear -> normal = blue)
Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED)

-Defect
-Pathology
Defect: defective regulator (AIRE) gene product leads to a lack of T cell negative selection by thymic medullary epithelial cells

Pathology: T cells damage multiple endocrine organs - paricularly the adrenals, parathyroids, and thyroid
Substances Released from Mast Cells in Activation Phase of Type I Hypersensitivity Reactions
Preformed Mediators:
Histamine
Serotonin
Heparin
Proteases
IL3, IL4, IL5, GM-CSF
IL-8
ECF-A

Newly Synthesized Mediators:
Leukotrienes (LTB4, LTC4, LTD4, LTE4)
Prostaglandins
Thromboxanes
Platelet Activating Factor
Three Phases of Type I Hypersensitivity (Allergic Reactions)
1) Sensitization Phase - exposure to allergen induces B cells to produce IgE

2) Activation Phase - IgE on mast cells & basophils is cross-linked by reexposure to allergen

3) Effector Phase - allergic symptoms due to substances produced/released by mast cells; eosinophils and neutrophils are attracted to the activation site and prolong the allergic response/symptoms
Environmental Risk Factors for Allergies
Early exposure to infectious agents
Pollution (diesel exhaust increases IgE greater than 20x)
Exposure to allergen
Genetic Factors Associated with IgE Responses
Numerous chromosome 5 genes: IL4(promoter mutations as well), IL13, and GM-CSF genes are all associated with elevated IgE

MHC class II alleles are associated with specific allergens (not all)

IgE Receptor (chromosome 11)

If both parents have allergy the risk for the child increases from 10% to 40-60%
Role of TH2 Cells in Development of Allergies
IL4 directs naive T cells into the TH2 lineage

TH2 cells induce B cells to switch Ig production to IgE by producing IL4 and CD40L
Major Allergen in Dust
DERp1 (enzyme found in house dust mite feces)
Substances Causing Serum Sickness
Most often drugs acting as haptens
Signs and Symptoms of Serum Sickness
Fever, urticaria, arthralgias, proteinuria, lymphadenopathy 5-10 days after antigen exposure
Pathophysiology of Serum Sickness
Immune complex disease (type III hypersensitivity) in which antibodies to the foreign proteins are produced (takes at least 5 days).

Immune complexes form and are deposited in membranes where they fix complement and lead to subsequent tissue damage.

More common than Arthus reaction.
Pathophysiology of Arthus Reaction
A local subacute antibody-mediated hypersensitivity (type III hypersensitivity) reaction.

Intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in the skin.

Characterized by edema, necrosis, and activation of complement.
Test Used to Diagnose Arthus Reaction
Immunofluorescent staining
Characteristics of Type III Hypersensitivity

- Antibody Isotype Invovled
- Three Typical Steps in Pathogenesis
(1) Antigen-antibody (IgG) complexes activate complement, which (2) attracts neutrophils, which in turn (3) release lysosomal enzymes

*Type III = 3 things stuck together: Ag, Ab, & Complement
Antibody Isotypes Involved in Type II Hypersensitivity
IgM
IgG
Three Mechanisms of of Cytolysis in Type II Hypersensitivity
1) Opsonization leading to phagocytosis or complement activation
2) Complement-mediated lysis (complement + antibody -> formation of membrane attack complex)
3) Antibody-dependent cell-mediated cytotoxicty (ADCC), usually due to NK cells or macrophages

*Type II is cy-"2"-toxic
Tests Used for Diagnosis of Type II Hypersensitivity
Direct and Indirect Coombs Test

Direct: detects antibodies that HAVE adhered to patient's RBCs (e.g. test an Rh+ infant of an Rh- mother)

Indirect: detects antibodies that CAN adhere to other RBCs (e.g. test an Rh- woman for Rh+ antibodies)
4 "T"s of Type IV Hypersensitivity Mnemonic
T lymphocytes
Transplant rejection
TB skin test (test: PPD)
Touching (contact dermatitis; test: patch test)
Three Major Steps in Pathogenesis of Type IV Hypersensitivity (DTH)

(After the sensitization stage
1) Activation of Ag-specific inflammatory TH1 and TH17 cells in a previously sensitized individual

2) Elaboration of proinflammatory cytokines (IFN-Γ, TH17 cytokines(IL17, IL21, IL22)) by the Ag-specific TH1/TH17 cells

3) Recruitment and activation of antigen-nonspecific inflammatory leukocytes

(*CTLs can also participate in damage associated with DTH reactions)
Types of Type IV Hypersensitivty
Contact Hypersensitivity: characterized by eczema which peaks 48-72 hours after allergen contact

