Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations

Abstract

A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4 ؉ T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-V␤ repertoire was polyclonal with a very low content of T-cell receptor excision circles (TRECs IntroductionSelective depletion of T lymphocytes is common in both primary and secondary immunodeficiencies. Idiopathic CD4 ϩ T lymphocytopenia (ICL) is defined by an unexplained persistent CD4 ϩ T lymphocyte count of Ͻ 300 cells/L or Ͻ 20% of the total T-cell count. 1 Since the discovery of human retroviruses, sporadic ICL patients were recognized with a CD4 ϩ lymphocytopenia not infected by HIV or HTLV-1. 2-7 Smith et al reviewed 230179 cases from the CDC AIDS Reporting System and described 47 ICL patients. 2,3 Of these cases, only 3 (6%) were asymptomatic. Screening of healthy blood donors confirmed a low prevalence of ICL of 0.2%-0.6%. 4,5 The disease may have a transient nature over the years but mostly persists. 3 The immunologic parameters of ICL consist of a prolonged decrease in CD4 ϩ T cell numbers, sometimes with a concomitant decrease in CD8 ϩ T cells and B cells as well. Immunoglobulin levels are normal, 2-5 which helps to distinguish ICL from Common Variable Immunodeficiency (CVID). 1,6 Although function declines with age, thymic output is well maintained into late adulthood. 7-9 Thymic size correlates with numbers of CD4 ϩ CD45RA ϩ naive T cells. At very young age T lymphocytopenia is often caused by congenital defects resulting in severe combined immunodeficiency syndromes (SCID). 10 Null mutations in RAG1 or RAG2 account for 70% of SCID cases with the classic T Ϫ B Ϫ SCID phenotype. 10 Hypomorphic mutations with residual RAG activity occur in typical Omenn syndrome, 10 or rare cases with lympocytopenia, hypogammaglobulinemia, granulomas in the skin, mucosa, internal organs and viral complications, including EBV-related lymphomas. 11,12 In the present paper, we describe hypomorphic RAG1 mutations that corresponds with mild CD4 ϩ T lymphocytopenia, normal in vitro lymphocyte function and in vivo vaccination responses. Methods Subjects and blood samplesHeparinized venous blood was collected from healthy (age-matched) donors, patient and family members. The study was approved by the institutional medical ethical committee and informed consent for the research purpose described was obtained from the parents of the child and age-matched controls in accordance with standards of the 1964 declaration of Helsinki. Lymphocyte phenotypingAbsolute numbers of T cells, B cells, and NK cells were determined with Multitest 6-color (FACSCantoII; BD-Biosciences). For T-and B-cell subset analysis directly conjugated monoclonal antibodies (MoAbs) ...

DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia

“…1,2 ICL is most frequently diagnosed in adults, although pediatric cases have been reported. [2][3][4][5] Patients may show opportunistic infections as a result of a profound deficiency in cellmediated immune responses. 2,6,7 Although the molecular mechanisms underlying this heterogeneous syndrome are still unclear, loss-offunction mutations have been described for genes encoding various regulators of T-cell receptor (TCR) diversity and signaling.…”

A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia

“…This is best illustrated by RAG (recombination activating gene) mutations, which produce variable immune defects. 8,28,29 Complete RAG deficiency with no (Ͻ 1% of wild type) recombination activity is associated with classic SCID and absence of T and B cells. In RAG deficiency with minimal residual activity (Ͼ 1% recombination activity of wild type), several clinical and immunologic phenotypes have been described: (1) classic Omenn syndrome with skin inflammation and ␣-␤ T-cell expansion; (2) incomplete Omenn syndrome with skin inflammation and without T-cell expansion; (3) RAG deficiency with ␥-␦ T-cell expansion; (4) RAG deficiency with granulomas; and (5) ICL.…”

“…The described patients had defects in the magnesium transporter gene (MAGT1) or the recombination activating gene 1 (RAG1). 7,8 Here we characterize a mutation in the Unc119 gene as a novel genetic defect in ICL. Unc119 is a signaling adaptor protein which is essential for activation of the key T-cell tyrosine kinase Lck.…”

Non-HIV AIDS presenting with adrenal histoplasmosis and pulmonary tuberculosis: a mesmerising case report and discussion

“…3 In an immunodeficiency syndrome featuring warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM), mutations of the chemokine receptor CXCR4 leading to neutropenia and immunodeficiency were recognized. 4 Other possible mechanisms proposed in the pathogenesis of ICL have been suggested to be in the Fas & Fas ligand, 5 enhanced apoptotic deletion of T-cells, 6 defective thymic maturation of T-cells, 7 reduction in the p56 (Lck) kinase activity, 8 reduced responsiveness of the circulating Tcells to IL-7 (may be due to IL-7 receptor defect), 9 RAG1 & RAG2 gene mutations, 10 a defect in the MAGT 1 (magnesium transporter gene), 11 defective production of TNF-alpha & IFN-gamma, 12 and a heterozygous dominant negative mis-sense mutation of the signalling adaptor protein Uncoordinated 119 (Unc119) that disrupts the association between Lck (lymphocyte specific kinase) and TCR (T-cell receptor). 13 Currently there are no definite treatment options for this novel condition and treatment is generally aimed at preventing infections and malignancies by prophylactic antibiotics and medications as used in a case of HIV infected patient.…”