Minor histocompatibility antigens (mHC)

JANEWAY'S VIEW

Mechanism explained

Minor histocompatibility antigens are alloantigens that are recognized on tissues of MHC-matched individuals. They are recognized by the responder because the matched MHC molecule presents a self peptide of the stimulator that differs from the corresponding self peptide of the responder. Two self peptides in two individuals may differ when they are processed from a self protein that is polymorphic in the population.

A polymorphic protein can be processed and presented by the stimulator cell itself (in the context of a compatible MHC-molecule) or a by a responder APC that has internalized fragments of the stimulator's tissue (cross-presentation). These 2 different pathway are very much like the indirect and direct pathway of presentation of incompatible MHC-molecules. Because the entity of the self-MHC molecule and the unknown peptide look like an unknown antigen, allorecognition of minor histocompatibility antigens is analogous to the recognition of a pathogen.

Incidence of mHC in transplantation

Minor histocompatibility antigens are weaker transplantation antigens than major histocompatibility antigens. During a response, the immune system responds to the strongest antigens only (immunodominance). Hence, when donor and recipient are mismatched for major as well as for minor histocompatibility antigens, the alloresponse will be directed predominantly to the incompatible major histocompatibility antigen.

Minor histocompatibility antigens are designated as "minor" because in the first transplantation experiments, they caused skin rejections that were much slower than a rejection caused by an incompatibility of a major histocompatibility antigen. Nevertheless, they represent important transplantation barriers in human HSC transplantation and around 30% of the MHC-matched donor recipients still suffer from GVHD after HSC transplantation because the allogeneic T cells recognize the mismatched minor histocompatibility antigens of the patient.

Examples of mHA	Chromosome
HA-1	19
HA-2	6
HA-8	9
HB-1	5
HY-A1	Y
HY-A2	Y
HY-B7	Y
HY-B8	Y
HY-B60	Y
HY-DQ5	Y
Although any genetic polymorphism could give rise to minor histoincompatibility, the number of genes encoding for minor antigens is limited. Around 10 minor antigens located on autosomal chromosomes have been identified among one hundred or so existing. The Y chromosome, regarded as a genetic wasteland, bears also some genes encoding for mHA. The first minor histocompatibility peptide identified was HA-2, a GVHD-associated mHA. The most studied of all mHA are HY-antigens.

Nature of mHC

At present, the nature of many minor histocompatibility antigens is not known. Obviously, any single or multiple amino acid polymorphism in a protein of the stimulator can be processed and be presented as a foreign antigen to the responder. An example of a human minor antigen are the HY-antigens. Because females do not express the proteins encoded by the male Y chromosome, the T lymphocytes of a female responder may recognize the male proteins encoded by the Y-chromosome of the stimulator.