Publications by authors named "Ziaur S M Rahman"

33 Publications

miRNA-Mediated Control of B Cell Responses in Immunity and SLE.

Front Immunol 2021 17;12:683710. Epub 2021 May 17.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, United States.

Loss of B cell tolerance is central to autoimmune diseases such as systemic lupus erythematosus (SLE). As such, the mechanisms involved in B cell development, maturation, activation, and function that are aberrantly regulated in SLE are of interest in the design of targeted therapeutics. While many factors are involved in the generation and regulation of B cell responses, miRNAs have emerged as critical regulators of these responses within the last decade. To date, miRNA involvement in B cell responses has largely been studied in non-autoimmune, immunization-based systems. However, miRNA profiles have also been strongly associated with SLE in human patients and these molecules have proven critical in both the promotion and regulation of disease in mouse models and in the formation of autoreactive B cell responses. Functionally, miRNAs are small non-coding RNAs that bind to complementary sequences located in target mRNA transcripts to mediate transcript degradation or translational repression, invoking a post-transcriptional level of genetic regulation. Due to their capacity to target a diverse range of transcripts and pathways in different immune cell types and throughout the various stages of development and response, targeting miRNAs is an interesting potential therapeutic avenue. Herein, we focus on what is currently known about miRNA function in both normal and SLE B cell responses, primarily highlighting miRNAs with confirmed functions in mouse models. We also discuss areas that should be addressed in future studies and whether the development of miRNA-centric therapeutics may be a viable alternative for the treatment of SLE.
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http://dx.doi.org/10.3389/fimmu.2021.683710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165268PMC
May 2021

Context-Dependent miR-21 Regulation of TLR7-Mediated Autoimmune and Foreign Antigen-Driven Antibody-Forming Cell and Germinal Center Responses.

J Immunol 2021 May 26. Epub 2021 May 26.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA; and

MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), although the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. In this study, using the TLR7 agonist, imiquimod-induced SLE model, we observed that loss of miR-21 in mice prevented the formation of plasma cells and autoantibody-producing Ab-forming cells (AFCs) without a significant effect on the magnitude of the germinal center (GC) response. We further observed reduced dendritic cell and monocyte numbers in the spleens of miR-21-deficient mice that were associated with reduced IFN, proinflammatory cytokines, and effector CD4 T cell responses. RNA sequencing analysis on B cells from miR-21-deficient mice revealed reduced activation and response to IFN, and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I IFN stimulation. Our findings in the B6.Yaa () spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and T follicular helper responses. Finally, immunization with T-dependent Ag revealed a role for miR-21 in foreign Ag-driven GC and Ab, but not AFC, responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign Ag-driven AFC and GC responses. Further study is warranted to delineate the cell-intrinsic requirements and mechanisms of miR-21 during infection and SLE development.
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http://dx.doi.org/10.4049/jimmunol.2001039DOI Listing
May 2021

STAT4 Is Largely Dispensable for Systemic Lupus Erythematosus-like Autoimmune- and Foreign Antigen-Driven Antibody-Forming Cell, Germinal Center, and Follicular Th Cell Responses.

Immunohorizons 2021 Jan 14;5(1):2-15. Epub 2021 Jan 14.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;

Genome-wide association studies identified variants in the transcription factor gene and several other genes in the STAT4 signaling pathway, such as , , , and , which are associated with an increased risk of developing systemic lupus erythematosus (SLE) and other autoimmune diseases. Consistent with the genome-wide association studies data, STAT4 was shown to play an important role in autoimmune responses and autoimmunity development in SLE mouse models. Despite such important role for STAT4 in SLE development in mice and humans, little is known whether and how STAT4 may regulate extrafollicular Ab-forming cell (AFC) and follicular germinal center (GC) responses, two major pathways of autoreactive B cell development and autoantibody production. To our surprise, we found STAT4 to be largely dispensable for promoting autoimmune AFC and GC responses in various autoimmune- and SLE-prone mouse models, which strongly correlated with autoantibody production, and immune complex deposition and immune cell infiltration in the kidney. We further observed that STAT4 deficiency had no effects on AFC, GC, and Ag-specific Ab responses during protein Ag immunization or influenza virus infection. Additionally, CD4 effector and follicular Th cell responses in autoimmune- and SLE-prone mice and protein Ag-immunized and influenza virus-infected mice were intact in the absence of STAT4. Together, our data demonstrate a largely dispensable role for STAT4 in AFC, GC, and Ab responses in SLE mouse models and in certain foreign Ag-driven responses.
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http://dx.doi.org/10.4049/immunohorizons.2000111DOI Listing
January 2021

IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection.

Sci Immunol 2020 09;5(51)

Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA 17033, USA.

Development of tissue-resident memory (T) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5 PD-1 CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R) fail to become bT IL-21 CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R brain CD8 T cells do not express CD103, depend on vascular CD8 T cells for maintenance, are antigen recall defective, and lack T core signature genes. CD4 T cell-deficient and IL21R brain CD8 T cells show similar deficiencies in expression of genes for oxidative metabolism, and intrathecal delivery of IL-21 to CD4 T cell-depleted mice restores expression of electron transport genes in CD8 T cells to wild-type levels. Thus, high-affinity CXCR5 PD-1 CD4 T cells in the brain produce IL-21, which drives CD8 bT differentiation in response to a persistent viral infection.
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http://dx.doi.org/10.1126/sciimmunol.abb5590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721466PMC
September 2020

TLR7 Negatively Regulates B10 Cells Predominantly in an IFNγ Signaling Dependent Manner.

Front Immunol 2020 28;11:1632. Epub 2020 Jul 28.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, United States.

