USMLE Step 1 High-Yield Immunology Bullet Notes

MHC Molecules

Two classes tested: MHC I vs MHC II
Location
- MHC I – all nucleated cells (not RBCs)
- MHC II – antigen-presenting cells (dendritic cells, macrophages, B cells)
Interacting lymphocyte
- MHC I → CD8⁺ cytotoxic T cells
- MHC II → CD4⁺ helper T cells
Structural / loading details
- MHC I associates with β₂-microglobulin + TAP; peptides loaded in RER after proteasomal degradation of intracellular proteins (e.g., viral)
- MHC II associates with invariant chain in RER; peptide loading occurs after invariant chain release in acidified endosome (extracellular/phagocytosed Ag)
Function
- MHC I → displays intracellular pathogens (viruses, some bacteria) for direct killing
- MHC II → displays phagocytosed extracellular pathogens (bacteria, fungi, parasites) for helper-T-cell orchestration
Drugs
- $\text{Bortezomib}$ (proteasome inhibitor) ↓ MHC I Ag presentation (NBME)
- Antiquated gold salts inhibit both classes

Innate vs Adaptive Immunity

Innate
- Players : neutrophils, macrophages, NK cells, complement, physical barriers
- Genetics : germ-line encoded receptors (TLRs, etc.)
- Onset : minutes – hours; short-lived, no memory
Adaptive
- Players : B cells, T cells, antibodies
- Genetics : $V(D)J$ recombination
- Onset : days; generates long-lived memory

Natural Killer (NK) Cells

Lymphoid lineage but innate immunity; activated by IL-12 & IFN-α/β
Recognise ↓/absent MHC I on virally-infected or tumor cells
Express CD16 (binds Fc of IgG) + CD56 (marker)
Antibody-dependent cell-mediated cytotoxicity (ADCC)
- Fab region of Ab binds Ag; Fc exposed
- CD16 cross-linking triggers release of perforin, granzyme, granulysin → apoptosis

B Cells (Humoral Arm)

Differentiate into plasma cells → antibody secretion
Undergo somatic hypermutation & affinity maturation in germinal centers (LN cortex, splenic white pulp)
Act as professional APCs via MHC II → activate CD4⁺ Th2 cells

T Cells

Major Subsets

CD8⁺ cytotoxic T lymphocytes (CTL) – kill infected cells via perforin/granzyme after MHC I recognition
CD4⁺ helper T cells
- Th0 precursor can polarise into Th1, Th2, Th17, Treg (plus others)

Activation (2-signal model)

Antigen signal
- MHC I ↔ TCR + CD8 OR MHC II ↔ TCR + CD4
Costimulatory signal
- B7-1/2 (CD80/86) on APC binds CD28 on naïve T cell

Differentiation of CD4⁺ Th0

Th1 – IL-12 + IFN-γ drive; secretes IFN-γ → activates macrophages; granuloma formation
Th2 – IL-4 + IL-10 drive; secretes IL-4, IL-5, IL-10, IL-13 → activates B cells (CD40L on Th2 binds CD40 on B cell) → isotype switching
Th17 – IL-6 + TGF-β drive (+IL-23); recruits neutrophils
Treg – driven by TGF-β & IL-2; prevents autoimmunity (express CD25, FOXP3)
Cross-inhibition
- IL-12/IFN-γ → ↑Th1 & ↓Th2
- IL-4/IL-10 → ↑Th2 & ↓Th1

Thymic Education

Cortex: double-negative → double-positive (CD4⁺CD8⁺). Positive selection (must bind self-MHC)
Medulla: single-positive (CD4 OR CD8). Negative selection (high-affinity self-reactive T cells apoptose)

Cell-Mediated vs Humoral Immunity

Cell mediated = CD8⁺ CTL + Th1 + macrophages; targets intracellular microbes (most viruses, Listeria, TB, etc.)
Humoral = B cells + Th2; targets extracellular bacteria, parasites, some viruses
NBME catch-phrases
- “Deficiency of cell-mediated immunity” → chronic mucocutaneous candidiasis, viral infections
- “Deficiency of humoral immunity” → Bruton's XLA, IgA deficiency

