Primary pneumococcal peritonitis can be the first presentation of a familial complement factor I deficiency1.

Primary pneumococcal peritonitis is a rare infection that has been described in women but has not been previously linked with immunodeficiency. The complement system plays a central role in immune defence against Streptococcus pneumoniae and, in order to evade complement attack, pneumococci have evolved a large number of mechanisms that limit complement-mediated opsonization and subsequent phagocytosis. We investigated an apparently immunocompetent woman with primary pneumococcal peritonitis and identified a family with deficiency for complement factor I. Primary pneumococcal peritonitis should be considered a possible primary immunodeficiency presentation.

H2-M3 major histocompatibility complex class Ib-restricted CD8 T cells induced by Salmonella enterica serovar Typhimurium infection recognize proteins released by Salmonella serovar Typhimurium.

Salmonella enterica serovar Typhimurium causes a typhoid-like disease in mice which has been studied extensively as a model for typhoid fever in humans. CD8 T cells contribute to protection against S. enterica serovar Typhimurium in mice, but little is known about the specificity and major histocompatibility complex (MHC) restriction of the response. We report here that CD8 T-cell lines derived from S. enterica serovar Typhimurium-infected BALB/c mice lysed bone marrow macrophages infected with S. enterica serovar Typhimurium or pulsed with proteins from S. enterica serovar Typhimurium culture supernatants. Cytoxicity was beta-2-microglobulin dependent and largely TAP dependent, although not MHC class Ia restricted, as target cells of several different MHC haplotypes were lysed. The data suggested the participation of class Ib MHC molecules although no evidence for the presence of Qa1-restricted T cells could be found, unlike in previous reports. Instead, the T-cell lines lysed H2-M3-transfected fibroblasts infected with S. enterica serovar Typhimurium SL3261 or treated with Salmonella culture supernatants. Thus, this report increases the number of MHC class Ib antigen-presenting molecules known for Salmonella antigens to three: Qa-1, HLA-E, and now H2-M3. It also expands the range of pathogens that induce H2-M3-restricted CD8 T cells to include an example of gram-negative bacteria.

Characterization of the synovial T cell response to various recombinant Yersinia antigens in Yersinia enterocolitica-triggered reactive arthritis. Heat-shock protein 60 drives a major immune response.

OBJECTIVE: In Yersinia enterocolitica-triggered reactive arthritis (Yersinia ReA), the synovial T cell response is primarily directed against bacterial components, which are mostly unknown. This study was performed to investigate the synovial proliferative T cell response to a panel of recombinant Yersinia antigens in patients with Yersinia ReA and in controls. METHODS: Synovial fluid mononuclear cells (SFMC) were obtained from 4 patients with Yersinia ReA and from 14 patients with arthritides of different etiology. SFMC were stimulated with 5 recombinant Yersinia antigens (the 19-kd urease beta subunit, 13-kd ribosomal L23 protein, 32-kd ribosomal L2 protein, 18-kd outer membrane protein H, and Y. enterocolitica heat-shock protein 60 [hsp60]), and with human, Chlamydia trachomatis, and Borrelia burgdorferi hsp60. Three T cell clones specific for Y. enterocolitica hsp60 were generated from 1 patient with Yersinia ReA. Antigen-induced cytokine release was measured by enzyme-linked immunosorbent assay. RESULTS: SFMC from all 4 patients with Yersinia ReA responded to each of the Yersinia antigens except the 13-kd protein. These antigens were also recognized by SFMC from a subgroup of patients with undifferentiated arthritis (n = 4), but not by SFMC from other patients with arthritis of different etiology (n = 10). Y. enterocolitica hsp60 induced the strongest proliferative response in all cases. Two types of hsp60-reactive T cell clones could be obtained. One clone responded to all hsp60 variants, including the human variant, and showed a type 2 T helper (Th2)-like cytokine-secretion pattern. In contrast, another clone with specificity for the bacterial hsp60 proteins, but not the human equivalent, reacted with a more Th1-like pattern. CONCLUSION: In Y. enterocolitica-triggered ReA, at least 4 immunodominant T cell antigens exist, which might be used in lymphocyte proliferation assays to identify patients with Yersinia ReA. The hsp60 is a strong antigen, inducing both bacteria-specific and potentially autoreactive CD4+ T cells of both the Th1 and Th2 type.

