Available online at www.sciencedirect.com Genetically determined lymphopenia and autoimmune manifestations Anna Villa 1,2 , Veronica Marrella 2 , Francesca Rucci 2,3 and Luigi D Notarangelo 3 Hypomorphic defects of V(D)J recombination in humans lead to residual T cell development. In these lymphopenic conditions, homeostatic lymphocyte proliferation occurs, and key mechanisms that normally maintain host tolerance are altered, allowing peripheral expansion of oligoclonal and autoreactive T cells. Recently described murine models support this notion. This review describes human and murine situations, in which genetically determined T and B cell lymphopenia is associated with autoimmune manifestations. Addresses 1 Istituto Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy 2 Istituto Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Istituto Clinico Humanitas, Rozzano (MI), Italy 3 Division of Immunology, Children’s Hospital, Harvard Medical School, Karp Family Building, 9th Floor, Room 9210, 02115 Boston, MA, USA Corresponding author: Villa, Anna (anna.villa@itb.cnr.it), Marrella, Veronica (veronica.marrella@itb.cnr.it), Rucci, Francesca (francesca.rucci@childrens.harvard.edu) and Notarangelo, Luigi D (luigi.notarangelo@childrens.harvard.edu) Current Opinion in Immunology 2008, 20:318–324 This review comes from a themed issue on Lymphocyte Activation Edited by Anjana Rao and Kathryn Calame Available online 9th April 2008 0952-7915/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2008.02.001 Introduction The ability of the immune system to mount specific responses to antigens relies upon V(D)J recombination, that rearranges and assembles variable (V), diversity (D) and joining (J) gene elements forming the variable domains of the antigen receptors of T and B cells. The recombination activating genes (Rag) initiate this process, by recognizing recombination signal sequences (RSS) that flank the coding regions, resulting in the generation of DNA double strand breaks. These are then resolved by the ubiquitous DNA repair machinery, non-homologous recombination end-joining (NHEJ), that includes multiple proteins: the Ku70/80 heterodimer, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Artemis (encoded by the DCLRE1C gene), polynucleotide kinase, DNA polymerases l and m; and the ligase complex composed of XRCC4, Cernunnos/XRCC4-like factor (encoded by the NHEJ1 gene) and DNA ligase IV [1,2,3  ,4  ,5,6](Figure 1). The fundamental role of non-homologous recombination factors in the development and function of the immune system has been demonstrated in several human primary immunodeficiencies and in murine models. In particular in humans, null mutations in RAG1, RAG2 and DCLRE1C lead to severe combined immune deficiency (SCID), with an early block in both T and B cell differentiation [7,8]. Conversely, hypomorphic mutations in some of the genes involved in V(D)J recombination allow for residual T cell (and less so, B cell) development. In some cases, expan- sion of activated oligoclonal T cells occurs, that may infiltrate target organs and cause tissue damage [9  ]. An increasing number of gene mutations are being associated with this unique phenotype of immune deficiency and autoimmune-like manifestations, and the cellular and molecular mechanisms involved are starting to be unra- veled. Omenn syndrome: an example of partial defect in V(D)J process Omenn syndrome (OS) is characterized by the presence of severe erythrodermia because of infiltration by acti- vated oligoclonal T cells with a skewed Th2 phenotype. The lymphocyte population consists of activated, poorly functional autologous T lymphocytes with a restricted T cell repertoire [10]. Laboratory investigations reveal eosi- nophilia, hypoproteinemia with low serum immunoglo- bulin but elevated IgE, and absent circulating B cells. Most patients suffer from severe infections, alopecia, chronic diarrhea, lymphoadenopathy and failure to thrive. The disease is rapidly fatal unless treated by allogeneic bone marrow transplantation [11,12]. Hypomorphic mutations of the RAG genes, allowing for residual protein expression and activity, have been reported in the majority of patients with OS [13,14,15  ]. Biochemical analysis of RAG1 and RAG2 mutants, has allowed identifying the role of various domains that reside outside the catalytic core of the proteins. In particular, most Rag1 hypomorphic mutations map to domains involved in DNA binding and in Rag2 recruitment. Moreover, a number of SCID-causing and OS-causing mutations have been identified in the RAG2 Current Opinion in Immunology 2008, 20:318–324 www.sciencedirect.com