Markedly Different Pathogenicity of Four Immunoglobulin G Isotype-Switch Variants of an Antierythrocyte Autoantibody Is Based on Their Capacity to Interact in Vivo with the Low-Affinity Fcγ Receptor III

Using three different Fcγ receptor (FcγR)-deficient mouse strains, we examined the induction of autoimmune hemolytic anemia by each of the four immunoglobulin (Ig)G isotype-switch variants of a 4C8 IgM antierythrocyte autoantibody and its relation to the contributions of the two FcγR, FcγRI, and FcγRIII, operative in the phagocytosis of opsonized particles. We found that the four IgG isotypes of this antibody displayed striking differences in pathogenicity, which were related to their respective capacity to interact in vivo with the two phagocytic FcγRs, defined as follows: IgG2a > IgG2b > IgG3/IgG1 for FcγRI, and IgG2a > IgG1 > IgG2b > IgG3 for FcγRIII. Accordingly, the IgG2a autoantibody exhibited the highest pathogenicity, ∼20–100-fold more potent than its IgG1 and IgG2b variants, respectively, while the IgG3 variant, which displays little interaction with these FcγRs, was not pathogenic at all. An unexpected critical role of the low-affinity FcγRIII was revealed by the use of two different IgG2a anti–red blood cell autoantibodies, which displayed a striking preferential utilization of FcγRIII, compared with the high-affinity FcγRI. This demonstration of the respective roles in vivo of four different IgG isotypes, and of two phagocytic FcγRs, in autoimmune hemolytic anemia highlights the major importance of the regulation of IgG isotype responses in autoantibody-mediated pathology and humoral immunity

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

International audienceAutism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs

Factors associated with caregiver burden among parents of individuals with ASD: Differences across intellectual functioning

DOI: 10.1111/fare.12081Symptoms of autism spectrum disorder (ASD) persist into adolescence and adulthood, when access to health services and supports become difficult. Consequently, most adolescents and adults with ASD remain reliant on their families for support, often resulting in caregiver burden among parents. This study aims to investigate factors associated with burden in parents of adolescents and young adults with ASD, and to understand how these factors differ across varying levels of intellectual functioning. Of the 297 parents sampled, ASD severity, externalizing behaviors, medical comorbidity, and parent age predicted burden in parents of adolescents and young adults with ASD and an intellectual disability (ID), whereas an inability to pay for services predicted burden in parents of individuals with ASD and no ID. Factors associated with caregiver burden differed among individuals with and without ID and were not limited to symptom severity or mental health problems, but also extended to system factors.Canadian Institutes of Health Research (MOP 102677

The CydDC family of transporters

The CydDC family of ABC transporters export the low molecular weight thiols glutathione and cysteine to the periplasm of a variety of bacterial species. The CydDC complex has previously been shown to be important for disulfide folding, motility, respiration, and tolerance to nitric oxide and antibiotics. In addition, CydDC is thus far unique amongst ABC transporters in that it binds a haem cofactor that appears to modulate ATPase activity. CydDC has a diverse impact upon bacterial metabolism, growth, and virulence, and is of interest to those working on membrane transport mechanisms, redox biology, aerobic respiration, and stress sensing/tolerance during infection

