Major Histo compatibility complex , refer from standard books of micro

Major Histo compatibility complex , refer from standard books of microbiology

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"Major Histocompatibility Complex" AND antigen presentation

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NCBI Bookshelf major histocompatibility complex MHC antigen presentation class I class II

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https://www.ncbi.nlm.nih.gov/books/NBK27156

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Major Histocompatibility Complex (MHC) / Human Leukocyte Antigen (HLA) Complex

The major histocompatibility complex (MHC) is a tightly linked group of genes whose products are cell-surface molecules that bind peptide antigens and present them to T lymphocytes. In humans, it is called the human leukocyte antigen (HLA) complex.

It was originally identified because differences in these molecules cause graft rejection. Its central physiological function, however, is antigen presentation to T cells. Unlike antibodies, which can bind native antigen directly, a conventional T-cell receptor recognizes an antigenic peptide only when it is displayed within the groove of a self-MHC molecule. This is called MHC restriction.

Reference: Jawetz, Melnick & Adelberg’s Medical Microbiology, 28th ed., pp. 138-139.

Location and genetic properties

Location: short arm of chromosome 6, at 6p21.3.
Human MHC = HLA complex.
Mouse MHC = H-2 complex.
MHC genes are inherited together as a haplotype, one haplotype from each parent.
Expression is codominant: both maternal and paternal HLA alleles are expressed.
The MHC is polygenic: several distinct class I and class II genes are present.
It is highly polymorphic, meaning that each locus has many alleles in the population. This diversity determines the peptide-binding range and explains the importance of HLA matching in transplantation.

As described in Immunobiology, polygeny, polymorphism, and codominant expression enable an individual to express multiple peptide-presenting MHC molecules.

Classes of MHC

Feature	MHC class I	MHC class II
Main HLA loci	HLA-A, HLA-B, HLA-C	HLA-DP, HLA-DQ, HLA-DR
Structure	One polymorphic α heavy chain + β2-microglobulin	One α chain + one β chain
Peptide source	Endogenous or cytosolic proteins	Exogenous proteins taken up by APCs
Expressed on	Almost all nucleated cells	Professional APCs
Presented to	CD8+ cytotoxic T cells	CD4+ helper T cells
Typical peptide length	8-10 amino acids	Usually 13-18 amino acids, can bind longer peptides
Main role	Killing of infected or malignant cells	Activation and direction of helper-T-cell responses

Reference: Jawetz, Melnick & Adelberg’s Medical Microbiology, 28th ed., p. 138.

1. MHC Class I

Structure

Class I MHC consists of:

A transmembrane α heavy chain, encoded by HLA-A, HLA-B, or HLA-C.
β2-microglobulin, noncovalently associated with the α chain. It is encoded on chromosome 15, not in the MHC locus.
A peptide-binding cleft formed by the α1 and α2 domains.

Distribution

Class I MHC is expressed on nearly all nucleated cells. Mature red blood cells do not express MHC class I because they lack a nucleus.

Antigen-processing pathway: endogenous pathway

This pathway presents proteins formed within the cell, such as:

Viral proteins in a virus-infected cell
Tumor-associated proteins
Intracellular microbial proteins

Steps:

Cytosolic proteins are degraded into peptides by the proteasome.
Peptides are transported from cytosol into rough endoplasmic reticulum by TAP-1 and TAP-2 transporters.
Peptides bind the newly synthesized class I heavy chain and β2-microglobulin in the ER.
The stable peptide-MHC I complex is carried through Golgi to the cell surface.
The complex is recognized by a CD8+ cytotoxic T lymphocyte.
The activated CTL kills the infected or altered target cell.

Key association:
Endogenous antigen -> MHC I -> CD8+ T cell

The MHC class I region also contains genes involved in antigen processing, including TAP genes.
Reference: Jawetz, Melnick & Adelberg’s Medical Microbiology, 28th ed., p. 139.

2. MHC Class II

Structure

MHC class II is a heterodimer made of:

An α chain
A β chain

Both chains are encoded within the HLA-D region. The peptide-binding groove is formed by the α1 and β1 domains and is open at both ends, allowing binding of longer peptides.

