| Mechanism | Description | Examples |
| Peptide Binding | Specificity of peptide binding associated with a particular disease in genetically susceptible individuals | In Coeliac disease presentation of citrullinated gluten peptide by DQ2, DQ8In IDDM absence of specific residues in the bind grove of DR17, DQ2 and DR4, DQ8 affects the peptides that can be bound and therefore presented to T cells. Key residues include Asp57 and Arg75 on DQB1α chain and Arg52 on the DQB1α chain |
| Shared Epitope | Sequence of the HLA gene may affect not just the peptide that can be bound but also the interaction with T cells | The shared epitopes associated with RA affect both the peptide that can be bound and also crucially, contact between MHC and T cells |
| Arthritogenic Peptide | Peptides derived from either the associated HLA antigen or from the affected site may cause activation of autoreactive T cells | Proposed that B27 may present an arthritogenic peptide in AS |
| Molecular Mimicry | A molecule from a pathogen may be similar enough to self antigens to crossreactive with it and activate autoreactive T cells. The mimicry means the host does not recognise the pathogen as foreign and does not therefore mount an adequate immune response against it | This is the proposed trigger for Behcet’s disease with HSP65 crossreactive for human HSP60 in HLA-B51 individualsThis is the proposed mechanisms of action of A29 in Birdshot Chorioretinopathy, following an infection or a role for retinal S-AntigenThis is also one of the proposed mechanisms of action of B27 in Reactive ArthritisAnd is also one of the proposed mechanisms for B27 in ASThis is also the proposed mechanisms of action of DR103 in Ulcerative Colitis |
| Thymic Involvement | Some autoreactive T cells escape thymic selection and are normally controlled by other post thymic selection mechanisms such as induction of anergy. This theory proposes that these T cell can, under certain circumstances, be activated. In addition defects in the thymus may be involved in disease initiation | This is one of the proposed mechanisms of B27 susceptibility in Reactive ArthritisIn MG, the hyperplastic thymus is involved in the initiation of the anti-AChR immune responses |
| Unusual Biology | Some HLA antigens, particularly B27, proposed to have unusual biology relative to other HLA. B27 for instance is thought to be expressed stably at the cell surface in some scenarios without binding peptide and can therefore bind and present extracellular peptides. In addition, B27 is able to bind unusually long peptides. HLA class I molecules normally present peptide to CD8+ T cells but B27 are thought capable of presenting to CD4+ T cells | This is one of the proposed mechanisms of B27 in AS and in Uveitis |
| Altered Self | Some HLA antigens such as B27 can form heavy chain homodimers at the cell surface without engaging β2-microglobulin. These molecules on the cell surface can act as targets for inflammatory responses. Transgenic mice studies have shown that B27 homodimers can bind NK cell receptors leading to inflammation without antigen presentation | This is one of the proposed mechanisms of B27 in AS and in Uveitis |
| Linkage to other disease associated gene | This theory proposes that the association may in fact be with another gene which is in linkage disequilibrium with the gene to which the disease is assigned | Haemochromatosis was initially thought to be associated with HLA-A3 before later being shown to be actually associated with HFE |
| Competition | Competition for receptor binding may affect the function of the receptor | Mutations in HFE affect the ability of HFE to bind the Transferrin receptor, thereby affecting ferritin levels |
| Epistasis | This describes a phenomenon in which the effects of one gene are modified by one or several other genes | In MS, presence of a conserved vitamin D response element in the promoter region of HLA-DRB1*15:01 may enhance the disease susceptibility of this gene. In addition, Homozygosity for HLA-DRB1*15:01 significantly (x6) increases disease susceptibility |
| HLA as receptor | Some HLA antigens such as B27 are proposed to act receptors for bacterial ligands, without T cell involvement. There is however very little evidence supporting this theory | This mechanisms may be involved in B27 susceptibility in Reactive Arthritis |
| Superantigen | Some HLA antigens such as B27 are proposed to bind directly to bacterial superantigens, without T cell involvement | This mechanisms may be involved in B27 susceptibility in Reactive Arthritis |