The functional consequences of IgA immune complex capture by FcRL4+ B cells

Barney, Kate (2025). The functional consequences of IgA immune complex capture by FcRL4+ B cells. University of Birmingham. Ph.D.

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Abstract

RA is a systemic, chronic autoimmune disease that is generally first observed in the small joints. An invasive, inflammatory filtrate develops in the synovium. If left untreated, in the long term, this leads to joint damage and disability. The success of B cell-depleting therapies has indicated a role for B cells in the pathogenesis of rheumatoid arthritis but the presence of autoantibodies post-treatment indicates B cells have an antibody-independent function. A subset of RANKL-producing B cells in rheumatoid arthritis synovial fluid has been defined by its expression of Fc receptor like 4 (FcRL4) and FcRL4 captures IgA immune complexes on their surface. Here, we addressed the hypothesis that capture of IgA immune complexes by FcRL4 lead to its internalisation before processing and presentation on the cell surface. We also addressed whether IgA IC binding to FcRL4 impacted signalling pathways activated by the BCR in primary cells. In transduced priess cells, tonsil B cells and rheumatoid arthritis synovial fluid B cells, IgA immune complexes bound to FcRL4 was internalised to acidified intracellular compartments. High expression of co-stimulatory molecules CD80, CD86 and HLA-DR by FcRL4+ B cells suggest that they can act as antigen presenting cells and that the internalised IgA immune complex is potentially processed and presented on the surface. Crosslinking of IgA immune complex-bound FcRL4 with the BCR increases phosphorylation of the inhibitory signalling molecules Hck, Fgr and SHP-1 whilst simultaneously decreasing phosphorylation of activatory signalling ERK1/2, PLCγ2 and Syk in FcRL4+ transduced priess cells, tonsil B cells and rheumatoid arthritis synovial fluid B cells. Together, these results suggest that expression of FcRL4 on B cells acts as a molecular switch to downregulate BCR signalling and prioritise internalisation of IgA immune complexes.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):