The role of delta-class B cell receptors in immunological tolerance and autoimmunity

• Applicant: Professor Dr. Hassan Jumaa
• Subject Area: Immunology ; Cell Biology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326914434

Mature B cells express two types B cell antigen receptors (BCRs) known as IgM and IgD, which differ in their heavy chains (HC) but possess identical variable regions and light chains (LC). IgM BCR is expressed at early developmental stages and when B cells pass the immature B cell stage and leave the bone marrow, they co-express IgM and IgD BCRs. In mature follicular B cells, IgD BCR is the predominant BCR type expressed while IgM BCR becomes downregulated on these cells. In contrast to other receptor classes, the function of IgD BCR on mature B cells remained largely unknown as IgM is sufficient for development, survival and activation of B cells. The tightly regulated and evolutionary conserved expression of IgD suggests that IgD BCR plays an important role in B cell biology. Based on our findings and available data we proposed a model for B cell function in which IgD BCR allows the discrimination between multivalent and monovalent antigen thereby adjusting the activation threshold of mature B cells towards antigens derived from self or non-self. More recently, we established a novel experimental system in which we perform immunization experiments using insulin as autoantigen and diabetes symptoms as signs for autoimmune responses. By monitoring the antibody responses against insulin, we found that IgD-deficient mice show an accelerated and long-lasting production of anti-insulin antibodies and deregulated blood glucose concentrations as compared with wildtype controls. Together, our data suggested that the IgD-mediated regulation of B cell activation and the subsequent affinity maturation are key for the prevention of autoreactive immune responses. Based on these findings, we proposed a novel mechanism for tolerance in which IgD-mediated affinity maturation is important for protection of self-structures from autoimmune destruction. We refer to this mechanism as adaptive tolerance. In the upcoming period, we will investigate how IgD-BCR improves affinity maturation and how high-affinity autoreactive IgM antibodies can prevent the autoimmune destruction by autoreactive IgG antibodies. Moreover, we will investigate how IgD-BCR expression is regulated by signaling processes under different physiological conditions. Particularly, the role of stress hormones such as glucocorticoids in the regulation of IgD expression and B cell function will be studied.

• DFG Programme: Research Grants