The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats.

Abstract

A number of inflammatory disease states occur with greatly increased frequency in individuals inheriting the human major histocompatibility complex class I allele HLA-B27. In a minority of cases, namely those with B27-associated reactive arthritis, there is good evidence that the disease state is triggered by infection with an enteric or genitourinary bacterial pathogen. For the majority of B27-associated disease, no definite pathogenetic role for bacteria has been established. However, in these latter cases intestinal inflammation can often be demonstrated, and it sometimes occupies a major part of the clinical picture. Rats transgenic for B27 are known to develop a disorder resembling B27-associated human disease, with prominent intestinal, joint, skin, and male genital inflammatory lesions. We report here that B27 transgenic rats raised in a germfree environment do not develop inflammatory intestinal or peripheral joint disease, whereas the skin and genital inflammatory lesions are unaffected by the germfree state. These findings support the concept that gut and joint inflammation are pathogenetically closely related, and they provide direct evidence that the commensal gut flora play an important role in the pathogenesis of B27-associated gut and joint inflammation.

Additional human β2‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

“…Occasional spondylitis has also been seen in histologic specimens of tail vertebrae (9). Neither gastrointestinal inflammation nor arthritis develop in these B27-transgenic rats when raised under germ-free conditions, whereas epididymo-orchitis and skin lesions are found (11,12). On the inbred LEW background, the prevalence of colitis in the B27-transgenic rats approaches 100%, whereas arthritis occurs in ϳ40% of the males and in a lower proportion of the females, and the onset of arthritis follows the onset of diarrhea by an average of ϳ1 month (13).…”

Transgenic models of autoimmune disease

“…Various high-copy number B27 transgenics develop disease while HLA-B7 controls do not [52]. The subsequent application of the HLA-B27 transgenic rats to investigate the factors contributing to disease demonstrates some of the potential benefits of a transgenic approach for elucidating disease mechanisms [53].…”

CD4+ T cells from 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rodents migrate to the recipient's colon upon transfer; down-regulation by CD8+ T cells

“…Evidence for the role of the bacterial flora in the induction of experimental colitis is that germ-free or specific pathogen-free animals develop no or less severe inflammation. This was shown in several colitis models, such as indomethacin-induced colitis [11], HLA-B27 transgenic rats [12], IL-2 knockout mice [2] and IL-10 knockout mice [13]. Recently, Brandwein et al [14] showed that C3H/HeJBir mice, which spontaneously develop colitis, produce antibodies to bacterial antigens of the enteric flora.…”