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

AbstractDifferences 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.

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Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis

10.1101/2021.01.20.427400 ◽

2021 ◽

Author(s):

Edd Ricker ◽

Michela Manni ◽

Danny Flores-Castro ◽

Daniel Jenkins ◽

Sanjay Gupta ◽

...

Keyword(s):

Sex Differences ◽

Immune Responses ◽

Pulmonary Inflammation ◽

Early Mortality ◽

Sex Bias ◽

Knock Out ◽

Antiviral Responses ◽

Knock Out Mice ◽

Lupus Syndrome ◽

Oligoclonal Expansion

ABSTRACTSex differences characterize immune responses to viruses like SARS-CoV2 and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+ T-bet+ B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c− effector populations with pathogenic and proinflammatory potential. 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 contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.

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Assessing the expression of immunosuppressive cytokines in the newly diagnosed systemic lupus Erythematosus patients: a focus on B cells

BMC Immunology ◽

10.1186/s12865-020-00388-3 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Mitra Abbasifard ◽

Zahra Kamiab ◽

Mohammad Hasani ◽

Amir Rahnama ◽

Pooya Saeed-Askari ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

Immune Responses ◽

Lupus Erythematosus ◽

Healthy Subjects ◽

Serum Levels ◽

Newly Diagnosed ◽

Systemic Lupus ◽

Moderate Disease ◽

Immunosuppressive Cytokines

Abstract Background The immunosuppressive effects of regulatory B-cells (Bregs) and their immunosuppressive cytokines on immune responses in autoimmune disorders, mainly systemic lupus erythematosus (SLE), have been recently established. Therefore, the purpose of this article has been the exploration of the expressions of cytokines produced by B cells in newly diagnosed SLE patients. Results The findings demonstrated that the gene expression of IL-10, TGF-β, IL-35, PD-L1, and FasL was significantly up-regulated in SLE patients compared to healthy subjects (P < 0.05). Additionally, the results revealed that serum levels of IL-10, TGF-β, IL-35, PD-L1 were remarkably increased in patients with SLE compared to healthy subjects (P < 0.0001). However, serum levels of IL-10 and TGF-β decreased significantly with increasing SLEDAI score in studied patients (P < 0.05). Conclusion It was concluded that the release of anti-inflammatory cytokines, particularly IL-10 and TGF-β, might inhibit immune responses and autoreactive immune cells in a compensatory manner in SLE patients with mild to moderate disease activity.

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Infection with Opportunistic Bacteria Triggers Severe Pulmonary Inflammation in Lupus-Prone Mice

Mediators of Inflammation ◽

10.1155/2019/1701367 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Wenchao Li ◽

Weiwei Chen ◽

Saisai Huang ◽

Xiaojun Tang ◽

Genhong Yao ◽

...

Keyword(s):

Immune Responses ◽

Lupus Erythematosus ◽

Early Stage ◽

Pulmonary Inflammation ◽

Infection Model ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Opportunistic Bacteria ◽

Enhanced Production ◽

Immune Dysfunctions

Infection is a common cause of hospitalization and mortality in patients with systemic lupus erythematosus (SLE). How the underlying immune dysfunctions affect the antimicrobial immunity remains largely unknown. In the present study, employing the pulmonary infection model, we determined the antimicrobial defence of lupus-prone mice. After infecting with opportunistic bacterium Haemophilus influenzae (Hi), lupus-prone mice (B6/lpr) exhibited inefficient bacterial elimination and recovered slowly. They generated severer inflammation at the early stage of infection, as excessive accumulation of neutrophils and enhanced production of proinflammatory cytokines were observed in the lung. In addition, a large number of apoptotic cells were detected in the lungs of B6/lpr mice. For adaptive immune responses, B6/lpr mice were capable to generate enough protective Hi-specific Th17 cells. They evoked stronger Hi-specific γδ T17 response in both lungs and spleens. Unexpectedly, both CD4 and γδ T cells from lupus-prone mice showed deficiency in IFN-γ production. For humoral immune responses, compared with those of WT mice, the concentrations of Hi-specific IgA, IgM, and IgG, especially IgG, were significantly higher in the B6/lpr mice. Our findings suggest that lupus mice are capable to generate antibacterial immune responses; however, the overwhelming inflammation and overactivated immune responses increase the severity of infection.

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B-Cells and Antibodies as Contributors to Effector Immune Responses in Tuberculosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.640168 ◽

2021 ◽

Vol 12 ◽

Author(s):

Willemijn F. Rijnink ◽

Tom H.M. Ottenhoff ◽

Simone A. Joosten

Keyword(s):

B Cells ◽

Immune Responses ◽

Disease Burden ◽

Therapeutic Strategies ◽

Current Evidence ◽

Cell Mediated Immunity ◽

Knock Out ◽

Major Threat ◽

Vaccination Strategies ◽

New Evidence

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is still a major threat to mankind, urgently requiring improved vaccination and therapeutic strategies to reduce TB-disease burden. Most present vaccination strategies mainly aim to induce cell-mediated immunity (CMI), yet a series of independent studies has shown that B-cells and antibodies (Abs) may contribute significantly to reduce the mycobacterial burden. Although early studies using B-cell knock out animals did not support a major role for B-cells, more recent studies have provided new evidence that B-cells and Abs can contribute significantly to host defense against Mtb. B-cells and Abs exist in many different functional subsets, each equipped with unique functional properties. In this review, we will summarize current evidence on the contribution of B-cells and Abs to immunity toward Mtb, their potential utility as biomarkers, and their functional contribution to Mtb control.

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Distinct cell-specific control of autoimmunity and infection by FcγRIIb

Journal of Experimental Medicine ◽

10.1084/jem.20072565 ◽

2008 ◽

Vol 205 (4) ◽

pp. 883-895 ◽

Cited By ~ 130

Author(s):

Rebecca J. Brownlie ◽

Kate E. Lawlor ◽

Heather A. Niederer ◽

Antony J. Cutler ◽

Zou Xiang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

Immune Responses ◽

Lupus Erythematosus ◽

Therapeutic Potential ◽

Systemic Lupus ◽

Collagen Induced Arthritis ◽

Distinct Cell ◽

Specific Control

FcγRIIb is an inhibitory Fc receptor expressed on B cells and myeloid cells. It is important in controlling responses to infection, and reduced expression or function predisposes to autoimmunity. To determine if increased expression of FcγRIIb can modulate these processes, we created transgenic mice overexpressing FcγRIIb on B cells or macrophages. Overexpression of FcγRIIb on B cells reduced the immunoglobulin G component of T-dependent immune responses, led to early resolution of collagen-induced arthritis (CIA), and reduced spontaneous systemic lupus erythematosus (SLE). In contrast, overexpression on macrophages had no effect on immune responses, CIA, or SLE but increased mortality after Streptococcus pneumoniae infection. These results help define the role of FcγRIIb in immune responses, demonstrate the contrasting roles played by FcγRIIb on B cells and macrophages in the control of infection and autoimmunity, and emphasize the therapeutic potential for modulation of FcγRIIb expression on B cells in inflammatory and autoimmune disease.

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