IL-2 receptor alpha deficiency and features of primary biliary cirrhosis Christopher A. Aoki a , Chaim M. Roifman b , Zhe-Xiong Lian c , Christopher L. Bowlus a , Gary L. Norman d , Yehuda Shoenfeld e , Ian R. Mackay f , M. Eric Gershwin c, * a Division of Gastroenterology, University of California at Davis, CA 95616, USA b Division of Immunology and Allergy, Department of Pediatrics, University of Toronto and the Hospital for Sick Children, Toronto, Ont., Canada c Division of Rheumatology, Allergy and Clinical Immunology, Genome and Biomedical Sciences Facility, University of California at Davis, CA 95616, USA d NOVA Diagnostics, Inc., San Diego, CA, USA e Department of Medicine B and Center for Autoimmune Disease, Sheba Medical Center, Tel-Aviv, Israel f Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Vic. 3168, Australia Received 17 February 2006; revised 10 April 2006; accepted 18 April 2006 Abstract Congenital immune deficiency states have often been valuable experimental models of nature that have significantly enhanced our understanding of the immune response. The relationship between CD4þ, CD25þ and Treg cells in the induction of autoimmunity has attracted significant atten- tion. We report herein a male child of consanguineous parents who developed at six months recurrent infections, and at age 5 years, liver dysfunction with serological expression of primary biliary cirrhosis (PBC), an autoimmune liver disease that usually affects middle-aged women. Histologically, there was intense mononuclear cell lymphoid infiltration of the intrahepatic portal tracts, CD3þ CD4þ T cell lymphopenia in blood and serum antibody to PDC-E2. Peripheral blood lymphocytes were completely deficient of the alpha subunit of the IL-2 receptor (IL-2Ra, CD 25), a marker for regulatory T cells (Tregs). Allogenic stem cell transplantation led to full recovery. This case illustrates the role of deficiency of CD4þ CD25þ Treg cells in causing autoimmunity, and speaks to the potential use of allogenic stem cell transplantation for immunoreconstitution in adult PBC. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Primary biliary cirrhosis; Pediatric; IL-2 receptor alpha deficiency; Molecular mimicry; CD4þ CD25þ T regulatory cells; Allogenic stem cell transplant 1. Introduction Primary biliary cirrhosis (PBC) is an autoimmune liver dis- ease, predominantly of middle aged-women, that leads to the destruction of intrahepatic bile ducts and includes the serologic signature of PBC, the anti-mitochondrial antibody (AMA) [1]. The immunodominant epitope is the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) [2]. Reactivity of serum to PDC-E2 is virtually pathognomonic for PBC [3]. In addition, anti-nuclear antibodies (ANA) are present in 20e30% of patients [4], showing a nuclear dot pattern [5] reflecting reactiv- ity to the sp100 [6] and/or promyelocytic leukemia (PML) pro- tein [7], or a nuclear rim pattern which reacts against gp210 [8] or p62 [9]. Histologically, there is a non-suppurative portal tract inflammation with progression to ductopenia, fibrosis and cir- rhosis. Although PBC has been described in two adolescents Abbreviations: ALT, amino alanine transferase; ANA, anti-nuclear anti- body; anti-LKM, anti-liver kidney microsome-1 antibody; AMA, anti-mito- chondrial antibody; AST, aspartate amino transferase; CENP-A, centromeric protein A; CENP-B, centromeric protein B; c-ANCA, cytoplasmic anti-neutro- phil antibody; CMV, cytomegalovirus; EBV, Epstein Barr virus; ELISA, enzyme-linked immunosorbent assay; GGT, Gamma-glutamyl transpeptidase; HIV, human immunodeficiency virus; IgA, immunoglobulin A; IgG, immuno- globulin G; IgM, immunoglobulin M; IL-2Ra, interleukin-2 receptor alpha (CD25); p-ANCA, perinuclear neutrophil cytoplasmic antibody; PDC-E2, pyruvate dehydrogenase-E2 subunit; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; PCR, polymerase chain reaction; RT-PCR, reverse-transcription polymerase chain reaction; SLE, systemic lupus erythe- matosus; Treg, regulatory T cells; tTG, tissue transglutaminase. * Corresponding author. Division of Rheumatology, Allergy and Clinical Immunology, Genome and Biomedical Sciences Facility, University of California at Davis, 451 E. Health Sciences Drive, Suite 6510, Davis, CA 95616, USA. Tel.: þ1 530 752 2884; fax: þ1 530 752 4669. E-mail address: megershwin@ucdavis.edu (M. Eric Gershwin). 0896-8411/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2006.04.005 Journal of Autoimmunity 27 (2006) 50e53 www.elsevier.com/locate/issn/08968411