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Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota. However, the effects of endocannabinoids on host susceptibility to infection has not been explored. Here, we show that mice with elevated levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG) are protected from enteric infection by Enterobacteriaceae pathogens. 2-AG directly modulates pathogen function by inhibiting virulence programs essential for successful infection. Furthermore, 2-AG antagonizes the bacterial receptor QseC, a histidine kinase encoded within the core Enterobacteriaceae genome that promotes the activation of pathogen-associated type three secretion systems. Taken together, our findings establish that endocannabinoids are directly sensed by bacteria and can modulate bacterial function.

Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to this autoimmune disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). We focused on IgA, which is the second-most prevalent isotype in serum and, along with IgG, is deposited in glomeruli in individuals with lupus nephritis. We show that individuals with SLE have serum IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoprotein (Sm/RNP), played a role in IC activation of pDCs. We found that pDCs expressed the IgA-specific Fc receptor, FcαR, and IgA1 autoantibodies synergized with IgG in RNA-containing ICs to generate robust primary blood pDC IFN-α responses in vitro. pDC responses to these ICs required both FcαR and FcγRIIa, showing synergy between these Fc receptors. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. Circulating pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcαR than pDCs from healthy control individuals. Although pDC FcαR expression correlated with the blood IFN-stimulated gene signature in SLE, Toll-like receptor 7 agonists, but not IFN-α, up-regulated pDC FcαR expression in vitro. Together, we show a mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis. Editor's summary: Autoantibodies to nuclear antigens contribute to pathology in systemic lupus erythematosus (SLE). However, it is not understood how different isotypes of these antibodies contribute to disease. Here, Waterman et al. characterized circulating immunoglobulin A1 (IgA1) autoantibodies in individuals with SLE, showing that they reacted against many of the same self-antigens as their immunoglobulin G (IgG) counterparts, including against Smith ribonuclear proteins. The authors further showed that interferon-α (IFN-α)–producing plasmacytoid dendritic cells expressed the IgA1 receptor, Fc α receptor (FcαR), and that IgA1-containing immune complexes could drive IFN-α production by these cells in vitro. The authors showed that these responses required the presence of both IgA1 and IgG. Last, the authors showed that, in 18 individuals with SLE, interferon-stimulated gene expression positively correlated with the amount of FcαR in whole blood. Together, these results suggest that targeting FcαR could be a potential therapeutic for SLE treatment. —Brandon Berry [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P

We report on 2 patients with compound heterozygous mutations in forkhead box N1 (FOXN1), a transcription factor essential for thymic epithelial cell (TEC) differentiation. TECs are critical for T cell development. Both patients had a presentation consistent with [T.sup.-/lo][B.sup.+][NK.sup.+] SCID, with normal hair and nails, distinct from the classic nude/SCID phenotype in individuals with autosomal-recessive FOXN1 mutations. To understand the basis of this phenotype and the effects of the mutations on FOXN1, we generated mice using CRISPR-Cas9 technology to genocopy mutations in 1 of the patients. The mice with the Foxn1 compound heterozygous mutations had thymic hypoplasia, causing a [T.sup.-][B.sup.+][NK.sup.+] SCID phenotype, whereas the hair and nails of these mice were normal. Characterization of the functional changes due to the Foxn1 mutations revealed a 5-amino acid segment at the end of the DNA-binding domain essential for the development of TECs but not keratinocytes. The transcriptional activity of this Foxn1 mutant was partly retained, indicating a region that specifies TEC functions. Analysis of an additional 9 FOXN1 mutations identified in multiple unrelated patients revealed distinct functional consequences contingent on the impact of the mutation on the DNA-binding and transactivation domains of FOXN1., Introduction The development of T cells expressing T cell receptors (TCRs) bearing a precise specificity for peptides embedded in self-HLA (MHC) molecules occurs in the thymus. At this site, T [...]

Lipids synthesized on the skin are critical to the antimicrobial barrier. Skin lipids also facilitate survival of lipophilic skin commensals in an otherwise dry and acidic ecological landscape. Thus, skin‐specific stearoyl‐coenzyme A desaturase 1 knockout mice (Scd1ΔK14) with sebocyte atrophy and decreased synthesis of monounsaturated fatty acids, triglycerides and wax diesters have dry, inflamed skin. Here, we used 16S rRNA (V1‐V2 and V1‐V9) and internal transcribed spacer 1 (ITS1) amplicon sequencing to compare bacterial and fungal skin microbiomes between Scd1ΔK14 mice and wildtype control mice (Scd1fl/fl) in a barrier facility. Saprophytic bacteria including Sporosarcina spp. and Staphylococcus lentus and saprophytic fungi including Alternaria infectoria were found in higher relative abundance in the Scd1ΔK14 group (ANCOM). Analysis of community diversity (Shannon index) revealed greater fungal alpha diversity in the Scd1ΔK14 group (p = 0.009, Kruskal–Wallis). Principal coordinates analysis (Bray–Curtis dissimilarity) showed that both bacterial (p = 0.002, PERMANOVA) and fungal communities (p = 0.006, PERMANOVA) of the Scd1ΔK14 group were unique from the wildtype group. Altogether, these results suggest that sebaceous gland‐derived lipids normally restrict the skin microbiome, and in the absence of these lipids, a greater diversity of opportunistic organisms are able to colonize the surface of skin. [ABSTRACT FROM AUTHOR]

Objectives: Families that contain multiple siblings affected with childhood onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus.Methods: Sanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional patients with SLE. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively.Results: The two familial ultra-rare, predicted loss-of-function (LOF) SAT1 variants exhibited X-linked recessive Mendelian inheritance in two unrelated African-American families. Each LOF variant was transmitted from the heterozygous unaffected mother to her two sons with childhood-onset SLE. The p.Asp40Tyr variant affected a splice donor site causing deleterious transcripts. The young hemizygous male and homozygous female Sat1p.Glu92Leufs*6 KI mice spontaneously developed splenomegaly, enlarged glomeruli with leucocyte infiltration, proteinuria and elevated expression of type I interferon-inducible genes. SAT1 is highly expressed in neutrophils and encodes spermidine/spermine-N1-acetyltransferase 1 (SSAT1), a rate-limiting enzyme in polyamine catabolism. Young male KI mice exhibited neutrophil defects and decreased proportions of Foxp3 +CD4+ T-cell subsets. Circulating neutrophil counts and proportions of Foxp3 +CD4+ T cells correlated with decreased plasma levels of spermine in treatment-naive, incipient SLE patients.Conclusions: We identified two novel SAT1 LOF variants, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism and identified SAT1 LOF variants as new monogenic causes for SLE. [ABSTRACT FROM AUTHOR]