Clinical manifestations and analyses of the cytotoxic T-lymphocyte associated-4 gene in two Japanese families with systemic lupus erythematosus

Although still incompletely understood, the etiology of systemic lupus erythematosus (SLE) is considered to involve both genetic and environmental factors. We encountered two boys with severe SLE from unrelated families and analyzed the gene that encodes cytotoxic T-lymphocyte-associated (CTLA)-4, a protein important in T-cell activation and immune tolerance. Abnormal function of the gene may participate in causation of autoimmune disease, including SLE. In family 1, a boy showed serious cardiovascular complications associated with heart failure, and his mother also had clinically active SLE, including nephritis. A boy in family 2 developed severe renal complications and peripheral vasculitis accompanied by disseminated petechiae in the lower extremities. His paternal grandfather had died from fibrinous pneumonia caused by SLE. They showed high SLE Disease Activity Index (SLEDAI) score. Analysis of the CTLA-4 gene indicated that the boy in family 1 and his mother and the boy in family 2 possess a GG genotype in CTLA-4 exon 1 at +49 together with a 106-bp fragment length of the 3′ untranslated region (UTR) in exon 4. No association with disease activity was found for polymorphism of the promoter region in exon 1 at −318 in either family. Disorders of the CTLA-4 gene, especially a GG genotype in exon 1 at +49 and/or 106-bp fragment length of the 3′UTR in exon 4, may be involved in early development of SLE in Japanese children, such as the boys described here.