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Breakage of B cell tolerance by antigens on follicular dendritic cells
  1. Mohey Eldin El Shikh1,
  2. Rania M El Sayed1,
  3. Maciej Kmieciak2,3,
  4. Masoud Manjili2,3,
  5. Andras Szakal4,
  6. Costantino Pitzalis1,
  7. John Tew2
  1. 1Experimental Medicine & Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK
  2. 2Microbiology and Immunology
  3. 3Massey Cancer Centre
  4. 4Anatomy and Neurobiology, VCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA

Abstract

Background and objectives Autoimmune disorders frequently display autoreactive germinal centres (GCs) with immune complex (IC)-bearing follicular dendritic cells (FDCs) suggesting that FDCs are involved in the pathogenesis of autoimmune diseases. The authors recently described induction of T cell-independent (TI) antibody (Ab) responses to T dependent (TD) antigens (Ags) by presenting the TD Ags on FDCs. Rather than presenting peptide fragments, FDCs multimerize monomeric Ags by trapping them in ICs via FDC-FcγRIIB and then present them polyvalently with a characteristic periodic spacing between epitopes of 200–500 Å. This allows extensive B cell receptor (BCR) cross-linking that induces TI B cell activation, GC formation, and Ag-specific Ig secretion in less than 48 h in the presence of FDC-derived co-stimulatory signals. These correlations prompted the hypothesis that multimerized self/neo-Ags on FDCs would break B cell tolerance; induce autoreactive GC formation, and auto-Ab responses.

Materials and methods ICs of autologous tumour necrosis factor α or IgE, were injected into BALB/c mice. In addition, soluble hen egg lysozyme transgenic (sHEL-Tg) and rat neu-Tg FVBN202 mice were challenged with HEL or the subdomain II of the extracellular domain of rat neu (ECDII), respectively, in the form of ICs. These auto/neo Ags were selected because Abs reactive with these Ags are used clinically or, in the case of sHEL-Tg mice, the profound tolerance to sHEL has been well verified.

Results Remarkably, in all cases, the ICs were trapped by FDCs; and autoreactive GCs, plasmablast differentiation and strong auto-Ab responses were induced within 48 h. In marked contrast, free Ag that would have unfettered access to BCRs did not load on FDCs and did not induce detectable auto-Abs.

Conclusions This is the first report of deliberately inducing auto-Abs by self/neo-Ags on FDCs. The data provide a mechanism by which FDCs may contribute to autoimmunity, and suggest a novel approach for targeting mediators of chronic inflammation, hypersensitivity and cancer. Therapeutic induction of auto-Abs by FDC-ICs may provide self-regulated high affinity Abs efficient in long-term disease control.

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