Genetic variation in the transforming growth factor-beta1 gene is associated with susceptibility to IgA nephropathy.

BACKGROUND: There is growing evidence of genetic risk for susceptibility to IgA nephropathy. Among several candidate genes related to immunological regulation in renal tissue, TGFB1 is known to be a contributor to proliferation and the development of fibrosis. METHODS: We analysed several SNPs in a region of this gene using 212 DNA samples from biopsy-proven IgA nephropathy patients, 146 men and 66 women and 477 healthy age-matched controls (321 men and 156 women) from the same population in Sweden. RESULTS: Frequencies of four out of five selected SNPs (rs6957, rs2241715, rs1800471, rs1982073 and rs1800469) were found to significantly differ between male patients and male controls in a co-dominant model (corrected P

Session 1: Feeding and infant development breast-feeding and immune function.

The newborn receives, via the placenta, maternal IgG antibodies against the microbes present in its surroundings, but such antibodies have a pro-inflammatory action, initiating the complement system and phagocytes. Although the host defence mechanisms of the neonate that involve inflammatory reactivity are somewhat inefficient, this defence system can still have catabolic effects. Breast-feeding compensates for this relative inefficiency of host defence in the neonate by providing considerable amounts of secretory IgA antibodies directed particularly against the microbial flora of the mother and her environment. These antibodies bind the microbes that are appearing on the infant's mucosal membranes, preventing activation of the pro-inflammatory defence. The major milk protein lactoferrin can destroy microbes and reduce inflammatory responses. The non-absorbed milk oligosaccharides block attachment of microbes to the infant's mucosae, preventing infections. The milk may contain anti-secretory factor, which is anti-inflammatory, preventing mastitis in mothers and diarrhoea in infants. Numerous additional factors in the milk are of unknown function, although IL-7 is linked to the larger size of the thymus and the enhanced development of intestinal Tgammadelta lymphocytes in breast-fed compared with non-breast-fed infants. Several additional components in the milk may help to explain why breast-feeding can reduce infant mortality, protecting against neonatal septicaemia and meningitis. It is therefore important to start breast-feeding immediately. Protection is also apparent against diarrhoea, respiratory infections and otitis media. There may be protection against urinary tract infections and necrotizing enterocolitis, and possibly also against allergy and certain other immunological diseases, and tumours. In conclusion, breast-feeding provides a very broad multifactorial anti-inflammatory defence for the infant.

Association of the -159 CD14 gene polymorphism and lack of association of the -308 TNFA and Q551R IL-4RA polymorphisms with severe chronic periodontitis in Swedish Caucasians.

BACKGROUND: Severe forms of periodontitis are suggested to have a genetic basis. OBJECTIVE: The aim of the present investigation was to study the association of gene polymorphisms related to some immune regulation components (G-308A TNFA, Q551R IL-4RA and C-159T CD14) with severe chronic periodontitis. MATERIALS AND METHODS: Sixty patients (aged 36-74 years; mean 54.5+/-8.5) with severe and generalized chronic periodontitis were included. The patients exhibited bone loss >50% at all teeth. Thirty-nine periodontally healthy subjects between 35 and 78 years of age (mean 51.0+/-10.9) were recruited as controls. DNA was isolated from peripheral blood cells and genotyping was performed by combination of PCR and restriction endonuclease mapping. RESULTS: While gene polymorphisms for TNFA and IL-4RA did not show any association with severe chronic periodontitis, the analysis of the -159 CD14 gene polymorphism revealed significant differences between test and control groups. The proportion of subjects that exhibited the TT genotype was significantly smaller in the group with severe periodontitis than in periodontal healthy group (p=0.028; Fisher's exact test). The C allele carriage was 90% in the periodontitis group and significantly higher than in the healthy control group (72%). CONCLUSION: It is suggested that the -159 CD14 gene polymorphism is associated with chronic periodontitis in Caucasian subjects of a north European origin.

Impaired kidney graft survival is associated with the TNF-alpha genotype.

BACKGROUND: The TNF2 allele at position -308 of the tumor necrosis factor (TNF)-alpha gene is associated with high TNF production. The purpose was to study the association of this gene polymorphism with rejection episodes and graft survival after kidney transplantation. METHODS: A retrospective analysis of transplant outcomes of patients who only had been treated with one single form of immunosuppression consisting of cyclosporine, azathioprine, and prednisolon was performed. RESULTS: We found that 115 (73%) patients had the TNF1/TNF1 genotype, whereas 42 (27%) were TNF2 positive. There was no difference in the overall acute rejection frequency between these two groups (50% in each), but our data showed a non-significant tendency towards a higher frequency of steroid resistant rejections in the TNF2 positive group (57% vs. 40%). There was no significant difference in graft survival between the two genotype groups, although an early tendency towards worse survival was seen in TNF2 recipients. However, the TNF2 positive recipients with rejection episodes had far worse graft survival compared with the TNF1/TNF1 recipients with rejection episodes (P<0.02). No difference was seen between the two genotype groups in patients without rejection episodes. CONCLUSION: Our data propose that potentially high TNF producers with the TNF2 allele do not have an increased risk for rejection episodes, but if rejection episodes occur, they have a significantly increased risk for early graft loss. TNF production may intensify rejection, but is not a primary factor for the induction of such acute immune activation.

