[7] Research is uncovering other genes that predispose to AS and associated diseases, and there are potential environmental factors that may play a role in susceptible individuals.
[9] HLA-B27 is implicated in other types of seronegative spondyloarthropathy, such as reactive arthritis, acute anterior uveitis, iritis, Crohn's and ulcerative colitis associated spondyloarthritis.
[13] These theories consider a specific combination of antigen peptide sequence and the binding groove (B pocket) of HLA-B27 (which will have different properties from the other HLA-B alleles).
The arthritogenic peptide hypothesis suggests that HLA-B27 has a unique ability to bind antigens from a microorganism that triggers a CD8 T-cell response that cross-reacts with a HLA-B27/self-peptide pair.
[14] The molecular mimicry hypothesis is similar, although it suggests that cross-reactivity between some bacterial antigens and self-peptides can break tolerance and lead to autoimmunity.
Cross-display is proposed to lead to the formation of large, soluble, high molecular weight (HMW), degradation-resistant, long-surviving aggregates of the HLA-B27 heavy chain.
Together with any homodimers formed either by cross-display or by a disulfide-linked homodimerization mechanism, it is proposed that such HMW aggregates survive on the cell surface without undergoing rapid degradation, and stimulate an immune response.