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Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation¹

Patricia K. A. Mongini^2,*,, John K. Inman, Hanna Han^*, Susan L. Kalled, Rasem J. Fattah and Steven McCormick^¶

^* Department of Rheumatology, Hospital for Joint Diseases, and Department of Pathology, New York University Medical Center, New York, NY 10003; Laboratory of Immunology, National Institutes of Health, Bethesda, MD 20892; Biogen Idec, Cambridge, MA 02142; and ^¶ Department of Pathology, New York Eye and Ear Infirmary, New York, NY 10003

Foci of autoantigen-specific B lymphocytes in nonlymphoid tissues have been associated with development of autoimmune disease. To better understand the genesis of such ectopic lymphoid tissue, this study investigated whether several B cell-tropic innate immune system molecules, known to be elevated in response to inflammatory stimuli, can cooperate in fostering the T cell-independent clonal expansion of mature human B2 cells under conditions of limiting BCR engagement. Notable synergy was observed between BCR coligation with the C3dg-binding CD21/CD19 costimulatory complex, B cell-activating factor belonging to the TNF family (BAFF), and IL-4 in generating B cell progeny with sustained CD86 and DR expression. The synergy was observed over a wide range of BCR:ligand affinities and involved: 1) cooperative effects at promoting early cell cycle progression and viability; 2) BCR:CD21 coligation-promoted increases in BAFF receptors that were highly regulated by IL-4; 3) reciprocal effects of IL-4 and BAFF at dampening daughter cell apoptosis typical of stimulation by BCR:CD21 and either cytokine alone; and 4) BAFF-sustained expression of antiapoptotic Mcl-1 within replicating lymphoblasts. The results suggest that significant clonal proliferation of recirculating B2 cells occurs upon limited binding to C3dg-coated Ag in an inflammatory in vivo milieu containing both BAFF and IL-4. When rare autoantigen-presenting B cells undergo such expansions, both B cell and T cell autoimmunity may be promoted.

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