Granulomatous Hypersensitivity: characterized by a granuloma that is maximal 21-28 days after antigen is introduced

Tuberculin-Type Hypersensitivity: characterized by an area of firm red erythema and induration that is maximal 48-72 hours after challenge

Others: reactions occuring in certain T-cell-mediated autoimmune diseases (RA, T1DM, MS) and in some individuals who have received allografts
Stages of Type IV Hypersensitivity (DTH)
1) Sensitization stage: Ag exposure expands the number of Ag-specific TH1 and TH17 cells

2) Elicitation stage: challenge with original Ag induces TH1/TH17 Ag-specific cells to produce cytokines that promote DTH reactions and result in tissue damage
Major Histological Feature of DTH
Phagocytic macrophages (which account for the protective outcome of this form of hypersensitivity when pathogens are involved)
Histological Characterization of Granulomas in Granulomatous Hypersensitivity (a type of DTH)
Presence of
macrophages, epithelioid cells, giant cells, CD4+ T cells, and CD8+ T cells

(*Granulomas are induced when macrophages are unable to destroy the pathogen)
Functions of the Reticuloendothelial System
1) Phagocytize microorganisms and foreign substances that are in the bloodstream and various tissues

2) Destruction of aged and imperfect cells such as RBCs

3) Present processed antigens to lymphocytes

(*RES is mostly monocytes and macrophages)
Biochemical Forces Involved in Ag-Ab Binding
Electrostatic,
hydrostatic, and
van der Waals forces
Definition of Titer in Agglutination Reactions
The highest serum dilution at which agglutination still takes place and beyond which (higher dilution) no agglutination takes place
Definition of Prozone in Agglutination Reactions
The tubes with high concentration where agglutination does not occur because Ab is in excess
General Principle of the Coombs Test
Using heterologous anti-immunoglobulins to detect a reaction between immunoglobulins and antigen
Difference Between Agglutination Reactions and Preciptation Reactions in Immunology
Agglutination Reactions:
Ab and particulate (insoluble) Ag

Precipitin Reactions:
Ab and soluble Ag
Lab Techniques/Tests Employing Reactions of Soluble Ag and Ab in Gels for Qualitative and Quantitative Analysis of Ag or Ab
Gel Diffusion
Radial Diffusion
Immunoelectrophoresis
Radioimmunoassay (RIA)

- Use
- Basis
Very sensitive test to quantitate antibody or antigen using radiolabeled antigen or antibody

Based on competitive inhibtion of nonlabeled and labeled antigen

Ab-bound Ag must be separated from nonbound labeled Ag

Separation is usually achieved by preciptation with anti-immunoglobulins
Solid-Phase Immunoassay

- Basis
- Steps
Employs the property of many proteins to adhere to plastic and form a monomolecular layer

1) Ag is applied to plastic wells
2) Abs are added to wells
3) Well is washed
4) Any Abs bound to Ag are measured by use of a radiolabeled or enzyme-linked anti-immunoglobulins

(*ELISA is essentially a solid-phase immunoassay in which an enzyme is linked to the anti-immunoglobulin; uses colorimetric evalution after addition of a substrate)
Immunofluorescence

- Use
- Basis
- Direct vs Indirect
Method in which an Ag or Ab is detected by the use of fluorescence-labeled immunoglobulins

Direct: primarily for the detection of Ag and involves reacting the target tissue or microorganism with fluorescently labeled specific Abs

Indirect: same as direct method, except instead of lableling the Ag-specific Abs, add a second Ab to the well which is a fluorescently-labeled anti-immunoglobulin; more widely use than the direct method (simpler procedure and amplified fluorescent signal)
Clinical Uses of Direct Immunofluorescence
Identifying lymphocytic subsets

Detecting protein deposition (auto-Abs, complement) in tissues such as kidney and skin in cases of SLE or skin in cases of HSP
Clinical Uses of Indirect Immunofluorescence
Detection of anti-DNA Abs in SLE

Used in dermatopathology for pemphigoid associated conditions
Approximate Serum Concentrations of Ig Isotypes
IgG: 10.0 mg/mL
IgA: 2.0 mg/mL
IgM: 1.2 mg/mL
IgD: 0.03 mg/mL
IgE: 0.0005 mg/mL
Complement Fixating Ig Isotypes
IgM > IgG

No fixation by IgA, IgD, IgE
Ability to Carry Out Bacterial Lysis by Ig Isotype
IgM > IgG, IgA
Antiviral Activity by Ig Isotype
IgA, IgG > IgM
How do antigen-specific antibodies create a negative feedback loop to inhibit B cell antibody production?
Ag-specific Ab binds the antigen

the Fc portion of that Ab in then bound by the B cell surface protein CD32 (an Fc Receptor) which signials activation of a phosphatase by the ITIM in the cytoplasmic region of CD32