Immunoglobulin Classes

IgM
- First (acute) response; pentamer (10 binding sites → highest avidity); excellent complement fixer; does NOT cross placenta/breast milk
- Hyper-IgM syndrome: CD40L defect → class-switch failure
IgG
- Secondary (memory) response; highest affinity; crosses placenta → hemolytic disease of newborn; most abundant serum Ab
IgA
- Dimer with J-chain; mucosal secretions + breast milk; produced in Peyer patches (GALT). Selective IgA deficiency = most common hereditary immunodeficiency (recurrent sinopulmonary infections, atopy, Giardia, anaphylaxis to blood products)
IgE
- Binds FcεRI on mast cells/basophils → cross-link → histamine/tryptase release (type I HS). Elevated in allergies, asthma, helminths (eosinophil activation via major basic protein). Hyper-IgE (Job) = STAT3 mutation (FATED mnemonic)
IgD – surface B-cell receptor; low serum; minimal USMLE relevance

Passive vs Active Immunity

Passive – give pre-formed Abs (IVIG, transplacental IgG, breast-milk IgA); immediate but short-lived
Active – natural infection or vaccination; delayed but long-lasting memory

Complement Overview

Liver-derived acute phase proteins → converge on MAC $C5b!\text{–}C9$ → lysis
Pathways
- Classic: $C1q$ binds Fc of IgG/IgM (“GM makes classic cars”)
- Alternative: spontaneous or C3b binding microbe surface
- Lectin: mannose-binding lectin binds pathogen mannose
Key facts
- $C3b$ & IgG = major opsonins
- $C3a, C4a, C5a$ = anaphylatoxins (mast cell degranulation)
- $C5a$ = potent neutrophil chemotaxin
- ↓C3 → SLE flares, PSGN; ↓C4 → cryoglobulinemia
- Terminal (C5-C9) deficiency → recurrent Neisseria infections
- C1 esterase inhibitor deficiency → hereditary angioedema
- PNH: absent GPI anchor → no CD55/59 → complement-mediated hemolysis

Thymus-Independent vs Thymus-Dependent Antigens

Only proteins can be presented on MHC → T-cell response (thymus-dependent)
Non-protein (polysaccharide) antigens → NO T-cell help; induce weak IgM only; fixed by conjugate vaccines (HiB, Strep pneumo, N. meningitidis, Salmonella Typhi Vi)
Toxoid vaccines = inactivated protein toxin (diphtheria, tetanus) – inherently thymus-dependent

Cytokines – High-Yield Snapshot

Macrophage cytokines : TNF-α (↓BP, cachexia), IL-1 (fever, osteoclast activation), IL-6 (acute phase, osteoporosis), IL-8 (PMN chemotaxis), IL-12 (→Th1, NK)
T-cell related
- IL-2 – global T-cell stimulator (blocked by cyclosporine/tacrolimus; recombinant aldesleukin for RCC & melanoma)
- IL-3 – myeloid growth (≈GM-CSF)
- IL-4, IL-10 – Th2 polarization, ↑B-cell class switch; anti-Th1
- IL-5 – eosinophil maturation (mepolizumab)
- IL-17 – neutrophilic inflammation (from Th17)
Interferons
- IFN-γ – from Th1/NK; activates macrophages; treat IL-12R deficiency & CGD
- IFN-β – MS maintenance therapy
TGF-β – anti-inflammatory; drives Th17 & Treg

Key Cell-Surface Markers

T cells: CD3 (with TCR), CD28 (binds B7), CD4 or CD8
B cells: CD19, CD20 (target of rituximab), CD21 (EBV receptor)
NK: CD16, CD56
Macrophage: CD14 (LPS receptor → TNF-α/IL-1 release)
Dendritic/Langerhans: CD1a, S-100, Birbeck granules
Hematopoietic stem cell: CD34
Regulatory T: CD25 (IL-2R α-chain), FOXP3
Leukocyte adhesion: CD18 (LFA-1 integrin) → deficiency = LAD
Others: CD10 (ALL), CD15/30 (Reed–Sternberg), CD40 (B cells, macrophages), CD55/59 (PNH)

