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Flashcards in Immuno Deck (52):
1

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

2

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

3

Post-splenectomy findings

Howell-Jolly bodies (nuclear remnants in an RBC)

Target cells

Thrombocytosis

4

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)

5

innate vs. adaptive immunity

innate - secreted proteins: lysozyme/complement/CRP, TLRs recognize PAMPs (LPS, flagellin, ssRNA)

adaptive - variation through VDJ recomb, based on Igs

6

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

7

MHC II

- MHC II: HLA-DR, HLA-DP, HLA-DQ,
- binds CD4,
- expressed on APCs only,
- loading happens in acidified endosome with invariant chain

8

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

9

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

10

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)

11

Cytotoxic T cells function

Release cytotoxic granules containing preformed proteins (perforin, granzyme) to induce apoptosis

12

Regulatory T cells

Maintain specific immune tolerance by suppressing CD4/CD8 T cells

Look for: CD3/4/25, FoxP3

Produce IL-10, TGF-B

13

Naive T-cell activation

1. DC samples/processes antigen
2. DC migrates to draining lymph node
3. MHC II/I presents foreign antigen to CD4/8
4. Costimulatory signal is given by interaction of B7 and CD28 (if no second signal, then anergy)
5. Th cell activates and produces cytokines. Tc cell activates and destroys

14

B-cell activation

1. Th cell activation
2. B-cell receptor mediated endocytosis, foreign antigen is presented to helper T
3. CD40 receptor on B cell binds CD40L on helper T cell
4. Helper T secretes cytokines to stimulate Ig class switching of B cell (IL-4, IL-5)

15

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)

16

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

17

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)

18

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

19

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

20

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

21

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)

22

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

23

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"

24

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

25

Antigenic variation

bacteria: Salmonella (flagella), Borrelia recurrentis (relapsing fever), N. gonorrheae (pilus)
viruses: influenza, HIV, HCV
parasites: trypanosomes

26

Administration of preformed antibodies

Passive immunity
Rapid onset
Tetanus, Botulinum, HBV, Varicella, Robies
ex: breast milk (IgA dimers), placental (IgG), antitoxin

27

Exposure to foreign antigens

Active immunity
slow onset, long-lasting protection

28

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

29

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

30

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

31

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

32

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

33

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!

34

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!)

35

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)

36

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

37

Airway/Gi infections, Autoimmune disease, Atopy

Selective IgA deficiency

Asymptomatic. Airway/Gi infections, Autoimmune disease, Atopy, Anaphylaxis to IgA-containing products

38

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

39

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+

40

Disseminated mycobacterial and fungal infections; appears after BCG vaccine (decreased Th1 response)

IL-12 deficiency

Decreased Th1 response. Autosomal recessive. Decreased IFN-y

41

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

42

Noninvasive Candidal infections

Chronic mucocutaneous candidiasis

T-cell dysfunction, absent T cell proliferation to Candidal antigens

43

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)

44

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

45

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

46

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

47

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

48

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

49

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

50

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

51

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

52

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