IL-10 producing B cells (B10 cells) play an important immunoregulatory role in various autoimmune and infection conditions. However, the factors that regulate their development and maintenance are incompletely understood. Recently, we and others have established a requirement for TLR7 in promoting autoimmune antibody forming cell (AFC) and germinal center (GC) responses. Here we report an important additional role of TLR7 in the negative regulation of B10 cell development. TLR7 overexpression or overstimulation promoted the reduction of B10 cells whereas TLR7 deficiency rescued these cells in both non-autoimmune and autoimmune-prone mice. TLR7 expression was further inversely correlated with B cell-dependent IL-10 production and its inhibition of CD4 T cell proliferation and IFNγ production in an B cell and T cell co-culture system. Further, B10 cells displayed elevated TLR7, IFNγR, and STAT1 expression compared to non-B10 cells. Interestingly, deficiency of IFNγR in TLR7 overexpressing lupus-prone mice rescued B10 cells from TLR7-mediated reduction. Finally, B cell intrinsic deletion of IFNγR was sufficient to restore B10 cells in the spleens of TLR7-promoted autoimmune mouse model. In conclusion, our findings demonstrate a novel role for the IFNγR-STAT1 pathway in TLR7-mediated negative regulation of B10 cell development.
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http://dx.doi.org/10.3389/fimmu.2020.01632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399053PMC
April 2021

Gut-resident CX3CR1 macrophages induce tertiary lymphoid structures and IgA response in situ.

Sci Immunol 2020 04;5(46)

Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.

Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious colitis and identified CX3CR1 MPs as the most prevalent inflammatory cell type. CX3CR1 MPs were further divided into three distinct populations, namely, CX3CR1, CX3CR1 (lymph migratory), and CX3CR1 (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1 macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing -specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1 macrophage subsets and identified mucosa-resident CX3CR1 macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4 T and B cells to the sites of invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed allele, we showed that this local IgA response developed independently of migration of the CX3CR1 population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.
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http://dx.doi.org/10.1126/sciimmunol.aax0062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296464PMC
April 2020

Serine Phosphorylation of the STAT1 Transactivation Domain Promotes Autoreactive B Cell and Systemic Autoimmunity Development.

J Immunol 2020 05 6;204(10):2641-2650. Epub 2020 Apr 6.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;

Although STAT1 tyrosine-701 phosphorylation (designated STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (designated STAT1-pS727) during systemic autoimmune and antipathogen responses remains unclear. Using autoimmune-prone B6.Sle1b mice expressing a STAT1-S727A mutant in which serine is replaced by alanine, we report in this study that STAT1-pS727 promotes autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, driving autoantibody production and systemic lupus erythematosus (SLE) development. In contrast, STAT1-pS727 is not required for GC, T follicular helper cell (Tfh), and Ab responses to various foreign Ags, including pathogens. STAT1-pS727 is also not required for gut microbiota and dietary Ag-driven GC and Tfh responses in B6.Sle1b mice. By generating B cell-specific bone marrow chimeras, we demonstrate that STAT1-pS727 plays an important B cell-intrinsic role in promoting autoimmune AFC, GC, and Tfh responses, leading to SLE-associated autoantibody production. Our analysis of the TLR7-accelerated B6.Sle1b.Yaa SLE disease model expressing a STAT1-S727A mutant reveals STAT1-pS727-mediated regulation of autoimmune AFC and GC responses and lupus nephritis development. Together, we identify previously unrecognized differential regulation of systemic autoimmune and antipathogen responses by STAT1-pS727. Our data implicate STAT1-pS727 as a therapeutic target for SLE without overtly affecting STAT1-mediated protection against pathogenic infections.
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http://dx.doi.org/10.4049/jimmunol.2000170DOI Listing
May 2020

Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity.

J Immunol 2020 02 3;204(4):796-809. Epub 2020 Jan 3.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;

TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely understood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-γ signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized indispensable role of TLR7-induced IFN-γ signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development. T1IFN signaling in contrast, only modestly contributed to autoimmune responses and the disease process in these mice. TLR7 ligand imiquimod treated IFN-γ reporter mice show that CD4 effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-γ. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-γR indicates that TLR7-induced IFN-γ activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of gene in peripheral B cells further demonstrates that TLR7-driven autoimmune AFC, GC and Tfh responses and SLE development are dependent on IFN-γ signaling in B cells. Finally, we show crucial B cell-intrinsic roles of STAT1 and T-bet in TLR7-driven GC, Tfh and plasma cell differentiation. Altogether, we uncover a nonredundant role for IFN-γ and its downstream signaling molecules STAT1 and T-bet in B cells in promoting TLR7-driven AFC, GC, and SLE development whereas T1IFN signaling moderately contributes to these processes.
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http://dx.doi.org/10.4049/jimmunol.1901175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002260PMC
February 2020

Strain-Dependent Contribution of MAVS to Spontaneous Germinal Center Responses.

