The following analyses do NOT support the notion that the molecular mimicry theory of pathogenesis of AS is gaining in acceptance within the scientific community:

1.
Molecular mimicry is theory number six out of nine theories presented in the following table summarizing theories proposed to explain the association of HLAB27 with AS/spondyloarthropathies. The comment on theory number 6 is : "This [theory] has difficulty explaining the tissue specificity of disease"
http://www-ermm.cbcu.cam.ac.uk/99001131h.htm

The preceding table is derived from the following review
http://www-ermm.cbcu.cam.ac.uk/99001118h.htm

2.
Nuki G.
Ankylosing spondylitis, HLA B27, and beyond.
Lancet. 1998 Mar 14;351(9105):767-9. No abstract available.
PMID: 9519942

ANKYLOSING SPONDYLITIS, HLA B27, AND BEYOND

Publication of the landmark Lancet paper showing the strong association between HLA B27 and ankylosing spondylitis 25 years ago[1] stimulated an avalanche of research into HLA/disease associations. The subsequent weaker associations of HLA B27 with anterior uveitis, reactive arthritis, sacroiliitis, late-onset pauciarticular juvenile chronic arthritis in boys, and inflammatory bowel disease with axial joint involvement suggested a common genetic determinant for a group of disorders already linked as seronegative spondyloarthropathies by the clinical observations and family studies of the late Verna Wright,[2] and others. Because reactive arthritis can be precipitated in B27-positive individuals by sexually acquired chlamydial infection or by enteric infections with Campylobacter, Clostridium, Salmonella, Shigella, and Yersinia spp, induction of disease by "arthritogenic" bacterial strains in genetically predisposed individuals has become a compelling idea for the pathogenesis of these disorders. This idea is supported by experiments in transgenic rats expressing HLA B27 and human b2- microglobulin. Such animals develop gut and joint inflammatory disease,[3] which is mediated by normal gut bacteria, including Bacteroides species,[4] and which does not occur when the animals are maintained in a germ-free environment.[5]

Has the research led to progress in the understanding of the mechanisms underlying the association between B27 and the spondyloarthritides? Several theories have been reviewed recently[6] and are summarised in the panel.

Although the rodent B27 transgenic models of ankylosing spondylitis imply direct involvement of B27 in the pathogenesis of disease, the development of spondyloarthritis in B27-positive, b2-microglobulin-negative mice[7] suggests that functional cell-surface B27 is not essential for antigen presentation. B27-derived peptides may be bound and presented by HLA class II molecules, a reaction consistent with the observation that CD4 lymphocytes are required for the transfer of disease from B27 transgenic rats to other strains.[8]

At present there is little evidence to support the altered self, linked-gene, or molecular-mimicry hypotheses. Variations in the frequency with which ankylosing spondylitis is associated with allelic subtypes of B27 would weigh against them.. Although most of the 11 B27 subtypes are associated with similar risk of disease, HLA-B*2706 has been negatively associated with spondyloarthritis in recent studies from Thailand[9] and Indonesia.[10] Data indicating that B*2703 was not associated with ankylosing spondylitis in the Gambia11 needs to be reinterpreted after more recent studies.[12] These did not reveal a single case of ankylosing spondylitis in 215 first-degree relatives of 48 B27-positive Gambian Fula twin pairs plus 900 Fula men-even though 6% of Fula are B27 positive (32% B*2703, 68% B*2705). The investigators concluded that the risk of developing ankylosing spondylitis was significantly lower in B27-positive Fula than in B27-positive whites (even when the most conservative estimates of risk are used), and that the absence of ankylosing spondylitis in the Fula could not be attributed to B27-subtype distribution. Possible explanations must include the absence of an environmental trigger or the presence of protective environmental or genetic factors. Because the relative risk of developing ankylosing spondylitis has also been shown to be lower in B27-positive American Africans than in B27-positive whites,[13] non-HLA-B27 genetic factors seem to be more likely candidates than environmental factors.

Review of studies3 of non-B27 HLA-B genes and HLA-DR genes showed that only HLA B60 and HLA DR1 are consistently associated with an increase in susceptibility to ankylosing spondylitis in B27-positive and B27-negative individuals. This was confirmed in some recent twin studies.[14] Pooling the data from their own and three previous studies of twins with ankylosing spondylitis, the research team from the Wellcome Trust Centre for Human Genetics, Oxford, UK, found that the concordance rate for ankylosing spondylitis was 67% in B27-positive monozygotic twins and 23% in dizygotic twins. Statistical modelling of the pooled data suggested that additive genetic effects accounted for 97% of the population variance, with only 16% attributable to HLAgenes.

