Immuno Flashcards
Lymph node structure
Where are... B-cells? T-cells? Lymphos/plasma cells? Macs/retics?
fxn: nonspecific filtration by macs, lympho storage
follicle - B-cells! primary (outer) = dense/dormant. secondary (inner) = germinal centers, active
medulla - medullary cords (lymphos + plasma cells), sinuses (reticular cells, macs)
paracortex - houses T cells, T/B cells enter from blood, site of engorgement during immune response
Spleen sinusoids
Where are…
T cells?
B cells?
APCs?
Red pulp = mechanical filtration of RBCs by fenestrated BM and macs, led to trabeculae
White pulp =
- periarteriolar lymphatic sheath (PALS): T cells
- follicles: B cells
Marginal zone = APCs capture blood-borne antigens for recognition by lymphocytes
Post-splenectomy findings
Howell-Jolly bodies (nuclear remnants in an RBC)
Target cells
Thrombocytosis
Thymus structure
Where are…
immature T cells?
mature T cells?
Where do positive and negative selection occur?
T-cell differentiation and maturation
derived from Third pharyngeal pouch
Cortex = immature T cells (site of positive selection: only T cells expressing TCRs that bind self-MHC survive)
Medulla = pale, mature T cells (site of negative selection: T cells with TCRs for high-affinity self-antigen binding are apoptosed)
innate vs. adaptive immunity
innate - secreted proteins: lysozyme/complement/CRP, TLRs recognize PAMPs (LPS, flagellin, ssRNA)
adaptive - variation through VDJ recomb, based on Igs
MHC I
- MHC I: HLA-A, HLA-B, HLA-C, all nucleated cells
- present viral/cytosolic proteins to CD8 cells
- loading happens in RER
- assoc with B-microglobulin
MHC II
- MHC II: HLA-DR, HLA-DP, HLA-DQ,
- binds CD4,
- expressed on APCs only,
- loading happens in acidified endosome with invariant chain
HLA subtypes and disease
A3 - hemochromatosis
B27 - PAIR: psoriatic arthritis, ank spondy, IBS, reactive arthritis
DQ2/DQ8 - celiac disease
DR2 - multiple sclerosis, hay fever, SLE, Goodpasture
DR3 - DM Type I, SLE, Graves, Hashimoto
DR4 - DM Type I, Rheum (4 walls in a room)
DR5 - pernicious anemia
NK cells function, cytokines, signals for activation
Apoptosis induction (using perforin and granzymes) Enhanced by IL-2, IL-12, IFN-a, IFN-B 2 signals: non-specific activation signal, absence of class I MHC
Helper T cells (CD4+)
Th1 (phagocytosis/cell-mediated) vs. Th2 (antibody response)
Give activating and inhibiting cytokines
Th1 = secretes IFN-y, macs/cytotoxic T, activated by IFN-y and IL-12 (from macs), inhibited by IL-4/10 (from Th2)
Th2 = secretes IL-4/5/10/13, activate B cells and recruit eosinophils, activated by IL-4, inhibited by IFN-y (from Th1)
Cytotoxic T cells function
Release cytotoxic granules containing preformed proteins (perforin, granzyme) to induce apoptosis
Regulatory T cells
Maintain specific immune tolerance by suppressing CD4/CD8 T cells
Look for: CD3/4/25, FoxP3
Produce IL-10, TGF-B
Naive T-cell activation
- DC samples/processes antigen
- DC migrates to draining lymph node
- MHC II/I presents foreign antigen to CD4/8
- Costimulatory signal is given by interaction of B7 and CD28 (if no second signal, then anergy)
- Th cell activates and produces cytokines. Tc cell activates and destroys
B-cell activation
- Th cell activation
- B-cell receptor mediated endocytosis, foreign antigen is presented to helper T
- CD40 receptor on B cell binds CD40L on helper T cell
