A B cell–driven EAE mouse model reveals the impact of B cell–derived cytokines on CNS autoimmunity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-11, Vol.120 (47), p.1-e2300733120
• Main Authors: Thomann, Anna S., McQuade, Courtney A., Pinjušić, Katarina, Kolz, Anna, Schmitz, Rosa, Kitamura, Daisuke, Wekerle, Hartmut, Peters, Anneli
• Format: Article
• Language: English
• Subjects: Animal models; Antigen presentation; Antigens; Autoimmunity; Cell activation; CRISPR; Cytokines; Experimental allergic encephalomyelitis; Germinal centers; Glycoproteins; IgG antibody; Immunoglobulin G; Inflammation; Lymphocytes; Lymphocytes B; Lymphocytes T; Multiple sclerosis; Myelin; Oligodendrocyte-myelin glycoprotein; Pathogenesis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2300733120

In multiple sclerosis (MS), pathogenic T cell responses are known to be important drivers of autoimmune inflammation. However, increasing evidence suggests an additional role for B cells, which may contribute to pathogenesis via antigen presentation and production of proinflammatory cytokines. However, these B cell effector functions are not featured well in classical experimental autoimmune encephalomyelitis (EAE) mouse models. Here, we compared properties of myelin oligodendrocyte glycoprotein (MOG)-specific and polyclonal B cells and developed an adjuvant-free cotransfer EAE mouse model, where highly activated, MOG-specific induced germinal center B cells provide the critical stimulus for disease development. We could show that high levels of MOG-specific immunoglobulin G (IgGs) are not required for EAE development, suggesting that antigen presentation and activation of cognate T cells by B cells may be important for pathogenesis. As our model allows for B cell manipulation prior to transfer, we found that overexpression of the proinflammatory cytokine interleukin (IL)-6 by MOG-specific B cells leads to an accelerated EAE onset accompanied by activation/expansion of the myeloid compartment rather than a changed T cell response. Accordingly, knocking out IL-6 or tumor necrosis factor α in MOG-specific B cells via CRISPR-Cas9 did not affect activation of pathogenic T cells. In summary, we generated a tool to dissect pathogenic B cell effector function in EAE development, which should improve our understanding of pathogenic processes in MS.