Distribution

It is constitutively expressed mainly on professional antigen-presenting cells:

Dendritic cells
Macrophages
B lymphocytes

Expression may be induced on some other cells, such as endothelial or epithelial cells, by interferon-gamma (IFN-γ).

Antigen-processing pathway: exogenous pathway

This pathway presents proteins acquired from outside the cell, such as bacterial toxins, bacterial cell-wall proteins, and soluble microbial antigens.

Steps:

The APC engulfs exogenous antigen by phagocytosis or endocytosis.
Antigen is degraded into peptides in acidified endosomes or lysosomes.
MHC class II molecules are synthesized in the ER while associated with the invariant chain (Ii).
The invariant chain prevents binding of endogenous peptides to the class II groove during transport.
In the endosomal compartment, Ii is degraded, leaving CLIP in the groove.
HLA-DM facilitates removal of CLIP and loading of antigenic peptide.
The peptide-MHC II complex moves to the APC surface.
It is recognized by a CD4+ helper T cell.

Key association:
Exogenous antigen -> MHC II -> CD4+ T cell

Reference: Jawetz, Melnick & Adelberg’s Medical Microbiology, 28th ed., p. 139.

MHC Class III

The class III region does not encode classical antigen-presenting MHC molecules. It contains genes for several immune-related proteins, including:

Complement components, notably C2, C4, and factor B
Cytokines such as TNF

Reference: Jawetz, Melnick & Adelberg’s Medical Microbiology, 28th ed., p. 139.

MHC restriction

A T cell responds to an antigen only if the antigen is presented with the appropriate self-MHC molecule.

For example:

A CD8+ T cell recognizes a viral peptide only when it is displayed by self-MHC class I.
A CD4+ T cell recognizes a bacterial peptide only when it is displayed by self-MHC class II.

Thus, TCR recognition is directed against a combined surface: peptide + self-MHC, not peptide alone.

Cross-presentation

Some dendritic cells can take up an exogenous antigen but present it through MHC class I. This is called cross-presentation.

It permits activation of naive CD8+ T cells against viruses or tumors that do not directly infect dendritic cells.

Exception to remember:
Exogenous antigen -> MHC I -> CD8+ T cell, through cross-presentation.

Importance in microbiology and clinical medicine

1. Defense against infection

MHC I allows CD8+ cells to identify and kill cells infected with viruses and other intracellular pathogens.
MHC II activates CD4+ helper cells, which stimulate macrophages, B cells, and cytotoxic T-cell responses against microbes.

2. Transplant rejection

Differences between donor and recipient HLA molecules are strongly immunogenic. The closer the HLA match, the lower the risk of graft rejection or graft-versus-host disease, particularly in hematopoietic stem-cell transplantation.

3. Disease associations

Certain HLA alleles are associated with increased susceptibility to disease:

HLA allele	Disease association
HLA-B27	Ankylosing spondylitis, reactive arthritis
HLA-DR3	SLE, type 1 diabetes, Graves disease
HLA-DR4	Rheumatoid arthritis, type 1 diabetes
HLA-DQ2/DQ8	Celiac disease
HLA-B51	Behçet disease
HLA-B*57:01	Abacavir hypersensitivity
HLA-B*15:02	Carbamazepine-associated Stevens-Johnson syndrome in genetically susceptible populations

These associations do not mean that an HLA allele alone causes disease. Rather, it modifies antigen presentation and immune responsiveness.

4. Pathogen immune evasion

Some viruses evade immunity by reducing MHC class I expression or interfering with TAP-mediated peptide transport. This can reduce CD8+ T-cell recognition, although loss of class I expression can make infected cells more vulnerable to NK-cell killing.

High-yield summary

MHC = HLA complex in humans, located on chromosome 6.
It is polygenic, highly polymorphic, inherited as haplotypes, and expressed codominantly.
Class I: HLA-A, B, C; all nucleated cells; endogenous antigen; CD8+ T cells.
Class II: HLA-DP, DQ, DR; APCs; exogenous antigen; CD4+ T cells.
Class III: complement and inflammatory proteins, not classical antigen presentation.
T cells recognize peptide only in association with self-MHC.
MHC is fundamental in antimicrobial immunity, transplantation, autoimmunity, and disease susceptibility.

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