MAJOR HISTOCOMPATIBILITY COMPLEX

BVM II IMMUNOLOGY LECTURE SERIES JPM 254: IMMUNOLOGY AND VACCINOLOGY BY DR MAHACLA ODONGO

© 2019

4/6/2020 1 Major Histocompatibility Complex (MHC)

❑ Major histocompatibility complex (MHC) = a chromosomal region containing a cluster of genes which encode many different protein molecules (glycoproteins) with related structures and functions.

❑ In humans, MHC genes occurs on chromosome number 6, whereas in the mouse, it occurs on chromosome number 17.

4/6/2020 2 MHC locus

❑ The MHC locus is about 2000-4000 kb long and encodes cell surface glycoproteins that regulate cellular interactions between sensitive cells (T cells and B cells) and antigen-presenting cells (macrophages and dendritic cells).

❑ All vertebrates from cartilaginous fish to mammals possess MHC genes.

❑ MHC molecules enable T cells to recognize epitopes of

and discriminate self from non-self4/6/2020. 3 MHC

❑ Both T and B cells use surface molecules to recognize antigen, they accomplish this in very different ways.

❑ In contrast to antibodies or B-cell receptors, which can recognize an antigen alone,

❑ T-cell receptors only recognize pieces of antigen that are positioned on the surface of other cells as a complex with a protein called the Major histocompatibility complex (MHC) molecule encoded by a cluster of genes collectively called the MHC locus.

4/6/2020 4 MHC

❑ These fragments are generated inside the cell following antigen digestion, and the complex of the antigenic peptide plus MHC molecule then appears on the cell surface.

❑ MHC molecules thus act as a cell surface vessel for holding and displaying fragments of antigen so that approaching T cells can engage with this molecular complex via their T-cell receptors.

❑ The MHC in humans is known as human leukocyte antigens (HLA) complex

4/6/2020 5 Classes of MHC genes and proteins

❑ The three classes of MHC genes and proteins include:

1. Class I MHC

2. Class II MHC

3. Class III MHC

4/6/2020 6 MHC class I Genes and molecules

❑ Encode glycoproteins expressed on the surface of nearly all nucleated cells.

❑ The major function of the class I gene product is presentation of peptide antigens to cytotoxic T cells.

❑ The cytotoxic T cell receptor for MHCI-antigen complex is CD8

4/6/2020 7 MHC class II genes and molecules

❑ Class II MHC genes encode glycoproteins expressed primarily on APCs, where they present processed antigenic peptides to TH cells.

❑ MHC class II genes encode proteins found on the cell surfaces of professional exogenous antigen processing cells (B cells, dendritic cells and macrophages), and variably on T cells, keratinocytes and vascular endothelial cells.

❑ Macrophages with MHC class II molecules predominate in the spleen, thymus, and liver of all species.

❑ Macrophages that lack MHC class II molecules are incapable of mounting an immune response.

4/6/2020 8 MHC class II genes and molecules

❑ Cells expressing MHC class II molecules vary with animal species, e.g., in rodents, these molecules are constitutively expressed on B cells, dendritic cells and macrophages, but must be induced in T cells, keratinocytes and vascular endothelial cells;

❑ They are constitutively expressed on all resting T cells of dogs, cats and horses;

❑ In pigs, they are constitutively expressed on T cells, macrophages and sperms but are induced on renal vascular endothelium and glomeruli;

4/6/2020 9 MHC class II genes and molecules

❑ In cattle, these molecules are called BoLA class II molecules and are found on epithelial cells, B cells, macrophages and dendritic cells;

❑ In humans, these molecules are also expressed on renal vascular endothelium and glomeruli besides the professional antigen presenting cells.

❑ MHC class II molecules main function is to present processed exogenous antigen to helper T cells.

❑ CD4 on helper T cells is the surface receptor for MHC class II molecules on APCs.

❑ MHC class II molecules also activates B cells to produce antibodies.

❑ MHC-II plays a significant role in graft versus host response.

4/6/2020 10 Differences between MHC class I and MHC class II molecules

MHC class I glycoproteins present endogenous antigens that originate from the MHC II proteins present exogenous antigens that originate extracellularly from Nature of cytoplasm. foreign bodies such as bacteria.

Size of peptide MHC Class I present 8-10 amino acid peptides MHC Class II presents 14-18 amino acid peptides.

Responsive T Cells Present antigen to cytotoxic T cell lymphocytes (CD8+ T Cells); Present antigen to helper T cell lymphocytes; (CD4+ T cells).

Co-receptor responsible Binds with CD8 coreceptors molecules on cytotoxic T cells Binds with CD4 co-receptors molecules on helper T cells

Cytosolic proteins (mostly synthesized in the cell, may enter cytosol from Endosomal/lysosomal proteins (mostly internalized from extracellular Sources of Protein Antigens phagosomes) environment)

Enzymes Responsible for peptide generation Cytosolic proteasome Endosomal and lysosomal proteases (e.g., cathepsins)

Site of peptide loading of MHC Endoplasmic reticulum Specialized vesicular compartment

Molecules involved in transport of peptides and loading of MHC Chaperones in ER; invariant chain in ER, Golgi and MHC Class II molecules Chaperones, TAP in ER compartment/Class II vesicle; DM

Presentation of foreign-intracellular antigens or altered self-antigens; targets cell Presentation of foreign extracellular antigens; induces antibody production, and End Result for destruction attracts immune cells to area of infection

4/6/2020 11 MHC class III genes and molecules

❑ Class III MHC genes encode, various secreted proteins that have immune functions, including components of the complement system and molecules involved in inflammation (e.g. TNF, Heat Shock proteins).

❑ MHC-III are not markers on cell surface

❑ MHC-III are involved in complement activation (complement factors C2, C4 and B)

❑ MHC-III are also involved in inflammation caused by cytokines, tumor necrosis factors (TNF-αTNF-β), etc

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