scholarly journals Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity

2012 ◽  
Vol 209 (12) ◽  
pp. 2307-2319 ◽  
Author(s):  
Marion Espéli ◽  
Menna R. Clatworthy ◽  
Susanne Bökers ◽  
Kate E. Lawlor ◽  
Antony J. Cutler ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Germinal Center ◽  
Genetic Manipulation ◽  
Critical Role ◽  
Wild Mouse ◽  
Affinity Maturation ◽  
Mouse Strains ◽  
Autoantibody Production ◽  
Complex Deposition ◽  
Mouse Promoter

Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1–binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation–induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity.

scholarly journals Cytokines and Their Roles in the Pathogenesis of Systemic Lupus Erythematosus: From Basics to Recent Advances

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Desmond Yat Hin Yap ◽  
Kar Neng Lai
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Immune Disorder ◽  
Autoantibody Production ◽  
Inflammatory Processes ◽  
Complex Deposition

Systemic lupus erythematosus (SLE) is a complex auto-immune disorder which involves various facets of the immune system. In addition to autoantibody production and immune complex deposition, emerging evidences suggest that cytokines may act as key players in the immunopathogenesis of SLE. These cytokines assume a critical role in the differentiation, maturation and activation of cells and also participate in the local inflammatory processes that mediate tissue insults in SLE. Certain cytokines such as the IL-6, IL-10, IL-17, BLys, type I interferons (IFN) and tumor necrosis factor-α(TNF-α) are closely linked to pathogenesis of SLE. The delineation of the role played by these cytokines not only fosters our understanding of this disease but also provides a sound rationale for various therapeutic approaches. In this context, this review focuses on selected cytokines which exert significant effect in the pathogenesis of SLE and their possible clinical applications.

scholarly journals Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus

2005 ◽  
Vol 202 (2) ◽  
pp. 321-331 ◽  
Author(s):  
Sean R. Christensen ◽  
Michael Kashgarian ◽  
Lena Alexopoulou ◽  
Richard A. Flavell ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Systemic Autoimmune Disease ◽  
Toll Like Receptor ◽  
Autoantibody Production ◽  
Nuclear Antigens ◽  
Deficient Mice

Systemic autoimmune disease in humans and mice is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. Autoantigens, such as double-stranded (ds) DNA and the RNA-containing Smith antigen (Sm), may be selectively targeted in systemic lupus erythematosus because of their ability to activate a putative common receptor. Toll-like receptor 9 (TLR9), a receptor for CpG DNA, has been implicated in the activation of autoreactive B cells in vitro, but its role in promoting autoantibody production and disease in vivo has not been determined. We show that in TLR9-deficient lupus-prone mice, the generation of anti-dsDNA and antichromatin autoantibodies is specifically inhibited. Other autoantibodies, such as anti-Sm, are maintained and even increased in TLR9-deficient mice. In contrast, ablation of TLR3, a receptor for dsRNA, did not inhibit the formation of autoantibodies to either RNA- or DNA-containing antigens. Surprisingly, we found that despite the lack of anti-dsDNA autoantibodies in TLR9-deficient mice, there was no effect on the development of clinical autoimmune disease or nephritis. These results demonstrate a specific requirement for TLR9 in autoantibody formation in vivo and indicate a critical role for innate immune activation in autoimmunity.

scholarly journals Regulatory T-Cell-Associated Cytokines in Systemic Lupus Erythematosus

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Akiko Okamoto ◽  
Keishi Fujio ◽  
Tomohisa Okamura ◽  
Kazuhiko Yamamoto
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Organ Damage ◽  
Interleukin 10 ◽  
Peripheral Tolerance ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Inflammatory Processes ◽  
Complex Deposition

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, complement activation, and immune complex deposition, resulting in tissue and organ damage. An understanding of the mechanisms responsible for homeostatic control of inflammation, which involve both innate and adoptive immune responses, will enable the development of novel therapies for SLE. Regulatory T cells (Treg) play critical roles in the induction of peripheral tolerance to self- and foreign antigens. Naturally occurring CD4+CD25+Treg, which characteristically express the transcription factor forkhead box protein P3 (Foxp3), have been intensively studied because their deficiency abrogates self-tolerance and causes autoimmune disease. Moreover, regulatory cytokines such as interleukin-10 (IL-10) also play a central role in controlling inflammatory processes. This paper focuses on Tregs and Treg-associated cytokines which might regulate the pathogenesis of SLE and, hence, have clinical applications.

scholarly journals Excessive CD11c+Tbet+B cells promote aberrant TFHdifferentiation and affinity-based germinal center selection in lupus

2019 ◽  
Vol 116 (37) ◽  
pp. 18550-18560 ◽  
Author(s):  
Wenqian Zhang ◽  
Huihui Zhang ◽  
Shujun Liu ◽  
Fucan Xia ◽  
Zijian Kang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Affinity Maturation ◽  
Antibody Affinity ◽  
Autoantibody Production ◽  
Cell Responses ◽  
Antigen Presenting

Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response―a process critical for antibody affinity maturation―is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ABCs and deregulated TFHcell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ABC differentiation, and blocking CD11c+Tbet+ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFHcell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.

scholarly journals Altered Germinal-Center Metabolism in B Cells in Autoimmunity

Metabolites ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 40
Author(s):  
Ashton K. Shiraz ◽  
Eric J. Panther ◽  
Christopher M. Reilly
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Germinal Center ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Cell Metabolism ◽  
Affinity Maturation ◽  
B Cell Differentiation ◽  
Contributing Factors

