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 and tertiary lymphoid tissues where they retain native antigens in the form of immune complexes for extended periods of time.
The cellular origin of FDCs is controversial and several cell types have been proposed as possible candidates. In fact, FDC ontogeny may be differentially regulated in various anatomical locations, under different sets of micro-environmental conditions, and by the cells and routes that deliver antigens to the FDC reticula. Our recent studies indicate that CNA42+/CD45–/CD34+/CD90– FDCs exist in the follicular and peri-vascular niches of secondary and tertiary lymphoid tissues where they critically regulate B cell activation and antibody/autoantibody production.
FDCs multimerize native antigens in arrays with 200 to 500 angstrom spacing between epitopes that extensively crosslink B cell receptors and induce B cell activation in a T cell dependent and independent fashion. In addition, FDCs provide B cells with homing and co-stimulatory signals; including FDC-CXCL13, -CD21L, -C4bBP, -BAFF, and -IL-6; which critically regulate B cell survival, homing, class switch recombination, and somatic hypermutation.
Like other accessory immune cells, FDCs are subject to activation. FDC engagement with immune complexes, Toll-like receptor ligands, or extracellular matrices induces FDC activation and upregulation of their membrane-bound and co-stimulatory molecules.
Autoimmune disorders frequently display follicles with immune complex-bearing FDCs, autoreactive germinal centers, and ongoing affinity maturation. Data in various models and human studies suggests the requirement for autoantigen to sustain the autoimmune response and that autoantigen withdrawal inhibits it. FDCs retain immune complexes for years, and provide constant antigen depot for memory B cell re-stimulation; and interference with FDC reticula attenuates autoreactive germinal centre formation, reduces pathogenic autoantibody titers, memory B cell differentiation and leads to arthritis amelioration. Our recent studies indicate that cyclic citrullinated peptides/proteins (CCPs) are retained on FDCs in rheumatoid synovium where they critically regulate AID expression, plasma cell differentiation and anti-cyclic citrullinated protein/peptide antibodies (ACPAs) production.
Not only do FDCs regulate pathogenic autoantibody production, but also they induce therapeutically potential antibodies against disease drivers and mediators. We have recently described the first FDC-immune complex-based immunotherapy where deliberate autoantigen retention induced autoreactive germinal center reactions and functionally active autoantibodies against TNF-alpha, HER2/neu- and IgE. This FDC-based auto-vaccination approach can be tailored to an unlimited number of endogenous mediators of chronic inflammatory, autoimmune and hypersensitivity diseases as well as monoclonal antibody-responsive cancers.
In summary, FDCs are key players in several human disorders including AIDS, prion diseases, autoimmune disorders, allergic diseases, and follicular lymphomas. Therefore, understanding the immuno-biology of FDCs is essential for better management of these disorders and paves the way for effective therapeutic manipulation of regulated and dysregulated immunity.
Disclosure of Interest None declared