Several non-mutually exclusive mechanisms have been proposed to explain association of DR/DQ with autoimmune diseases.
- Variation in binding groves of associated DR/DQ molecules could lead to preferential presentation of only a specific limited set of self-peptides or low affinity self-peptides may allow autoreactive T cells to escape tolerance and enter the periphery. This could affect thymic T cell education, causing incomplete thymic tolerance and a Th and Treg cell population that does not recognize all self-molecules
- Polymorphic residues of the T cell receptor-exposed surfaces of DR/DQ could select autoreactive T cells or fail to select a good Treg population
- Promiscuous restriction where some T cell receptor will use a series of different restriction elements to bind to and, therefore, interact with a wider variety of different peptides
- Preferential binding in DR/DQ heterozygous subjects could be occuring through epitope stealing by one HLA molecule over another which depending on T cell receptor restriction of CD4 Th cells, could affect whether an immune response is mounted
- Presentation of endogenous antigens by HLA class II. Although class II molecules traditionally present exogenous antigens and class I present endogenous antigens, this system is not absolute and presentation of endogenous antigens by class II and exogenous antigen by class I can be seen. This could alter how these antigens are presented to the immune system and the response triggered. These hypothesis suggest a series of potential mechanistic pathways by which the HLA class II molecules could be involved in disease onset by altering the Th and Treg cell repertoire or through changes in how the antigen is recognized in the periphery