H. Öhman

IL-10 polymorphism and cell-mediated immune response to Chlamydia trachomatis

Chlamydia trachomatis infection induces an inflammatory response that is crucial in resolving acute infection but may also play a key role in the pathogenesis of C trachomatis associated infertility. The immune response is linked to cytokine secretion pattern which is influenced by the host genetic background. To study a relationship between interleukin-10 (IL-10) promoter −1082 polymorphism and cell-mediated immune response during C trachomatis infection in vitro, lymphocyte proliferation and cytokine (IL-10, IFN-γ, TNF-α, IL-2, IL-4 and IL-5) secretion were analysed in subjects with different IL-10 genotypes. Enhanced IL-10 secretion and reduced antigen-specific lymphocyte proliferative and IFN-γ responses were found in subjects with IL-10 −1082 GG genotype when compared to those with −1082 AA genotype. CD14+ monocytes were main source of IL-10 indicating that these cells are important regulators of the antigen-specific cell-mediated responses during active C trachomatis infection. We conclude that impaired cell-mediated response to C trachomatis is associated with IL-10 genotype in subjects with high IL-10 producing capacity. A comparison of immune markers between subjects with a history of noncomplicated and complicated infection is needed to further understand the confounding factors associated with the development of C trachomatis associated sequelae.

Cytokine gene polymorphism and Chlamydia trachomatis-specific immune responses.

Chlamydia trachomatis-induced fallopian tube damage leading to tubal factor infertility (TFI) is linked with TNF, IL-10, and probably IFNG gene polymorphisms. The aim of this study was to clarify the contribution of these cytokine gene polymorphisms to interindividual variation in C trachomatis-specific immune responses and the cross-regulation of secreted cytokines and single nucleotide polymorphisms (SNPs). Cytokine polymorphisms (IL-10 -1082A/G, -819T/C, and -592A/C, IFNG +874T/A, and TNF -308G/A) were genotyped by polymerase chain reaction in 139 women. C trachomatis-specific immune responses were measured using lymphocyte proliferation (LP) induced by C trachomatis E and F strains and chlamydial heat shock protein 60 antigens. Cytokine secretion was measured in culture supernatants of infected and uninfected mononuclear leukocytes. IL-10 -1082/-819/-592 and IFNG +874 SNPs were associated with the intensity of LP responses to C trachomatis antigens. These cytokines also interact with each other and a cumulative effect of IL-10 -1082 and IFNG +874 genotypes was seen in LP responses to C trachomatis antigens. Our data suggest that interleukin-10 and interferon-γ regulate C trachomatis-specific immune responses in humans and that genetic variation in the expression of their coding genes explains interindividual variation in host immune responses to C trachomatis infection.

Population-Based Study of Prediagnostic Antibodies to Chlamydia trachomatis in Relation to Adverse Pregnancy Outcome.

Background Chlamydia trachomatis infection is one of the most common sexually transmitted reported bacterial infections worldwide. The well-known sequelae of chlamydial infection include pelvic inflammatory disease and tubal factor infertility, but the evidence linking C. trachomatis infection and adverse pregnancy outcome is inconsistent and has been largely based on case-control studies with limited study populations. We evaluated this link in a population-based longitudinal biobank health registry setting. Methods The association between C. trachomatis major outer membrane protein (MOMP) peptide-specific IgG antibodies and ectopic pregnancy, miscarriage, and preterm delivery was examined in a prospective case-control study nested in the Finnish Maternity Cohort. Ectopic pregnancy and miscarriage cases were identified through the Hospital Discharge Register 1998–2005; cases with preterm deliveries were identified through the Finnish Medical Birth register 1988–2005. Control samples were retrieved from the Finnish Maternity Cohort serum bank. A total of 800 cases of ectopic pregnancy, 800 cases of miscarriage, and 1350 cases of preterm birth were included. Equal number of pregnant women without the outcome diagnosis served as controls. The cases and controls were matched by sampling time, at the serum sampling and postal code district. Results Antichlamydial IgG antibodies were associated with ectopic pregnancy. Positive antibody levels were found in 21.0% of cases and 14.6% of controls (P = 0.001; odds ratio, 1.56; 95% confidence interval, 1.20–2.03). Previous exposure to C. trachomatis, as indicated by serum antibodies, doubled the risk of ectopic pregnancy within age and was highest among women 35 years or older. Antichlamydial IgG antibody rates between the cases with miscarriage (16.3% in cases vs. 16.8% in controls) or preterm delivery (18.1% vs. 18.1%) and controls did not differ. Conclusions Our findings confirm the association between previous exposure to C. trachomatis and ectopic pregnancy. We found no association between C. trachomatis seropositivity and miscarriage or preterm birth.

An increasing proportion of reported Chlamydia trachomatis infections are repeated diagnoses.

