Follicular dendritic cells in health and disease

Follicular dendritic cells (FDCs) are unique immune cells that contribute to the regulation of humoral immune responses. These cells are located in the B cell follicles of secondary lymphoid tissues where they trap and retain antigens (Ags) in the form of highly immunogenic immune complexes (ICs) consisting of Ag plus specific antibody (Ab) and/or complement proteins. FDCs multimerise Ags and present them polyvalently to B cells in periodically arranged arrays that extensively crosslink the B cell receptors for Ag (BCRs). FDC-Fc-gamma-RIIB mediates IC periodicity, and FDC-Ag presentation combined with other soluble and membrane bound signals contributed by FDCs, like FDC-BAFF, -IL-6 and -C4bBP, are essential for the induction of the germinal centre (GC) reaction, the maintenance of serological memory, and the remarkable ability of FDC-Ags to induce specific Ab responses in the absence of cognate T cell help. On the other hand, FDCs play a negative role in several disease conditions including chronic inflammatory diseases, autoimmune diseases, HIV/AIDS, prion diseases and follicular lymphomas. Compared to other accessory immune cells, FDCs have received little attention, and their functions have not been fully elucidated. This review gives an overview of FDC structure, and recapitulates our current knowledge on the immunoregulatory functions of FDCs in health and disease. A better understanding of FDCs should permit better regulation of Ab responses to suit the therapeutic manipulation of regulated and dysregulated immune responses

Extracellular traps and PAD4 released by macrophages induce citrullination and auto-antibody production in autoimmune arthritis

Barts Charity grant number MRC0177

Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production

The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007 2013) under REA grant agreement n° 608765. This work was supported in part by grants from the Ministero dell’Istruzione, Università e Ricerca (MIUR) and Regione Campania CISILab Project, CRÈME Project, and TIMING Project. The Pathobiology of Early Arthritis Cohort (PEAC) was funded by the MRC grant 36661. Additional funding from MRC funded Maximising Therapeutic Utility for Rheumatoid Arthritis using genetic and genomic tissue responses to stratify medicines (MATURA) Grant Ref: MR/K015346/1 and ARUK funded Experimental Arthritis Treatment Centre (EATC) Grant Ref: 20022. The animal work was supported by Arthritis Research UK Grants Reference 20305 and 20770

LLT1 and CD161 Expression in Human Germinal Centers Promotes B Cell Activation and CXCR4 Downregulation

Germinal centers (GC) are microanatomical structures critical for the development of high-affinity antibodies and B-cell memory. They are organised into two zones, light and dark, with coordinated roles, controlled by local signalling. The innate Lectin-like transcript 1 (LLT1) is known to be expressed on B-cells, but its functional role in the GC reaction has not been explored. Here we report high expression of LLT1 on GC-associated B-cells, early plasmablasts and GC-derived lymphomas. LLT1 expression was readily induced via BCR, CD40 and CpG stimulation on B-cells. Unexpectedly, we found high expression of the LLT1 ligand, CD161, on Follicular dendritic cells (FDCs). Triggering of LLT1 supported B-cell activation, CD83 upregulation and CXCR4 downregulation. Overall, these data suggest that LLT1-CD161 interactions play a novel and important role in B-cell maturation within the GC in humans