Immunohorizons 2019 10 8;3(10):463-477. Epub 2019 Oct 8.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033

Germinal centers (GCs) are essential for the production of somatically hypermutated, class-switched Abs that are protective against infection, but they also form in the absence of purposeful immunization or infection, and are termed spontaneous GCs (Spt-GCs). Although Spt-GCs can arise in nonautoimmune-prone mice, aberrant regulation of Spt-GCs in autoimmune-prone mice is strongly associated with the development of autoimmune diseases like systemic lupus erythematosus. The formation of Spt-GCs is crucially driven by TLR7-mediated RNA sensing. However, the impact of MAVS-dependent, Rig-like receptor-mediated RNA sensing on the Spt-GC response remains unknown. In this study, we assessed the Spt-GC response and splenic B cell development in two MAVS-deficient mice with distinct genetic backgrounds. Importantly, we found that MAVS differentially controls Spt-GC responses and B cell development, depending on genetic background. B6/129 mixed background MAVSKO mice had nearly absent Spt-GC responses in the spleen and cervical lymph nodes, which were associated with impaired splenic B cell development, in addition to impaired B cell activation and TLR7 expression. Interestingly, treatment of mice with TLR7 agonist could partially rescue GC responses by overcoming follicular B cell activation deficits. Contrastingly, the absence of MAVS on a B6 background resulted in normal B cell development and Spt-GC formation. Our results highlight important differences in the contribution of MAVS to B cell development and Spt-GC function, depending on the genetic background, warranting greater regard for the impact of genetic background in further studies using these mice for the study of autoimmunity.
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http://dx.doi.org/10.4049/immunohorizons.1900048DOI Listing
October 2019

Selenium supplementation suppresses immunological and serological features of lupus in B6.Sle1b mice.

Autoimmunity 2019 03 22;52(2):57-68. Epub 2019 Apr 22.

b Department of Biochemistry and Molecular Biology , Pennsylvania State University College of Medicine , Hershey , PA , USA.

Systemic lupus erythematosus (SLE) is a debilitating multi-factorial immunological disorder characterized by increased inflammation and development of anti-nuclear autoantibodies. Selenium (Se) is an essential trace element with beneficial anti-cancer and anti-inflammatory immunological functions. In our previous proteomics study, analysis of Se-responsive markers in the circulation of Se-supplemented healthy men showed a significant increase in complement proteins. Additionally, Se supplementation prolonged the life span of lupus prone NZB/NZW-F1 mice. To better understand the protective immunological role of Se in SLE pathogenesis, we have investigated the impact of Se on B cells and macrophages using in vitro Se supplementation assays and the B6.Sle1b mouse model of lupus with an oral Se or placebo supplementation regimen. Analysis of Se-treated B6.Sle1b mice showed reduced splenomegaly and splenic cellularity compared to untreated B6. Sle1b mice. A significant reduction in total B cells and notably germinal center (GC) B cell numbers was observed. However, other cell types including T cells, Tregs, DCs and pDCs were unaffected. Consistent with reduced GC B cells there was a significant reduction in autoantibodies to dsDNA and SmRNP of the IgG2b and IgG2c subclass upon Se supplementation. We found that increased Se availability leads to impaired differentiation and maturation of macrophages from mouse bone marrow derived progenitors in vitro. Additionally, Se treatment during in vitro activation of B cells with anti-CD40L and LPS inhibited optimal B cell activation. Overall our data indicate that Se supplementation inhibits activation, differentiation and maturation of B cells and macrophages. Its specific inhibitory effect on B cell activation and GC B cell differentiation could be explored as a potential therapeutic supplement for SLE patients.
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http://dx.doi.org/10.1080/08916934.2019.1603297DOI Listing
March 2019

The Post-GWAS Era: How to Validate the Contribution of Gene Variants in Lupus.

Curr Rheumatol Rep 2019 01 23;21(1). Epub 2019 Jan 23.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, H107, 500 University Drive, Hershey, PA, 17033-0850, USA.

Purpose Of Review: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong genetic associations. Here, we provide an update on recent advancements in validating SLE candidate genes and risk variants identified in genome-wide association studies (GWAS).

Recent Findings: A pairing of computational biology with new and emerging techniques has significantly increased our understanding of SLE associated variants. Specifically, generation of mutations within mice and examination of patient samples has been the dominant mechanisms for variant validation. While progress has been made in validating some genes, the number of associated genes is growing with minimal exploration of the effects of individual variants on SLE. This indicates that further examination of SLE risk variants in a cell-type-specific manner is required for better understanding of their contributions to SLE disease mechanisms.
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http://dx.doi.org/10.1007/s11926-019-0801-5DOI Listing
January 2019

B-Cell-Intrinsic Type 1 Interferon Signaling Is Crucial for Loss of Tolerance and the Development of Autoreactive B Cells.

Cell Rep 2018 07;24(2):406-418

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA. Electronic address:

Type 1 interferon (T1IFN) signaling promotes inflammation and lupus pathology, but its role in autoreactive B cell development in the antibody-forming cell (AFC) and germinal center (GC) pathways is unclear. Using a lupus model that allows for focused study of the AFC and GC responses, we show that T1IFN signaling is crucial for autoreactive B cell development in the AFC and GC pathways. Through bone marrow chimeras, DNA-reactive B cell transfer, and GC-specific Cre mice, we confirm that IFNαR signaling in B cells promotes autoreactive B cell development into both pathways. Transcriptomic analysis reveals gene expression alterations in multiple signaling pathways in non-GC and GC B cells in the absence of IFNαR. Finally, we find that T1IFN signaling promotes autoreactive B cell development in the AFC and GC pathways by regulating BCR signaling. These data suggest value for anti-IFNαR therapy in individuals with elevated T1IFN activity before clinical disease onset.
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http://dx.doi.org/10.1016/j.celrep.2018.06.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089613PMC
July 2018

Mer Receptor Tyrosine Kinase Signaling Prevents Self-Ligand Sensing and Aberrant Selection in Germinal Centers.

