On the mechanism of staphylococcal protein A immunomodulation (original) (raw)
Related papers
Journal of Clinical Immunology, 1995
Protein A (PA), a cell wail component of SAC, activates human B cells by cross-linking the Fabs of membrane immunoglobulins. Recent data indicate that PA binds only to Fabs that use VH3 heavy chains, and thus it has been designated as a B-cell superantigen. We previously reported that Staphylococcus aureus Cowan I (SAC) -induced IgM rheumatoid factor (RF) by human PBMC was mediated by PA. Therefore, we sought to determine if SAC-induced IgMRF production was confined to PA-binding B ceils and if these B cells were enriched for the expression of VH3 heavy chains. We observed that the elicitation of IgMRF in response to SAC was limited to a subset of B cells that bind PA and that this subset was enriched for VH3 mRNA expression. Taken together, these results suggest that IgMRFs produced in response to SAC are enriched for usage of VH3 heavy chains. Thus, this SAC-induced autoantibody response appears to represent a new B-cell superantigenic property of PA.
Staphylococcus aureus Cowan I. Potent stimulus of immunoglobulin M rheumatoid factor production
Journal of Clinical Investigation, 1986
These studies demonstrate that Staphylococcus aureus Cowan I (SAC), a protein A-positive Staphylococcal strain, is a potent and consistent inducer of IgM rheumatoid factor production by normal human peripheral blood mononuclear cells. The frequency and magnitude of this response greatly exceeded that of parallel cultures stimulated with pokeweed mitogen or the protein Anegative S. aureus Wood strain, although all three agents induced a similar amount of total IgM. Cell fractionation studies indicated that SAC-induced IgM rheumatoid factor is T cell-dependent. The striking ability of SAC to induce IgM rheumatoid factor may relate to its protein A content, since cultures stimulated with protein A-coupled sepharose beads also consistently produced this autoantibody. Thus SAC is a new probe of in vitro 1gM rheumatoid factor production and its use has provided further evidence that most healthy individuals harbor precursors of IgM rheumatoid factor secreting cells. Unlike other polyclonal activators, SAC is unique in its capacity to bind immunoglobulin, a property that may account for its prominent anti-IgG inducing capacity.
The effects of staphylococcal protein A on human lymphokine-activated killer cell induction
Cancer Immunology Immunotherapy, 1991
Staphylococcal protein A (Cowan strain; SpA), a biologically active molecule capable of inducing augmented natural killer (NK) cell cytotoxicity, was smdied in regard to its effects on lymphokine-activated killer (LAK) cell development. SpA, when co-cultured with interleukin-2 (IL-2) for 4 days, significantly augmented both LAK activity against NK-resistant M14 (melanoma) target cells and DNA synthesis of peripheral blood mononuclear cells (PBMC). This enhancement occurred with SpA concentrations of 1-100 gg/ml in a dose-dependent fashion; concentrations above 100 Bg/ml were no more effective. When SpA (10 ~tg/ml) was added to PBMC culmres with various IL-2 concentrations, cytotoxicity was increased over controls with IL-2 alone. The peak cytotoxic effect reached a plateau at 80 U/tal IL-2. SpA alone induced early (day 1) cytotoxicity, which rapidly declined. SpA alone did not induce PBMC proliferation but it did increase expression of CD25 (Tac), IL-2 receptor c~ chain, on CD56(Leu19)-positive and -negative cells. The potentiating effect of SpA was significantly enhanced in serum-free medium. If either human AB serum or human IgG was added to cultures SpA-enhanced LAK cytotoxicity was diminished. The addition of anti-interferon 7 (anti-IFNT) antibody, but not anti-IFNcq inhibited (SpA+IL-2)-induced cytotoxicity, indicating that IFN7is partially responsible for the additive cytotoxic effect.
Scientific Reports
The immunodominant staphylococcal antigen A (IsaA) is a potential target for active or passive immunization against the important human pathogen Staphylococcus aureus. Consistent with this view, monoclonal antibodies against IsaA were previously shown to be protective against S. aureus infections in mouse models. Further, patients with the genetic blistering disease epidermolysis bullosa (EB) displayed high IsaA-specific IgG levels that could potentially be protective. Yet, mice actively immunized with IsaA were not protected against S. aureus infection. The present study was aimed at explaining these differences in IsaA-specific immune responses. By epitope mapping, we show that the protective human monoclonal antibody (humAb) 1D9 recognizes a conserved 62-residue N-terminal domain of IsaA. The same region of IsaA is recognized by IgGs in EB patient sera. Further, we show by immunofluorescence microscopy that this N-terminal IsaA domain is exposed on the S. aureus cell surface. In contrast to the humAb 1D9 and IgGs from EB patients, the non-protective IgGs from mice immunized with IsaA were shown to predominantly bind the C-terminal domain of IsaA. Altogether, these observations focus attention on the N-terminal region of IsaA as a potential target for future immunization against S. aureus. Staphylococcus aureus can cause a wide variety of diseases and has a strong tendency of developing resistance against multiple antibiotics 1. Methicillin-Resistant S. aureus (MRSA)-associated infections are becoming increasingly harder to treat. Therefore, a renewed focus on the development of alternative means of treatment has arisen. Whereas many infectious diseases are nowadays controlled through vaccination, S. aureus immunity has proven hard to achieve with vaccines 2-5. As an alternative to the active immunization against S. aureus with vaccines, passive immunization with monoclonal antibodies specifically targeting S. aureus is currently explored 6-11. Invariantly expressed cell surface-exposed proteins are attractive potential targets for immunization, due to their high accessibility to the human immune system 12. This focused attention on the immunodominant S. aureus antigen A (IsaA). The IsaA protein was first described in the year 2000 as an antigen recognized by IgGs from patients with sepsis caused by MRSA 13. Subsequent, proteomic analyses of the S. aureus exoproteome revealed that the IsaA protein was invariantly produced by all investigated isolates of this pathogen 14, 15. More specifically, IsaA is a non-covalently cell wall attached protein that is both exposed to the cell surface and secreted 13, 16, 17. The IsaA protein has a putative soluble lytic transglycosylase domain at the C-terminus, indicating a role in peptidoglycan turnover and cell wall hydrolysis 17, 18. Interestingly, this C-terminal active site domain is exposed to the staphylococcal cell surface while the precise localization of the N-terminal domain was so far not known 12, 18 .
Current status of pathogenetic mechanisms in staphylococcal arthritis
Fems Microbiology Letters, 2002
Interactions between staphylococci and the joint tissues of the host lead typically to rapidly progressing and highly destructive processes. Staphylococci possess a vast arsenal of components and products that contribute to the pathogenesis of joint infection. Occasionally these compounds have overlapping activities and act either in concert or alone. Host responsiveness to staphylococcal infection displays an even more complex pattern. Most of the cells and molecules that participate in the innate immune system protect the host against bacteria. However, the staphylococci have developed systems that counteract endogenous protective mechanisms. Interestingly, certain cells and molecules of the acquired immune system potentiate the severity of infection by triggering exaggerated responses to the staphylococcal danger signals. This review deals with the intricate host–bacterium interactions that occur during experimental septic arthritis, and outlines potential preventive and treatment modalities.