The adaptor protein SLy2 (Src homology domain 3 lymphocyte protein 2) is located on human chromosome 21 and was reported to be among a group of genes amplified in Down's syndrome (DS) patients. DS patients characteristically show an impaired immunity to pneumococcal infections. However, molecular mechanisms linking gene amplifications with specific DS phenotypes remain elusive. To investigate the effect of SLy2 gene amplification on the mammalian immune system, we studied SLy2 overexpressing transgenic-SLy2 (TG) mice. We found that baseline immunoglobulin M (IgM) levels as well as IgM responses following Pneumovax immunizations were reduced in TG mice. Moreover, B-1 cells, the major natural IgM-producing population in mice, were reduced in the peritoneal cavity of TG mice, while other immune cell compartments were unaltered. Mechanistically, SLy2 overexpression attenuated the expression of the IL-5 receptor α chain on B-1 cells, resulting in decreased B-1 cell numbers and decreased differentiation into Ab-secreting cells. Since B-1 cells essentially contribute to immunity against Streptococcus pneumoniae, the present study provides a novel molecular link between SLy2 expression and pneumococcal-specific IgM responses in vivo. These studies suggest that the adaptor protein SLy2 is a potential future target for immunomodulatory strategies for pneumococcal infections.

BackgroundThe prevalence of obesity has dramatically increased in children in the last few decades and is associated with chronic inflammatory diseases. Fat tissue produces IL-6 and TNF-α, which are stimuli for TH17 cell differentiation. These cells are characterized by expression of the transcription factor receptor-related orphan receptor C (RORC) and by IL-17A production. In murine models, obesity has been linked with elevated TH17 cell frequencies. The aim of this study was to explore whether being overweight was associated with an elevated frequency of circulating TH17 cells or elevated messenger RNA (mRNA)-levels of IL-17A and RORC in children without chronic inflammatory diseases.MethodsWe studied peripheral blood samples from 15 overweight and 50 non-overweight children without a history of autoimmune diseases, asthma, atopic dermatitis or allergic rhinoconjunctivitis. TH17 cells were quantified in Ionomycin stimulated peripheral blood mononuclear cells by flow cytometry using intracellular IL-17A staining. RORC- and IL-17A expressions were measured by real-time PCR.ResultsWe found significantly elevated TH cell frequencies in overweight children compared then on-overweight controls with 34.7 ± 1.5% of CD3+CD4+ cells versus 25.4 ± 2.4% (mean ± SEM, p = 0.0023), respectively. Moreover, TH cell frequencies correlated positively with body mass index (r = 0.42, p = 0.0005, respectively). The relative mRNA expression of RORC (p = 0.013) and IL-17A (p = 0.014) were upregulated in overweight compared to non-overweight children.ConclusionChildhood obesity is an independent factor that is associated with an elevated frequency of circulating TH17 cells and higher expression of RORC- and IL-17A-mRNA after in vitro stimulation with Ionomycin. This might be due to the inflammatory activity of the fat tissue. Studies on TH17 immunity should not only be adjusted for acute and chronic inflammatory diseases but also for overweight.

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Uremic pneumonitis is included in the "adult respiratory distress syndrome". Diffuse alveolo-capillary damage, interstitial and intraalveolar edema, widespread atelectases, alveolar haemorrhages and pulmonary hyaline membranes are characteristic but not pathognomonic findings in uremic pneumonitits. Investigations showed that uremic pneumonitis results from diffuse permeability disorders of the alveolo-capillary permeability combined with an intrarenal or generalized consumption of coagulation factors, and a subsequent state of hypercoagulability. A comparative morphological and clinical analysis of 66 autopsy cases with severe uremia showed that neither the intensity of the urea retention nor the intensity of the creatinine retention correlate with the morphologic symptoms of uremic pneumonitis. Uremia may induce the basic alveolocapillary damage and the subsequent plasmatic leakage into the alveoli and alveolar ducts but uremia has obviously no influence on the simultaneous formation of pulmonary hyaline membranes and intraalveolar bleedings. Hyaline membranes and intraalveolar bleedings are the entire equivalents of the immediate procoagulative activity of the underlying diseases.

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