Journal Article

Altered function and differentiation of age-associated B cells contribute to the female bias in lupus mice

Meng, Wenzhao, Rivera-Correa, Juan, Flores-Castro, Danny, Sculco, Peter K., Rosenfeld, Aaron M., Bachu, Mahesh, Jessberger, Rolf, Jenkins, Daniel, Ricker, Edd, Chinenov, Yurii, Pernis, Alessandra B., Gupta, Sanjay, Prak, Eline T. Luning, Manni, Michela, Pannellini, Tania

2021

Overview

Differences in immune responses to viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) can show sexual dimorphism. Age-associated B cells (ABC) are a population of CD11c + T-bet + B cells critical for antiviral responses and autoimmune disorders. Absence of DEF6 and SWAP-70, two homologous guanine exchange factors, in double-knock-out (DKO) mice leads to a lupus-like syndrome in females marked by accumulation of ABCs. Here we demonstrate that DKO ABCs show sex-specific differences in cell number, upregulation of an ISG signature, and further differentiation. DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c + and CD11c − effector B cell populations with pathogenic and pro-inflammatory function as demonstrated by BCR sequencing and fate-mapping experiments. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs, resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function and differentiation of ABCs that accompanies TLR7-driven immunopathogenesis. Autoimmunity mediated by age-associated B cells (ABC) can affect males and females differently. Here, using a lupus-like mouse model that affects females more severely, the authors observe an ABC mediated and guanine nucleotide exchange factor (GEF) restrained pathogenic process involving TLR7.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/21 / 13/31 / 13/51 / 13/95 / 38/15 / 38/23 / 38/77 / 38/91 / 631/250/1619/40 / 631/250/249/1313/1613 / 631/250/38 / 64/110 / 64/60 / Age / Age Factors / Aging - genetics / Aging - immunology / Animals / Antiviral drugs / Autoimmune diseases / Autoimmunity / B-Lymphocytes - cytology / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Bias / CD11c antigen / CD11c Antigen - immunology / CD11c Antigen - metabolism / Cell differentiation / Cell Differentiation - genetics / Cell Differentiation - immunology / Cell fate / Cell number / Cells, Cultured / Chronic conditions / DNA-Binding Proteins - genetics / DNA-Binding Proteins - immunology / DNA-Binding Proteins - metabolism / Female / Females / Guanine / Guanine nucleotide exchange factor / Guanine Nucleotide Exchange Factors - genetics / Guanine Nucleotide Exchange Factors - immunology / Guanine Nucleotide Exchange Factors - metabolism / Homology / Humanities and Social Sciences / Immunopathogenesis / Inflammation / Kaplan-Meier Estimate / Lupus / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - immunology / Lupus Erythematosus, Systemic - metabolism / Lymphocytes B / Male / Males / Mice / Mice, Inbred C57BL / Mice, Knockout / Minor Histocompatibility Antigens - genetics / Minor Histocompatibility Antigens - immunology / Minor Histocompatibility Antigens - metabolism / multidisciplinary / Nuclear Proteins - genetics / Nuclear Proteins - immunology / Nuclear Proteins - metabolism / Nucleotides / Pathogenicity / Pathogens / Science / Science (multidisciplinary) / Sequences / Sex Factors / Sexual dimorphism / Systemic lupus erythematosus / T-Box Domain Proteins - immunology / T-Box Domain Proteins - metabolism / TLR7 protein / Toll-like receptors