Immunopathology of Omeprazole-Induced Acute Insterstitial Nephritis

Aim: The aim of this study was to define the nature of the inflammatory infiltrate that occurs with omeprazole-induced acute interstitial nephritis (AIN) and further to compare and contrast the histology of omeprazole-induced AIN with the interstitial renal lesions seen in PR3 and MPO positive small vessel vasculitis. Background: Omeprazole is now the most common cause of drug-induced acute interstitial nephritis. However, how omeprazole-induced acute interstitial nephritis is mediated is unknown. We observed in all patients the histological pattern is unlike the classical picture of an acute allergic drug-induced interstitial nephritis as seen with methicillin, but rather it is akin to that seen with PR3/MPO small vessel vasculitis or acute cellular rejection in renal transplant recipients. The nature of the cellular infiltrate in omeprazole-induced acute interstitial nephritis has not been characterized. Given the similarity in appearance to the renal involvement in small vessel vascultits, we postulated that the inflammatory process is predominantly a cell-mediated process involving TH1/TH17 cells. Methods: Data from 25 biopsy-proven cases of omeprazole-induced acute interstitial nephritis (AIN) and 27 patients with renal involvement with PR3/MPO ANCA positive small vessel vasculitis, who have presented to the renal service (Dunedin Hospital, NZ) over the last 10 years, were reviewed. The lesions were graded according to the updated Banff classification of 1997 to compare the severity of the inflammatory infiltrate. The underlying immune reaction was characterized using immunohistochemical and fluoroscopic chromogenic in situ hybridization (IHC and F-CISH) to detect T-cells (and particular markers associated with Th1, Th2, Th17 and Treg effector T cells) and B-cells. The following antibodies were used CD20 for B-cells, CD4, CD8, IL17A, IL17F and Foxp3 for T-cells. Results: All patients presented with evidence of acute kidney injury (AKI). Urinalysis demonstrated a sterile pyuria with varying amounts of proteinuria. There were no urinary eosinophils. There were no systemic symptoms to suggest a vasculitis and ANCA (PR3 & MPO titres) were negative in all cases. Histologically, all cases had 4 evidence of inflammatory cells crossing the tubular basement membrane and showing an active tubulitis. The occurrence of any eosinophils in our patients was 52%. However, in contrast to previous studies only one patient has an eosinophilic infiltrate, the other cases showed only small numbers (3 – 7 eosinophils per high powerfield in some but not all views) of scattered eosinophils in the infiltrate. Similar findings were evident in the vasculitis group. The lack of a substantial eosinophilic infiltrate argues against a pre-dominant Th-2 mediated mechanism for omeprazole-induced AIN. Our cases showed numerous CD4 positive cells, and fewer numbers of CD20 and CD8 positive cells. CD4 positive cells were present in clusters in 77% of the PPI-IN patients and 67% of the vasculitis patients. CD20 positive cells were present in clusters in 58% of all omeprazole-induced AIN patients and 37% of vasculitis patients. However CD8 positive cells were present in clusters only in 17% of omeprazole-induced AIN patients and 13% of vasculitis patients. Comparing the IL17A and CD4 double staining with the IL17F and CD4 double staining for the omeprazole-induced AIN group the grading of the staining looks very similar (for IL17A and CD4 50% of patients showing clusters, 4% intermediate, 32% of scattered and 14 % of patients without any IL17A and CD4 cells versus the staining for the IL17F and CD4 staining with 48% in clusters, 17% intermediate, 31% scattered and 4% with no staining for IL17F and CD4). Foxp3 regulatory cells were found within the interstitium and tubular epithelium of both vasculitis and omeprazole-induced AIN cases. Conclusion: This is the largest reported biopsy series of omeprazole-induced AIN. In this series of 25 renal biopsies with omeprazole-induced acute interstitial nephritis, the predominant inflammatory cells were mainly of a Th1-Th17 lineage, suggesting this is the major type of cell-mediated inflammatory process rather than a Th2-mediated response, which has been reported with the classic allergic acute drug-induced interstitial nephritis. With the increasing prevalence of omeprazole-induced AIN, it is now crucial to identify how omeprazole might induce these presumed Th1-Th17 mediated inflammatory pathways of injury within the kidney. Once better defined, more appropriate therapy can be introduced

