免疫細胞タイピングによる関節リウマチの臨床免疫研究

学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 佐藤 伸一, 東京大学教授 田中 廣壽, 東京大学教授 田中 栄, 東京大学教授 岡崎 仁, 東京大学講師 清水 潤University of Tokyo(東京大学

Immune Profiling and Precision Medicine in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a wide range of clinical symptoms. Enormous progress has been made in the immunological and genetic understanding of SLE. However, the biology of disease heterogeneity in SLE has remained largely unexplored. Human immune profiling studies, helped by recent technological advances especially in single-cell and “omics„ analyses, are now shedding light on the cellular and molecular basis of clinical symptoms and disease flares in individual patients. Peripheral blood immunophenotyping analysis with flow cytometry or mass cytometry are identifying responsible cell subsets and markers characteristic of disease heterogeneity. Transcriptome analysis is discovering molecular networks responsible for disease activity, disease subtype and future relapse. In this review, we summarize recent advances in the immune profiling analysis of SLE patients and discuss how they will be used for future precision medicine

Pathophysiology and stratification of treatment-resistant rheumatoid arthritis

AbstractEarly diagnosis and timely therapeutic intervention are clinical challenges of rheumatoid arthritis (RA), especially for treatment-resistant or difficult-to-treat patients. Little is known about the immunological mechanisms involved in refractory RA. In this review, we summarize previous research findings on the immunological mechanisms of treatment-resistant RA. Genetic prediction of treatment-resistant RA is challenging. Patients with and without anti-cyclic citrullinated peptide autoantibodies are considered part of distinct subgroups, especially regarding long-term clinical prognosis and treatment responses. B cells, T cells and other immune cells and fibroblasts are of pathophysiological importance and are associated with treatment responses. Finally, we propose a new hypothesis that stratifies patients with RA into two subgroups with distinct immunological pathologies based on our recent immunomics analysis of RA. One RA subgroup with a favorable prognosis is characterized by increased interferon signaling. Another subgroup with a worse prognosis is characterized by enhanced acquired immune responses. Increases in dendritic cell precursors and diversified autoreactive anti-modified protein antibodies may have pathophysiological roles, especially in the latter subgroup. These findings that improve treatment response predictions might contribute to future precision medicine for RA

The Impact of Obesity and a High-Fat Diet on Clinical and Immunological Features in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiple organ involvement predominantly affecting women of childbearing age. Environmental factors, as well as genetic predisposition, can cause immunological disturbances that manifest as SLE. A habitual high-fat diet and obesity have recently been reported to play a role in the pathogenesis of autoimmune diseases. The frequency of obesity is higher in patients with SLE than in general populations. Vitamin D and adipokines, such as leptin and adiponectin, are possible mediators connecting obesity and SLE. Serum leptin and adiponectin levels are elevated in patients with SLE and can impact innate and adaptive immunity. Vitamin D deficiency is commonly observed in SLE. Because vitamin D can modulate the functionality of various immune cells, we review vitamin D supplementation and its effects on the course of clinical disease in this work. We also discuss high-fat diets coinciding with alterations of the gut microbiome, or dysbiosis. Contingent upon dietary habits, microbiota can be conducive to the maintenance of immune homeostasis. A high-fat diet can give rise to dysbiosis, and patients who are affected by obesity and/or have SLE possess less diverse microbiota. Interestingly, a hypothesis about dysbiosis and the development of SLE has been suggested and reviewed here

Carriers of HLA-DRB1*04:05 have a better clinical response to abatacept in rheumatoid arthritis

