Hypothesis: The etiology of ankylosing spondylitis: Does a plasmid trigger the disease in genetically susceptible individuals?

Abstract

There is at present only one well-documented clue to the pathogenesis of ankylosing spondylitis (AS): the tissue antigen HLA-B27 occurs in about 8% of a normal Caucasian population but is present in over 9 0 ~ of patients with AS and is increased in frequency in Reiter's syndrome and some other seronegative arthropathies [ 1,2]. This important clue, together with the observation that some identical twins are discordant for AS [3] and the frequent finding that certain forms of HLA-B27-associated reactive arthritis follow infections with enteric organisms such as Shigella and Yersinia [4,5] suggests an interplay between an environmental agent and HLA-B27, possibly during the early stages of pathogenesis. The nature of the interaction between a specific cell-surface alloantigen and an environmental agent is still not understood but studies by at least two groups indicate that certain organisms, notably Klebsiella. may be antigenically related to HLA-B27 [6,7] or to a physically closely-associated structure [8,9]. This suggestion is based on the finding that antibodies raised against certain Klebsiella isolates (as well as against some isolates of Salmonella newport. S. (yphimurium, and Shigella sp.. J.K. Prendergast, unpublished results) specifically lyse the HLA-B27-positive lymphocytes of about 8 0 ~ of patients with ankylosing spondylitis and of 60% of those with Reiter's syndrome or asymmetrical peripheral arthritis, but not the HLA-B27-positive lymphocytes of clinically normal individuals [10]. An extension of these studies has shown that B27-positive lymphocytes from normal individuals, which are not normally lysed by antiKlebsiella serum, can be rendered susceptible to lysis following their incubation in the culture filtrate (containing modifying factor) of certain Klebsiella organisms [11]. Further support for the role of an environmental agent in B27Klebsiella interactions is provided by the demonstration that the lymphocytes of clinically normal family members who share the HLA-B27 haplotype with some of their AS-affected siblings, are not lysed by anti-Klebsiella serum [10]. These observations suggest that the modification of B27 is not a direct genetic effect. By contrast, the persistence of the Klebsiella-cross-reactive marker on cultured