J Immunol 2017 12 8;199(12):4001-4015. Epub 2017 Nov 8.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; and

Mer tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells (ACs) and inducing immunoregulatory signals. We previously showed that Mer-deficient mice (Mer) have increased germinal center (GC) responses, T cell activation, and AC accumulation within GCs. Accumulated ACs in GCs can undergo necrosis and release self-ligands, which may influence the outcome of a GC response and selection. In this study, we generated Mer mice with a global MyD88, TLR7, or TLR9 deficiency and cell type-specific MyD88 deficiency to study the functional correlation between Mer and TLRs in the development of GC responses and autoimmunity. We found that GC B cell-intrinsic sensing of self-RNA, but not self-DNA, released from dead cells accumulated in GCs drives enhanced GC responses in Mer mice. Although self-ligands directly affect GC B cell responses, the loss of Mer in dendritic cells promotes enhanced T cell activation and proinflammatory cytokine production. To study the impact of Mer deficiency on the development of autoimmunity, we generated autoimmune-prone B6. mice deficient in Mer (Mer). We observed accelerated autoimmunity development even under conditions where Mer mice did not exhibit increased AC accumulation in GCs compared with B6. mice, indicating that Mer immunoregulatory signaling in APCs regulates B cell selection and autoimmunity. We further found significant expansion, retention, and class-switching of autoreactive B cells in GCs under conditions where ACs accumulated in GCs of Mer mice. Altogether, both the phagocytic and immunomodulatory functions of Mer regulate GC responses to prevent the development of autoimmunity.
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http://dx.doi.org/10.4049/jimmunol.1700611DOI Listing
December 2017

The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity.

Hepatology 2018 04 18;67(4):1408-1419. Epub 2018 Feb 18.

Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, and Leidos Frederick, Frederick, MD.

We have reported on a murine model of autoimmune cholangitis, generated by altering the AU-rich element (ARE) by deletion of the interferon gamma (IFN-γ) 3' untranslated region (coined ARE-Del ), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the sex bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del mice with IFN type I receptor alpha chain (Ifnar1) knockout mice. We report herein that loss of type I IFN receptor signaling in the double construct of ARE-Del Ifnar1 mice dramatically reduces liver pathology and abrogated sex bias. More importantly, female ARE-Del mice have an increased number of germinal center (GC) B cells as well as abnormal follicular formation, sites which have been implicated in loss of tolerance. Deletion of type I IFN signaling in ARE-Del Ifnar1 mice corrects these GC abnormalities, including abnormal follicular structure.

Conclusion: Our data implicate type I IFN signaling as a necessary component of the sex bias of this murine model of autoimmune cholangitis. Importantly these data suggest that drugs that target the type I IFN signaling pathway would have potential benefit in the earlier stages of PBC. (Hepatology 2018;67:1408-1419).
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http://dx.doi.org/10.1002/hep.29524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856578PMC
April 2018

A systemic macrophage response is required to contain a peripheral poxvirus infection.

PLoS Pathog 2017 Jun 14;13(6):e1006435. Epub 2017 Jun 14.

Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA, United States of America.

The goal of the innate immune system is to reduce pathogen spread prior to the initiation of an effective adaptive immune response. Following an infection at a peripheral site, virus typically drains through the lymph to the lymph node prior to entering the blood stream and being systemically disseminated. Therefore, there are three distinct spatial checkpoints at which intervention to prevent systemic spread of virus can occur, namely: 1) the site of infection, 2) the draining lymph node via filtration of lymph or 3) the systemic level via organs that filter the blood. We have previously shown that systemic depletion of phagocytic cells allows viral spread after dermal infection with Vaccinia virus (VACV), which infects naturally through the skin. Here we use multiple depletion methodologies to define both the spatial checkpoint and the identity of the cells that prevent systemic spread of VACV. Subcapsular sinus macrophages of the draining lymph node have been implicated as critical effectors in clearance of lymph borne viruses following peripheral infection. We find that monocyte populations recruited to the site of VACV infection play a critical role in control of local pathogenesis and tissue damage, but do not prevent dissemination of virus. Following infection with virulent VACV, the subcapsular sinus macrophages within the draining lymph node become infected, but are not exclusively required to prevent systemic spread. Rather, small doses of VACV enter the bloodstream and the function of systemic macrophages, but not dendritic cells, is required to prevent further spread. The results illustrate that a systemic innate response to a peripheral virus infection may be required to prevent widespread infection and pathology following infection with virulent viruses, such as poxviruses.
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http://dx.doi.org/10.1371/journal.ppat.1006435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484545PMC
June 2017

Spontaneous germinal centers and autoimmunity.

Autoimmunity 2017 Feb;50(1):4-18

a Department of Microbiology and Immunology, Penn State College of Medicine , USA.

Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs). In autoimmune-prone mice and patients with autoimmune disease, aberrant regulation of Spt-GCs is thought to promote the development of somatically mutated pathogenic autoantibodies and the subsequent development of autoimmunity. The mechanisms that control the formation of Spt-GCs and promote systemic autoimmune diseases remain an open question and the focus of ongoing studies. Here, we discuss the most current studies on the role of Spt-GCs in autoimmunity.
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http://dx.doi.org/10.1080/08916934.2017.1280671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669068PMC
February 2017

IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity.

