Session 7

Lars Klareskog
Karolinska Institutet, Department of Medicine, Solna, Division of Rheumatology, Stockholm, Schweden

Adaptive immunity in rheumatoid arthritis – a challenging diversity
Lars Klareskog, in collaboration with Vivianne Malmström and Caroline Grönwall groups

Rheumatoid arthritis is a heterogenous disease, where the major subset is characterized by immunity to post-translationally modified antigens which is triggered from gene-environment interaction between MHC class II alleles and mucosal stimuli from noxious agents and certain microbes. A challenge discussed in this presentation is to understand how and where immune tolerance to these antigens is broken in a few individuals and which specific immune reactions are triggered and perpetuated over long times before onset of disease.

MHC class II restricted T cell responses are dominated by reactivities to a restricted number of citrullinated epitopes. B cell reactivity and antibody repertoires are directed against a much broader group of mainly linear structures containing citrulline or other posttranslational modifications including carbamylation and acetylation. Monoclonal autoantibodies generated from these B-cells cells display extensive somatic mutations indicating long-standing T cell help as well as very heterogenous effector functions, some being pro-inflammatory, others anti-inflammatory.

This lecture will discuss both mechanisms whereby this immunity may be triggered and how diversity in reactivities and effector functions may explain diversity of symptoms in RA.

Biosketch

Lars Klareskog is senior professor of rheumatology at Karolinska Institutet  His main research interests are in translational medicine, i.e. in understanding etiology and molecular pathogenesis of inflammatory rheumatic diseases and to use such knowledge for the development of therapy and prevention of these diseases.

More specifically, he has for many years investigated how genes and environment/lifestyle interact in the etiology and molecular pathogenesis of RA and found that airway exposures including smoking can trigger autoimmunity, in particular antibodies against citrullinated proteins (ACPA). These studies have laid the ground for an etiological hypothesis for RA, where a mucosal origin of pathogenic autoimmunity is central. Data from these studies, together with many other observations on the emergence of autoimmunity prior to the development of clinical arthritis have enabled efforts towards prevention of the disease in individuals with symptoms and autoimmunity that predict a high risk for development of RA.

Falk Hiepe
Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology and German Rheumatism Research Centre Berlin, an Institute of the Leibniz Association, Berlin, Germany

Mir-Farzin Mashreghi
German Rheumatism Research Centre Berlin, an Institute of the Leibniz Association, Berlin, Germany

Recruitment of plasma cells from follicular and extrafollicular immune reactions to the bone marrow

Bone marrow plasma cells (BMPC) are pivotal for maintaining humoral immunity through continuous antibody production. This talk deals with the heterogeneity of BMPC and tracks the recruitment of antibody-secreting cells (ASC) from vaccine responses to the bone marrow. Utilizing single-cell transcriptomic analyses, we uncover that BMPC compartments are sequentially populated by ASC, with CD19 expression levels distinguishing their origins. CD19low-BMPC are derived from follicular immune reactions, whereas CD19high-BMPC originate from extrafollicular responses. During primary immune responses, both CD19low and CD19high BMPC compartments are populated. In contrast, secondary immune responses primarily recruit to the CD19high compartment, indicative of their extrafollicular origin. This recruitment pattern is also observed in vaccinated-convalescent individuals and following diphtheria/tetanus/pertussis booster vaccinations, highlighting the evolving nature of humoral immune responses.

Biosketch

Dr. Mir-Farzin Mashreghi is the Deputy Scientific Director at the German Rheumatology Research Center (DRFZ) and leads the “Systems Rheumatology” programme area. He obtained his Ph.D. from Charité – Universitätsmedizin Berlin focusing on transplantation immunology. Dr. Mashreghi’s current research deals with the regulation and differentiation of T helper cells, memory B cells, and plasma cells. His work employs single-cell sequencing to elucidate immune cell heterogeneity and their roles in chronic inflammatory diseases. His significant publications include studies on microRNAs in T cell regulation and adaptive immune responses after vaccination and in conditions such as rheumatoid arthritis and systemic lupus erythematosus.