Immunopathology of Omeprazole-Induced Acute Insterstitial Nephritis

Aim: The aim of this study was to define the nature of the inflammatory infiltrate that occurs with omeprazole-induced acute interstitial nephritis (AIN) and further to compare and contrast the histology of omeprazole-induced AIN with the interstitial renal lesions seen in PR3 and MPO positive small vessel vasculitis. Background: Omeprazole is now the most common cause of drug-induced acute interstitial nephritis. However, how omeprazole-induced acute interstitial nephritis is mediated is unknown. We observed in all patients the histological pattern is unlike the classical picture of an acute allergic drug-induced interstitial nephritis as seen with methicillin, but rather it is akin to that seen with PR3/MPO small vessel vasculitis or acute cellular rejection in renal transplant recipients. The nature of the cellular infiltrate in omeprazole-induced acute interstitial nephritis has not been characterized. Given the similarity in appearance to the renal involvement in small vessel vascultits, we postulated that the inflammatory process is predominantly a cell-mediated process involving TH1/TH17 cells. Methods: Data from 25 biopsy-proven cases of omeprazole-induced acute interstitial nephritis (AIN) and 27 patients with renal involvement with PR3/MPO ANCA positive small vessel vasculitis, who have presented to the renal service (Dunedin Hospital, NZ) over the last 10 years, were reviewed. The lesions were graded according to the updated Banff classification of 1997 to compare the severity of the inflammatory infiltrate. The underlying immune reaction was characterized using immunohistochemical and fluoroscopic chromogenic in situ hybridization (IHC and F-CISH) to detect T-cells (and particular markers associated with Th1, Th2, Th17 and Treg effector T cells) and B-cells. The following antibodies were used CD20 for B-cells, CD4, CD8, IL17A, IL17F and Foxp3 for T-cells. Results: All patients presented with evidence of acute kidney injury (AKI). Urinalysis demonstrated a sterile pyuria with varying amounts of proteinuria. There were no urinary eosinophils. There were no systemic symptoms to suggest a vasculitis and ANCA (PR3 & MPO titres) were negative in all cases. Histologically, all cases had 4 evidence of inflammatory cells crossing the tubular basement membrane and showing an active tubulitis. The occurrence of any eosinophils in our patients was 52%. However, in contrast to previous studies only one patient has an eosinophilic infiltrate, the other cases showed only small numbers (3 – 7 eosinophils per high powerfield in some but not all views) of scattered eosinophils in the infiltrate. Similar findings were evident in the vasculitis group. The lack of a substantial eosinophilic infiltrate argues against a pre-dominant Th-2 mediated mechanism for omeprazole-induced AIN. Our cases showed numerous CD4 positive cells, and fewer numbers of CD20 and CD8 positive cells. CD4 positive cells were present in clusters in 77% of the PPI-IN patients and 67% of the vasculitis patients. CD20 positive cells were present in clusters in 58% of all omeprazole-induced AIN patients and 37% of vasculitis patients. However CD8 positive cells were present in clusters only in 17% of omeprazole-induced AIN patients and 13% of vasculitis patients. Comparing the IL17A and CD4 double staining with the IL17F and CD4 double staining for the omeprazole-induced AIN group the grading of the staining looks very similar (for IL17A and CD4 50% of patients showing clusters, 4% intermediate, 32% of scattered and 14 % of patients without any IL17A and CD4 cells versus the staining for the IL17F and CD4 staining with 48% in clusters, 17% intermediate, 31% scattered and 4% with no staining for IL17F and CD4). Foxp3 regulatory cells were found within the interstitium and tubular epithelium of both vasculitis and omeprazole-induced AIN cases. Conclusion: This is the largest reported biopsy series of omeprazole-induced AIN. In this series of 25 renal biopsies with omeprazole-induced acute interstitial nephritis, the predominant inflammatory cells were mainly of a Th1-Th17 lineage, suggesting this is the major type of cell-mediated inflammatory process rather than a Th2-mediated response, which has been reported with the classic allergic acute drug-induced interstitial nephritis. With the increasing prevalence of omeprazole-induced AIN, it is now crucial to identify how omeprazole might induce these presumed Th1-Th17 mediated inflammatory pathways of injury within the kidney. Once better defined, more appropriate therapy can be introduced

Clostridium Ramosum - A Rare Cause of Peritoneal Dialysis-Related Peritonitis

We present the first report of a patient with peritoneal dialysis (PD)-related peritonitis due to , an anaerobe bacterium that is commonly found in normal fecal flora. On rare occasions, it can be pathogenic in immunocompromised individuals. species, including , should be included in the differential diagnosis of PD-related peritonitis