Until recently, there have been very few studies of non-HLA genes in patients with ankylosing spondylitis. Secretor status was of interest because non-secretion of ABO blood-group antigens is associated with susceptibility to certain infections, and because preliminary studies had suggested an increased prevalence of non-secretors among patients with ankylosing spondylitis. Recent re-evaluation has, however, not confirmed this finding.[15] Most recently, a preliminary genome-wide screen for susceptibility loci has been undertaken by the Oxford group.[16] Linkage was studied in 105 families with 121 affected sibling-pairs with ankylosing spondylitis, by the use of 254 polymorphic microsatellite markers. The study confirmed the MHC as the major region of genetic susceptibility to ankylosing spondylitis but also identified and localised several non-MHC genes that may significantly influence susceptibility to the disease. Further multicentre studies using much larger numbers of multiplex families will be required to confirm these findings and identify the new candidate genes, but the prospects for new insights into the aetiology of ankylosing spondylitisare exciting.

Hypotheses for association of HLA B27 with spondyloarthropathies*

• Molecular mimicry-Cross reaction of cellular or humoral immune response to bacterial epitope with B27.

• Arthritogenic peptide-Cellular reaction to peptide presented by B27 or B27-peptide complex.

• Altered self- Loss of tolerance resulting from altered antigenicity of B27 following oxidation of cysteine 67 at mouth of B aminoacid recognition pocket.

• Linked gene- B27 acts as marker for linked MHC disease-determining gene or linked gene increases penetrance of B27.

• Defective immunity- B27 impairs immunity to arthritogenic organisms by association with arthritogenic epitopes from other HLA molecules or by altering T-cell responses to inhibitory cytokines.

• Promiscuous peptide- B27-derived peptides elicit immune reponse following presentation by HLA-class II (DR)

*Modified from ref 6.*Modified from ref 6.

1 Brewerton DA, Hart FD, Nicholls A, Caffrey M, James DCO, Sturrock RD. Ankylosing spondylitis and HLA-27. Lancet 1973; ii: 904-07.

2 Wright V, Moll JMH. Seronegative polyarthritis. Amsterdam: North Holland Publishing Company 1976: 1-483.

3 Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD. Spontaneous inflammatory disease in transgenic rats expressing HLA B27 and human b2m: an animal model of HLA B27 associated with human disorders. Cell 1990; 63: 1099-12.

4 Rath HC, Herfarth HH, Ikeda JS, et al. Normal luminal bacteria, especially bacteroides species, mediate chronic colitis, gastritis,and arthritis in HLA B27/human beta2 microglobulin transgenic rats. J Clin Invest 1996; 98: 945-53.

5 Taurog JD, Richardson JA, Croft JT, et al. The germ free state prevents development of gut and joint inflammatory disease in HLA B27 transgenic rats. J Exp Med 1994; 180: 2359-64.

6 Brown M, Wordsworth P. Predisposing factors to spondyloarthropathies. Curr Opin Rheumatol 1997; 9: 308-14.

7 Khare SD, Luthra HS, David CS. Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta[2] microglobulin: a model of human spondyloarthropathies. J Exp Med 1995; 182: 1153-58.

8 Breban M, Fernandez-Sueiro J, Richardson J, et al. T cells but not thymic exposure to HLA-B27 are required for the inflammatory disease of HLA-B27 transgenic rats. J Immunol 1996; 156: 794-803.

9 Lopez-Larrea C, Sujrachato K, Mehra NK, et al. HLA-B27 subtypes in Asian patients with ankylosing spondylitis: evidence for new associations. Tissue Antigens 1995; 45: 169-76.

10 Nasution AR, Mardjuadi A, Kunmartini S, et al. HLA-B27 subtypes positively and negatively associated with spondyloarthropathy. J Rheumatol 1997; 24: 1111-14.

11 Hill AV, Allsopp CE, Kwaitkowski D, Anstey NM, Greenwood BM, McMichael AJ. HLA-class I typing by PCR: HLA-B27 and an African B27 subtype. Lancet 1991; 337: 640-42.

12 Brown MA, Jepson A, Young A, Whittle HC, Greenwood BM, Wordworth BP. Ankylosing spondylitis in West Africans-evidence for a non-HLA-B27 protective effect. Ann Rheum Dis 1997; 56: 68-70.

13 Khan M, Braun W, Jushner J, Grecek DE, Wuir WA, Steiberg AG. HLA-B27 in ankylosing spondylitis: differences in frequency and relative risks in American blacks and Caucasians. J Rheumatol 1997; 4 (suppl 3): 39-43.

14 Brown MA, Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLAand the environment. Arthritis Rheum 1997; 40: 1823-28.

15 Smith GW, James V, Mackenzie DAC, et al. Ankylosing spondylitis and secretor status: a re-evaluation. Br J Rheumatol 1997; 36: 778-80.

16 Brown MA, Pile KD, Kennedy LG, et al. A genome-wide screen for susceptibility loci in ankylosing spondylitis. Br J Rheumatol 1997; 36 (suppl 1).