REVIEWS MOLECULAR DEFECTS IN T AND BCELL PRIMARY IMMUNODEFICIENCY DISEASES Charlotte Cunningham-Rundles and Prashant P. Ponda Abstract | More than 120 inherited primary immunodeficiency diseases have been discovered in the past five decades, and the precise genetic defect in many of these diseases has now been identified. Increasing understanding of these molecular defects has considerably influenced both basic and translational research, and this has extended to many branches of medicine. Recent advances in both diagnosis and therapeutic modalities have allowed these defects to be identified earlier and to be more precisely defined, and they have also resulted in more promising long-term outcomes. The prospect of gene therapy continues to be included in the armamentarium of treatment considerations, because these conditions could be among the first to benefit from gene-therapy trials in humans. The human immune system is confronted with the chal- cells or complement, whereas opportunistic infections lenge of host defence. This is accomplished through vari- with viruses or fungi are particularly common in ous innate immune responses (which are non-specific) patients with T-cell deficiencies. A subset of primary and adaptive immune responses (which are specific) immunodeficiencies is associated with inflammatory that work synergistically to achieve this goal. Cells of or autoimmune manifestations, and certain subgroups the adaptive immune system include T and B cells, of patients are susceptible to developing malignancies. which are derived from a common multipotent haemato- This Review focuses on the recent advances in the poietic stem cell. Defects involving T and B cells have field, with an emphasis on newly identified genetic been described with respect to their development, effec- deficiencies and therapeutic options for patients. tor function and roles in immuno regulation1. Although SCID — an immunodeficiency that is character- defined primary natural killer (NK)-cell deficiencies ized by severely reduced numbers or an absence of are rare among primary immuno deficiency diseases, functional T cells, which in turn results in the absence other cells of the innate immune system, which were of an adaptive immune response — is a consequence of previously thought to function independently of adap- a mutation in any one of ten distinct genes that are tive immune responses, are now seen as important inherited in an autosomal recessive or an X-linked Division of Clinical partners in the development of adaptive immunity. manner2–10. Four lymphocyte phenotypes are possible Immunology, Mount Sinai The clinical presentation of patients with a primary on the basis of the influence of the defective gene on School of Medicine, 1425 Madison Avenue, immunodeficiency reflects the complex underpinnings B-cell and NK-cell development TABLE 1. A diag- Box 1089, New York, of the immune system and depends on the underlying nosis is possible at birth, with most affected infants New York 10029, USA. genetic defect. Patients with severe combined immuno- having lymphopaenia (less than 2,000 lymphocytes Correspondence to C.C.R. deficiency (SCID) generally present with opportunistic per mm3 of blood) and their lymphocytes showing e-mail: charlotte. cunningham- infections and fail to thrive within a few months of decreased proliferation in vitro after stimulation with 11 [email protected] life. Recurrent bacterial infections are the hallmark mitogen, antigen or allogeneic cells . Although these doi:10.1038/nri1713 of disease in patients with defects in B cells, phagocytic infants have a severely reduced amount of thymic 880 | NOVEMBER 2005 | VOLUME 5 www.nature.com/reviews/immunol © 2005 Nature Publishing Group REVIEWS TCELLRECEPTOR EXCISION tissue, accompanied by the absence of normal thymic for thymic insufficiency leading to a T-cell deficiency, CIRCLES architecture, T-cell development is achievable after although it also involves abnormal development of spa- (TRECs). DNA episomes the introduction of normal haematopoietic stem tially related embryological tissues that leads to cardiac, that are normally produced cells12. At present, bone-marrow transplantation using parathyroid and other abnormalities. DiGeorge syn- during the thymic maturation of T cells, specifically during either unfractionated HLA-identical haematopoietic drome is characterized by a decrease in the number of + + recombination of the T-cell- stem cells or T-cell-depleted haploidentical (parental) CD3 cells or an absence of CD3 cells as a consequence receptor genes. haematopoietic stem cells is the standard of care for of hypoplasia or aplasia of the thymus. Depending on these infants, with improved survival in patients who the number of peripheral T cells, the