The phosphatase removes phosphate groups from CD79a/b, inhibiting any activating signals that would've been transmitted via that adjacent B Cell Receptor Complex (BCR complex = surface Ig + CD79a/b)
Ligands of B7 and Result of Binding
B7 is found on macrophages, dendritic cells, and certain B cells

B cell B7 <-> T cell CD28 = B cell stimulation and T cell IL2 synthesis

B cell B7 <-> T cell CTLA-4(CD152) = T cell inhibition
Components of the T Cell Receptor Complex
TCR: α chain (Vα + Cα) + ß chain (Vß + Cß) + some carbohydrates (signal reception)

CD3: Γ,δ,ε chains (signal transduction)

Zeta homodimer (signal transduction)
Major Differences in the Diversity of Binding Epitopes Between Ig/BCR and the TCR
Ig/BCR is divalent and has much more variety in what it can bind to: anything from short linear peptide chains to three-dimensional conformational epitopes as well as carbohydrates, DNA, and lipids.

The TCR is monovalent and equipped only to bind either:
1. [MHC class I + 8-9 amino acid peptide]
or
2. [MHC class II + 12-17 amino acid peptide]
Major Costimulatory Molecules on T Cells
CD28: interacts with B7 expressed on APC and B cell (activation of T cell)

CTLA-4(CD152): same as above (inhibition of T cell)

CD40L: Interacts with CD40 expressed on APC and B cell

ICOS: Interacts with ICOS ligand on B cell (important for germinal center formation)
Molecules Required for Lymphocyte Entry to Lymph Nodes through High Endothelial Venules
L-selection (CD62L): binds addressins (glycoproteins) expressed on the cells of HEVs

CCR7: A chemokine receptor on naive T cells
Two Types of TCR Variable Chains with V and J Gene Segments
α (TCRA) and Γ (TCRG) are composed of V and J gene segements like Ig light chains, plus either a Cß1 or Cß2 constant region

(TCRA is the locus shared with TCRD, where TCRD sits between and separates the Vα and Jα gene segments.
Two Types of TCR Variable Chains with V, D, and J Gene Segments
ß (TCRB) and δ (TCRD) are composed of V,D, and J gene segements like Ig heavy chains, plus either a Cß1 or Cß2 constant region
Gene Associated with Development of Autoimmune Lymphoproliferative Syndrome (ALPS)
defective Fas gene, which leads to impaired Fas-mediated apoptosis of lymphocytes
HLA Subtypes Associated with T1DM
DR3
DR4
HLA Subtype Associated with Rheumatoid Arthritis
DR4 (four walls in a rheum)
HLA Subtypes Associated with SLE
DR2 (Japanese)
DR3 (Europeans)
HLA Subtype Associated with Myasthenia Gravis
DR3
HLA Subtype Associated with MS
DR2
HLA Subtypes Associated with Celiac Disease
DR3 (DQA1*0501), CDQ2/DQ8
HLA Subtype Associated with Sjögren's Syndrome (primary)
DR3
Diseases Associated with HLA Subtype DR5
Pernicious anemia -> vitamin B12 deficiency
Hashimoto Thyroiditis
Diseases Associated with HLA Subtype DR3
T1DM
SLE
Graves Disease
Difference Between Antigen Loading in MHC Class I and MHC Class II
MHC Class I: antigen peptides are loaded onto MHC in RER after delivery via TAP peptide transporter

MHC Class II: antigen is loaded following release of invariant chain in an acidified endosome; antigen is then loaded onto MHC class II in place of CLIP (peptide exchange process mediated by HLA-DM)
Autoimmune Diseases with CD4+ T Cell, CTL, and B Cell/Autoantibody Effectors
T1DM
Rheumatoid Arthritis
Autoimmune Diseases with Specifically CD4+ and B Cell/Autoantibody Effectors (but no CTLs)
Hashimoto's Thyroiditits

(Autoantibody is against thyroid proteins: thyroglobulin, microsomal antigens, thyroid peroxidase)

*MS kind of fits in this category, but the role of the antibodies in MS pathogenesis are not quite understood
Mechanisms of Central Tolerance
- Negative Selection: Immature (IgM+) B cells, CD4+ T cells, and CD8+ Tells cells

- Anergy: B cells only

- Receptor editing: B cells only
Mechanisms of Peripheral Tolerance
- Anergy: B and T cells

- ThReg Cells (CD25+ T Cells): release IL10 and TGF-ß to suppress immune response

- Fas-FasL-Mediated Apoptosis: removal of mature autoreactive B and T cells (B and T cells express Fas)
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