AFF3, a susceptibility factor for autoimmune diseases, is a molecular facilitator of immunoglobulin class switch recombination

Immunoglobulin class switch recombination (CSR) plays critical roles in controlling infections and inflammatory tissue injuries. Here, we show that AFF3, a candidate gene for both rheumatoid arthritis and type 1 diabetes, is a molecular facilitator of CSR with an isotype preference. Aff3-deficient mice exhibit low serum levels of immunoglobulins, predominantly immunoglobulin G2c (IgG2c) followed by IgG1 and IgG3 but not IgM. Furthermore, Aff3-deficient mice show weak resistance to Plasmodium yoelii infection, confirming that Aff3 modulates immunity to this pathogen. Mechanistically, the AFF3 protein binds to the IgM and IgG1 switch regions via a C-terminal domain, and Aff3 deficiency reduces the binding of AID to the switch regions less efficiently. One AFF3 risk allele for rheumatoid arthritis is associated with high mRNA expression of AFF3, IGHG2, and IGHA2 in human B cells. These findings demonstrate that AFF3 directly regulates CSR by facilitating the recruitment of AID to the switch regions

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

A Feasible Technique in Laparoscopic Excision for Juvenile Cystic Adenomyosis: A Case Report, Literature Review, and Surgical Video

Background: Juvenile cystic adenomyosis (JCA) is a rare uterine lesion. We present the case of a young woman who was diagnosed with JCA and subsequently managed with laparoscopic cyst removal with sharp and blunt dissection. Moreover, we provide a literature review and a surgical video. Case: A 22-year-old nulliparous woman presented with severe dysmenorrhea and was assessed using contrast-enhanced abdominal computed tomography, transvaginal ultrasonography and pelvic magnetic resonance imaging, and diagnosed with a cystic lesion on the left side of the myometrium. She underwent laparoscopic cyst excision and uterine reconstruction. Histology was suggestive of JCA. The dysmenorrhea resolved postoperatively. Conclusion: Surgical resection is the first choice of treatment for cystic adenomyosis, and a laparoscopic approach using scissor forceps is effective

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

Supplemental Material - Autotaxin is a potential link between genetic risk factors and immunological disturbances of plasmacytoid dendritic cells in systematic lupus erythematosus

Supplemental material for autotaxin is a potential link between genetic risk factors and immunological disturbances of plasmacytoid dendritic cells in systematic lupus erythematosus by Yumi Tsuchida, Hirofumi Shoda, Masahiro Nakano, Mineto Ota, Tomohisa Okamura, Kazuhiko Yamamoto, Makoto Kurano, Yutaka Yatomi, Keishi Fujio, and Tetsuji Sawada in lupus</p

CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.

γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background1-5. γδ T cells can sense conserved cell stress signals prevalent in transformed cells2,3, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 T cells-the most abundant subset of human γδ T cells4-recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs. 6-8), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ T cell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ T cells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vγ9Vδ2 T cell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ T cell stress surveillance and suggests new avenues available to enhance γδ T cell anticancer activity

TGF-β3 Inhibits Antibody Production by Human B Cells

<div><p>TGF-β is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-β, TGF-β1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-β3 may play an important role in the regulation of immune system in mice. Murine CD4⁺CD25^-LAG3⁺ regulatory T cells suppress B cell function through the production of TGF-β3, and it has been reported that TGF-β3 is therapeutic in a mouse model of systemic lupus erythematosus. The effect of TGF-β3 on human B cells has not been reported, and we herein examined the effect of TGF-β3 on human B cells. TGF-β3 suppressed B cell survival, proliferation, differentiation into plasmablasts, and antibody secretion. Although the suppression of human B cells by TGF-β1 has long been recognized, the precise mechanism for the suppression of B cell function by TGF-β1 remains elusive; therefore, we examined the effect of TGF-β1 and β3 on pathways important in B cell activation and differentiation. TGF-β1 and TGF-β3 inhibited some of the key molecules of the cell cycle, as well as transcription factors important in B cell differentiation into antibody secreting cells such as IRF4, Blimp-1, and XBP1. TGF-β1 and β3 also inhibited B cell receptor signaling. Our results suggest that TGF-β3 modifying therapy might be therapeutic in autoimmune diseases with B cell dysregulation in humans.</p></div

TGF-β1 and β3 inhibit TFs essential for B cell differentiation into ASCs.

<p>(a-d) B cells were cultured under IL-21 and CD40L stimulation for 3 days (a, b) or 5 days (c, d), and the expression of the indicated genes was assessed by quantitative PCR. Expression relative to <i>GAPDH</i> is shown. TGF-β treated cells were compared with TGF-β untreated cells using one way ANOVA, Dunnett test (n = 5). Results are representative of two (b), three (d), or four (a,c) independent experiments. (e) B cells were cultured under IL-21, CD40L, and CpG-ODN2006 stimulation for 4 days with or without TGF-β. Expression of Blimp-1 on CD19⁺ B cells was assessed by intracellular staining. TGF-β treated cells were compared with TGF-β untreated cells using one way ANOVA, Dunnett test (n = 3). Results are representative of three similar experiments.</p

TGF-β1 and β3 inhibit phosphorylation of Syk.

<p>(a) B cells were cultured overnight without TGF-β or with TGF-β, and BCR stimulation was induced for 3 minutes. Results are representative of three similar experiments. (b) B cells were treated overnight with medium, TGF-β1, or TGF-β3 and stimulated with IL-21 and sCD40L for 3 minutes. Results are representative of two similar experiments. (c) B cells were treated overnight with medium, TGF-β1, or TGF-β3 and stimulated with IL-21 for the indicated times. Results are representative of two similar experiments. (d) B cells were cultured overnight without TGF-β or with TGF-β, and the expression of <i>FCRL4</i> was examined by quantitative PCR. Expression relative to <i>GAPDH</i> is shown. TGF-β treated cells were compared with TGF-β untreated cells using one way ANOVA, Dunnett test (n = 3). Results are representative of two similar experiments.</p