Are B Lymphocytes of Importance in SevereStaphylococcus aureusInfections?

Abstract

To investigate the role of B cells in experimental, superantigen-mediated Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell-deficient mice. The mice were inoculated intravenously with a toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and thus agamma-globulinemic mice showed striking similarities to the wild-type control animals with respect to the development of arthritis, the mortality rate, and the rate of bacterial clearance. Surprisingly, we found that the levels of gamma interferon in serum were significantly lower (P < 0.0001) in B-cell-deficient mice than in the controls, possibly due to impaired superantigen presentation and a diminished expression of costimulatory molecules. In contrast, the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both groups. Our findings demonstrate that neither mature B cells nor their products significantly contribute to the course of S. aureus-induced septic arthritis.We have previously described a murine model of hematogenously induced Staphylococcus aureus arthritis and sepsis (7,8). Using this model, approximately 80 to 90% of mice inoculated with S. aureus LS-1 develop clinical arthritis. Immunohistochemical analysis of arthritic joints demonstrated the presence of phagocytes and T cells, predominantly of the CD4 phenotype (4). The infected mice displayed increased levels of inflammatory cytokines, such as tumor necrosis factor and interleukin-6 (IL-6) in serum (7). We have also shown that toxic shock syndrome toxin 1 (TSST-1), a superantigen produced by S. aureus LS-1, contributes to the arthritogenicity of S. aureus (3,5). A series of studies using this model suggested that S. aureus arthritis is a T-cell-dependent and superantigen mediated disease.As to the role of B cells in S. aureus arthritis, we have found that a striking feature in this model is the occurrence of polyclonal B-cell activation with highly increased levels of immunoglobulins and autoantibodies in serum (7). Using X-linked immunodeficiency (xid) mice to investigate the contribution of the B1 subset of B cells to the development of septic arthritis, it was found that this defect provided resistance (21). Since the B1 subset is considered to be of importance in the production of autoantibodies, it was hypothesized that the outcome of the experiment might have been due to this fact.The aim of this study was to investigate if mature B cells, irrespective of their B1 or B2 phenotype, and their products including cytokines, autoantibodies, and antibodies to bacterial constituents would affect the outcome of S. aureus-induced arthritis and sepsis. We report here that a complete absence of mature B cells has no impact on the outcome of these very severe and life-threatening conditions. MATERIALS AND METHODSMice. Gene-targeted B-cell-deficient MT mice (C57BL/6 ϫ 129) (11) were backcrossed to B10.Q (H-2 q ) mice for eight generations and then further intercrossed for two generations to provide homozygous B10.Q mice lacking fu...

Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

“…5B). It was previously reported that B cells do not play a major role against S. aureus infections3861. On the contrary, our results seem to directly correlate decrease of B cell number in the joints and blood with the S. aureus early infection phase, suggesting that the pathogen might be directly involved in suppressing B cell responses systemically and in the joints, through different known mechanisms396263, and that this suppression might cause underestimation of the effective role of these cells in joint infections, as recently postulated in other models64.…”

“…Mice have been considered good models for SA and OM3637, and since blood is the most frequent source of infection in humans737, efforts were made to set up and characterize an acute hematogenously-derived murine model of arthritis2528383940, with most of the reports being concentrated on observations made in the paws3637. Recently, also thanks to the great improvement in the preclinical imaging, other groups focused their attention in the field and were able to set up long lasting models of OM which evolved from an acute to a chronic phase264142.…”

T-box transcription-factor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis

“…Furthermore, the MyD88 knock-out mice, with defects in TLR/IL-1R/IL-18R signal transmission, are similarly to IL-1R knock-out mice, highly susceptible to S. aureus infection, MyD88-deficient mice being non-responsive to S. aureus with regard to proinflammatory cytokine response [6], while an intact innate immune response seems predominantly beneficial with regard to disease outcome, the role of the adaptive immune response in protection is less convincing. Firstly, absence of mature B cells does not aggravate septic arthritis [7], possibly due to the inability to produce protective antibodies to bacterial virulence factors [8] and/or a major polyclonal B cell activation [9]. Secondly, depletion of CD4+ cells ameliorates septic arthritis and decreases the risk of septic death, indicat-> The animal experiments were approved by the ethical committee of Göteborg, Sweden.…”

Current status of pathogenetic mechanisms in staphylococcal arthritis

“…Mice that were totally deleted for B cells using a gene-targeted approach and thus being agammaglobulinemic showed striking similarities to congeneic littermates with respect to the development of S. aureus arthritis and mortality [42]. This ¢nding indicates that the entire B cell compartment is of minor importance in the defence against severe S. aureus infection.…”