High-Yield Autoantibodies

SLE – anti-dsDNA (renal flare, prognosis), anti-Smith (specific), antiphospholipid (β₂-glycoprotein I) → miscarriage & ↑PTT
Drug-induced lupus – anti-histone (SHIPP mnemonic)
Goodpasture – anti-collagen IV → linear IF kidney + lung
Pemphigus vulgaris – anti-desmoglein 1/3 (net-like IF)
Bullous pemphigoid – anti-hemidesmosome (linear IF)
Vasculitides: PR3-ANCA (c-ANCA) Wegener; MPO-ANCA (p-ANCA) for microscopic polyangiitis & Churg-Strauss
Myasthenia – anti-postsynaptic AChR; Lambert–Eaton – anti-presynaptic Ca²⁺ channel
Scleroderma: Anti-centromere (limited/CREST); anti-topoisomerase I (diffuse)
PBC – antimitochondrial; Autoimmune hepatitis – anti-smooth muscle
Celiac – anti-tTG IgA, anti-endomysial (false neg if IgA-def.)
T1DM – anti-GAD65, anti-ZnT8
PNH – anti-phospholipase A2 R (kidney variant)

Hypersensitivity Reactions

Type I (immediate) – IgE-mast cell cross-link (anaphylaxis, atopy)
Type II (cytotoxic) – IgG/IgM vs cell surface/receptors (Graves, MG, Goodpasture, HIT, pemphigus, etc.)
Type III (immune complex) – Ag-Ab deposition (SLE, PSGN, serum sickness, Arthus, PAN)
Type IV (delayed/cell-mediated) – T cells (PPD, contact dermatitis, GVHD)

Vaccine Categories

Killed/inactivated: Rabies, Influenza (IM), Polio (Salk), Pertussis, Hep A (mnemonic RIPP Always)
Live-attenuated: Yellow fever, Varicella, Rotavirus (oral), Influenza (intranasal), Polio (Sabin oral), MMR, Typhoid (oral)
- Elicit strong cellular & humoral immunity; contraindicated in immunodeficiency (except MMR/VZV if CD4>200)
Recombinant subunit: HBV, HPV
Toxoid: Diphtheria, Tetanus

Immunodeficiencies (Selected High Yield)

SCID – XR (common γ-chain, IL-2R) or AR (ADA); ↓T & B; absent thymic shadow + lymphoid tissue; infections of all types; Tx = BM transplant
Bruton's X-linked agammaglobulinemia – BTK defect; ↓B/Ig (all classes); recurrent bacterial infections after 6 mo; scanty nodes/tonsils; treat w/ IVIG
Selective IgA deficiency – recurrent sinopulmonary infections, atopy, Giardia, transfusion anaphylaxis; often answer “deficiency of humoral/mucosal Ig”
DiGeorge (22q11) – 3rd/4th pouch failure → thymic aplasia (↓T), hypocalcemia (tetany), congenital heart defects (ToF, truncus), cleft palate
Chronic mucocutaneous candidiasis – T-cell dysfunction → persistent Candida; choose “deficiency of cell-mediated immunity”
CGD (NADPH oxidase) – XR > AR; recurrent catalase (+) infections (Staph, Serratia, Aspergillus, Candida, Pseudomonas, E coli, H. pylori); diagnosis via dihydrorhodamine test; treat IFN-γ
MPO deficiency – AR; impaired H₂O₂ → HOCl; mix of Staph & Candida; decreased bleach production
Wiskott-Aldrich (XR) – WAS gene; triad eczema, thrombocytopenia, recurrent infections; ↑IgE/IgA, ↓IgM
Leukocyte adhesion deficiency – CD18 defect; delayed cord separation, recurrent bacterial infections without pus, neutrophilia; impaired integrin-mediated adhesion/chemotaxis
Chediak-Higashi – LYST defect (microtubule); giant granules in neutrophils, albinism, neuropathy
Hyper-IgM – CD40L defect (class-switch failure); severe pyogenic/opportunistic infections; ↑IgM, ↓others
Hyper-IgE (Job) – STAT3; FATED mnemonic
IL-12 receptor deficiency – ↓Th1 → recurrent disseminated mycobacterial/TB;
CVID – defective B cell differentiation; ↓IgG/IgA/IgM; adult onset sinopulmonary infections, autoimmunity, ↑lymphoma risk
Terminal complement (C5-C9) – recurrent Neisseria

