Major histocompatibility complex

= human leukocyte antigen (HLA) in humans

MHC class I: heterodimer α (3 domains) and ß2 microglobulin (1 domain), 1 transmembrane domain

MHC class II: heterodimer α and ß, two domains per chain, 2 transmembrane chains, α Ig-like domain

constant domain: two sheets of ß-strands linked with an S-S bridge, 3 & 4 strands build barrel-like 3D

variable domain: 3 hypervariable loops interact specifically with antigens, additional 2 strands & otherwise similar to constant domain

• to be able to present at least one peptide from any pathogen

• via polygeny (multiple class I and II genes) and polymorphism (several sequence differences per isotype), one sequence defines one allel

classical MHC

MHC class I: HLA-A, -B, -C

MHC class II: HLA-DP, -DQ, -DR

on chromosome 6

specific combination of alleles in an individual defines the MHC haplotypes

gene expression is codominant—>each allele expressed

class I: minimal 3 (homozygous) / maximal 6 (heterozygous)

class II: minimal 4 (homozygous) / maximal >8

—>because of hybrid molecules

—>interisotype (DR with DP)

—>interhaplotypes (DQ mother with DQ father)

MHCI: number of different sequences quite similar among isotypes

MHCII: not similar, DR more polymorphic & polymorphism on ß-chain, α-chain less sequence differences —>polygomorphic

MHCI: 2 helices on top, bottom wall of ß-strand defining peptide binding groove, variations in wall & helix

MHCII: ß-barrel with variations

• ancestral MHC gene undergoes gene duplication and divergence (polygeny)

• multiple MHC genes

• gene conversion between misaligned chromosomes during meiosis (polymorphism)

• separated chromosome after meiosis

peptide presentation to T-cells

MHCI: binds shorter peptide —>walls closed

MHCII: peptide can go across the two helices

similar length: 8-10 AA

anchor residues different (defines affinity to peptide, depends on alleles different position)

usually binding at N-ter (bulky hydrophobic) and C-ter (small hydrophobic) —>location anchor residues

longer 13-17 AA

variable length (groove open)

no binding at C/N terminus—>anchor residues in the middle

TCR recognizes complex of MHC & antigen

both for specificity needed

involved in MHCI presentation

—>TAP=transporter associated with antigen processing

—>TAPBP=Tapasin

—>LMP= proteins associated to the proteasomes

involved in MHCII presentation

—>HLA-DO

—>HLA-DM

MHCI: H-2D, -2K, -L —>equal polygeny

MHCII: I-A, I-E -->less polygeny, several mouse strains lacking I-E

not all have function in antigen presentation

classical (HLA-A/B/C): polymorphic, ß2m association, TAP-dependent, peptide fixation

non-classical (encoded in the MHCI locus)

• oligomorphic, ß2m association, TAP-dependent, peptide fixation restricted (binds less peptides)

• oligomorphic, no ß2m association, no peptide fixation

in the MHC class III locus (in between class II & I)

MHC-related (MIC) and immune-related (complement and TNK) molecules

neonatal Fc receptor

non-encoded in the MHC locus (non classical)

binds only to IgG

passive immunisation of the fetus by maternal IgG (transfer of Ab via placenta)

non-classical MHC, non-encoded in the MHC locus

in humans 5 molecules, CD1a-e

MHCI related for structure: association with ß2 microglobulin

MHCII related for function: no dependency on TAP, loading of extracellular antigens

presentation of antigen to unconventional CD4-CD8- T cells —>highly hydrophobic groove binds lipids & Ag protrudes outside the groove & not flat