Association of the -1087 IL 10 gene polymorphism with severe chronic periodontitis in Swedish Caucasians.

BACKGROUND: Severe forms of periodontitis are suggested to have a genetic basis. OBJECTIVE: The aim of the present investigation was to study association of an IL10 gene polymorphism (G to A transition at the -1087 position) with severe chronic periodontitis. MATERIALS AND METHODS: Two groups of Swedish Caucasian subjects were included. One group consisted of 60 patients (aged 36-74 years; mean 54.5+/-8.5) with severe and generalized chronic periodontitis. The patients exhibited bone loss >50% at all teeth. Thirty-nine periodontally healthy subjects between 35-78 years of age (mean 51.0+/-10.9) were also recruited. DNA was isolated from peripheral blood cells and genotyping was performed by combination of PCR with restriction endonuclease mapping. RESULTS: The proportion of subjects that exhibited the GG genotype was significantly larger in the group with severe periodontitis than in the periodontally healthy group. The difference regarding the occurrence of the GG genotype between the two groups was more conspicuous in non-smokers and yielded an odds ratio of 6.1. The G allele carriage in non-smokers was >90 % in the periodontitis group and was significantly higher than in the healthy controls. CONCLUSION: It is suggested that the -1087 IL10 polymorphism in Caucasian subjects of a north European origin is associated with severe chronic periodontitis.

Long term enhancement of the IgG2 antibody response to Haemophilus influenzae type b by breast-feeding.

SUBJECTS: Sets of sera were obtained from 30 children <6 years of age with invasive type b (Hib) infection and their mothers. Duration and mode of breast-feeding were monitored. Titers of IgG1, IgG2, IgA and IgM antibodies against Hib capsular polysaccharide were determined in sera taken during the acute illness and during early and late convalescence. RESULTS: Children 18 months or older with longer durations of exclusive breast-feeding (13 weeks or more; mean, 19.3 weeks) had higher Hib antibody concentrations of the IgG1, IgG2, IgA and IgM isotypes than those with a shorter duration of exclusive breast-feeding (<13 weeks; mean, 5.4 weeks). The difference was greatest for the IgG2 isotype. In regression analyses the association between the duration of exclusive breast-feeding and the anti-Hib IgG2 concentration was significant when breast-feeding, type of Hib infection, maternal Hib antibody titer and age were used as explanatory factors. In the group of 14 children <18 months of age no significant differences were noted. DISCUSSION: This study indicates the presence of a long lasting enhancing effect of breast-feeding on the antibody response to Hib in children, in particular on IgG2 Hib antibody production. This may result from the content in the milk of IFN-gamma and IFN-gamma-producing cells and possibly other factors, which can support IgG2 antibody production.

Maternal history, sensitization to allergens, and current wheezing, rhinitis, and eczema among children in Costa Rica.

Little is known about the factors associated with asthma, allergic rhinitis, and eczema in Latin American countries. We investigated the relation between potential risk factors and current wheezing, allergic rhinitis, and eczema among 208 Costa Rican children aged 10-13 years participating in phase II of the International Study of Asthma and Allergies in Childhood (ISAAC). The geometric mean ( +/- SD) serum total IgE level of children with current wheezing was significantly higher than that of children without current wheezing (533.8 +/- 5.2 vs. 144.7 +/- 6.0 IU/mL, P < 0.01). In a multivariate analysis, a maternal history of asthma, skin test reactivity (STR) to house dust mites, and STR to Alternaria were significantly associated with current wheezing. Children who had a maternal history of asthma had 2.4 times higher odds of current wheezing than those without maternal history of asthma (95% CI for OR = 1.1-5.3). Sensitization to either house dust mite or Alternaria was associated with 3.3 times increased odds of current wheezing (95% CI for OR for STR to dust mite = 1.6-6.7; 95% CI for OR for STR to Alternaria = 1.1-11.0). In a multivariate analysis, STR to house dust mite and STR to cat dander were significantly associated with allergic rhinitis, and a maternal history of eczema and STR to dog dander were associated with eczema in the child. The interaction between familial factors and lifestyle changes resulting from social reforms implemented 60 years ago may explain the high prevalence of atopic diseases in Costa Rica.

Aberrations in placental cytokine mRNA related to intrauterine growth retardation.

During normal pregnancy, a predominance of Th2 type cytokines prevails and is considered to protect the fetus. Animal experiments suggest that an increase of Th1 type cytokines may instead have deleterious effects. We have studied with the reverse transcription PCR technique mRNA for IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, tumor necrosis factor-alpha, and interferon-gamma in placentas from full-term appropriately grown newborns, newborns with intrauterine growth retardation (IUGR) and newborns who were only small for gestational age. The mRNA for IL-10 was significantly reduced in the IUGR placentas (p < 0.05), whereas the mRNA for IL-8 was significantly higher (p < 0.05) for the IUGR cases compared with the full-term neonates. It might be that reduced IL-10 in the placenta is involved in the pathogenesis of IUGR.