Background In recent decades, increasing rates of Chlamydia cases have contrasted with decreasing Chlamydia trachomatis seroprevalence rates and decreasing Chlamydia-associated complication rates. We elucidated the conflicting trends by studying incidence of repeated Chlamydia infections over time. Methods Chlamydia cases reported during 1995 to 2009 were identified in the Finnish National Infectious Diseases Registry. Trends of single and repeated diagnoses of Chlamydia infection were analyzed. Results Our study population comprised 147,148 individuals with a total of 177,138 genital chlamydial infections. The proportion of annual repeated diagnoses of genital infections increased among female and males from 4.9% to 7.3% and from 3.8% to 5.3%, respectively. In 2009, 24.8% of the females and 20.3% of the males had had an earlier Chlamydia infection ever during the follow-up time. Of all the repeated diagnoses, 34.1% occurred within 12 months. The highest rates of repeated infection diagnoses occurred in 25-year-old women (37.0%) and in 29-year-old men (30.9%) in a cohort of individuals born in 1979. Conclusions A gradual increase of repeated Chlamydia infections resulted in 43% increase in annual infections between 1996 and 2009. The result is supportive of the existing seroprevalence data suggesting that Chlamydia infection burden is not increasing in the whole population. The increasing infection rates in males, in particular, justify development of effective strategy in preventing reinfections and onward transmission.

Effect of IL12A and IL12B polymorphisms on the risk of Chlamydia trachomatis-induced tubal factor infertility and disease severity

BACKGROUND Interleukin-12 (IL-12) and related cytokines induce activation and differentiation of T cells. Our aim was to investigate the associations between genetic differences in IL-12-family cytokines and the pathogenesis of chlamydial disease. METHODS The final study population consisted of 100 women with Chlamydia trachomatis-induced tubal factor infertility (TFI) and 125 pregnant women as controls. Three single nucleotide polymorphisms (SNPs) of IL12A and seven SNPs of IL12B genes were determined from isolated DNA using the Sequenom system with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. RESULTS We found that the IL12B SNP rs3212227 was associated with both susceptibility and severity of TFI. The minor allele C was rare and only one CC homozygote was found among the controls. AC heterozygotes were more common among TFI cases than among controls (P = 0.009) and were associated with increased risk of TFI [odds ratios (OR) = 2.44, 95% confidence intervals (CI) = 1.23-4.87]. Carrying the minor allele C was also associated with disease severity (P for trend = 0.008) and moderate (OR = 2.51, 95% CI = 1.06-5.95) and severe tubal damage (OR = 2.73, 95% CI = 1.15-6.52). CONCLUSIONS The results suggest that variation in the IL12B gene partly explains inter-individual differences in disease susceptibility and severity.

Contribution of IL-12A and IL-12B Polymorphisms to Chlamydia trachomatis-Specific Cell-Mediated Immune Responses

Inherited variance in the IL‐12B gene is associated with susceptibility to Chlamydia trachomatis‐induced tubal factor infertility and disease severity. In this study, our aim was to discover how polymorphisms in IL‐12‐coding genes influence C. trachomatis‐induced immune responses and IL‐12 production. The study population consisted of 240 women. IL‐12A and IL‐12B single nucleotide polymorphisms (SNPs) were determined from isolated DNA using the Sequenom system with matrix‐assisted laser desorption/ionization time‐of‐flight (MALDI‐TOF) mass spectrometry. We studied lymphocyte proliferative (LP) responses to C. trachomatis strains E and F elementary bodies (EBs) and recombinant chlamydial heat‐shock protein 60 (CHSP60) antigen. IL‐12p40 and IL‐12p70 levels were measured using the BD Flex Set method. We found a statistically significant association between the C. trachomatis EB antigen‐specific LP response and the rs2853694 SNP (P = 0.02). Our study demonstrates that the IL‐12 cytokine family is involved in C. trachomatis‐specific immune responses. Moreover, C. trachomatis‐induced IL‐12 production and the IL‐12B rs2853694 SNP partially explain individual variation in the C. trachomatis LP response.

Changes over time in the Chlamydia trachomatis serotype distribution in Finnish women

Abstract The distribution of Chlamydia trachomatis serotypes in the sexually active population may change over time. Serum from C. trachomatis seropositive women representing the 1980s, 1990s, and 2000s were available from a stratified random sample (11,067) of the Finnish Maternity Cohort for microimmunofluorescence-based classification. The C. trachomatis serotype distributions in the 1980s and 2000s were comparable, with serotypes G, E, and J being the most prevalent. In the 1990s the numbers of women seropositive for ≥ 2 serotypes peaked, and serotypes G/J were replaced by serotypes E/D. The temporary C. trachomatis serotype replacement parallels changes in the sexually active population in the 1990s in Finland.

Predicting tubal factor infertility by using markers of humoral and cell-mediated immune response against Chlamydia trachomatis

The accuracy of Chlamydia trachomatis antibody test in predicting tubal factor infertility (TFI) is limited, and more accurate methods are needed. Cell‐mediated immune response (CMI) is crucial in the resolution of pathogen, but it may play an important role in the pathogenesis of C trachomatis‐associated tubal damage. We studied whether combining the markers of C trachomatis‐induced CMI to humoral immune response improves the accuracy of serology in TFI prediction.