A novel mechanism for autoimmunity based on a new principle for T-B cell cooperation

Feild of study: Immunology. Interactions and collaboration between B and T cells in vivo in mice: basic principles and pathogenicity. Regulation of T and B cell clonal size. Clinical correlates: Rheumatic disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis.

The PhD fellow will be working on the topic of Id-driven T-B collaboration in terms of basic principles and relationship to autoimmunity. 

Inter-mouse lymphocyte transfer experiments will be undertaken to study B cell collaboration with T cells that recognize the B cell's endogenous Idiotype (antibody V region) presented as Id-peptide on MHC class II (see below). The activation, selection and differentiation of B cell subpopulations will be studied. The genesis and pathogenicity of autoreactive B cells will be investigated. The in vivo activation will be followed with time utilizing a full-body bioluminescence assay of living mice and a novel cell activation-dependent light-emitting transgenic mice. Further targeted transgenic mice models will be available for study.

BACKGROUND. Self-reactive T cells have often been difficult to find in association with autoimmune disease. This raises the possibility that self-reactive B cells receive help from other sources of T cells. In 1989 BB and colleagues proposed that self-reactive B cells receive help from T cells that recognise processed Ig variable (V) regions on the B cell surface (Weiss & Bogen, PNAS 1989; Weiss & Bogen, Cell 1991). BB and collaborators have since substantiated this theory, called idiotope-driven T-B cooperation. Their approach involved numerous experiments in transgenic mice (e.g. Munthe et al, J Immunol 2004; Munthe et al, 2005 J Immunol) and in patients with autoimmune diseases such as multiple sclerosis (Holmøy et al, Eur J Immunol 2005). Although initially a small area of research, it is expanding.  In the proposed project we will use idiotope-driven T-B cooperation as a model to identify regulatory mechanisms shared between different immune-mediated disorders and to test novel therapeutic strategies based on engineered proteins.

Idiotope-driven T-B cooperation. Ig V regions are highly diverse. Each Ig molecule expresses in its V regions unique antigenic determinants called idiotopes (Ids). B cells express Ids on their BCR. In addition, they partially degrade their BCR and present short Id peptides in complex with their MHC class II molecules. Thus, B cells express two types of Id: 1) Id on BCRs that can be recognised by anti-Id antibodies (the basis of the Nobel prize-awarded concept formulated by Niels Jerne) [see1) in fig. below]; and 2) short Id peptides on MHC class II molecules that can be recognised by Id-specific CD4⁺ T cells [see 2) in fig. below]. 

Id-driven T-B cooperation and autoimmunity in the λ2³¹⁵ model system. We have recently transferred Id-specific T cells and Id⁺ B cells from transgenic mice to non-transgeneic mice and demonstrated production of Id⁺ antibodies. Thus, complementary T and B cells find each other in vivo, establish contact, and initiate B-T collaboration. Importantly, antigen binding to the BCR was required for mature antibody secretion (switch from IgM to IgG antibody). Moreover, chronic Id-driven T-B cooperation led to the production of a multitude of different autoantibodies as well as serious autoimmune disease, including skin affection, inflammatory bowel disease, and arthritis (Munthe et al, J Immunol 2005). On the basis of these findings, a model was proposed in which autoantigen binding to the BCR, concomitant with Id-specific T cell help, induces B cell differentiation and production of IgG autoantibodies (Munthe et al, J Immunol 2004) [see fig. below].