immune pheno- XLINKED receive a transplant within the first 4 weeks of life13. type falls within a range of immunodeficiencies, from LYMPHOPROLIFERATIVE SYNDROME Successful intervention depends on early identifica- full immunocompetence to a SCID-like phenotype. (XLP). A rare, often fatal, tion of infants, before the development of opportunistic Unlike other forms of SCID, severe DiGeorge syndrome primary immunodeficiency infections that contribute to the increased morbidity can be treated effectively by thymic transplantation, disease that is characterized and mortality that is associated with delayed transplan- which allows for the maturation of recipient T cells. by an inability to mount an effective immune response tation. Nevertheless, there is no programme in place Several candidates for the genetic defect in DiGeorge to Epstein–Barr virus. This for screening newborns for SCID; such a programme syndrome have been identified; most recently, a mem- can lead to lymphoma or would allow therapy to be provided within this vital ber of the T-box transcription-factor family, TBX1, has hypogammaglobulinaemia. window of opportunity. In the United States, the been implicated as a cause of most of the main signs of Centers for Disease Control and Prevention has identi- DiGeorge syndrome16,17. fied SCID as a candidate for the development of a new- Genetic defects also affect the signal-transduction born-screening protocol, because SCID meets many of pathways that are essential for T-cell activation. the accepted screening criteria14. Many modalities Components of these pathways include the γ-chain of testing have been explored; most recently, the of CD3 (CD3γ), CD3ε, MHC class I molecules, MHC examination of TCELLRECEPTOR EXCISION CIRCLES (TRECs) class II molecules, LCK, ZAP70 (ζ-chain-associated in DNA isolated from dried blood spots has shown protein kinase of 70 kDa) and CD8α18–25. The result- promise15. TRECs are more abundant in T cells from ing defects are highly variable and range from severe a healthy newborn than from an adult. Their absence cellular dysfunction (from a deficiency in MHC has been confirmed in patients with SCID15, and large- class II molecules) to negligible dysfunction (from a scale implementation of this screening tool might help deficiency in CD8α). to identify affected infants. In addition to genetic defects that reduce or elimi- nate T-cell-based immunity, there is a growing list of Defects that involve T-cell immunity immune defects that result in overactive or abnormal Patients with defects that involve T cells do not have T-cell function that leads to immunodeficiency. An adequate cellular immune responses and are predis- example of a functional mutation is seen in patients posed to developing opportunistic infections. These with XLINKED LYMPHOPROLIFERATIVE SYNDROME (XLP); these T-cell deficiencies are reflected in reduced absolute individuals have a mutation in SH2D1A, which encodes cell numbers, defective activation and function, and SLAM-associated protein (SAP), a cytoplasmic adap- disrupted immunoregulation (FIG. 1; TABLE 2. DiGeorge tor protein that binds signalling lymphocytic activation syndrome has classically been thought of as the model molecule (SLAM) and other SLAM-family molecules26. SLAM is a transmembrane protein that is expressed at low levels at the surface of resting cells and at higher Table 1 | Aetiologies of severe combined immunodeficiency levels after cellular activation; intracytoplasmic binding Type of SCID Chromosomal location Reference of SLAM by SAP has an inhibitory role. For reasons that are unclear, defects in SAP result in uncontrolled prolif- – + + T B NK eration of T cells in individuals who are infected with Interleukin-7 receptor α-chain deficiency 5p13 2 Epstein–Barr virus, as well as ineffective viral elimina- CD3 δ-chain deficiency 11q23 3 tion, lymphoma or hypogammaglobulinaemia. SH2D1A mutations result in fatal infectious mononucleosis in a CD3 ε-chain deficiency 11q23 4 high proportion of cases. T –B+NK– Another emerging role for T cells is that of γ X-linked recessive SCID ( c deficiency) Xq13.1 5 regulation of the immune response to prevent the CD45 deficiency 1q31–1q32 6 recognition of self. Recent studies have outlined aspects of the molecular basis of T-cell defects in JAK3 deficiency 19p13.1 7 three disease states that are characterized by T-cell T –B–NK+ immunodysregulation. Artemis gene-product deficiency 10p13 8 IPEX. Immunodysregulation, polyendocrinopa- RAG1 and RAG2 deficiency 11p13 9 thy and enteropathy, X-linked syndrome (IPEX) T –B–NK– can often be fatal and is a recessive disorder of early Adenosine-deaminase deficiency 20q13.11 10 childhood that involves the classic clinical triad γ γ of endocrinopathy (most commonly in the form