Immunology — Lymphoid Organs, MHC/HLA & Lymphocyte Activation — USMLE Step 1 Notes

Lymph node: structure & function

• Function: filters lymph and is where adaptive responses are mounted — antigen is presented to lymphocytes.
• Cortex (outer): contains follicles. Primary follicles are dense and dormant; secondary follicles have pale germinal centres where B cells proliferate, undergo somatic hypermutation and class switching (activity here means B-cell activation).
• Paracortex (T-cell zone): between cortex and medulla; houses T cells and dendritic cells, with high endothelial venules where lymphocytes enter. It is underdeveloped in DiGeorge (no thymus) and enlarges in a viral (T-cell) response.
• Medulla: medullary cords (plasma cells, B cells, macrophages) and medullary sinuses (macrophages) that drain toward the efferent lymphatic.
• Lymph flows in via afferent vessels → sinuses → out via the single efferent vessel at the hilum.

Lymph node groups & drainage (with associated pathology)

• Cervical: head and neck — pharyngitis, EBV, head/neck and thyroid cancers.
• Hilar/mediastinal: lungs — sarcoidosis, TB, lung cancer.
• Axillary: upper limb and breast — breast cancer spread, arm infection.
• Para-aortic: testes, ovaries, kidneys, uterus — testicular/ovarian cancer (testes drain to para-aortic, NOT inguinal).
• Superficial inguinal: scrotum/vulva, skin below the umbilicus (not testes), and anal canal below the dentate line.
• Coeliac / superior mesenteric / inferior mesenteric: foregut / midgut / hindgut respectively.

Spleen

• White pulp: immune tissue — periarteriolar lymphatic sheath (T cells) and follicles (B cells); it screens blood-borne antigen.
• Red pulp: sinusoids and cords that filter and remove old/defective red cells and clear encapsulated organisms.
• Function: removes encapsulated bacteria and makes IgM and opsonising antibody; a key site of opsonisation.
• Asplenia/splenectomy: risk of overwhelming sepsis from encapsulated organisms (pneumococcus, H. influenzae, meningococcus) — vaccinate. The film shows Howell-Jolly bodies, target cells and thrombocytosis.

Thymus, thymoma & involution

• Thymus: where T cells mature; derived from the third pharyngeal pouch (epithelium) with bone-marrow-derived lymphocytes. Cortex is dense with immature T cells (positive selection); medulla is paler with Hassall corpuscles (negative selection).
• Involution: the thymus is largest relative to the body in childhood and progressively involutes (shrinks, replaced by fat) from puberty; T-cell output falls with age.
• Thymoma: an anterior mediastinal mass associated with myasthenia gravis, pure red cell aplasia and hypogammaglobulinaemia; part of the "4 T's" of anterior mediastinal masses (Thymoma, Teratoma, Thyroid, Terrible lymphoma).

Innate vs adaptive immunity

• Innate: fast (minutes-hours), no memory, germline-encoded. Components: physical barriers, neutrophils, macrophages, dendritic cells, NK cells, complement, and pattern-recognition. Recognises conserved PAMPs/DAMPs via pattern-recognition receptors such as Toll-like receptors (e.g. TLR4 senses LPS).
• Adaptive: slower on first exposure, highly specific, has memory, uses rearranged receptors. Humoral (B cells/antibody) and cell-mediated (T cells). Antigen-presenting cells (especially dendritic cells) bridge innate to adaptive.

MHC / HLA

• MHC I (HLA-A, B, C): on all nucleated cells; presents endogenous (cytosolic/viral) peptides loaded in the ER to CD8 cytotoxic T cells. Loaded via TAP.
• MHC II (HLA-DP, DQ, DR): on antigen-presenting cells (dendritic cells, macrophages, B cells); presents exogenous (phagocytosed) peptides to CD4 helper T cells.
• Bare lymphocyte syndrome: type I = defective MHC I (TAP mutations) → low CD8; type II = defective MHC II → low CD4, severe combined-like immunodeficiency.

