Biology subjects

Makuch, M.

Publications and source records attributed to Makuch, M..

3 recordsLinked to original sources

bioRxiv2025

Aging-Associated Autoimmunity in Genetically Diverse UM-HET3 Mice Shows a Female Sex Bias

C57BL/6 (B6) mice, often considered a non-autoimmune control strain, spontaneously develop autoantibodies and lymphocytic infiltration in the salivary glands (SG) with aging. However, as an inbred strain, B6 mice have a limited genetic background and do not fully represent a genetically diverse population. To assess whether genetic diversity influences the development of age-related autoimmunity, we studied UM-HET3 mice, a four-way cross that is commonly used in aging research. By 14-20 months of age, females showed significantly higher frequencies and endpoint titers of anti-nuclear antibodies. Older females also exhibited increased levels of splenic atypical/age-associated B cells and follicular helper T cells, populations associated with the production of autoantibodies. Similar immune cell changes were observed in the SG, with some female mice developing organized lymphocytic foci consisting of T and B cells. Our findings demonstrate that UM-HET3 mice naturally develop systemic autoimmunity and sialadenitis with age, with a clear female bias. Since female UM-HET3 mice have a longer median lifespan than males, these autoimmune responses may reflect benign autoimmunity, representing a heightened immune response associated with aging.

immunology↗

bioRxiv2025

Permissive central tolerance plus defective peripheral checkpoints licence pathogenic memory B cells in CASPR2-antibody encephalitis

Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the developmental pathway of disease-causing B cells and autoantibodies. While such autoreactivities are believed to be generated during germinal centre reactions, the roles of earlier immune checkpoints in autoantigen-specific B cell tolerance are poorly understood. We address this concept in patients with CASPR2-autoantibody encephalitis and healthy controls. In both groups, comparable and high ([~]0.5%) frequencies of unmutated CASPR2-reactive naive B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with heterogenous binding kinetics. These effector molecules possessed epitope-dependent pathogenic effects in vitro neuronal cultures and in vivo. The unmutated common ancestors of these memory B cells showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results are the first to propose mechanisms underlying autoantigen-specific tolerance in humans. We identify permissive central tolerance, defective peripheral tolerance and heterogenous autoantibody binding properties as sequential pathogenic steps which licence CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches in CASPR2-antibody diseases. This paradigm is applicable across autoimmune conditions.

immunology↗

bioRxiv2024

Age-associated B cell infiltration in salivary glands represents a hallmark of Sjögren's-like disease in aging mice

Sjogrens disease (SjD), characterized by circulating autoantibodies and exocrine gland inflammation, is typically diagnosed in women over 50 years of age. However, the contribution of age to SjD pathogenesis is unclear. C57BL/6 female mice at different ages were studied to investigate how aging influences the dynamics of salivary gland inflammation. Salivary glands were characterized for immune cell infiltration, inflammatory gene expression, oxidative stress, and saliva production. At 8 months, gene expression of several chemokines involved in immune cell trafficking was significantly elevated. At this age, Age-associated B cells (ABCs), a unique subset of B cells expressing the myeloid markers CD11b and/or CD11c, were preferentially enriched in the salivary glands compared to other organs like the spleen or liver. The salivary gland ABCs increased with age and positively correlated with increased CD4 T follicular helper cells. By 14 months, lymphocytic foci of well-organized T and B cells spontaneously developed in the salivary glands. In addition, the mice progressively developed high titers of serum autoantibodies. A subset of aged mice developed salivary gland dysfunction mimicking SjD patients. Our data demonstrates that aging is a significant confounding factor for SjD. Thus, aged female C57BL/6 mice are more appropriate and a valuable preclinical model for investigating SjD pathogenesis and novel therapeutic interventions.

immunology↗