Components of Immune System and MHC

Lymphoid Organs

Primary/central (lymphocyte development): Bone marrow, Thymus. Secondary/peripheral (antigen encounter): Lymph nodes, Spleen, MALT.

Primary

Bone marrow: origin of all blood cells (HSC). B cells COMPLETE maturation here (central tolerance — receptor editing, negative selection).

Thymus: T cell precursors (from marrow) mature here. Positive selection (cortex): weak self-MHC recognition = survive (ensures MHC restriction). Negative selection (corticomedullary junction/medulla): strong self-antigen binding = deleted (central T cell tolerance). Largest/most active in childhood, involutes with age → ↓T cell output in elderly.

Secondary

Lymph node: filters LYMPH. Cortex (B cell-rich, follicles+germinal centers) + Paracortex (T cell-rich) + Medulla (plasma cells).

Spleen: filters BLOOD. White pulp (PALS = T cell-rich periarteriolar sheath + B cell follicles/marginal zone) = immune response to blood antigen. Red pulp = clears aged RBC + ENCAPSULATED BACTERIA. Splenectomy → lifelong ↑risk encapsulated organisms (pneumococcus, meningococcus, H. influenzae) → needs vaccination.

MALT (mucosa-associated lymphoid tissue): GALT (Peyer’s patches-small intestine, tonsils, appendix) + BALT (bronchus). Site of secretory IgA generation.

Cells of Immune System

All from bone marrow HSC → Myeloid + Lymphoid lineage.

Lymphocytes:

• T cells (thymus-matured): CD4+ helper (TH1/TH2), CD8+ cytotoxic, Treg (suppress self-reactive)
• B cells (marrow-matured): → plasma cells (antibody) + memory cells
• NK cells: separate lineage, INNATE, no prior sensitization

Mononuclear phagocytes: Monocyte (blood) → Macrophage (tissue). Phagocytose + kill + APC + secrete cytokines (IL-1, TNF, IL-12).

Granulocytes: Neutrophil (dominant acute phagocyte, bacterial first responder), Eosinophil (anti-helminthic, allergic inflammation), Basophil (blood counterpart of mast cell, IgE degranulation).

Mast cells: tissue-resident (skin, mucosa, near vessels). IgE cross-link degranulation = type I hypersensitivity (same as basophil).

Dendritic cells: MOST EFFICIENT professional APC. UNIQUELY activates NAIVE T cells (macrophage/B cell mainly present to already-primed T cells). Bridge innate→acquired immunity.

MHC (Major Histocompatibility Complex)

= HLA in humans, chromosome 6. Encodes surface molecules displaying peptide for T cell recognition. Most important transplantation antigens. MHC restriction: TCR only recognizes peptide IN MHC groove (unlike antibody which binds free antigen).

Class I vs Class II MHC

Logic: Obligate intracellular pathogens (make own protein IN host cell) → Class I → CTL clearance. Extracellular pathogens/toxins (phagocytosed) → Class II → CD4/antibody response.

MHC Class III

No antigen-presenting role. Includes: complement components (C2, C4, Factor B), TNF, heat-shock proteins. Just co-located in same chromosomal region.

HLA-Disease Association

MHC/HLA = MOST polymorphic human gene cluster. HLA-B27 — ankylosing spondylitis, seronegative spondyloarthropathies (classic). HLA-DR alleles — type 1 DM, rheumatoid arthritis.

Polymorphism = why HLA typing essential pre-transplant (mismatch → recognized as foreign → rejection).

Organs of the Immune System

The immune system is organized around lymphoid organs, split functionally into primary (central) organs, where lymphocytes develop and mature, and secondary (peripheral) organs, where mature lymphocytes actually encounter antigen and mount a response.

Primary Lymphoid Organs

Bone marrow is where all blood cells, including lymphocytes, originate from haematopoietic stem cells; B cells complete their entire maturation here, including the central tolerance checks (receptor editing, negative selection) that delete self-reactive clones before release into circulation.

Thymus is where T cell precursors, which originate in the bone marrow, migrate to complete their maturation. Within the thymus, developing thymocytes undergo positive selection (in the cortex — thymocytes whose receptor can weakly recognize self-MHC survive; those that cannot are eliminated by apoptosis, ensuring the surviving T cell repertoire is at least MHC-restricted and functional) and negative selection (at the corticomedullary junction and medulla — thymocytes whose receptor binds self-antigen too strongly are deleted, the central tolerance mechanism for T cells). The thymus is largest and most active in childhood and involutes with age, which is part of why T cell output and overall immune vigour decline somewhat in older adults.

Secondary Lymphoid Organs

Lymph nodes filter lymph draining from tissue, organized into a B-cell-rich cortex (containing lymphoid follicles, which develop germinal centres during an active antibody response) and a T-cell-rich paracortex, with a central medulla where plasma cells concentrate before antibody enters efferent lymph and eventually the bloodstream.

Spleen filters blood rather than lymph, with white pulp (lymphoid tissue organized around central arterioles — a periarteriolar lymphoid sheath, PALS, that is T-cell-rich, surrounded by B-cell follicles including the marginal zone) mounting immune responses to blood-borne antigen, and red pulp clearing aged/damaged red cells and, importantly, encapsulated bacteria — which is exactly why a splenectomized patient faces lifelong heightened risk from encapsulated organisms (pneumococcus, meningococcus, H. influenzae) and needs corresponding vaccination.

