Host Genes Related to Paneth Cells and Xenobiotic Metabolism Are Associated with Shifts in Human Ileum-Associated Microbial Composition

The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn’s disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD). Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial intestinal surgery. Both RNA and DNA were extracted from the mucosal biopsy samples. Patients were genotyped for the three major NOD2 variants (Leufs1007, R702W, and G908R) and the ATG16L1T300A variant. Whole human genome mRNA expression profiles were generated using Agilent microarrays. Microbial composition profiles were determined by 454 pyrosequencing of the V3–V5 hypervariable region of the bacterial 16 S rRNA gene. The results of permutation based multivariate analysis of variance and covariance (MANCOVA) support the hypothesis that host mucosal Paneth cell and xenobiotic metabolism genes play an important role in host microbial interactions

Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype

Background: Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. Methods: We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. Results: The siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood. Conclusions: This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders

T cells with Fc receptors for IgA: induction of T alpha cells in vivo and in vitro by purified IgA.

Abstract Previous studies demonstrated that BALB/c mice with the IgA-secreting plasmacytomas MOPC-315 (alpha lambda 2), MOPC-167 (alpha kappa), McPC-603 (alpha kappa) and TEPC-15 (alpha kappa) developed large numbers of T cells with surface membrane receptors for IgA (T alpha cells). The lack of T alpha cell expansion in mice with variant plasmacytomas that were nonsecretors or low secretors of IgA implied that elevated serum IgA contributed to the increase in T alpha cells. The present studies show that normal BALB/c mice that were given daily injections of 30 mg of IgA (M315 protein) develop a marked increase in the number of T alpha cells. These studies also show that the T alpha cells induced by injection of IgA are Lyt1-2+ T cells. In addition, the data presented demonstrate that nylon wool nonadherent T cells, treated with purified polymeric IgA (M315 protein) in vitro, develop a marked increase in the number of T alpha cells. The in vitro induction of T alpha cells by IgA requires DNA and protein synthesis. These findings indicate that the T alpha cell expansion observed in mice with IgA myeloma is related to the high serum level of IgA and not to the myeloma tumor per se. In addition, these observations have a more general relevance to the issue of B cell regulation because they demonstrate that secreted immunoglobulin can directly induce expansion of immunoregulatory T cells.</jats:p