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Background Immune responses to infection are uniquely regulated during gestation to allow for antimicrobial defence and tissue repair, whilst preventing damage to developing fetal organs or the triggering of preterm labour.Objective A review and analysis of studies delineating gestationspecific immune modulation and intra-amniotic regulation of pro-inflammatory immunity.Search strategy Identification of the alterations between the fetus/ neonate and adult with regard to the endogenous and infectioninduced expression of molecules with immune regulatory properties, and the characterisation of intra-amniotic immune mediators that inhibit bacterial-induced pro-inflammatory cytokine production.Selection criteria English and non-English publications from 1985 to the present.Data collection and analysis An electronic literature search using MEDLINE, PubMed, articles cited in the primary sources, as well as pregnancy-related immunology research from our laboratory at Weill Medical College of Cornell University.Main results During fetal development, interleukin (IL)-23, IL-10 and IL-6, as well as T-helper-17 (Th17)-mediated immune responses, are upregulated, whereas tumour necrosis factor-a (TNF-a) and IL-1b-and Th1-mediated immune responses are downregulated in the intrauterine environment (both the fetal compartment and the amniotic compartment). Infection-related immunity during gestation is preferentially directed towards combating extracellular microbial pathogens. Amniotic fluid and the neonatal circulation contain multiple components that improve the ability of the developing neonate to tolerate microbial-induced immune activation.Conclusions The repertoire of immune mechanisms to control infection and inflammation differ between fetal and adult life. The dual mechanisms of resistance to infection and tolerance to infection-induced immune activation prevent damage to the developing fetus and the triggering of premature labour.

The relationship between a localized genital tract humoral immune response to Chlamydia trachomatis and the presence of antisperm antibodies on the surface of motile spermatozoa in the ejaculate was examined in 227 asymptomatic male partners of infertile couples with no history of exposure to C.trachomatis. Semen and serum samples were assayed for immunoglobulin (Ig) A and IgG antibodies to C.trachomatis by enzyme-linked immunosorbent assay employing a recombinant Chlamydia-specific lipopolysaccharide fragment (Medac, Hamburg, Germany), while motile spermatozoa were tested for bound autoantibodies by immunobead binding. Semen samples from 24.7 and 10.9% of the men were positive for IgA and IgG antibodies to C.trachomatis respectively. In comparison, antichlamydial IgA was less prevalent in sera (14.5%) than in semen (P = 0.01), while antichlamydial IgG was most prevalent (21.5%) in sera (P = 0.003). In 75.0% of the men with antichlamydial IgA in their semen, this antibody was undetectable in sera obtained at the time of semen collection. Conversely, 84.0% of the men with seminal antichlamydial IgG were also IgG seropositive. Antisperm IgG and/or IgA were detected on motile spermatozoa from 16.3% of the men; their occurrence was strongly correlated with the presence of antichlamydial IgA in semen (P < 0.0001). Weaker associations between antisperm antibodies and either seminal IgG antibodies to C.trachomatis (P = 0.01) or circulating IgA and IgG antichlamydial antibodies (P = 0.03) were also observed. Men with antichlamydial IgA in their semen had a lower median sperm count (82 versus 144 x 10(6)/ml) than those men without (P = 0.003); sperm morphology and motility were comparable in both groups. These data suggest that asymptomatic male genital tract exposure to C.trachomatis is a frequent event among this population and that the presence of a humoral immune response to this organism is correlated with the development of an autoimmune response to spermatozoa.

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Lactic acid is the predominant acid present in the vagina. We evaluated the consequences of lactic acid, at physiological levels present in the vagina, on cytokine responses of peripheral blood mononuclear cells (PBMCs) obtained from 10 individuals in the presence or absence of bacterial lipopolysaccharide. Preincubation of PBMCs in 15 mM lactic acid before the addition of lipopolysaccharide resulted in a 246% mean increase in interleukin-23 (IL-23) secretion over that released in the presence of lipopolysaccharide alone (P = 0.0068). The lipopolysaccharide-induced production of tumor necrosis factor-a, IL-6, IL-10 and IL-12 was unaffected by lactic acid. IL-23 stimulation was not observed if the lactic acid was neutralized before its addition to the culture medium or if hydrochloric acid was substituted for lactic acid. In the absence of lipopolysaccharide, lactic acid did not stimulate the production of IL-23 or any of the other cytokines. The increase in IL-23 production was proportional to the lactic acid concentration over a 15-60 mM range. We conclude that at body sites characterized by lactic acid accumulation, such as in the human vagina, exposure to gram-negative bacteria results in selective IL-23 production, leading to a subsequent preferential stimulation of the Th17 T lymphocyte pathway.

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Lactic acid enhances the release of selective mediators from vaginal epithelial cells and stimulates antiviral immune responses.

Background Streptococcus agalactiae (group B Streptococcus) is a bacterial pathogen that causes severe intrauterine infections leading to fetal morbidity and mortality. The pathogenesis of GBS infection in this environment is poorly understood, in part because we lack a detailed understanding of the adaptation of this pathogen to growth in amniotic fluid. To address this knowledge deficit, we characterized the transcriptome of GBS grown in human amniotic fluid (AF) and compared it with the transcriptome in rich laboratory medium.MethodsGBS was grown in Todd Hewitt-yeast extract medium and human AF. Bacteria were collected at mid-logarithmic, late-logarithmic and stationary growth phase. We performed global expression microarray analysis using a custom-made Affymetrix GeneChip. The normalized hybridization values derived from three biological replicates at each growth point were obtained. AF/THY transcript ratios representing greater than a 2-fold change and P-value exceeding 0.05 were considered to be statistically significant.Principal FindingsWe have discovered that GBS significantly remodels its transcriptome in response to exposure to human amniotic fluid. GBS grew rapidly in human AF and did not exhibit a global stress response. The majority of changes in GBS transcripts in AF compared to THY medium were related to genes mediating metabolism of amino acids, carbohydrates, and nucleotides. The majority of the observed changes in transcripts affects genes involved in basic bacterial metabolism and is connected to AF composition and nutritional requirements of the bacterium. Importantly, the response to growth in human AF included significant changes in transcripts of multiple virulence genes such as adhesins, capsule, and hemolysin and IL-8 proteinase what might have consequences for the outcome of host-pathogen interactions.Conclusions/SignificanceOur work provides extensive new information about how the transcriptome of GBS responds to growth in AF, and thus new leads for pathogenesis research.