J Exp Med 2016 05 11;213(5):715-32. Epub 2016 Apr 11.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033

Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development. We further demonstrate that IFN-γR and STAT1 signaling control Spt-GC and Tfh cell formation by driving T-bet expression and IFN-γ production by B cells. Global or B cell-specific IFN-γR deficiency in autoimmune B6.Sle1b mice leads to significantly reduced Spt-GC and Tfh cell responses, resulting in diminished antinuclear Ab reactivity and IgG2c and IgG2b auto-Ab titers compared with B6.Sle1b mice. Additionally, we observed that the proliferation and differentiation of DNA-reactive B cells into a GC B cell phenotype require B cell-intrinsic IFN-γR signaling, suggesting that IFN-γR signaling regulates GC B cell tolerance to nuclear self-antigens. The IFN-γR deficiency, however, does not affect GC, Tfh cell, or Ab responses against T cell-dependent foreign antigens, indicating that IFN-γR signaling regulates autoimmune, but not the foreign antigen-driven, GC and Tfh cell responses. Together, our data define a novel B cell-intrinsic IFN-γR signaling pathway specific to Spt-GC development and autoimmunity. This novel pathway can be targeted for future pharmacological intervention to treat systemic lupus erythematosus.
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http://dx.doi.org/10.1084/jem.20151722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854731PMC
May 2016

Distinct and synergistic roles of FcγRIIB deficiency and 129 strain-derived SLAM family proteins in the development of spontaneous germinal centers and autoimmunity.

J Autoimmun 2015 Sep 7;63:31-46. Epub 2015 Jul 7.

Microbiology and Immunology, Pennsylvania State University College of Medicine, USA. Electronic address:

The inhibitory IgG Fc receptor (FcγRIIB) deficiency and 129 strain-derived signaling lymphocyte activation molecules (129-SLAMs) are proposed to contribute to the lupus phenotype in FcγRIIB-deficient mice generated using 129 ES cells and backcrossed to C57BL/6 mice (B6.129.RIIBKO). In this study, we examine the individual contributions and the cellular mechanisms by which FcγRIIB deficiency and 129-derived SLAM family genes promote dysregulated spontaneous germinal center (Spt-GC) B cell and follicular helper T cell (Tfh) responses in B6.129.RIIBKO mice. We find that B6 mice congenic for the 129-derived SLAM locus (B6.129-SLAM) and B6 mice deficient in FcγRIIB (B6.RIIBKO) have increased Spt-GC B cell responses compared to B6 controls but significantly lower than B6.129.RIIBKO mice. These data indicate that both FcγRIIB deficiency and 129-SLAMs contribute to elevated Spt-GC B cell responses in B6.129.RIIBKO mice. However, only 129-SLAMs contribute significantly to augmented Tfh responses in B6.129.RIIBKO mice, and do so by a combination of T cell-dependent effects and enhanced B cell and DC-dependent antigen presentation to T cells. Elevated Spt-GC B cell responses in mice with FcγRIIB deficiency and polymorphic 129-SLAMs were associated with elevated metabolic activity, improved GC B cell survival and increased differentiation of naïve B cells into GC B cell phenotype. Our data suggest that the interplay between 129-SLAM expression on B cells, T cells and DCs is central to the alteration of the GC tolerance checkpoint, and that deficiency of FcγRIIB on B cells is necessary to augment Spt-GC responses, pathogenic autoantibodies, and lupus disease.
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http://dx.doi.org/10.1016/j.jaut.2015.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564365PMC
September 2015

B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance.

J Immunol 2015 May 23;194(9):4130-43. Epub 2015 Mar 23.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;

Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint are not clear. In this study, we generated several bacterial artificial chromosome-transgenic mice that overexpress C57BL/6 (B6) alleles of different SLAM family genes on an autoimmune-prone B6.Sle1b background. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the spontaneously developed GC response and autoantibody production compared with B6.Sle1b mice. These data suggest a prominent role for Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance, leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling and a lower frequency of B cell-T cell conjugates; the reverse is seen in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared with B6 controls. Our study establishes a central role for GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity.
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http://dx.doi.org/10.4049/jimmunol.1403023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402266PMC
May 2015

B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers.

J Immunol 2014 Nov 24;193(9):4400-14. Epub 2014 Sep 24.

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;

Spontaneous germinal center (Spt-GC) B cells and follicular helper T cells generate high-affinity autoantibodies that are involved in the development of systemic lupus erythematosus. TLRs play a pivotal role in systemic lupus erythematosus pathogenesis. Although previous studies focused on the B cell-intrinsic role of TLR-MyD88 signaling on immune activation, autoantibody repertoire, and systemic inflammation, the mechanisms by which TLRs control the formation of Spt-GCs remain unclear. Using nonautoimmune C57BL/6 (B6) mice deficient in MyD88, TLR2, TLR3, TLR4, TLR7, or TLR9, we identified B cell-intrinsic TLR7 signaling as a prerequisite to Spt-GC formation without the confounding effects of autoimmune susceptibility genes and the overexpression of TLRs. TLR7 deficiency also rendered autoimmune B6.Sle1b mice unable to form Spt-GCs, leading to markedly decreased autoantibodies. Conversely, B6.yaa and B6.Sle1b.yaa mice expressing an extra copy of TLR7 and B6.Sle1b mice treated with a TLR7 agonist had increased Spt-GCs and follicular helper T cells. Further, TLR7/MyD88 deficiency led to compromised B cell proliferation and survival after B cell stimulation both in vitro and in vivo. In contrast, TLR9 inhibited Spt-GC development. Our findings demonstrate an absolute requirement for TLR7 and a negative regulatory function for TLR9 in Spt-GC formation under nonautoimmune and autoimmune conditions. Our data suggest that, under nonautoimmune conditions, Spt-GCs initiated by TLR7 produce protective Abs. However, in the presence of autoimmune susceptibility genes, TLR7-dependent Spt-GCs produce pathogenic autoantibodies. Thus, a single copy of TLR7 in B cells is the minimal requirement for breaking the GC-tolerance checkpoint.
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http://dx.doi.org/10.4049/jimmunol.1401720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201954PMC
November 2014

Prolonged apoptotic cell accumulation in germinal centers of Mer-deficient mice causes elevated B cell and CD4+ Th cell responses leading to autoantibody production.

