Chapter 8 Major Histocompatibility Complex Dr Capers IMMUNOLOGY

Chapter 8 Major Histocompatibility Complex Dr. Capers IMMUNOLOGY

Antibodies can recognize antigen alone T-cell receptors can only recognize antigen that has been processed and presented by Major Histocompatibility Complex (MHC) Involves: - Antigen processing - Antigen presentation

Inheritance of MHC coded by cluster of genes ○ Rejection of foreign tissue is due to immune response against cell surface molecules, histocompatibility antigens

Inheritance of MHC Collection of genes on chromosome 6 in humans (HLA complex) and chromosome 17 in mice (H-2 complex) ○ Class I MHC genes - Encode glycoproteins expressed on all nucleated cells ○ Class II MHC genes - Encode glycoproteins expressed on antigenpresenting cells (macrophages, B cells, dendritic cells) ○ Class III MHC genes - Encode various products involved in complement and inflammation

Inheritance of MHC

Inheritance of MHC Many different alleles exist at each locus among the population ○ Each set of alleles is called a haplotype ○ Genes of MHC lie close together so crossing over during meiosis occurs infrequently ○ Individual inherits one haplotype from mom, one from dad - Many in the population are heterozygous - Alleles are codominant so expressed simultaneously

Inheritance of MHC Inbred strains will express identical haplotypes – homozygous ○ Inbred mice are solid colors

Inheritance of MHC

MHC molecules Both Class I and Class II are membranebound glycoproteins ○ Antigen-presenting molecules

Class I MHC Alpha α chain ○ Transmembrane ○ Encoded by A, B, and C regions in human MHC complex Beta β 2 -microglobulin ○ Encoded by highly conserved gene on different chromosome

Class II Molecule α 1 and α 2 chain ○ Transmembrane β 1 and β 2 chain ○ transmembrane

Figure b shows top View of peptide cleft

Every individual expresses small number of different Class I and Class II ○ Limited number of MHC must be able to present enormous array of different antigens ○ MHC does not display specificity of Antibodies ○ MHC is “promiscuous”

Generation of B-cell receptors (antibodies) and T-cell receptors is dynamic, changing over-time ○ Gene rearrangement In contrast, MHC molecules are fixed in the genes ○ Differences in population due to large number of alleles - In humans, ~370 A alleles, 660 B alleles, 190 C alleles

Location of genes Human Class I MHC are red ○ Telomeric end of HLA complex Class II MHC are blue ○ Centromeric end of HLA complex

Cellular Expression of MHC

MHC Restriction CD 8+ Tc cells are MHC Class I restricted Can only recognize antigen presented by MHC Class I molecules Therefore, cells with MHC Class I are called “taget cells”, killed by cytotoxic T cells CD 4+ TH cells are MHC Class II restricted Cells with MHC Class II are called antigen- presenting cells (APCs)

MHC Restriction Mice immunized with lymphocytic choriomenigitis virus (LCM) Animal’s spleen cells were extracted (containing Tc cells) ○ Cells were labeled with radioactive chromium, if lysed the chromium is released

Antigen Presenting Pathways Cystolic Pathway ○ Endogeneous antigens – produced in cell, in infected cell ○ Antigens presented on MHC Class I to Tc cells Endocytic Pathway ○ Exogeneous antigen – taken in by endocytosis by antigen-presenting cells and presented to TH cells by MHC Class II

Ubiquitin – targets protein for proteolysis TAP – transporter protein that takes the target molecule into the RER to join with forming MHC

Figure below: ○ (a) shows degradation of misfolded protein in infected cell ○ (b) shows intact proteins linked to ubiquitin to be degraded in antigen presenting cells

Endocytic Pathway Exogenous

Invariant chain – since APCs have both MHC I and II, there Must be way to prevent antigen meant for MHC I from binding To MHC II