Mucosa-associated lymphoid tissue (MALT) guards the vast surface area of mucosal barriers directly, including gut-associated lymphoid tissue (GALT — Peyer’s patches in the small intestine, tonsils, appendix) and bronchus-associated lymphoid tissue (BALT); these sites are where secretory IgA responses are actually generated, feeding directly into the mucosal immunity described under antibody effector function.

Cells of the Immune System

All immune cells ultimately derive from bone-marrow haematopoietic stem cells, branching into a myeloid lineage and a lymphoid lineage.

Lymphocytes: T cells (matured in the thymus) split by function into CD4+ helper T cells (TH1/TH2 subsets, orchestrating the immune response) and CD8+ cytotoxic T cells (direct killing of infected/abnormal cells), plus regulatory T cells (Treg, suppressing self-reactive responses). B cells (matured in bone marrow) differentiate on activation into antibody-secreting plasma cells and long-lived memory cells. NK cells are a distinct lymphoid lineage, part of innate rather than adaptive immunity, killing without prior sensitization.

Mononuclear phagocytes: monocytes circulate in blood and differentiate into tissue-resident macrophages once they migrate out — both phagocytose, kill microbes, and act as antigen-presenting cells, secreting inflammatory cytokines (IL-1, TNF, IL-12) along the way.

Granulocytes: neutrophils (the dominant acute-phase phagocyte, first responders to bacterial infection), eosinophils (anti-helminthic defence, mediators of allergic inflammation), and basophils (blood-circulating counterpart of the tissue mast cell, IgE-mediated degranulation in type I hypersensitivity).

Mast cells reside in tissue (skin, mucosa, near blood vessels) and, like basophils, degranulate on IgE cross-linking to drive type I hypersensitivity.

Dendritic cells are the most efficient professional antigen-presenting cell (APC), uniquely capable of activating naive T cells (macrophages and B cells can present antigen too, but mainly to already-primed T cells) — the essential bridge connecting innate antigen capture to the initiation of an acquired immune response.

MHC (Major Histocompatibility Complex)

What MHC Is and Why It Matters

The MHC is a cluster of genes — in humans specifically called HLA (human leukocyte antigen), on chromosome 6 — encoding cell-surface molecules whose job is to display processed antigenic peptide for T cell recognition. MHC molecules are the most important transplantation antigens (the reason organ matching matters so much) and, more fundamentally, the mechanism by which T cells recognize antigen at all — a T cell receptor never binds free antigen the way an antibody can; it can only recognize a peptide already sitting in an MHC molecule’s groove, a requirement called MHC restriction.

Class I and Class II MHC

MHC class I is expressed on essentially every nucleated cell in the body (though most densely on lymphocytes) and presents endogenous antigen — peptide derived from proteins synthesized within that cell, whether normal self-protein, viral protein from an infected cell, or a mutated tumour protein — processed via the cytosolic (endogenous) pathway: cytoplasmic protein is degraded by the proteasome, transported into the endoplasmic reticulum by TAP (transporter associated with antigen processing), loaded onto MHC-I, and displayed at the cell surface. MHC-I peptide is recognized specifically by CD8+ cytotoxic T cells — the surveillance mechanism by which the immune system finds and kills virus-infected or malignant cells from the inside out, since a cell has no other way to signal “something is wrong with my own internal proteins.”

MHC class II is expressed only on professional antigen-presenting cells — dendritic cells, macrophages, and B cells — and presents exogenous antigen, material taken up from outside the cell by phagocytosis or endocytosis, processed via the endocytic (exogenous) pathway: the ingested material is degraded within an endosome/lysosome and loaded onto MHC-II there before surface display. MHC-II peptide is recognized specifically by CD4+ helper T cells.

This split — class I/CD8/endogenous versus class II/CD4/exogenous — is the organizing logic of the entire antigen-presentation system, and is exactly why obligate intracellular pathogens (which synthesize their own protein inside the host cell) are cleared by cytotoxic T cells via class I, while extracellular pathogens and their toxins (taken up by phagocytosis) drive a class-II/helper-T/antibody-generating response instead.

MHC Class III and Structural Genes

The MHC locus also encodes a stretch of genes with no direct antigen-presenting role at all, loosely grouped as class III — including several complement components (C2, C4, factor B), TNF, and heat-shock proteins — genes that happen to sit within the same chromosomal region but serve entirely different immune functions.

HLA and Disease Association

Because MHC/HLA genes are extraordinarily polymorphic (the most polymorphic gene cluster in the human genome), certain HLA alleles are statistically associated with specific diseases — most famously HLA-B27 with ankylosing spondylitis and the seronegative spondyloarthropathies, and specific HLA-DR alleles with several autoimmune diseases (type 1 diabetes, rheumatoid arthritis). This polymorphism is also precisely why HLA typing (see Transplant Immunology) is essential before organ transplantation — a poorly matched HLA profile is what actually gets recognized as foreign and rejected.

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