- Helper T secretes cytokines to stimulate Ig class switching of B cell (IL-4, IL-5)
Antibody structure, function, diversity (3 mechs)
Light and heavy chains (light = Fab only, heavy = both),
Fc binds complement (one arm, Constant, Carboxy terminal, Complement, Carbo side chains)
Fab binds antigen (two arms)
Diversity: VJ/VDJ recomb, somatic hypermutation, terminal deoxynucleotidyl transferase (DNA nuc addition)
IgG, IgA, IgM, IgE
IgG - fixes complement, crosses placenta
IgA - prevents microbe attachment to mucous membranes, does not fix complement, produced in GI tract to protect against GI infxns, released in secretions as a dimer (notably breast milk)
IgM - immediate response to antigen, serves as antigen receptor to B cells, pentamer form allows avid binding to antigen
IgE - binds mast cells/basophils, cross-links when exposed to allergen, mediates Type I hypersensi rxn, mediates worm resistance through Eos
Acute phase reactants (produce in liver in response to inflammation, induced by IL-6)
Upregulated: CRP (fixes complement), ferritin (sequesters iron), fibrinogen (coagulation factor, correlates with ESR), hepcidin (prevents release of iron bound to ferritin, leads to AOCD)
Downregulated: albumin (reduction conserves amino acids for acute phase proteins), transferrin (sequester iron)
Complement pathways
Classic - IgG, IgM mediated (GM makes classic cars), C1
Alternative - microbe surface molecules, C3
Lectin - mannose or other sugars on microbe surface, C1-like complex
Complement proteins (3b, 3a/4a/5a, 5b-9, DAF)
C3b - opsonization, C3b binds bacteria (also helps clear immune complexes)
C3a/4a/5a - anaphylaxis (5a also does neut chemotaxis)
C5b-9 - cytolysis by MAC
Inhibitors: DAF = CD55, combines with C1 esterase inhibitor to help prevent complement activation on self cells
Complement disorders
C1 esterase inhibitor deficiency (results in longer C1 half life) - hereditary angioedema, ACEis are contraindicated
C3 deficiency - increases severe, recurrent sinopulmonary infections, increased Type III hypersensitvity rxns (lack of immune complex clearance)
C5-C9 deficiencies - increased Neisseria infections
DAF deficiency - complement-mediated destruction of RBCs (hemolysis). PNH (dz of decreased GPI-anchored proteins) leads to DAF (GPI-anchored protein) deficiency
Important cytokines secreted by…
Macrophages
All T cells
Th1 cells
Th2 cells
Macrophages:
Hot T-Bone stEAK: 1 = fever, 2 = stimulate T cells, 3 = bone marrow (GM-CSF analog), 4= IgE, 5= IgA, 6= aKute phase reactants
IL-8: chemotaxis for neutrophils
IL-12: differentiation of T cells into Th1 cells, NK activator
TNF-a: septic shock, WBC recruitment, vascular leak
Th1 cells:
IFN-y: stimulates macs to kill pathogens (also activates NK cells to kill virus-infected cells)
Th2 cells:
Il-10: modulates inflammatory response, decreases cytokines, inhibits macs/DCs (works in concert with TGF-b)
Respiratory burst, NADPH oxidase, CGD
Activation of neutrophil NADPH oxidase, leads to rapid release of ROS/hypochlorite to kill microbes
CGD: phagocytes don’t make their own peroxide (due to lack of NADPH oxidase) so use microbial peroxide. However, microbes with their own catalase (which breaks down peroxide) survive! Watch for S. aureus and Aspergillus
Interferons
Glycoproteins synthesized by virus-infected cells that act locally on non-infected cells to ramp up viral defenses.
Essentially results in apoptosis.
