The role of HLA-B27 in arthritis.

We postulate (Table I) that ReA is an antigen or immune complex induced condition caused by chronic intracellular bacterial infection at a distant site. The main predisposing factor is a failure to resist this infection. If the bacteria happen to carry MF, the inflammation is exacerbated in B27 positive patients. In contrast AS occurs in individuals who lack immunity to MF and eventually become infected by an intracellular organism which synthesizes it (virus or plasmid?). HLA-B27 acts only at the site of inflammation.

HLA-B27 and ankylosing spondylitis: an anti-idiotypic model.

Ankylosing spondylitis (AS) is strongly associated with possession of the HLA (Human Leucocyte Antigen)-B27 histocompatibility alloantigen. It is proposed that immunological tolerance to HLA-B27 allows the emergence of a lymphocyte clone with specificity for connective tissue antigens. Such a pathogenic clone would possess idiotypic determinants cross-reactive with determinants on HLA-B27. This hypothesis was investigated using immunoglobulins from HLA-B27 subjects with active definite AS. Immunoglobulin fractions were assayed for HLA-B27-like idiotopes by inhibition of the cytotoxicity of an anti-HLA-B27 antiserum, and by an ELISA technique. The postulated HLA-B27-like idiotope was not detected using these methods.

Soluble HLA antigens not detected in human immunoglobulin preparations.

Immunoglobulin concentrates prepared from subjects of known HLA specificity were assayed for the presence of soluble HLA antigens by the inhibition of cytotoxic HLA alloantisera using a microabsorption procedure. The immunoglobulin preparations inhibited alloantisera of all specificities tested, regardless of the HLA type of the immunoglobulin donor, indicating that the observed inhibition was non-specific. Addition of extra complement reduced the inhibitory effects of the immunoglobulin concentrates. It is concluded that the inhibition of HLA alloantisera demonstrated by this technique is due to the anticomplementary activity of the immunoglobulin preparations, rather than their content of specific soluble HLA antigens.

Specific antibody response to the mycobacterial 65 kDa stress protein in ankylosing spondylitis and rheumatoid arthritis.

Immune responses to conserved, immunogenic homologues of the mycobacterial 65 kDa stress protein (SP65) have been implicated in inflammatory arthritis. Serum anti-SP65 was measured in AS, RA and healthy controls using an indirect enzyme immunoassay with recombinant SP65. IgA anti-SP65 was elevated in 19 of 59 AS patients, but the elevation in median level was not statistically significant. Anti-SP65 of all isotypes was increased in RA, but achieved significance (P less than 0.01) for IgA only. Adjusting specific antibody results for elevations in total serum Ig levels reduced AS and RA anti-SP65 to near normal levels, suggesting that a major component of the increased anti-SP65 may be secondary to polyclonal activation.

Effect of a free sulphydryl group on expression of HLA-B27 specificity.

Sequence studies indicate that the alpha-1 domain of the HLA-B27 molecule has a characteristic unpaired cysteine residue at position 67, adjacent, because of secondary structure, to a lysine at position 70. Simple chemical considerations predict that this cysteine should have an exceptionally reactive sulphydryl group. We have shown by ELISA and flow cytometry that the binding of some monoclonal antibodies to B27 on lymphoid cell lines can be inhibited by reagents which react with sulphydryl groups. However this inhibition is never complete: the evidence suggests 2 forms of B27 molecule, one of which is already blocked. We propose that some HLA molecules with oxidised sulphydryls are recognised as different from the reduced forms. Whether they are also recognised as foreign will depend on an individual's history of thymic learning. Oxidation to 'foreign' HLA in the adult is likely to predispose to inflammatory reactions.

Inflammatory disease in HLA-B27 transgenic rats.

UNLABELLED: A spontaneous inflammatory disease in rats transgenic for HLA-B27 resembles the B27-associated human spondyloarthropathies. Colitis and arthritis, the two most important features, require T cells, gut bacteria, and high expression of B27 in bone marrow-derived cells. Control rats with HLA-B7 remain healthy. Most rats with HLA-Cw6 (associated with psoriasis vulgaris) remain healthy; a minority develop mild and transient disease. Rats with a mutant B27 with a Cys67-->Ser substitution resemble wild-type B27 transgenics, but with a lower prevalence of arthritis. A similar phenotype is seen in B27 rats co-expressing a viral peptide that binds B27. Disease-prone LEW but not F344 B27 rats develop high serum IgA levels concurrent with disease progression. Colitis is associated with high interferon-gamma, arthritis with high interleukin-6. Disease is similar in B27 LEW, F344, and PVG rats, but the DA background is protective. CONCLUSIONS: The spondyloarthropathy-like disease in rats is specific for HLA-B27 but does not require Cys67. Arthritis but not colitis is particularly sensitive to B27 peptide-binding specificity. Genetic background exerts a strong influence, but some phenotypic differences exist between permissive strains that do not influence disease susceptibility. The data favor a role for B27 peptide presentation in arthritis, but other mechanisms to explain the role of B27 have not been excluded.