Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population.

OBJECTIVE: The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome's role in RA pathology by a comprehensive metagenome-wide association study (MWAS). METHODS: We conducted MWAS of the RA gut microbiome in the Japanese population (ncase=82, ncontrol=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis). RESULTS: Phylogenetic case-control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case-control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case-control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls. CONCLUSION: Our shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome's role in RA aetiology.

Single-cell multi-omics analysis identifies two distinct phenotypes of newly-onset microscopic polyangiitis.

The immunological basis of the clinical heterogeneity in autoimmune vasculitis remains poorly understood. In this study, we conduct single-cell transcriptome analyses on peripheral blood mononuclear cells (PBMCs) from newly-onset patients with microscopic polyangiitis (MPA). Increased proportions of activated CD14+ monocytes and CD14+ monocytes expressing interferon signature genes (ISGs) are distinctive features of MPA. Patient-specific analysis further classifies MPA into two groups. The MPA-MONO group is characterized by a high proportion of activated CD14+ monocytes, which persist before and after immunosuppressive therapy. These patients are clinically defined by increased monocyte ratio in the total PBMC count and have a high relapse rate. The MPA-IFN group is characterized by a high proportion of ISG+ CD14+ monocytes. These patients are clinically defined by high serum interferon-alpha concentrations and show good response to immunosuppressive therapy. Our findings identify the immunological phenotypes of MPA and provide clinical insights for personalized treatment and accurate prognostic prediction.

Autoimmune myelofibrosis associated with systemic lupus erythematosus: a case report.

A 66-year-old woman presented with severe anaemia, thrombocytopenia and lymphopenia. The bone marrow biopsy demonstrated hypocellular marrow with myelofibrosis (MF); there was no evidence of malignancy, but infiltration of peripheral T and B cells were noticed. Magnetic resonance imaging (MRI) revealed that bone marrow of the spine exhibited low signal intensity (SI) with spotty high SI in T1- and T2-weighted images. Because there was evidence of autoimmune abnormality, she had fulfilled the classification criteria for systemic lupus erythematosus (SLE). She was diagnosed with autoimmune myelofibrosis (AIMF) associated with SLE and was treated with corticosteroid. Cytopenia improved after 1 month of corticosteroid therapy. A repeated bone marrow biopsy demonstrated that cellularity had increased and that the amount of reticulin fibre had reduced after treatment. Compared with primary MF, AIMF has generally a favourable prognosis and is often associated with autoimmune diseases, especially SLE. Bone marrow biopsy, but not aspiration, was useful for diagnosing bone marrow fibrosis. Although the association between SLE and MF has been rarely reported, we should pay attention to MF as a possible cause of pancytopenia.