Age-associated-susceptibility to B cell autoimmunity in murine epidermolysis bullosa acquisita

• Applicant: Professor Dr. Rudolf Manz
• Subject Area: Immunology ; Dermatology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497070163

B cells/plasma cells are essential for the development and pathogenesis of many autoimmune diseases. They produce autoantibodies, present autoantigens to T cells and modulate inflammation via the production of cytokines. Previous studies brought some insights into molecular mechanisms underlying the development of autoimmune diseases. However, why some individuals develop an autoimmune disease and why they develop it at a certain time is still unknown.For most diseases, the relevant autoantigens are unknown. This limits the investigation of the specific autoimmune B cell response. This is different in epidermolysis bullosa acquisita (EBA), an autoimmune skin disease caused by autoantibodies to type VII collagen (COL7). In our preliminary work, we have used a murine model of this disease to investigate the autoreactive, COL7-specific B cell/plasma cell and T cell responses. This work provides detailed insights on the contribution of B cells and plasma cells in EBA, which might be prototypic for other antibody-mediated autoimmune diseases.Particularly, we provided evidence that depending on the expression of a susceptible MHCII haplotype and the production of the cytokines IL-21 and IFN-gamma by CD4 T cells, autoreactive plasma cells are formed that produce COL7-specific IgG-antibodies with a strong inflammatory potential. We also found that plasma cell derived IL-10 inhibits modulates the cytokine response of COL7-specific T cells and limits EBA skin pathogenesis.We also showed that in healthy mice, IL-10+ plasma cells accumulate with age and that this affects innate immune cells. Accordingly, a recent finding demonstrated that the weaker immune response observed in the elderly is partly mediated through an age-associated increase of systemic IL-10 levels. Generally, aging of the immune system is known to be associated with increased susceptibility to infections and tumors, decreased vaccine efficacy and an increased prevalence of autoimmune diseases. A popular example of age-related changes of an immune response is the increased susceptibility to COVID-19 development seen in older individuals.Based on these results we propose that together with MHCII-haplotype and diet, aging is a crucial factor for controlling the balance between the cytokines IL-10, IL-21 and IFN-gamma, which finally determines the onset of an autoreactive B cell/plasma cell response and disease. In this project, we aim to test this hypothesis using the immune response to COL7 and our established EBA model as an example. We expect the findings to be of general relevance also for other autoimmune diseases.

• DFG Programme: Research Grants