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Familial hypercholesterolemia (FH) is a monogenic disease characterized by a lifelong exposure to high LDL-C levels that can lead to early onset coronary heart disease (CHD). The main causes of FH identified to date include loss-of-function mutations in

Purpose To develop a comprehensive genetic test for female and male infertility in support of medical decisions during assisted reproductive technology (ART) protocols. Methods We developed a next-generation sequencing (NGS) gene panel consisting of 87 genes including promoters, 5′ and 3′ untranslated regions, exons, and selected introns. In addition, sex chromosome aneuploidies and Y chromosome microdeletions were analyzed concomitantly using the same panel. Results The NGS panel was analytically validated by retrospective analysis of 118 genomic DNA samples with known variants in loci representative of female and male infertility. Our results showed analytical accuracy of > 99%, with > 98% sensitivity for single-nucleotide variants (SNVs) and > 91% sensitivity for insertions/deletions (indels). Clinical sensitivity was assessed with samples containing variants representative of male and female infertility, and it was 100% for SNVs/indels, CFTR IVS8-5T variants, sex chromosome aneuploidies, and copy number variants (CNVs) and > 93% for Y chromosome microdeletions. Cost analysis shows potential savings when comparing this single NGS assay with the standard approach, which includes multiple assays. Conclusions A single, comprehensive, NGS panel can simplify the ordering process for healthcare providers, reduce turnaround time, and lower the overall cost of testing for genetic assessment of infertility in females and males, while maintaining accuracy. Electronic supplementary material The online version of this article (10.1007/s10815-018-1204-7) contains supplementary material, which is available to authorized users.

We have previously reported the molecular signature of murine pathogenic TH17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γ+IL-17+ (TH1/17) and IFN-γ−IL-17+ (TH17) CD4+ T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to TH17 cells, TH1/17 cells have gene signatures with marked similarity to mouse pathogenic TH17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that TH1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in TH17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory TH17 cells, which can be used to both identify pathogenic TH17 cells and to measure the effect of treatment on TH17 cells in human autoimmune diseases.

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis., The gut microbiome has been implicated in several autoimmune disorders. Here, the authors study the gut microbiome of patients with multiple sclerosis, and find correlations between altered abundance of certain gut microorganisms and changes in expression of immune defence genes.

After upregulation of AHR in astrocytes by type I interferons, commensal-microbe-derived metabolites of dietary tryptophan act on astrocytes to suppress CNS inflammation.

Yeste, Ada et al., Type 1 diabetes (T1D) is a T cell-dependent autoimmune disease that is characterized by the destruction of insulin-producing β cells in the pancreas. The administration to patients of ex vivo-differentiated FoxP3 regulatory T (T) cells or tolerogenic dendritic cells (DCs) that promote T cell differentiation is considered a potential therapy for T1D; however, cell-based therapies cannot be easily translated into clinical practice. We engineered nanoparticles (NPs) to deliver both a tolerogenic molecule, the aryl hydrocarbon receptor (AhR) ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and the β cell antigen proinsulin (NP) to induce a tolerogenic phenotype in DCs and promote T cell generation in vivo. NP administration to 8-week-old nonobese diabetic mice suppressed autoimmune diabetes. NP induced a tolerogenic phenotype in DCs, which was characterized by a decreased ability to activate inflammatory effector T cells and was concomitant with the increased differentiation of FoxP3 T cells. The induction of a tolerogenic phenotype in DCs by NPs was mediated by the AhR-dependent induction of Socs2, which resulted in inhibition of nuclear factor κB activation and proinflammatory cytokine production (properties of tolerogenic DCs). Together, these data suggest that NPs constitute a potential tool to reestablish tolerance in T1D and potentially other autoimmune disorders., This work was supported by grants ES025530, AI075285, and AI093903 from the NIH, 17-2011-371 from the Juvenile Diabetes Research Foundation, the Boston Area Diabetes Endocrinology Research Center (to F.J.Q.), and PI14-1600 from the Spanish Ministry of Economy and Competitiveness (ISCIII) with FEDER cofunding (to D.P.). M.C.T. received support from an educational grant from Mallinckrodt Pharmaceuticals (A113307) and from a postdoctoral fellowship (0571-15-6) from Coordination for the Improvement of Higher Education Personnel, Brazil. I.D.M. received support from an educational grant from Questcor (A219074) and from a postdoctoral fellowship (FG 2036-A1/1) from the National Multiple Sclerosis Society. S.C.K. received support from The Helmsley Charitable Trust.

Objective: To determine whether peripheral immune responses as measured by serum antigen arrays are linked to cerebral MRI measures of disease severity in multiple sclerosis (MS). Methods: In this cross-sectional study, serum samples were obtained from patients with relapsing-remitting MS (n = 21) and assayed using antigen arrays that contained 420 antigens including CNS-related autoantigens, lipids, and heat shock proteins. Normalized compartment-specific global brain volumes were obtained from 3-tesla MRI as surrogates of atrophy, including gray matter fraction (GMF), white matter fraction (WMF), and total brain parenchymal fraction (BPF). Total brain T2 hyperintense lesion volume (T2LV) was quantified from fluid-attenuated inversion recovery images. Results: We found serum antibody patterns uniquely correlated with BPF, GMF, WMF, and T2LV. Furthermore, we identified immune signatures linked to MRI markers of neurodegeneration (BPF, GMF, WMF) that differentiated those linked to T2LV. Each MRI measure was correlated with a specific set of antibodies. Strikingly, immunoglobulin G (IgG) antibodies to lipids were linked to brain MRI measures. Based on the association between IgG antibody reactivity and each unique MRI measure, we developed a lipid index. This comprised the reactivity directed against all of the lipids associated with each specific MRI measure. We validated these findings in an additional independent set of patients with MS (n = 14) and detected a similar trend for the correlations between BPF, GMF, and T2LV vs their respective lipid indexes. Conclusions: We propose serum antibody repertoires that are associated with MRI measures of cerebral MS involvement. Such antibodies may serve as biomarkers for monitoring disease pathology and progression.

Summary: Existing therapies for inflammatory bowel disease that are based on broad suppression of inflammation result in variable clinical benefit and unwanted side effects. A potential therapeutic approach for promoting immune tolerance is the in vivo induction of regulatory T cells (Tregs). Here we report that activation of the aryl hydrocarbon receptor using the non-toxic agonist 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces human Tregs in vitro that suppress effector T cells through a mechanism mediated by CD39 and Granzyme B. We then developed a humanized murine system whereby human CD4+ T cells drive colitis upon exposure to 2,4,6-trinitrobenzenesulfonic acid and assessed ITE as a potential therapeutic. ITE administration ameliorated colitis in humanized mice with increased CD39, Granzyme B, and IL10-secreting human Tregs. These results develop an experimental model to investigate human CD4+ T responses in vivo and identify the non-toxic AHR agonist ITE as a potential therapy for promoting immune tolerance in the intestine. : Therapeutic approaches aimed at expanding regulatory T cells in the gut to promote immune tolerance in patients with inflammatory bowel disease (IBD) are of clinical significance. Goettel et al. establish a humanized murine model of IBD driven by human T cells and find that activation of AHR by the non-toxic agonist ITE can prevent experimental colitis. Keywords: AHR, treg, humanized mice, IBD, ITE