The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction. So far, there have been no reports to our knowledge of a human deficiency in a tyrosine-specific phosphatase. Here, we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site. The patient presented at 2 months of age with severe combined immunodeficiency disease. The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation. Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age. Thus, CD45 deficiency in humans results in T- and B-lymphocyte dysfunction.

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To investigate the role of cytokines in interactions between lactic acid bacteria and the immune system, we measured production of tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-10 from human peripheral blood mononuclear cells after stimulation with live or glutaraldehyde-fixed bacteria. Production of tumor necrosis factor alpha, IL-6, and, in some cases, IL-10 was induced in amounts even greater than those obtained with lipopolysaccharide as a stimulant. Our results suggest that lactic acid bacteria can stimulate nonspecific immunity. Strains of the genera Lactobacillus, Lactococcus, and Bifidobacterium are commonly referred as lactic acid bacteria (LAB). LAB are considered nonpathogenic and are believed to be beneficial to human health (7, 8, 14). So-called probiotic effects of LAB could include stimulation of the immune system. LAB have been shown to induce proliferation of immune cells and to enhance synthesis of antibodies to microbial pathogens (5, 15, 16, 29). The fact that they are nonpathogenic and safe for humans when administered orally, as shown by their use in many dairy products, makes LAB attractive as live vectors for oral or local vaccines (11, 19). Lipopolysaccharide (LPS) of gram-negative bacteria induces production of proinflammatory cytokines tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), as well as IL-10, which is known to inhibit the synthesis of the former two cytokines (20, 32). These cytokines contribute to defense mechanisms of the host in response to bacterial colonization or invasion, and when secreted in excess, they may induce immunopathological disorders. Many components of gram-positive bacterial cell wall, e.g., capsular polysaccharides, peptidoglycans, and lipoteichoic acids, have been shown to be involved in cytokine induction. However, studies have been focused mostly on pathogenic streptococci and staphylococci (2, 10, 17, 21, 24, 28, 31). The ability of LAB and their cell wall components to induce cytokine release has been previously poorly studied. Only production of alpha interferon and TNF-␣ from murine cells and gamma interferon from human peripheral blood lymphocytes have been reported (5, 9, 12, 13, 23, 25). Since LAB have been suggested to stimulate the immune system, we investigated whether LAB exert their effects through induction of the cytokines TNF-␣, IL-6, or IL-10 from human peripheral blood mononuclear cells (PBMCs). We compared the abilities of 10 different LAB strains to induce cytokine release. To assess the role of bacterial surface structures in these interactions, we used both live and glutaraldehyde-fixed whole bacterial cells. Bifidobacterium longum E505 and Lactobacillus paracasei subsp. paracasei E506 were obtained from C. Hansen A/S;

Human peripheral blood mononuclear cells (PBMC) were stimulated with three nonpathogenic Lactobacillus strains and with one pathogenic Streptococcus pyogenes strain, and cytokine gene expression and protein production were analyzed. All bacteria strongly induced interleukin-1β (IL-1β), IL-6, and tumor necrosis factor alpha mRNA expression and protein production. S. pyogenes was the most potent inducer of secretion of IL-12 and gamma interferon (IFN-γ), and two of three Lactobacillusstrains induced IL-12 and IFN-γ production. All strains induced IL-18 protein production. IL-10 and IL-4 production was induced weakly and not at all, respectively. Our data show that nonpathogenic lactobacilli and pathogenic streptococci can induce Th1 type cytokines IL-12, IL-18, and IFN-γ in human PBMC.

The importance of T cells in Chlamydia pneumoniae infection in mice was assessed by comparing wild-type BALB/c mice with nude mice and mice depleted in vivo of either CD4+ or CD8+ T cells. Whereas wild-type mice cleared the primary infection in 3 weeks, nude mice were only able to restrict the infection and could not clear it during the observation period of 56 days. Nude mice exhibited a greater number of macrophages in their lungs and the pulmonary cells secreted a higher level of tumour necrosis factor-alpha (TNF-alpha) than wild-type mice. Depletion of CD4+ cells did not change the overall infection kinetics of the primary infection. However, depletion of CD8+ cells resulted in a slightly impaired clearance of the bacteria in the late stages of primary infection. To assess the role of the two T-cell subsets in the acquired immunity that develops during primary infection in wild-type BALB/c mice, in vivo depletions were performed during reinfection. Prior to reinfection, immunocompetent wild-type mice were infected and natural immunity was allowed to form. During reinfection, depletion of CD4+ cells did not have any effect on infection kinetics, whereas depletion of CD8+ cells abolished the protection, reverting the infection kinetics and bacterial load to the same levels found in wild-type mice during primary infection. These results show that T cells are necessary for clearing C. pneumoniae infection in mice. Furthermore, whereas neither of the two main T-cell subsets, separately, were essential for clearance of primary infection, the induced protective immunity was strongly CD8 dependent.