Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.     

Evidence of resilience: neuroimaging in former prisoners of war

In this study, single voxel proton magnetic resonance spectroscopic imaging ((1)H-MRS) and volumetric analysis of hippocampal magnetic resonance imaging (MRI) images were used to determine if any differences in hippocampal biochemistry or volume were present between former prisoners of war (POWs) with and without posttraumatic stress disorder (PTSD) and control subjects matched for age and education. This study did not find lower hippocampal concentrations of N-acetylaspartate (NAA), smaller hippocampal volumes, or more impaired memory function in older veterans with PTSD compared with a group matched for traumatic experience or a nontraumatized control group.     

Immunologic thrombopenic purpura in children: therapeutic trial with high dose of intravenous gamma globulins

Fifteen children with immunological thrombocytopenic purpura were treated by first intention with high dose intravenous gammaglobulins (Venoglobulins and Sandoglobulins). Nine children recovered after the first injection with platelet counts greater than 50,000/mm3 after 2 days' treatment, so countering the risk of haemorrhage. One child required a second course of treatment and was then cured. Three children had temporary rises in their platelet counts and then relapsed; two children did not react at all to the treatment. The most interesting feature of this new therapeutic approach is the possibility of preventing serious haemorrhagic complications in cases of severe thrombocytopaenia (less than 10,000/mm3) by inducing a rapid rise in the platelet count.     

Expression of hybrid class I genes of the major histocompatibility complex in mouse L cells.

The class I genes of the major histocompatibility complex of the mouse can be divided into two categories: those encoding the transplantation antigens and those encoding the Qa and Tla antigens. The inbred BALB/c mouse has 28 potential Qa/Tla genes. The sites of tissue expression, developmental regulation, and functions of these genes are virtually unknown. We have used the technique of exon shuffling to construct hybrid genes between each of three Qa region genes (Q5, Q7, and Q8) and two other class I genes (H-2Ld and Q6). The hybrid genes have been transfected into mouse L cells, in which intact transplantation antigen genes generally are expressed and in which intact Qa genes generally are not expressed. Analysis of expression of the hybrid gene constructs indicates that the 5' half of two of the Qa genes (Q5 and Q8) can readily be expressed in the context of a hybrid molecule, whereas the 3' half prevents cell-surface expression. The exon shuffling approach described here will be useful in characterizing Qa/Tla genes and in identifying or producing new reagents to study the Qa/Tla gene products, their tissue distribution, their developmental stages of expression, and, ultimately, their functions.     

Calcium-sensing receptor attenuates AVP-induced aquaporin-2 expression via a calmodulin-dependent mechanism

Recent evidence suggests that arginine vasopressin (AVP)-dependent aquaporin-2 expression is modulated by the extracellular calcium-sensing receptor (CaSR) in principal cells of the collecting duct, but the signaling pathways mediating this effect are unknown. Using a mouse cortical collecting duct cell line (mpkCCD(cl4)), we found that increasing the concentration of apical extracellular calcium or treating with the CaSR agonists neomycin or Gd(3+) attenuated AVP-dependent accumulation of aquaporin-2 mRNA and protein; CaSR gene-silencing prevented this effect. Calcium reduced the AVP-induced accumulation of cAMP, but this did not occur by increased degradation of cAMP by phosphodiesterases or by direct inhibition of adenylate cyclase. Notably, the effect of extracellular calcium on AVP-dependent aquaporin-2 expression was prevented by inhibition of calmodulin. In summary, our results show that high concentrations of extracellular calcium attenuate AVP-induced aquaporin-2 expression by activating the CaSR and reducing coupling efficiency between V(2) receptor and adenylate cyclase via a calmodulin-dependent mechanism in cultured cortical collecting duct cells.     

Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis in the world, is characterized by IgA immune complex-mediated mesangial cell proliferation. The transferrin receptor (TfR) was identified previously as an IgA1 receptor, and it was found that, in biopsies of patients with IgAN, TfR is overexpressed and co-localizes with IgA1 mesangial deposits. Here, it is shown that purified polymeric IgA1 (pIgA1) is a major inducer of TfR expression (three- to four-fold increase) in quiescent human mesangial cells (HMC). IgA-induced but not cytokine-induced HMC proliferation is dependent on TfR engagement as it is inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. It is dependent on the continued presence of IgA1 rather than on soluble factors released during IgA1-mediated activation. In addition, pIgA1-induced IL-6 and TGF-beta production from HMC was specifically inhibited by mAb A24, confirming that pIgA1 triggers a TfR-dependent HMC activation. Finally, upregulation of TfR expression induced by sera from patients with IgAN but not from healthy individuals was dependent on IgA. It is proposed that deposited pIgA1 or IgA1 immune complexes could initiate a process of auto-amplification involving hyperexpression of TfR, allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation and activation, features that are commonly implicated in the chronicity of mesangial injuries observed in IgAN and that could explain the recurrence of IgA1 deposits in the mesangium after renal transplantation.