J Immunol 2013 Feb 14;190(4):1433-46. Epub 2013 Jan 14.

Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Mer receptor tyrosine kinase is a member of the Tyro-3/Axl/Mer (TAM) subfamily of receptor tyrosine kinases, and its expression on phagocytes facilitates their clearance of apoptotic cells (ACs). Mer expression in germinal centers (GCs) occurs predominantly on tingible body macrophages. B and T cells do not express Mer. In this study, we show that Mer deficiency ((Mer(-/-)) resulted in the long-term accumulation of ACs primarily in GCs and not in the T cell zone, marginal zone, or red pulp areas of the spleen. AC accumulation in GCs led to augmented Ab-forming cell, GC, and IgG2 Ab responses in Mer(-/-) mice, which were sustained for at least 80 d. Enhanced responses in Mer(-/-) mice were due to increased activation and proliferation of B cells and CD4(+) Th cells, including follicular helper T cells, which resulted in high titers of anti-nuclear Abs in Mer(-/-) mice compared with wild-type controls. Secondary IgG-producing Ab-forming cell, total IgG, and IgG2 Ab responses were also increased in Mer(-/-) mice. Finally, compared with wild-type controls, Mer(-/-) mice had increased percentage of IFN-γ-producing CD4(+) Th cells and elevated levels of Th1 (i.e., IL-2 and IFN-γ) and proinflammatory (i.e., TNF and IL-6) cytokines, consistent with elevated levels of Th1-biased IgG2 Abs in Mer(-/-) mice. Together, our results demonstrate that Mer deficiency induces prolonged accumulation of ACs in GCs, resulting in dysregulation of GC B cell and CD4(+) Th cell responses and Th1 cytokine production, leading to alteration of B cell tolerance and the development of autoantibodies.
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http://dx.doi.org/10.4049/jimmunol.1200824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563756PMC
February 2013

The lupus-prone NZM2410/NZW strain-derived Sle1b sublocus alters the germinal center checkpoint in female mice in a B cell-intrinsic manner.

J Immunol 2012 Dec 9;189(12):5667-81. Epub 2012 Nov 9.

Department of Microbiology and Immunology, Jefferson Medical College, Philadelphia, PA 19107, USA.

C57BL/6 (B6) mice carrying the Sle1b sublocus (named B6.Sle1b), which harbors the lupus-associated NZM2410/NZW SLAM family genes, produce antinuclear Abs (ANAs). However, the role and mechanism(s) involved in the alteration of the germinal center (GC) tolerance checkpoint in the development of ANAs in these mice is not defined. In this study, we show significantly higher spontaneously formed GCs (Spt-GCs) in B6.Sle1b female mice compared with B6 controls. We also found a significant increase in CD4(+)CXCR5(hi)PD-1(hi) spontaneously activated follicular Th cells in B6.Sle1b female mice. Compared with B6 controls, B6.Sle1b female mice had increased numbers of proliferating B cells predominantly located in Spt-GCs. The elevated Spt-GCs in B6.Sle1b female mice were strongly associated with increased ANA-specific Ab-forming cells and ANA titers. The increased numbers of Spt-GCs and spontaneously activated follicular Th cells in B6.Sle1b mice were not the result of a generalized defect in B cells expressing Sle1b. Consistent with the elevated spontaneous response in B6.Sle1b mice, the attenuated GC response characteristic of DNA and p-azophenylarsonate reactive B cells from Ig V(H) knock-in mice (termed HKIR) were relieved in adoptively transferred recipients in the presence of Sle1b. Finally, by generating mixed bone marrow chimeras, we showed that the effect of Sle1b on Spt-GC, follicular Th cell, and autoantibody responses in B6.Sle1b mice was B cell autonomous. These data indicate that the NZM2410/NZW-derived Sle1b sublocus in conjunction with the female sex primarily affects B cells, leading to the alteration of the GC tolerance checkpoint and the generation of ANA-specific Ab-forming cells.
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http://dx.doi.org/10.4049/jimmunol.1201661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518623PMC
December 2012

Impaired clearance of apoptotic cells in germinal centers: implications for loss of B cell tolerance and induction of autoimmunity.

Authors:
Ziaur S M Rahman

Immunol Res 2011 Dec;51(2-3):125-33

Department of Microbiology and Immunology, Thomas Jefferson University, Jefferson Alumni Hall, Room 461, 1020 Locust Street, Philadelphia, PA 19107-5541, USA.

Germinal centers (GCs) comprise lymphoid microenvironments where antigen-stimulated B cells undergo rapid proliferation and somatic hypermutation (SHM), resulting in the generation of B cells with high affinity for antigen. However, this process also generates B cell clones with low antigen affinity and with the potential for autoreactivity. It has been suggested that GC B cells with low antigen affinity and autoreactivity are eliminated via apoptosis and are rapidly cleared by tingible body macrophages (TBMφs). Inefficient clearance of apoptotic cells (ACs) results in autoimmunity that is thought to be mediated by various intracellular molecules possessing danger-associated molecular patterns (DAMPs), including nuclear self-Ags. DAMPs can be released from ACs undergoing "secondary necrosis" due to a disruption in AC clearance within GCs. This review discusses the role and mechanisms associated with impaired clearance of ACs in GCs in loss of B cell tolerance leading to autoantibody production and the development of autoimmunity.
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http://dx.doi.org/10.1007/s12026-011-8248-4DOI Listing
December 2011

Impaired apoptotic cell clearance in the germinal center by Mer-deficient tingible body macrophages leads to enhanced antibody-forming cell and germinal center responses.