Abstract HLA-DRB1 shared epitope risk alleles are the strongest genetic risk factors for rheumatoid arthritis (RA) and potential biomarkers for treatment response to biological disease-modifying antirheumatic drugs (bDMARDs). This study aimed to investigate the association between treatment response and individual HLA-DRB1 alleles in RA patients receiving different bDMARDs. We recruited 106 patients with active RA who had started abatacept, tocilizumab, or TNF inhibitors as a first-line bDMARDs. We examined the relationship between Simplified Disease Activity Index (SDAI) improvement at 3 months and HLA-DRB1 allele carriage. The results revealed that the HLA-DRB1*04:05 allele, a shared-epitope allele, was significantly associated with better SDAI improvement only after abatacept treatment (SDAI improvement 28.5% without the allele vs 59.8% with allele, p = 0.003). However, no significant association was found with other treatments. Both multivariate linear regression and mediation analysis confirmed that the HLA-DRB1*04:05 allele was independently associated with abatacept treatment response, regardless of anti-CCP antibody titers. The study concluded that in patients with RA receiving their first-line bDMARD treatment, carrying the HLA-DRB1*04:05 allele was associated with better SDAI improvement specifically in abatacept-treated patients. These disease-risk HLA alleles have the potential to serve as genomic biomarkers for predicting treatment response with co-stimulation blockage therapy

Serum Amphiregulin and Heparin-Binding Epidermal Growth Factor as Biomarkers in Patients with Idiopathic Inflammatory Myopathy

Background. The epidermal growth factors amphiregulin (AREG) and heparin-binding epidermal growth factor (HB-EGF) are implicated in the pathogenesis of several autoimmune diseases, but their clinical and pathological roles in idiopathic inflammatory myopathy (IIM) are unclear. Methods. Serum AREG and HB-EGF levels were measured by ELISA in patients with IIM (n = 37), systemic sclerosis (n = 17), and rheumatoid arthritis (n = 10), and for seven age- and sex-matched healthy controls (HCs). Associations between serum AREG or HB-EGF levels and the clinical parameters were analyzed. Results. Serum AREG levels in IIM patients were significantly elevated compared to those in HCs (median, 20.7 and 10.7 pg/mL, respectively; p = 0.025). In particular, serum AREG levels in IIM patients with interstitial lung disease (ILD) were higher than those of HCs (22.4 pg/mL, p = 0.027). The disease duration in patients with elevated serum AREG levels was significantly shorter compared to those who had normal serum AREG levels (7 and 21 months, respectively; p = 0.0012). Serum HB-EGF levels were significantly increased in IIM patients with elevated CK levels (136.2 pg/mL; p = 0.020) and patients with anti-Mi-2 antibody (183.7 pg/mL; p = 0.045) compared to those in HCs (74.9 pg/mL). Conclusion. These results suggested that AREG could be a promising biomarker associated with early-phase IIM-related ILD, and that HB-EGF expression was associated with muscle injury and regeneration in IIM

Transcriptome analysis of peripheral blood from patients with rheumatoid arthritis: a systematic review

Abstract In the era of precision medicine, transcriptome analysis of whole gene expression is an essential technology. While DNA microarray has a limited dynamic range and a problem of background hybridization, RNA sequencing (RNA-seq) has a broader dynamic range and a lower background signal that increase the sensitivity and reproducibility. While transcriptome analyses in rheumatoid arthritis (RA) have generally focused on whole peripheral blood mononuclear cells (PBMC), analyses of detailed cell subsets have an increased need for understanding the pathophysiology of disease because the involvement of CD4+ T cells in the pathogenesis of RA has been established. Transcriptome analysis of detailed CD4+ T cell subsets or neutrophils shed new light on the pathophysiology of RA. There are several analyses about the effect of biological treatment. Many studies report the association between type I interferon signature gene expression and response to therapy

Additional file 2: Figure S1. of Increased serum concentrations of IL-1 beta, IL-21 and Th17 cells in overweight patients with rheumatoid arthritis

Frequencies of peripheral immune cells (Th17 cells and Plasmablast (PB)) and BMI. A comparison of the frequencies of Th17 cells and PB between the three BMI groups among healthy donors. A p value <0.05 was defined as a significant difference. ns not significant (TIF 569 kb