There are several theories that have been developed in order to try to explain how the HLA-B27 molecule mediates arthritis in mice and rats, and how P2m plays a role in the pathogenesis. Among the first theories presented was that the HLA-B27 molecule itself was a target of the immune system. Khare et al. found that whereas HLA-B27 was not expressed on the surface of cells in HLA-B27+/ P2m-/- mice, expression could be induced by stimulation of cells from these mice with con-canavalin A (con A) . This cell surface expression of HLA-B27 in the absence of P2m was hypothesized by Khare et al. to result in an immune response against the HLA-B27+ cells by CD8+ T-cells that had not been exposed to HLA-B27 during their thymic development. Alternatively, Mear et al. have suggested that the amino acid composition of the peptide-binding B pocket of HLA-B27  causes the HLA-B27 molecule to fold inefficiently . These investigators hypothesized that this misfolding, which normally triggers protein degradation, could result in an excess of intracellular HLA-B27 in the protein degradation pathways. This could result in either an excess of HLA-B27-derived peptides being presented by other Class I molecules, or possibly the B27-derived peptides being shunted into the Class II presentation pathway. The potential involvement of CD4+ T-cells in HLA-B27-associated pathogenesis is an intriguing possibility that will be discussed later in this section.
The concept that excess HLA-B27 contributes to autoimmunity was also tested by Allen et al. who found that HLA-B27 could form homodimers via an unpaired cysteine residue in the molecule's a1 domain . These homodimers were expressed on the cell surface in the absence of P2m and retained some peptide binding ability. This finding provided a possible mechanism for the spontaneous arthritis occurring in HLA-B27 transgenic mice deficient in P2m, i.e., that imperfectly folded HLA-B27 that escapes degradation may be expressed on the cell surface without P2m and either serve as an antigen itself, present peptides that are arthrito-genic, or serve as a ligand for receptors other than T-cell receptors. A potential role of HLA-B27 homodimers (B272) is supported by the demonstration of their existence on the surface of splenocytes from HLA-B27 transgenic mice that are either lacking P2m or are also transgenic for human P2m . To determine if these homodimers bound a ligand other than T-cell receptor, Kollnberger et al. used tetrameric B272 to probe murine splenocytes. They found that the B272 tetramer bound to a subset of splenocytes via the paired Ig-like receptors, PIRs, expressed on the B-cells and monocytes in these mice. Related studies strengthened the relevance of this model to human spondyloarthropathies by showing that human AS patients express HLA-B27 homodimers as well as non T-cell receptor ligands for these homodimers .
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