Major histocompatibility complex Study Guide

📖 Core Concepts Major Histocompatibility Complex (MHC) – a large, highly polymorphic region of vertebrate DNA that encodes cell‑surface proteins presenting peptide fragments to T cells. Human Leukocyte Antigen (HLA) – the protein products of the human MHC; “MHC” refers to the genomic region, “HLA” to the molecules. Codominant expression – both parental alleles of each MHC gene are expressed, giving each individual up to six class I and up to eight class II specificities. Class I molecules – heavy α‑chain (α1, α2, α3) + β₂‑microglobulin; expressed on virtually all nucleated cells; present endogenous peptides to CD8⁺ cytotoxic T cells (CD8 co‑receptor). Class II molecules – heterodimer of polymorphic α and β chains; expressed only on professional antigen‑presenting cells (APCs); present exogenous peptides to CD4⁺ helper T cells (CD4 co‑receptor). Class III genes – located between class I and II; encode secreted immune proteins (e.g., complement components), do not present peptides. Positive selection – thymic epithelial cells present self‑MHC/peptide; only T cells that recognize self‑MHC receive survival signals. --- 📌 Must Remember Expression pattern: Class I → all nucleated cells; Class II → dendritic cells, macrophages, B cells. HLA naming: HLA‑A, ‑B, ‑C = class I; HLA‑DP, ‑DQ, ‑DR = class II. Allelic diversity: Thousands of alleles per gene; no two unrelated people share the same HLA set. Transplant relevance: More HLA mismatches → lower 5‑year graft survival; cross‑match testing screens for pre‑existing anti‑HLA antibodies. Autoimmunity link: Certain alleles (e.g., HLA‑B27) increase disease risk. Balancing selection: Heterozygote advantage and frequency‑dependent selection maintain MHC diversity. --- 🔄 Key Processes Class I processing Cytosolic proteins → proteasome → peptide fragments. Peptides transported into ER (via TAP). Load onto nascent class I heavy chain + β₂‑microglobulin → Golgi → plasma membrane. Class II processing Extracellular proteins → phagocytosis/endocytosis → acidic lysosome → peptide fragments. Invariant chain guides class II to endosome; CLIP removed, peptide loads → surface. Positive selection (thymus) Thymic epithelial cells present self‑MHC/peptide. TCRs that bind with low‑to‑moderate affinity receive survival signal → mature T cell. Cross‑match test (transplant) Recipient serum mixed with donor cells. Detect binding of recipient antibodies to donor HLA → predicts hyperacute rejection. --- 🔍 Key Comparisons Class I vs Class II Expression: all nucleated cells vs professional APCs. Peptide source: endogenous (cytosolic) vs exogenous (extracellular). Co‑receptor: CD8 vs CD4. Classical vs Non‑classical Class I Polymorphism: high vs limited. Expression: ubiquitous vs specialized (e.g., HLA‑E, HLA‑G). Hyperacute vs Acute cellular vs Chronic rejection Trigger: pre‑existing antibodies vs cytotoxic T cells vs antibodies + chronic damage. Timing: minutes–hours vs days–weeks vs months–years. --- ⚠️ Common Misunderstandings MHC = HLA – MHC is the gene region; HLA are the protein products. Class I presents extracellular antigens – false; it presents intracellular peptides. All HLA genes are highly polymorphic – class III genes are not peptide‑presenting and may be less polymorphic. One allele = one peptide – each allele can bind many different peptides; polymorphism expands the repertoire. --- 🧠 Mental Models / Intuition Billboard analogy: MHC molecules are billboards on every cell; the billboard (MHC) shows a “snippet” (peptide) of whatever the cell is processing. T cells scan the billboard, ignoring the sign unless the snippet is foreign. Heterozygote advantage: Carrying two different alleles is like having two different lock‑picks; you can open more “doors” (present more peptides) against pathogens. --- 🚩 Exceptions & Edge Cases Non‑classical class I (e.g., HLA‑E, HLA‑G) – limited polymorphism, tissue‑restricted expression, specialized roles (e.g., NK cell regulation). Class III proteins – secreted (complement, cytokines); not involved in peptide presentation. --- 📍 When to Use Which Ask “Where did the peptide originate?” → endogenous → think Class I; extracellular → think Class II. Identify the T‑cell type involved: CD8⁺ cytotoxic response → Class I; CD4⁺ helper response → Class II. Transplant assessment: use HLA matching and cross‑match testing to predict rejection risk. Autoimmune association: look for specific HLA alleles (e.g., HLA‑B27) linked to disease. --- 👀 Patterns to Recognize Peptide length: Class I grooves bind 8–10 aa; Class II grooves accommodate longer (13–25 aa) peptides. Allele‑specific disease clusters: Certain HLA types repeatedly appear in the same autoimmune condition. MHC mismatch count: The more mismatched HLA loci, the higher the probability of rejection – a linear‑ish relationship in graft survival data. --- 🗂️ Exam Traps Confusing CD4/CD8 co‑receptors – CD4 pairs with Class II, CD8 with Class I. Assuming all nucleated cells lack HLA‑DP/DQ/DR – professional APCs express class II, but many nucleated cells do not. Choosing “class III” for antigen presentation – class III genes are secreted, not presenters. Believing a single HLA allele determines disease – it increases risk; environmental and other genetic factors also play roles. Mixing up “codominant” with “dominant” – both parental alleles are expressed equally; heterozygotes show multiple specificities.