HLA-B27 modulates the survival of Salmonella enteritidis in transfected L cells, possibly by impaired nitric oxide production

Abstract

Reactive arthritis is triggered by certain microbes that cause primary infections mainly on the gastrointestinal or urogenital mucosa. The disease is strongly associated with HLA-B27. Long persistence of causative microbes or their structures in the body has been thought to have an important role in the pathogenesis of reactive arthritis. This suggests that the elimination of the microbes causing reactive arthritis is ineffective or disturbed in HLA-B27-positive individuals developing this complication. We examined the role of the HLA-B27 antigen in microbe-host interaction in vitro by monitoring the invasion and intracellular survival of Salmonella enteritidis in mouse fibroblasts transfected with HLA-B27, HLA-B7, or ␤ 2-microglobulin only. S. enteritidis invaded into all the three transfectants with the same efficiency. However, at 6 and 10 days after incubation, there were more living intracellular Salmonella organisms in HLA-B27 transfectants than in the other transfected cell lines (P < 0.05), suggesting that the bactericidal effect is impaired in these cells. Impaired NO production in HLA-B27-transfected cells was indicated as a possible mechanism, since the amount of nitrite in the supernatants of the Salmonella-infected HLA-B27-transfected cells was smaller than that in the supernatants of the Salmonella-infected HLA-B7-or ␤ 2-microglobulin-transfected cells (P < 0.001). The inhibition of NO synthesis by N-monomethyl-L-arginine resulted in impaired elimination of Salmonella also in HLA-B7and ␤ 2-microglobulin-transfected cells. The inverse correlation between intracellular survival of Salmonella and the amount of nitrite detected in culture supernatants supports the hypothesis that the L-argininedependent NO pathway plays an important role in the murine fibroblast response against Salmonella. We suggest that a major histocompatibility complex class I antigen, HLA-B27, may contribute to the intracellular persistence of Salmonella by a mechanism which involves the NO pathway.

Evidence that the p38 MAP kinase pathway is dysregulated in HLA–B27–expressing human monocytic cells: Correlation with HLA–B27 misfolding

“…This has prompted us to study whether B27 expression alters the function of host cells that encounter ReA‐triggering bacteria in vitro. We observed impaired elimination of Salmonella enteritidis in B27‐transfected cell lines as compared with appropriate controls (16, 17). Further studies showed that B27‐expressing cells were more permissive of intracellular replication of S enteritidis .…”

Inflammatory Disease in HLA-B27 Transgenic Rats

“…It has long been known that patients with reactive arthritis triggered by Yersinio or Salmonella show prolonged immune responses to these microorganisms, suggesting bacterial persistence (reviewed in (6.S)). Recently, B27, unlike other HI.A I genes, has been shown to be associated with marked impairment of clearance of intracellular bacteria from transfected human and mouse cell lines (66,67), with impaired nitric oxide production suggested as at least one possible mechanism. Increased bacterial persistence would then be expected to provoke a heightened immune response.…”

HLA–B27 modulates nuclear factor κB activation in human monocytic cells exposed to lipopolysaccharide

“…Traditionally, the main function of the major histocompatibility complex (MHC) class I molecules has been thought to be antigen presentation (16), but an increasing number of reports indicate other putative functions. We have previously demonstrated impaired elimination of Salmonella enteritidis in HLA–B27–transfected human monocytic cells compared with HLA–A2–transfected counterparts (17), and in HLA–B27–transfected murine fibroblasts compared with HLA–B7 or human β 2 ‐microglobulin–transfected counterparts (17, 18). Certain mouse MHC class I molecules have been shown to play a role in modulating the replication of intracellular Sindbis virus (19).…”