ARTHRITIS & RHEUMATISM Vol. 48, No. 12, December 2003, pp 3497–3502 DOI 10.1002/art.11346 © 2003, American College of Rheumatology Intravenous Immunoglobulin Abrogates Dendritic Cell Differentiation Induced by Interferon- Present in Serum From Patients With Systemic Lupus Erythematosus Jagadeesh Bayry, 1 Se ´bastien Lacroix-Desmazes, 1 Sandrine Delignat, 1 Luc Mouthon, 2 Bernard Weill, 3 Michel D. Kazatchkine, 1 Srini V. Kaveri 1 Objective. Alterations in the function of dendritic cells (DCs) may explain the systemic autoimmune re- sponses that characterize systemic lupus erythematosus (SLE). Even though several reports have documented the beneficial effect of intravenous immunoglobulin (IVIG) in SLE, the underlying mechanisms of action remain poorly understood. Considering the effect of serum factors, including interferon- (IFN), on the activity of DCs, we investigated the effects of IVIG on the differentiation of DCs mediated by serum from SLE patients. Methods. DCs were differentiated from peri- pheral blood monocytes obtained from SLE patients and from healthy blood donors, in the presence of SLE serum. IVIG was used at a concentration of 0.15 mM.A functional assay was performed to assess the inhibitory effect of IVIG on the uptake of nucleosomes by DCs. Results. IVIG interfered with the differentiation of DCs from SLE patients and healthy donors cultured in the presence of SLE serum. Treatment of DCs with IVIG inhibited the ingestion of nucleosomes by imma- ture DCs, by up to 36%. Conclusion. The present findings indicate that IVIG, by down-regulating the IFN-mediated differen- tiation of DCs and by inhibiting uptake of nucleosomes, may exert an essential immunoregulatory effect in SLE patients at the onset of the immune response, at the DC level. Given the critical role of HLA molecules and the costimulatory signals delivered by CD80 and CD86 in optimal antigen presentation and T cell activation, inhibition of expression of HLA and CD80/CD86 on DCs by IVIG offers a plausible explanation for the efficacy of IVIG in SLE and other immune-mediated inflammatory conditions. Systemic lupus erythematosus (SLE) is an auto- immune disease characterized by a waxing and waning course and by the involvement of multiple organs, including the skin, kidneys, and central nervous system. Among the immunologic features of SLE is the presence of high titers of autoantibodies predominantly specific for DNA and nucleosomes (1). Dendritic cells (DCs) play a central role in the initiation of primary immune responses and stimulate naive T cells (2). Alterations in the function of DCs may explain the systemic auto- immune responses that characterize SLE. Indeed, Blanco and colleagues previously reported that serum from SLE patients induced monocytes from healthy donors to differentiate into DCs, and that this process depended on the presence of interferon- (IFN) in patients’ serum (3). Therefore, “unabated induction of DCs by IFN may drive the autoimmune responses in SLE” (3). Therapeutic preparations of polyspecific IgG (in- travenous immunoglobulin [IVIG]) are used in a large number of autoimmune diseases. Despite several reports documenting the beneficial effect of IVIG in SLE (4–7), the underlying mechanisms of action remain poorly Supported by INSERM and CNRS, and by a grant from ZLB Bioplasma AG, Bern, Switzerland. Dr. Bayry is the recipient of a fellowship from the Fondation de la Recherche Me ´dicale (France). 1 Jagadeesh Bayry, DVM, Se ´bastien Lacroix-Desmazes, PhD, Sandrine Delignat, BSc, Michel D. Kazatchkine, MD, Srini V. Kaveri, DVM, PhD: INSERM (Unite ´ 430) and Universite ´ Pierre et Marie Curie, Institut des Cordeliers, Paris, France; 2 Luc Mouthon, MD, PhD: Ho ˆpital Avicenne, Paris, France; 3 Bernard Weill, MD: Ho ˆpital Cochin, AP-HP, and Universite ´ Paris V, Paris, France. Address correspondence and reprint requests to Srini V. Kaveri, DVM, PhD, INSERM Unite ´ 430, Institut des Cordeliers, 15 rue de l’Ecole de Me ´decine, Paris 75006, France. E-mail: srini.kaveri@u430.bhdc.jussieu.fr. Submitted for publication December 2, 2002; accepted in revised form August 8, 2003. 3497