ARTHRITIS & RHEUMATISM Vol. 60, No. 9, September 2009, pp 2767–2771 DOI 10.1002/art.24760 © 2009, American College of Rheumatology Regression of Systemic Lupus Erythematosus After Development of an Acquired Toll-like Receptor Signaling Defect and Antibody Deficiency Marcella Visentini, Valentina Conti, Maria Cagliuso, Francesca Tinti, Giulia Siciliano, Amelia C. Trombetta, Anna Paola Mitterhofer, Massimo Fiorilli, and Isabella Quinti Toll-like receptor 9 (TLR-9) and TLR-7 may have a role in the production of anti-DNA and anti-RNA autoantibodies, respectively, but murine models do not clearly demonstrate their contribution to the develop- ment of systemic lupus erythematosus (SLE). Herein we describe a patient with SLE who had long-lasting remis- sion of her autoimmune disease after development of an antibody deficiency resembling common variable immu- nodeficiency (CVID). After CVID had developed, anti– double-stranded DNA antibodies disappeared, although antinuclear antibodies remained positive for >10 years. In vitro studies revealed that the patient’s B cells proliferated poorly and failed to differentiate into plas- mablasts after stimulation of either TLR-9 or TLR-7, providing evidence for an acquired defect of the signal- ing pathway downstream of these TLRs. These observa- tions suggest, although indirectly, that signaling through TLR-9 and TLR-7 is important in the patho- genesis of human SLE, and indicate that investigation of potential treatment strategies with TLR antagonists is warranted. Toll-like receptors (TLRs) are innate receptors that sense pathogen-associated molecular patterns. Re- cent studies have revealed a complex interplay between TLRs and cells of the immune system, which could be important with regard to the initiation and maintenance of autoimmune diseases (1). TLR-7 and TLR-9, which are expressed by human B cells and share the myeloid differentiation factor 88 (MyD88) signaling pathway, recognize viral single-stranded RNA and unmethylated oligonucleotides (CpG) mimicking bacterial DNA, re- spectively (1). Based on this, it has been demonstrated that the dual engagement of the B cell receptor (BCR) and TLR-9 (2) or TLR-7 (3) by DNA-containing or RNA-containing immune complexes, respectively, may prime autoantibody production by naive B cells. Fur- thermore, deficiencies of TLR-7 or TLR-9, respectively, suppress the production of anti-RNA or anti-DNA autoantibodies in murine models of systemic lupus ery- thematosus (SLE) (4,5). However, the relevance of these findings to the clinical manifestations of SLE has yet to be determined. Primary immunodeficiency disorders may offer interesting opportunities for understanding the patho- physiology of human autoimmune disorders. In common variable immunodeficiency (CVID), the most frequent symptomatic primary antibody deficiency syndrome, pa- tients with reduced numbers of IgM+ memory B cells are highly susceptible to infection by encapsulated bac- teria, whereas those with selective deficiency of switched memory B cells are, surprisingly, prone also to autoim- munity (6). While the association of low levels of memory B cells with infection is explained by the fact that these cells produce antipneumococcal polysaccha- ride antibodies, the association of decreased levels of switched memory B cells with autoimmunity in CVID is puzzling. We describe herein a woman with SLE who developed a CVID-like disorder and, thereafter, long- lasting remission of her autoimmune disease. Anti– double-stranded DNA (anti-dsDNA) antibodies became Supported by EuroPADnet (European Primary Antibody Deficiency Network) grant 2008-201549. Marcella Visentini, MD, Valentina Conti, MD, Maria Cag- liuso, MD, Francesca Tinti, MD, Giulia Siciliano, MS, Amelia C. Trombetta, MD, Anna Paola Mitterhofer, MD, PhD, Massimo Fiorilli, MD, Isabella Quinti, MD, PhD: Sapienza University, Rome, Italy. Address correspondence and reprint requests to Massimo Fiorilli, MD, Sapienza University of Rome, Department of Clinical Immunology, Viale dell’Universita ` 37, 00185 Rome, Italy. E-mail: massimo.fiorilli@uniroma1.it. Submitted for publication November 27, 2008; accepted in revised form May 26, 2009. 2767