Type I interferon induces CXCL13 to support ectopic germinal center formation.

Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation

Tailoring Immune Responses toward Autoimmunity: Transcriptional Regulators That Drive the Creation and Collusion of Autoreactive Lymphocytes

T-dependent humoral immune responses to infection involve a collaboration between B and CD4 T cell activation, migration, and co-stimulation, thereby culminating in the formation of germinal centers (GCs) and eventual differentiation into memory cells and long-lived plasma cells (PCs). CD4 T cell-derived signals drive the formation of a tailored B cell response. Downstream of these signals are transcriptional regulators that are the critical enactors of immune cell programs. In particular, a core group of transcription factors regulate both B and T cell differentiation, identity, and function. The timing and expression levels of these transcription factors are tightly controlled, with dysregulated expression correlated to immune cell dysfunction in autoimmunity and lymphomagenesis. Recent studies have significantly advanced our understanding of both extrinsic and intrinsic regulators of autoreactive B cells and antibody-secreting PCs in systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune conditions. Yet, there are still gaps in our understanding of the causative role these regulators play, as well as the link between lymphoid responses and peripheral damage. This review will focus on the genesis of immunopathogenic CD4 helper and GC B cells. In particular, we will detail the transcriptional regulation of cytokine and chemokine receptor signaling during the pathogenesis of GC-derived autoimmune conditions in both murine models and human patients

Tailoring Immune Responses toward Autoimmunity: Transcriptional Regulators That Drive the Creation and Collusion of Autoreactive Lymphocytes

T-dependent humoral immune responses to infection involve a collaboration between B and CD4 T cell activation, migration, and co-stimulation, thereby culminating in the formation of germinal centers (GCs) and eventual differentiation into memory cells and long-lived plasma cells (PCs). CD4 T cell-derived signals drive the formation of a tailored B cell response. Downstream of these signals are transcriptional regulators that are the critical enactors of immune cell programs. In particular, a core group of transcription factors regulate both B and T cell differentiation, identity, and function. The timing and expression levels of these transcription factors are tightly controlled, with dysregulated expression correlated to immune cell dysfunction in autoimmunity and lymphomagenesis. Recent studies have significantly advanced our understanding of both extrinsic and intrinsic regulators of autoreactive B cells and antibody-secreting PCs in systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune conditions. Yet, there are still gaps in our understanding of the causative role these regulators play, as well as the link between lymphoid responses and peripheral damage. This review will focus on the genesis of immunopathogenic CD4 helper and GC B cells. In particular, we will detail the transcriptional regulation of cytokine and chemokine receptor signaling during the pathogenesis of GC-derived autoimmune conditions in both murine models and human patients

c-Myb is required for plasma cell migration to bone marrow after immunization or infection

Plasma cell migration is crucial to immunity, but little is known about the molecular regulators of their migratory programs. Here, we detail the critical role of the transcription factor c-Myb in determining plasma cell location. In the absence of c-Myb, no IgG antigen- specific plasma cells were detected in the bone marrow after immunization or virus infection. This was correlated with a dramatic reduction of plasma cells in peripheral blood, mislocalization in spleen, and an inability of c-Myb-deficient plasma cells to migrate along a CXCL12 gradient. Therefore, c-Myb plays an essential, novel role in establishing the longlived plasma cell population in the BM via responsiveness to chemokine migration cues

Assessing the role of the T-box transcription factor Eomes in B cell differentiation during either Th1 or Th2 cell-biased responses.

Successful T-dependent humoral responses require the production of antibody-secreting plasmablasts, as well as the formation of germinal centers which eventually form high-affinity B cell memory. The ability of B cells to differentiate into germinal center and plasma cells, as well as the ability to tailor responses to different pathogens, is driven by transcription factors. In T cells, the T-box transcription factors T-bet and Eomesodermin (Eomes) regulate effector and memory T cell differentiation, respectively. While T-bet has a critical role in regulating anti-viral B cell responses, a role for Eomes in B cells has yet to be described. We therefore investigated whether Eomes was required for B cell differentiation during either Th1 or Th2 cell-biased immune responses. Here, we demonstrate that deletion of Eomes specifically in B cells did not affect B cell differentiation in response to vaccination, as well as following viral or helminth infection. In contrast to its established role in CD8+ T cells, Eomes did not influence memory B cell differentiation. Finally, the use of an Eomes reporter mouse confirmed the lack of Eomes expression during immune responses. Thus, germinal center and plasma cell differentiation and the formation of isotype-switched memory B cells in response to infection are independent of Eomes expression

Targeting BMI‐1 to deplete antibody‐secreting cells in autoimmunity

Abstract Objectives B cells drive the production of autoreactive antibody‐secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long‐term organ damage. Current treatments for antibody‐mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre‐existing long‐lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI‐1 could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods Use of a BMI‐1 inhibitor in both mouse and human autoimmune settings was investigated. Lyn−/− mice, a model of SLE, were treated with the BMI‐1 small molecule inhibitor PTC‐028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast‐based assay was established, and the impact of PTC‐028 on ASCs derived from Sjögren's syndrome patients was evaluated. Results BMI‐1 inhibition significantly decreased splenic and bone marrow ASCs in Lyn−/− mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti‐DNA IgG. PTC‐028 was also efficacious in reducing ex vivo plasma cell survival from both Sjögren's syndrome patients and age‐matched healthy donors. Conclusion These data provide evidence that inhibiting BMI‐1 can deplete ASC in a variety of contexts and thus BMI‐1 is a viable therapeutic target for antibody‐mediated autoimmune diseases