Respiratory Burst & Catalase(+) Organisms

Enzymatic cascade in neutrophils:
1. NADPH oxidase: $O2 \to O2^-$ (superoxide)
2. SOD: $O2^- \to H2O_2$
3. MPO: $H2O2 \to HOCl$ (bleach)
CGD lacks step 1 → can’t overwhelm catalase(+) microbes (SPACES/C SHAPES mnemonic)

Leukocyte Extravasation (4 Steps)

Margination/Rolling – selectins (L-, E-, P-selectin)
Adhesion – integrins (LFA-1 = CD11a/CD18)
Diapedesis – PECAM-1
Chemotaxis – IL-8, C5a, LTB₄, kallikrein, PAF, bacterial N-formyl-methionine peptides

Transfusion Reactions (Snapshot)

Febrile non-hemolytic – cytokines vs donor leukocytes; acetaminophen; Coombs(-)
Acute hemolytic – ABO mismatch; IgM complement; fever, flank pain; stop transfusion, IVF; Coombs(+)
Delayed hemolytic – anamnestic IgG vs minor antigens (Kell, Duffy); days–weeks; ↑bilirubin
TRALI – donor anti-leukocyte Abs → neutrophil activation → non-cardiogenic pulmonary edema
TACO – volume overload; give diuretics

High-Yield Lymph Node & Lymphatic Drainage

Testes/ovaries → para-aortic
Uterus/cervix → external iliac; bladder, upper rectum → internal iliac
Anal canal below pectinate, scrotum, vulva → superficial inguinal
R arm & R hemithorax/face → right lymphatic duct; rest → thoracic duct (drains to left venous angle)

Immunosuppressants & mAbs

Calcineurin / mTOR Axis

Drug	Binds	Effect on IL-2	Nephrotoxic	Neurotoxic	Diabetes
Cyclosporine	Cyclophilin	↓Transcription	Yes	Yes	No
Tacrolimus	FK506-binding protein	↓Transcription	Yes	Yes	Yes (high yield)
Sirolimus (rapamycin)	FKBP-12 → inhibits mTOR	↓Responsiveness	No	No	Yes

Key Monoclonal Antibodies

Anti-TNF-α : infliximab, adalimumab (IBD, RA); etanercept = soluble receptor decoy
Rituximab : anti-CD20 (B-cell NHL, CLL) — risk PML
Trastuzumab : anti-HER2/neu (breast CA) — cardiotoxic
Omalizumab : anti-IgE (severe allergic asthma)
Denosumab : anti-RANKL (osteoporosis)
Natalizumab : anti-α4 integrin (MS) — risk PML
Tocilizumab : anti-IL-6 R (severe RA)
Basiliximab / Daclizumab : anti-IL-2 R (transplant; MS-withdrawn)
Eculizumab : anti-C5 (PNH)
Abciximab : anti-GpIIb/IIIa (PCI antiplatelet)
Palivizumab : anti-RSV F protein (RSV prophylaxis in premies)

Miscellaneous High-Yield Clinical Nuggets

b₂-microglobulin knockout mice lack MHC I → defective CD8⁺ responses
Invariant chain/endosome pH ↓ → necessary for MHC II peptide loading (chloroquine ↑pH → ↓Ag presentation)
Endotoxin (lipid A) binds TLR4 (CD14) on macrophages → TNF-α / IL-1 → septic shock; vs superantigen (TSST) bridges TCR/MHC II → massive cytokine release
Waterhouse-Friderichsen: adrenal hemorrhage in meningococcemia → treat hydrocortisone
Howell-Jolly bodies & target cells after splenectomy; administer vaccines vs encapsulated bugs (S. pneumo, HiB, N. meningitidis)
IL-2 gene transfection → ↑T-cell-mediated tumor killing (basis for aldesleukin therapy)
Positive PPD = type IV HS; infiltrate mainly macrophages, not CD8⁺ CTL