B lymphocytes play an important role in the pathophysiology of many autoimmune disorders by producing autoantibodies, secreting cytokines, and presenting antigens. B cells undergo extreme physiological changes as they develop and differentiate. Aberrant function in tolerogenic checkpoints and the metabolic state of B cells might be the contributing factors to the dysfunctionality of autoimmune B cells. Understanding B-cell metabolism in autoimmunity is important as it can give rise to new treatments. Recent investigations have revealed that alterations in metabolism occur in the activation of B cells. Several reports have suggested that germinal center (GC) B cells of individuals with systemic lupus erythematosus (SLE) have altered metabolic function. GCs are unique microenvironments in which the delicate and complex process of B-cell affinity maturation occurs through somatic hypermutation (SHM) and class switching recombination (CSR) and where Bcl6 tightly regulates B-cell differentiation into memory B-cells or plasma cells. GC B cells rely heavily on glucose, fatty acids, and oxidative phosphorylation (OXPHOS) for their energy requirements. However, the complicated association between GC B cells and their metabolism is still not clearly understood. Here, we review several studies of B-cell metabolism, highlighting the significant transformations that occur in GC progression, and suggest possible approaches that may be investigated to more precisely target aberrant B-cell metabolism in SLE.

scholarly journals Transcription factors IRF8 and PU.1 are required for follicular B cell development and BCL6-driven germinal center responses

2019 ◽  
Vol 116 (19) ◽  
pp. 9511-9520 ◽  
Author(s):  
Hongsheng Wang ◽  
Shweta Jain ◽  
Peng Li ◽  
Jian-Xin Lin ◽  
Jangsuk Oh ◽  
...  
Keyword(s):  
Transcription Factors ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Cell Development ◽  
Affinity Maturation

The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of the molecular mechanisms of each family member has been limited due to their redundancy and broad effects on multiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class-switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq (sequencing) and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of B-cell lymphoma protein 6 (BCL6), which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.

scholarly journals Interleukin-17 and lupus: enough to be a target? For which patients?

Lupus ◽  
2019 ◽  
Vol 29 (1) ◽  
pp. 6-14 ◽  
Author(s):  
M Robert ◽  
P Miossec
Keyword(s):  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Interleukin 17 ◽  
Disease Heterogeneity ◽  
Autoantibody Production ◽  
Complex Deposition ◽  
The Many ◽  
The Right ◽  
Circulating Levels ◽  
Selection Of

The involvement of the interleukin (IL)-17 axis in many inflammatory and autoimmune diseases is now well established, and this has led to the development of successful targeted therapies. Its role in systemic lupus erythematosus (SLE) is less described, since SLE is characterized by the impairment of many other immune actors. However, results from animal models and patients strongly suggest that IL-17 and its producing cells are involved in SLE pathogenesis. Circulating levels of IL-17 are increased in lupus, and tissue staining shows the presence of IL-17-producing cells in organ lesions. Through different mechanisms, the IL-17 axis promotes autoantibody production, immune complex deposition, complement activation and then tissue damage. There are also many interactions with other immune and non-immune actors, which account for the broad spectrum of clinical manifestations and disease heterogeneity. SLE treatment faces challenges with many disappointing trials and persistent unmet needs. The identification of subsets of SLE patients with an IL-17-driven disease now constitutes the key priority before starting trials. More preclinical studies are needed to improve the selection of the right patients able to respond and tolerate the many inhibitors that are already available.

scholarly journals The Progress of Investigating the CD137-CD137L Axis as a Potential Target for Systemic Lupus Erythematosus

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1044 ◽  
Author(s):  
Anselm Mak ◽  
Herbert Schwarz
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Costimulatory Molecules ◽  
Tumour Necrosis Factor Receptor ◽  
Systemic Lupus ◽  
Activated T Cells ◽  
Autoantibody Production ◽  
Proinflammatory Responses

Costimulatory molecules facilitate cross-talks among leukocytes via mutual stimulatory and inhibitory signalling, contributing to diverse immunological outcomes in normal physiological responses and pathological conditions. Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune condition in which cellular communication through the involvement of costimulatory molecules is crucial in driving proinflammatory responses from the stage of autoantigen presentation to the subsequent process of pathogenic autoantibody production. While the physiology of the costimulatory systems including OX40-OX40L, CD28/CTLA-4-CD80/86, ICOS-B7RP1 and CD70-CD27 has been relatively well studied in SLE, recent data on the immunopathology of the CD137-CD137 ligand (CD137L) system in murine lupus models and patients with SLE highlight the critical role of this costimulatory system in initiating and perpetuating the diverse clinical and serological phenotypes of SLE. CD137, a membrane-bound receptor which belongs to the tumour necrosis factor receptor superfamily, is mainly expressed on activated T cells. Activation of the CD137 receptor via its interaction with CD137L which is expressed on antigen present cells (APC) including B cells, triggers bi-directional signalling; that is, signalling through CD137 as well as signalling through CD137L (reverse signalling), which further activates T cells and polarizes them to the Th1/Tc1 pathway. Further, via reverse CD137L signalling it enhances differentiation and maturation of the APC, particularly of dendritic cells, which subsequently drive proinflammatory cytokine production. In this review, recent data including our experience in the manipulation of CD137L signalling pertaining to the pathophysiology of SLE will be critically reviewed. More in-depth understanding of the biology of the CD137-CD137L co-stimulation system opens an opportunity to identify new prognostic biomarkers and the design of novel therapeutic approaches for advancing the management of SLE.

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