Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection.

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.

A Touch of Immunology: improving accessibility to the science of antibodies for people with blindness, low vision and diverse needs.

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.

Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity.

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.

Targeting BMI-1 in B cells restores effective humoral immune responses and controls chronic viral infection.

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.

Antibody glycosylation directs innate and adaptive immune collaboration.

Neutralizing antibody is fundamental for the effective clearance of many pathogens. In addition, non-neutralizing antibody functions have rapidly gained prominence. The N-glycan structure of antibody can help direct appropriate innate cell effector functions. Thus, dynamic communication between innate and adaptive arms via antibody glycosylation can be crucial for modulating between pro-inflammatory or anti-inflammatory responses. Antibody N-glycan profiles are increasingly used as biomarkers to distinguish between disease states and severity. Emerging evidence suggests that aberrant glycan profiles may impede effective immune responses, but whether they are a consequence or cause of pathology remains unclear. Untangling the role of antibody glycan profiles in pathogenesis and how they are modulated by the microenvironment will expand our ability to assess and modify disease outcomes.