J Immunol 2010 Nov 15;185(10):5859-68. Epub 2010 Oct 15.

Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107-5541, USA.

Germinal centers (GCs) are specialized microenvironments that generate high-affinity Ab-forming cells (AFCs) and memory B cells. Many B cells undergo apoptosis during B cell clonal selection in GCs. Although the factors that regulate the AFC and GC responses are not precisely understood, it is widely believed that dysregulated AFCs and GCs contribute to autoimmunity. The Mer receptor tyrosine kinase (Mer) facilitates macrophage clearance of apoptotic cells. The Tyro-3, Axl, and Mer receptors, including Mer, suppress TLRs and cytokine-mediated inflammatory responses. We report in this study that tingible body macrophages (TBMφs) in GCs express Mer. Compared to C57BL/6 (B6) controls, Mer-deficient (Mer(-/-)) mice had significantly higher AFC, GC, and Th1-skewed IgG2 Ab (especially IgG2c) responses against the T cell-dependent Ag (4-hydroxy-3-nitrophenyl) acetyl-chicken γ globulin. Mer(-/-) mice had a significantly higher percentage of GC B cells on days 9, 14, and 21 postimmunization compared with B6 controls. Significantly increased numbers of apoptotic cells accumulated in Mer(-/-) GCs than in B6 GCs, whereas the number of TBMφs remained similar in both strains. Our data are the first, to our knowledge, to demonstrate a critical role for Mer in GC apoptotic cell clearance by TBMφs and have interesting implications for Mer in the regulation of B cell tolerance operative in the AFC and GC pathways.
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http://dx.doi.org/10.4049/jimmunol.1001187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563244PMC
November 2010

The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints.

J Immunol 2009 Nov 14;183(9):5716-27. Epub 2009 Oct 14.

Department of Microbiology and Immunology, Jefferson Medical College, Jefferson Alumni Hall, Philadelphia, PA 19107, USA.

We have described a line of V(H) knock-in mice termed HKIR in which the transgenic Igh locus partially encodes "dual-reactive" antichromatin and anti-p-azophenylarsonate (Ars) BCRs. HKIR B cells termed canonical, expressing a particular Vkappa L chain, evade central tolerance by down-regulating BCR levels. Canonical HKIR B cells can be recruited into the primary germinal center (GC) and Ab-forming cell (AFC) compartments via Ars immunization. However, their participation in the GC response rapidly wanes and they do not efficiently contribute to the memory compartment, indicating that they are regulated by a GC tolerance checkpoint. We analyzed the influence of the Sle1 genetic interval, shown to break tolerance of chromatin-reactive B cells, on the behavior of HKIR B cells during the anti-Ars response. Canonical B cells from congenic HKIR.Sle1 mice gave rise to elevated short and long-lived AFC responses, and the attenuated GC and memory responses characteristic of these B cells were relieved in adoptive, wild-type recipients. HKIR GC B cells containing Sle1 expressed increased levels of Bcl-2 and c-FLIP and decreased levels of Fas RNA compared with HKIR controls, suggesting direct alteration of the regulation of the GC response by Sle1. High titers of canonical and anti-dsDNA Abs spontaneously developed in many aged HKIR.Sle1 mice. Together, these data indicate that Sle1 perturbs the action of peripheral tolerance checkpoints operative on antinuclear Ag B cells in both the AFC and GC pathways in a cell autonomous fashion.
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http://dx.doi.org/10.4049/jimmunol.0804215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879885PMC
November 2009

Strain distribution pattern of immune nephritis--a follow-up study.

Int Immunol 2008 Jun 1;20(6):719-28. Epub 2008 Apr 1.

Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.

Previous studies have indicated that the NZW, DBA/1, 129/sv and BUB strains are particularly sensitive to experimental anti-glomerular basement membrane (GBM)-induced immune nephritis. The present study extends previous observations by examining eight additional inbred mouse strains for their susceptibility to immune nephritis. Unlike the ALR/Lt, CAST/Ei, DDY/JclSidSeyFrk, FVB/NJ, PERA/Ei, SB/Le and BALB/c strains, the C58 mouse strain was observed to be particularly susceptible to experimental immune nephritis, with CBA mice being a close second. In contrast to the other strains, C58 mice uniformly developed heavy proteinuria, azotemia and severe glomerulonephritis with prominent crescent formation and tubulointerstitial nephritis following challenge with anti-GBM sera. These differences were associated with increased murine Ig deposition, leukocyte infiltration and IFN-gamma production within the kidneys of C58 mice. Studies aimed at elucidating the genetic factors and molecular pathways responsible for the enhanced renal disease in C58 mice are warranted.
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http://dx.doi.org/10.1093/intimm/dxn030DOI Listing
June 2008

Quantitatively reduced participation of anti-nuclear antigen B cells that down-regulate B cell receptor during primary development in the germinal center/memory B cell response to foreign antigen.

J Immunol 2007 May;178(9):5623-34

Department of Microbiology and Immunology and The Kimmel Cancer Center, Jefferson Medical College, 233 South 10th Street, Philadelphia, PA 19017, USA.

