Journal of Clinical Immunology, Vol. 27, No. 1, January 2007 ( C  2006) DOI: 10.1007/s10875-006-9049-8 CTLA-4 Gene Exon-1 + 49 A/G Polymorphism: Lack of Association with Autoimmune Disease in Patients with Common Variable Immune Deﬁciency ADINA KAY KNIGHT, 1,2 DAVIDE SERRANO, 1,3 YARON TOMER, 4 and CHARLOTTE CUNNINGHAM-RUNDLES 1,5 Received July 31, 2006; accepted September 25, 2006 Published online: 28 December 2006 The presence of the G allele of exon-1 +49 A/G polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene has been described as a risk factor associated with the development of autoimmune diseases. Since Common Variable Immune De- ﬁciency (CVID) is associated with autoimmune manifestations in approximately 25% of patients, we sought to examine the as- sociation of the CTLA-4 single nucleotide polymorphism with autoimmunity and other inﬂammatory complications. Sixteen of 47 CVID (34%) patients had a history of autoimmunity, and 15 (32%) had known granulomatous disease with or without lym- phoid hyperplasia. CTLA-4 genotype frequencies were AA 40% (19), AG 45% (21), and GG 15% (7). Allele frequencies were A 63% and G 37%, similar to control populations. There were no signiﬁcant associations between CTLA-4 exon-1 +49 A/G polymorphism and autoimmune or lymphoid hyperplasia and granulomatous disease in this mostly Caucasian CVID patient population. KEY WORDS: Common variable immune deﬁciency; autoimmunity; granuloma; lymphoid hyperplasia . INTRODUCTION Polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene have been described as a risk factor 1 Mount Sinai School of Medicine, Departments of Clinical Immunology and Endocrinology, 1425 Madison Avenue, New York, NY, USA. 2 Allergy and Immunology, LSU-HSC, Shreveport, LA, USA. 3 European Institute of Oncology Department of Chemoprevention, Milan, Italy. 4 Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 5 To whom correspondence should be addressed to Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1089, Room 1120, New York, NY 10029; e-mail: Charlotte.Cunningham-Rundles@mssm.edu. associated with the development of a number of autoim- mune diseases. Since about 20–25% of patients with the primary immunodeﬁciency syndrome Common Variable Immune Deﬁciency (CVID) exhibit autoimmunity, we sought to examine the relationship between CTLA-4 poly- morphisms and autoimmunity in this condition. The CTLA-4 gene is located on chromosome 2q33 and is a member of the immunoglobulin superfamily (1). It is expressed on activated T cells and ligates B7 (CD80/CD86), a constitutively expressed surface recep- tor on antigen presenting cells, including B cells, mono- cytes, macrophages, and dendritic cells. Upon activation CTLA-4 downregulates immunologic responses in con- trast to the activating effects of its homolog CD28 (2). Blockade of CTLA-4 with monoclonal anti-CTLA-4 an- tibody is associated with increased responsiveness to self- antigens and the development of autoimmunity in both a mouse model and human cancer vaccine trials (3–5). In contrast, ligation of B7 (CD80/CD86) with CTLA4– immunoglobulin [Ig], a biologic construct that combines the extracellular domain of human CTLA4 with a por- tion of the Fc domain of IgG1, interferes with CD28 binding to B7 (CD80/CD86) and may be useful in the treatment of autoimmune disease (6, 7). CTLA-4 is re- lated to the inducible costimulator (ICOS) and both use a PI3K-dependent pathway (8). CTLA-4 ligation can block the effects of ICOS stimulation (9). Curiously, defects in ICOS result in a recessive form of CVID in a related kindred (10) and defects in T cell CD28 costimulation have been described (11). The CTLA-4 exon-1 +49 A to G polymorphism re- sults in a change at codon 17 of the leader sequence of the peptide from threonine to alanine (12). This codon change may not be the causative polymorphism for au- toimmune disease, as it is in linkage disequilibrium with 95 0271-9142/07/0100-0095/0 C  2006 Springer Science+Business Media, LLC