Soil-transmitted helminths are one of the most common infections globally, yet how to promote effective gut-associated humoral responses is not well understood. We identify the histone methyltransferase MLL1 as a key target to promote IgA-driven responses. Mll1 was increased in germinal center B cells in gut-associated lymphoid tissues, and Mll1-deficiency led to changes in the histone modification H3K4me3 on key B cell and immune-regulatory genes. Correspondingly, MLL1-deficient B cells had defective germinal centers and IgG1 in response to the helminth Trichuris muris. Yet Mll1f/fCd23cre/+ mice expelled worms more rapidly compared to control mice. Accelerated worm clearance correlated with elevated immunoglobulin A (IgA)+ plasma cells, as well as both serum and fecal IgA. RNA-sequencing identified CCR9 as a key MLL1-regulated molecule. As such, Mll1f/fCd23cre/+ mice infected with T. muris had increased IgA+CCR9+ PC localized in the large intestine. Regulation of IgA by MLL1 was confirmed beyond T. muris infection. In vitro cultures confirmed Mll1-deficiency increased IgA+ plasma cells in a B cell-intrinsic manner, and IgA production was also increased in Mll1f/fCd23cre/+ mice infected with the bacterium Citrobacter rodentium. This study reveals MLL1 as a key target to promote IgA responses to gut-associated infections.

One way memory B cells provide protection is by rapidly differentiating into plasma cells. Plasma cells are vital in providing long-term protection against pathogens; however, they can also be detrimental to health in the case of antibody-mediated autoimmunity. Therefore, compounds which modulate the survival of plasma cells have been of interest for therapeutic intervention. Investigation of ex vivo plasma cell survival has previously been limited by the low frequency of plasma cells in the blood. Here we describe a novel ex vivo culture system that only requires 3000-5000 cells per condition. This method permits the assessment of human plasma cell survival derived from blood and can assess the impact of small molecule inhibitors on plasma cell viability.

Immunology for all: Most scientific communication has historically been limited to visual imagery and the written or spoken word, often in the form of dense articles obscured by jargon. Clear communication of science is vital to enable the public to engage with important scientific discoveries and to limit medical distrust. However, scientific communication is often executed in a way which neglects people with blindness, low vision and diverse needs. Our aim for the exhibit at the Monash Sensory Science Exhibition on Autoimmunity 2023 at Monash University was to develop novel, tactile and informative models to help better communicate the scientific principles that underpin autoimmune disease and immunology. As B-cell biologists, we decided to focus our exhibit for this workshop on antibody-mediated autoimmunity. Antibodies are key components of the immune system, providing protection against a range of diverse pathogens. However, in the context of autoimmunity, they can also drive pathology.

The proliferation marker Ki67 has been attributed critical functions in maintaining mitotic chromosome morphology and heterochromatin organization during the cell cycle, indicating a potential role in developmental processes requiring rigid cell-cycle control. Here, we discovered that despite normal fecundity and organogenesis, germline deficiency in Ki67 resulted in substantial defects specifically in peripheral B and T lymphocytes. This was not due to impaired cell proliferation but rather to early lymphopoiesis at specific stages where antigen–receptor gene rearrangements occurred. We identified that Ki67 was required for normal global chromatin accessibility involving regulatory regions of genes critical for checkpoint stages in B cell lymphopoiesis. In line with this, mRNA expression of Rag1 was diminished and gene rearrangement was less efficient in the absence of Ki67. Transgenes encoding productively rearranged immunoglobulin heavy and light chains complemented Ki67 deficiency, completely rescuing early B cell development. Collectively, these results identify a unique contribution from Ki67 to somatic antigen–receptor gene rearrangement during lymphopoiesis.

Immunology for all: Most scientific communication has historically been limited to visual imagery and the written or spoken word, often in the form of dense articles obscured by jargon. Clear communication of science is vital to enable the public to engage with important scientific discoveries and to limit medical distrust. However, scientific communication is often executed in a way which neglects people with blindness, low vision and diverse needs. Our aim for the exhibit at the Monash Sensory Science Exhibition on Autoimmunity 2023 at Monash University was to develop novel, tactile and informative models to help better communicate the scientific principles that underpin autoimmune disease and immunology. As B-cell biologists, we decided to focus our exhibit for this workshop on antibody-mediated autoimmunity. Antibodies are key components of the immune system, providing protection against a range of diverse pathogens. However, in the context of autoimmunity, they can also drive pathology.

Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c+CD80+ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.

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.

SUMMARYMemory B cells are key providers of long-lived immunity against infectious disease, yet in chronic viral infection they do not produce effective protection. How chronic viral infection disrupts memory B cell development, and whether such changes are reversible, remains unknown. Here, we uncover type-I interferon (IFN-I) dynamics as a key determinant in shaping chronic memory B cell development. Through single-cell (sc)ATAC-sequencing and scRNA-sequencing, we identified a unique memory subset enriched for IFN-stimulated genes (ISGs) during chronic lymphocytic choriomeningitis virus infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic memory B cells, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing a phenotypic change in the dominating memory B cell subset. However, timing was critical, with memory B cells resistant to intervention after 4 weeks post-infection. Together, our research identifies a key mechanism to instruct memory B cell identity during viral infection.One Sentence Summary:IFN dynamics in chronic versus acute viral infection determines memory B cell development.

Ineffective antibody-mediated responses are a key characteristic of chronic viral infection. However, our understanding of the intrinsic mechanisms that drive this dysregulation are unclear. Here, we identify that targeting the epigenetic modifier BMI-1 in mice improves humoral responses to chronic lymphocytic choriomeningitis virus. BMI-1 was upregulated by germinal center B cells in chronic viral infection, correlating with changes to the accessible chromatin landscape, compared to acute infection. B cell-intrinsic deletion of Bmi1 accelerated viral clearance, reduced splenomegaly and restored splenic architecture. Deletion of Bmi1 restored c-Myc expression in B cells, concomitant with improved quality of antibody and coupled with reduced antibody-secreting cell numbers. Specifically, BMI-1-deficiency induced antibody with increased neutralizing capacity and enhanced antibody-dependent effector function. Using a small molecule inhibitor to murine BMI-1, we could deplete antibody-secreting cells and prohibit detrimental immune complex formation in vivo. This study defines BMI-1 as a crucial immune modifier that controls antibody-mediated responses in chronic infection.