“Interfere with viruses”
Superantigens
Endotoxins
Superantigen: cross-link B-region of T-cell receptor to the MHC class II on APCs - T cells (IL-2) and macrophages (IL-1 and TNF-a) lead to massive cytokine release
Endotoxin: direct stimulation of macrophages by binding to endotoxin receptor TLR4
Antigenic variation
bacteria: Salmonella (flagella), Borrelia recurrentis (relapsing fever), N. gonorrheae (pilus)
viruses: influenza, HIV, HCV
parasites: trypanosomes
Administration of preformed antibodies
Passive immunity
Rapid onset
Tetanus, Botulinum, HBV, Varicella, Robies
ex: breast milk (IgA dimers), placental (IgG), antitoxin
Exposure to foreign antigens
Active immunity
slow onset, long-lasting protection
Vaccine with cellular and humoral responses
Live, attentuated vaccine
Microbe has lost pathogenicity but retains capacity for growth
Life long immunity
MMR, polio (sabin), intranasal flu, chicken pox, yellow fever
Vaccine with only humoral response
Inactivated/Killed vaccine
Epitope structure is maintained on surface antigens
Weaker immune response, booster shots required
RIP Always: Rabies, Influenza (shot), Polio (Salk), hep A
Anaphylactic hypersensitivity
Type I
free antigen cross-links IgE, triggers mast cell and basophil degranulation (delayed response = leukotrienes)
First and Fast
test: skin test for specific IgE
Cytotoxic hypersensitivity
Type II - cy-two-toxic
IgM/IgG bind antigen on foreign cell, tag for destruction (phagocytosis, complement-mediated inflammation, Ab-mediated cellular dysfunction)
Direct Coombs’: detect antibodies that have adhered to RBCs
Indirect Coombs’: detect free serum antibodies that can adhere to RBCs
Immune complex mediated hypersensitivity
Type III (3 things! Antigen - antibody - complement)
Immune complex attract neutrophils, which release lysosomal enzymes
serum sickness - 5 days post-exposure, deposition of complexes in membranes leading to tissue damage. Now commonly caused by drugs, look for fever, urticaria, arthralgia, etc.
Arthus reaction - local subacute rxn after intradermal injection of antigen. Look for edema, necrosis, activation of complement
T-cell mediated hypersensitivity
Type IV - delayed
4 T’s: T cells, Transplant rejection, TB skin test, Touching
Sensitized T cells release cytokines after stimulation by antigen. No antibodies involved!
Examples of disorders Type I Type II Type III Type IV
I: Allergic/atopic disorders, anaphylaxis
II: antibody mediated hemolysis, Goodpasture, Graves, GB syndrome, ITP, MG, rheumatic fever
III: Arthus rxn, SLE, polyarteritis nodosa, PSGN (vasculitidies)
IV: Contact derm, GVHD, MS, PPD (no antibodies!)
Blood transfusion reactions
Allergic - Type I against plasma proteins
Anaphylaxis - severe allergic rxn (breathing problems)
Febrile non-hemolytic - Type II, host antibodies against donor HLA antigens and WBCs
Acute hemolytic - Type II, intravascular/ABO incompatibility (hemoglobinuria) or extravascular/host antibody rxn (jaundice)
Recurrent bacterial/enterovial infections after age of 6mos (loss of maternal IgG)
X-linked agammaglobulinemia
B’s!