Thalidomide therapy of established collagen-induced arthritis (CIA) not accompanied by an evident Th2 shift.

Thalidomide, a drug likely to affect the cytokine pattern, was administered orally to mice at various stages of CIA. Treatment (150 mg/kg per day by gavage, 5 days/week), started 6 weeks post-immunization, i.e. at the height of the disease, significantly reduced arthritis, and appeared also to reduce the level of inflammation as judged by neutrophil chemiluminescence. With treatment started 9 weeks post-immunization the effect on arthritis was no longer statistically significant, and when started at 14 weeks was lost. Over a dose range of up to 150 mg/kg per day the treatment had no effect on either interferon-gamma (IFN-gamma) or IL-4 mRNA levels. The treatment is therefore not likely to have operated via a shift in the Th1/Th2 balance.

Recognition of chlamydial antigen by HLA-B27-restricted cytotoxic T cells in HLA-B*2705 transgenic CBA (H-2k) mice.

OBJECTIVE: The association of reactive arthritis (ReA) with HLA-B27 and the presence of bacterial antigen in joints with ReA suggest that bacterial peptides might be presented by the HLA-B27 molecule and thus stimulate CD8 T cells. This study was performed to investigate the B27-restricted cytotoxic T lymphocyte (CTL) response to Chlamydia trachomatis, using the model of HLA-B27 transgenic mice. METHODS: CBA (H-2k) mice homozygous for HLA-B*2705 and human beta2-microglobulin expression were immunized with C trachomatis or with the chlamydial 57-kd heat-shock protein (hsp57) coupled to latex beads. Cytotoxicity of lymphocytes from in vivo-primed transgenic mice was tested against C trachomatis-infected targets. Blocking experiments were performed with monoclonal antibodies (MAb) against class I major histocompatibility complex molecules. RESULTS: A Chlamydia-specific lysis of both B27-transfected and nontransfected target cells was observed. This response could be inhibited by anti-B27 and anti-H2 MAb. CTL from mice immunized with hsp57 were not able to lyse Chlamydia-infected target cells, and Chlamydia-specific CTL could not destroy targets loaded with hsp57. CONCLUSION: These results suggest the existence of at least 2 CTL populations in this mouse model: one recognizing peptide of bacteria-infected cells restricted by HLA-B*2705 and the other recognizing peptide of bacteria-infected cells restricted by the murine H-2Kk molecule. It does not appear that hsp57 is a major target for the CD8 T cell response directed against Chlamydia. This animal model opens the way for identifying bacterial epitopes presented by HLA-B27, and might thus help to clarify the pathogenesis of B27-associated diseases.

A single nonamer from the Yersinia 60-kDa heat shock protein is the target of HLA-B27-restricted CTL response in Yersinia-induced reactive arthritis.

The reason for the high association of HLA-B27 with diseases such as ankylosing spondylitis and reactive arthritis is not clear. In reactive arthritis, the triggering bacteria are known, thus allowing investigation of their interaction with HLA-B27. CTL lines derived from five patients with Yersinia-induced reactive arthritis were raised by repeated stimulation in vitro with either Yersinia-infected autologous macrophages (four patients) or pooled peptides (three patients) having the HLA-B27-binding motif. The peptides were derived from five Yersinia proteins and from the chlamydial 57-kDa heat shock protein (hsp). Cytotoxicity of T cell lines was then tested against these peptides. Lytic activity was obtained with T cells stimulated with viable Yersinia or pooled peptides. Targets successfully used for lysis were cells pulsed with peptides from the Yersinia 60-kDa hsp, but not cells pulsed with peptides from other Yersinia proteins or the chlamydial hsp. T cell lines raised with 60-kDa peptides also lysed targets infected with Yersinia. Most interestingly, all three CTL lines tested (one raised with Yersinia; two with pool of peptides) recognized only one single peptide (321-329) of seven tested from the Yersinia hsp60. Cytotoxicity occurred only when target cells were matched for HLA-B27. This identification of an immunogenic peptide derived from an arthritogenic bacterium and presented by HLA-B27 opens the way for future investigation of the role of T cells specific for this peptide or cross-reacting peptides, in the immunopathology of HLA-B27-associated diseases.