HLA associations with disease

• HLA-B27: seronegative spondyloarthropathies — ankylosing spondylitis, reactive arthritis, psoriatic arthritis, IBD-associated arthritis (PAIR).
• HLA-DQ2 / DQ8: coeliac disease.
• HLA-DQB1*06:02: narcolepsy (type 1, with cataplexy; loss of orexin).
• HLA-DR3: type 1 diabetes, SLE, Graves, Hashimoto, Addison, coeliac.
• HLA-DR4: type 1 diabetes, rheumatoid arthritis (also DR4).
• HLA-DR5: pernicious anaemia and Hashimoto thyroiditis.
• HLA-DRB1*15:01: multiple sclerosis.
• HLA-B*58:01: allopurinol severe cutaneous reaction (SJS/TEN) risk.
• HLA-B*57:01: abacavir hypersensitivity (screen before prescribing).
• HLA-DRB1*01:03: associated with inflammatory bowel disease-related severe colitis.

B cells, T cells & NK cells

• B cells: humoral immunity — differentiate into plasma cells (antibody) and memory B cells; present antigen on MHC II. Pathology: agammaglobulinaemia, CVID, B-cell lymphomas.
• T cells: CD4 helper (coordinate via cytokines; Th1 for intracellular pathogens/macrophage activation, Th2 for helminths/allergy, Th17 for extracellular bacteria/fungi) and CD8 cytotoxic (kill infected/tumour cells via perforin/granzyme and Fas).
• NK cells: innate lymphocytes that kill cells with low/absent MHC I ("missing self", e.g. virus-infected or tumour cells) and perform antibody-dependent cellular cytotoxicity (CD16); enhanced by IL-2, IL-12 and interferons.

T-cell development: positive & negative selection

• Progenitors enter the thymus, rearrange the TCR, and become double-positive (CD4+CD8+).
• Positive selection (cortex): T cells that can bind self-MHC survive; those that cannot are deleted (ensures MHC restriction).
• Negative selection (medulla): T cells that bind self-antigen too strongly are deleted (central tolerance). AIRE drives expression of self-antigens here; AIRE mutations cause APECED/APS-1.
• Survivors become single-positive CD4 or CD8 T cells and leave for the periphery.

Cytotoxic & regulatory T cells

• Cytotoxic T cells (CD8): recognise antigen on MHC I and kill via perforin/granzyme and Fas-FasL; critical against viruses and tumours.
• Regulatory T cells (Treg, CD4+CD25+ FOXP3+): suppress immune responses and maintain peripheral tolerance via IL-10 and TGF-beta. FOXP3 mutation causes IPEX syndrome (autoimmune enteropathy, endocrinopathy, dermatitis).

Macrophage-lymphocyte interaction & T-cell/B-cell activation

• T-cell activation (two signals): (1) TCR binds antigen on MHC; (2) costimulation — B7 (CD80/86) on the APC binds CD28 on the T cell. Signal 1 without signal 2 causes anergy. CTLA-4 and PD-1 are inhibitory checkpoints (targets of checkpoint inhibitors).
• Macrophage-lymphocyte loop: Th1 cells secrete interferon-gamma to activate macrophages; activated macrophages secrete IL-12 to drive Th1 — central to granuloma formation and control of intracellular pathogens.
• B-cell activation & class switching: B cell presents antigen on MHC II to a helper T cell; CD40 on the B cell binds CD40L on the T cell, and T-cell cytokines drive class switching and somatic hypermutation in the germinal centre (IL-4 → IgE/IgG; TGF-beta → IgA). CD40L defects cause hyper-IgM syndrome (high IgM, low IgG/A/E).

Central vs peripheral tolerance

• Central tolerance: deletion of strongly self-reactive lymphocytes in the thymus (T cells, via AIRE) and bone marrow (B cells, via receptor editing/deletion).
• Peripheral tolerance: controls self-reactive cells that escape — anergy (no costimulation), Treg suppression, and activation-induced apoptosis (Fas-FasL; defects cause autoimmune lymphoproliferative syndrome).

High-yield revision notes; verify against a primary source before clinical use.