The peripheral B cell compartment contains high levels of "polyreactivity" including autospecificities. We have described a pathway that certain autoreactive B cells may take in gaining stable access to the foreign Ag-responsive peripheral compartment. This pathway was revealed in mice expressing a targeted Ig H chain transgene encoding BCRs with "multireactivity" for the hapten arsonate and DNA-based autoantigens. B cells expressing such BCRs develop to mature follicular phenotype and locale, and are not short-lived. These B cells express very low levels of BCR, indicating that they are not "ignorant" of self Ag, but do not display features of anergy in in vitro assays. Nonetheless, a variety of states of lymphocyte anergy has been described, and some may only be manifested in vivo. As such, we analyzed the ability of these B cells to participate in a T cell-dependent immune response to arsonate in vivo. These B cells mount an early primary response similar to control B cells, including homing to follicles, migration to the T-B interface, and induction of costimulatory molecules, proliferation, differentiation to AFCs, class switching, and entry into GCs and somatic hypermutation. Nonetheless, these B cells display reduced participation in the latter stages of the GC response and in the anamnestic AFC response. In total, these data suggest that while the autoreactivity of this type of B cell does not result in anergy, the ability of such B cells to participate in a cross-reactive immune response to foreign Ag is compromised.
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http://dx.doi.org/10.4049/jimmunol.178.9.5623DOI Listing
May 2007

FcgammaRIIB regulates autoreactive primary antibody-forming cell, but not germinal center B cell, activity.

J Immunol 2007 Jan;178(2):897-907

Department of Microbiology and Immunology and Kimmel Cancer Center, Thomas Jefferson Medical College, 233 South 10th Street, Philadelphia, PA 19107, USA.

The low-affinity FcR for IgG FcgammaRIIB suppresses the development of IgG autoantibodies and autoimmune disease in normal individuals, but how this effect is mediated is incompletely understood. To investigate this issue, we created FcgammaRIIB-deficient versions of two previously described targeted BCR-transgenic lines of mice that contain follicular B cells with specificity for the hapten arsonate, but with different levels of antinuclear autoantigen reactivity. The primary development and tolerance of both types of B cells were unaltered by the absence of FcgammaRIIB. Moreover, the reduced p-azophenylarsonate-driven germinal center and memory responses characteristic of the highly autoreactive clonotype were not reversed by an intrinsic FcgammaRIIB deficiency. In contrast, the p-azophenylarsonate-driven primary Ab-forming cell responses of both clonotypes were equivalently increased by such a deficiency. In total, our data do not support the idea that FcgammaRIIB directly participates in the action of primary or germinal center tolerance checkpoints. In contrast, this receptor apparently contributes to the prevention of autoimmunity by suppressing the production of autoreactive IgGs from B cells that have breached tolerance checkpoints and entered the Ab-forming cell pathway due to spontaneous, or cross-reactive, Ag-mediated activation.
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http://dx.doi.org/10.4049/jimmunol.178.2.897DOI Listing
January 2007

The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells.

J Immunol 2006 Jun;176(11):6852-61

Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

The Fas-associated death domain protein (FADD)/Mort1 is a signaling adaptor protein which mediates the activation of caspase 8 during death receptor-induced apoptosis. Disruption of FADD in germ cells results in death receptor-independent embryonic lethality in mice. Previous studies indicated that in addition to its function in apoptosis, FADD is also required in peripheral T cell homeostasis and TCR-induced proliferative responses. In this report, we generated B cell-specific FADD-deficient mice and showed that deletion of FADD at the pro-B cell stage had minor effects on B cell development in the bone marrow, and resulted in increased splenic and lymph node B cell numbers and decreased peritoneal B1 cell numbers. As in T cells, a FADD deficiency inhibited Fas-induced apoptosis in B cells. However, B cell-proliferative responses induced by stimulation of the BCR and CD40 using anti-IgM or anti-CD40 Abs were unaffected by the absence of FADD. Further analyses revealed that FADD-deficient B cells were defective in proliferative responses induced by treatments with dsRNA and LPS which stimulate TLR3 and TLR4, respectively. Therefore, in addition to its apoptotic function, FADD also plays a role in TLR3- and TLR4-induced proliferative responses in B cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110081PMC
http://dx.doi.org/10.4049/jimmunol.176.11.6852DOI Listing
June 2006

Failed up-regulation of the inhibitory IgG Fc receptor Fc gamma RIIB on germinal center B cells in autoimmune-prone mice is not associated with deletion polymorphisms in the promoter region of the Fc gamma RIIB gene.

J Immunol 2005 Aug;175(3):1440-9

Department of Microbiology and Immunology and Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA 19107-5541, USA.

FcgammaRIIB, a low-affinity FcR for IgG, inhibits BCR-mediated activation when these two receptors are co-cross-linked by Ags and IgG-containing immune complexes. Although a role for FcgammaRIIB in the germinal center (GC) reaction has been proposed, conflicting results have been published regarding the levels of FcgammaRIIB expressed on GC B cells in normal and autoimmune-prone mice and humans. In the present study, we investigate this issue in detail in mice by using multiple GC B cell markers, two different antigenic systems, primary and secondary GC responses, and by excluding the influence of splenic influx of immature B cells and passive acquisition of FcgammaRIIB from follicular dendritic cells. Our results are in concordance with previous data indicating that FcgammaRIIB expression is up-regulated on GC B cells in normal mice. In contrast, we observe comparable levels of FcgammaRIIB on GC and non-GC B cells in New Zealand White, New Zealand Black, and B6.Sle1 autoimmune-prone strains. Therefore, we suggest that these strains exhibit failed up-regulation of FcgammaRIIB on GC B cells, rather than down-regulation, as previously suggested. Also, in contrast to previous indications, this perturbed regulation is not uniquely associated with deletion polymorphisms in the promoter region of the FcgammaRIIB gene but does appear to be independent of genetic background. Finally, we present evidence indicating that FcgammaRIII, a low-affinity activating IgG FcR, is expressed on the GC B cells of normal but not autoimmune-prone mice.
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http://dx.doi.org/10.4049/jimmunol.175.3.1440DOI Listing
August 2005