Defect in BTK, no B-cell maturation, X-linked recessive (more common in Boys)
Look for absent B cells in peripheral blood and low number of all immunoglobulins
Airway/Gi infections, Autoimmune disease, Atopy
Selective IgA deficiency
Asymptomatic. Airway/Gi infections, Autoimmune disease, Atopy, Anaphylaxis to IgA-containing products
Autoimmune disease, brochiectasis, lymphoma, sinopulmonary infections
Common variable immunodeficiency
Defect in B-cell differentiation. Can be acquired in 20s-30s. Decreased plasma cells and decreased immunoglobulins
Tetany, recurrent viral/fungal infections, conotruncal abnormalities
Thmyic aplasia (DiGeorge) - 22q11 deletion failure to develop 3rd and 4th branchial pouches (absent thymus and parathyroid), T cell disorder
Decreased T cells, PTH, Ca2+
Disseminated mycobacterial and fungal infections; appears after BCG vaccine (decreased Th1 response)
IL-12 deficiency
Decreased Th1 response. Autosomal recessive. Decreased IFN-y
coarse Facies, Abscesses, Teeth, increased igE, Derm lesions (FATED)
autosomal dominant hyper-IgE syndrome (Jobs)
deficiency of Th17 cells due to STAT3 defect –> impaired neutrophil recruitment to site of infection
Noninvasive Candidal infections
Chronic mucocutaneous candidiasis
T-cell dysfunction, absent T cell proliferation to Candidal antigens
Failure to thrive, chronic diarrhea, thrush. Recurrent bacterial, viral, fungal infections
Severe combined immunodeficiency (SCID)
Major types: IL-2R deficiency, adenosine deaminase deficiency
tx: bone marrow transplant (no concern for rejection)
Cerebellar defects, spider angiomas/telengiectasias, IgA deficiency
Ataxia-telengiectasia
Defects in ATM gene –> failure to repair DNA double stand breaks –> cell cycle arrest
increased AFP, decreased IgA/G/E, lymphopenia
Also, hypersensitivity to ionizing radiation
Severe pyogenic infections, opportunistic infections, only IgM present
Hyper-IgM syndrome
Defective CD40L on T cell leads to inability for B cells to undergo class-switching
Thrombocytopenic purpura, eczema, recurrent infections
Wiskott-Aldrich (WATER)
Mutation in WAS gene = T cells unable to reorganize actin cytoskeleton
Increased risk of autoimmune disease and malignancy
low to normal IgG, IgM, increased IgE, IgA
Fewer and smaller platelets
Recurrent skin/mucosal infections, absent pus, impaired wound healing, delayed separation of umbilical cord
Leukocyte Adhesion Deficiency type 1
Defect in LFA-1 integrin (CD18) on phagocytes –> impaired migration and chemotaxis
Increased neutrophils, but absence at infection sites
Recurrent staph/strep infections, partial albinism, peripheral neuropathy, neurodegeneration
Chediak-Higashi
Defect in lysosomal trafficking regular gene (LYST)
Microtubule dysfunction in phagosome-lysosome fusion
Look for giant granules in granulocytes and platelets
Increased susceptibility to catalase + organisms (Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E. coli, S. aureus, Serratia)
Chronic granulomatous disease
Defect of NADPH oxidase –> decreased ROS/respiratory burst in neutrophils
Abnormal dihydrorhodamine test
Transplant rejections
minutes…
weeks to months…
months to years…
Hyperacute - pre-exisiting antibodies in recipient react to donor antigen (type II hypersensivity) - leads to widespread thrombosis/ischemia/necrosis
Acute - CD8 T cells activate against donor MHCs and antibodies develop after transplant. Vasculitis with dense interstitial lymphocytic infiltrate. Prevent with immunosuppressives!
Chronic - CD4 T cells respond to recipient APCs presenting donor peptides, secrete cytokines, leads to proliferation of vascular smooth muscle and parenchymal fibrosis
Graft-vs-host disease
Grafted T cells proliferate in the recipient due to immunocompromised status (usually after liver/BMT)
Also, rash, jaundice, diarrhea, HSM
Potentially beneficial after BMT for leukemia
Immunosuppresants
IL-2 transcription blockers - cyclosporine (cyclophilin), tacrolimus (FKBP), both are very nephrotoxic
IL-2 response blocker - sirolimus (binds mTOR), not nephrotoxic, good for kidney transplant
Nucleotide synth blocker - azathioprine (6-MP precursor), good for other AI dzs, toxicity increased by allopurinol (6-MP degraded by xanthine oxidase)
Steroids - NF-KB inhibitor, suppress cytokine transcription, iatrogenic Cushing syndrome
