Immuno Fa Mnemonics & Pharm

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MHC I & II

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MHC I: HLA--A/B/C; not on RBCs; present endogenously processed antigens to CD8+ cells-->ags loaded in RER; beta2-microglobulin used to transport to cell membrane

MHC II: HLA-DR/DP/DQ; expressed only on APCs (dendritic cells, M0's, b-lymphocytes); presents exogenous proteins to T-helper cells; **ag loaded following release of invariant chain in an acidified endosome

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HLA subtypes associated with diseases--
Seronegative spondyloarthropathy
RA
Hashimoto
Celiac

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SNS: B27 (HLA class I)
RA: DR4--"there are 4 walls in a 'rheum'"
H: DR5
C: DQ2/DQ8--Dairy Queen

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T and B cell activation

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T: MHC II or MHC I bind TCR on respective Th or Tc cells--->B7 (APC) and CD28 (T cell) interact for second signal

B: MHC II binds TCR on Th cell (signal 1)-->CD40 receptor on B cell binds CD40L on Th cell (signal 2)

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Ab structure--Fab, Fc

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Fab: ag-binding fragment; comprised of both a heavy and light chain

Fc: constant, complement binding (not tail), determines isotype (IgM, IgD), comprised of only heavy chain

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Acute phase reactants--
Production site
Induction
Examples & purpose

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Made in the liver in response to acute or chronic inflammation; IL-1, IL-6, TNF-a and IFN-g all induce production.

Serum amyloid A: prolonged elevation can lead to amyloidosis (AA)
CRP: opsonin, sign of ongoing inflammation
Ferritin: sequesters iron from blood to inhibit microbial iron scavenging; iron storage
Fibrinogen: coag factor, correlates w/ESR
Hepcidin: prevents release of iron bound by ferritin

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Complement
Classic pathway
Fxn C3a, C5a
Opsonins
Inhibitors

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GM makes classic cars

C3a & C5a are associated with anaphylaxis
C5a, along w/IL-8, LTB4, are PMN chemotaxis

Primary opsonins are C3b and IgG

DAF (decay-accelerating factor, CD55) and C1 esterase inhibitor prevent complement activation on self

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Complement disorders
C1 esterase inhibitor deficiency
DAF (GPI anchored enzyme) deficiency

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C1: causes hereditary angioedema-->tx w/ danazol; ACE inhibitors are contra'd

DAF: causes complement-mediated RBC lysis & paroxysmal nocturnal hemoglobinuria

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Important cytokines--M0
IL-1
IL-6
IL-8
IL-12
TNF-a

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1: endogenous pyrogen; fever, acute inflammation
6: endogenous pyrogen; stimulates acute-phase proteins
8: PMN chemotaxis--along w/LTB4 & C5a
12: induce Th differentiation into Th1; activates NK cells (CD16/56)
TNF-a: mediates septic shock

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Important cytokines--all T cells
IL-2
IL-3

TH1: IFN-g
TH2: IL-4, IL-5, IL-10

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2: stimulates growth of all T cells, B cells, and overall stimulates immune system
3: supports growth of bone marrow stem cells

IFN-g: activates NK & M0 cells; important for granuloma formation, ypac to fight TB

IL-4: IgE class switching
IL-5: IgA class switching, eosinophil chemotactic
IL-10: along w/TGF-b, both are anti-inflammatory

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IFN-a & b

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Part of innate host defense against RNA and DNA viruses; acts on locally uninfected cells-->priming them for viral defense

Primed cells sense viral dsRNA and activate:
RNAaseL degrades both viral & host mRNA
Protein kinase inhibits viral & host protein synthesis

Both effects essentially trigger apoptosis

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When to use passive immunity?

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Exposure to tetanus toxin, botulinum toxin, HBV, or rabies virus

rapid protection that only last a couple weeks

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Hypersensitivity Rxns

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ACID--Anaphylactic & Atopic (type I); Cytotoxic (ab-mediated, type II); Immune complex (type III); Delayed (cell-mediated, type IV)

Type I: IgE cross-links presensitized mast cells and basophils-->release histamine/heparin which dilates postcapillary venule-->delayed response associated w/leukotrienes

Type III: serum sickness, arthus rxn

Type IV: PPD, candida skin test, sarcoidosis, contact dermatitis

**Types I-III present w/in minutes; type IV takes days**

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Serum sickness

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Most often due to drugs--immune complexes form and deposit in tissue

Pt presents w/fever, urticaria, arthralgias, proteinuria, LAD all 5-10 days post-exposure

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Transplant rejection
Hyperacute versus Acute

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HA: w/in minutes; pre-existing recipient abs react to donor ags (type II HS)-->thrombosis of graft vessels->ischemia/necrosis

A: weeks to months; cellular (interstitial lymphocytic infiltrate) or humoral (vasculitis similar to hyperacute); tx aim is to prevent this type of rejection

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Transplant rejection
Chronic
GVHD

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C: months to years; irreversible; leads to obliterative intimal smooth muscle hypertrophy & fibrosis--atherosclerosis, bronchiolitis obliterans, vanishing bile ducts...

GVHD: grafted immunocompetent T cells proliferate and attack recipient-->severe organ dysfxn
**potentially beneficial in bone marrow transplant for leukemia (kills remaining host cancer)**

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Cyclosporine; Tacrolimus

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Calcineurin inhibitor-->prevents IL-2 transcription blocking T cell activation

Nephrotoxic

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Siroliums (Rapamycin)

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mTOR inhibitor; prevent IL-2 signal transduction

Non-nephrotoxic-->used for kidney transplant pts

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Basiliximab

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IL-2R monoclonal ab

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Azathioprine

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"azathio-PURINE"--anti-metabolite precursor of 6-mercaptopurine; 6-MP degraded by xanthine oxidase THUS allopurinol increases toxicity

Toxicity--leukopenia

Inhibits lymphocyte proliferation by blocking nucleotide synthesis

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Recombinant cytokines--
Epoetin alfa
Thrombopoietin
Filgrastim
Aldesleukin
IFN-a
IFN-b
IFN-g

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E: EPO, anemias
T: thrombocytopenia
F: recovery of bone marrow
A: IL-2; used for RCC & metastatic melanoma
a: chronic HBV & HCV, Kaposi sarcoma, hairy cell leukemia
b: multiple sclerosis
g: granulomatous disease

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Therapeutic abs--Cancer Tx
Alemtuzumab
Bevacizumab
Rituximab
Trastuzumab

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A: "aLYMtuzumab" for chronic LYMphocytic leukemia

B: targets VEGF

R: targets CD20

T: targets HER2/neu

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Therapeutic abs--Autoimmune disease tx
Infliximab
Adalimumab

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"rheumatoid arthritis 'inflix' pain in 'da limbs'"
--anti-TNFa

used for RA, IBD, psoriasis, ankylosing spondylitis

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Therapeutic abs--Others
Abciximab
Denosumab
Digoxin immune Fab
Omalizumab

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A: IIb times IIIa equals 'absiximab'--binds GPIIb/IIIa

D: dino (flintstone's dog) protecting big bone--targets RANKL, used for osteoporosis, (mimics osteoprotegrin)

DiF: antidote for dig toxicity

O: targets IgE, used for allergic asthma