Monogenetic Immune Dysregulation Syndromes and their Effect on the Plasma Cell Compartment
Long-term immunity is shaped by the immune system's interactions with infectious agents or vaccinations. In individuals with immune dysregulation, such as patients with primary immunodeficiency (PID) or rheumatic diseases, these interactions are altered. Plasma cells (PC) and their B cell progenitors, that play a key role in maintaining humoral and cellular memory, are impaired within these patients. We characterised different features of plasma cells in immune dysregulated individuals via flow cytometry and ELISA in three different settings; I. 23 Patients with PID were recruited. Patients had altered frequencies of PC subsets and higher frequencies of naïve B cells, indicating poor maturation. Patients had decreased serum levels of BCMA, and a subset of patients had increased serum levels of BAFF. Both cytokines are involved in B cell maturation. II. As a model for the possible action of Abatacept, 8 treated patients with arthritis (RA) were studied. Abatacept is a biological agent, stabilising CTLA-4 signalling, used for many years to treat RA, it is currently under investigation for the treatment of CHAI: a condition caused by CTLA-4 insufficiency leading to unchecked immunomodulation. The frequencies of CCR10+ PC, were significantly altered, it may lead to lower antibody serum concentrations, possibly resulting in reduced patient autoantibodies. III. The efficiency of SARS-CoV-2 mRNA-based vaccinations in 7 PID patients was investigated. PIDs have a marginal immune response to the SARS-CoV-2 vaccine when we consider both the humoral and cellular responses together. Some patients were able to generate specific antibodies. However, all demonstrated SARS-CoV-2 specific T cell responses. XLA patients, had the highest T cell response of all, which demonstrates that B cell defects can partly be compensated by T cells. In conclusion, this thesis shows that a residual pool of B cells can be important for immune reactions and that even in T cell dependent diseases, B cells can play a significant role. It also showed first indications, on how different immune dysregulation syndromes affect multiple pathways within the adaptive immune system. To our knowledge, this is the first study showing vaccination specific plasma cells in PID patients.
plasma cells, Immune dysregulation, inborn errors of immunity
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