Hereditary CD4+ T lymphocytopenia

Internal Medicine, 2009

Idiopathic CD4+ T-lymphocytopenia (ICL) is a new disease entity characterized by CD4+ T-lymphocyte depletion without evidence of HIV infection. We report a 27-year-old ICL patient with a long history of multiple immune abnormalities. His CD4+ T-lymphocyte count started to decrease after generalized lymphadenopathy of an unknown cause at age 3. He satisfied the criteria for ICL at age 9, and the decreased CD4+ Tlymphocyte count persisted for more than 18 years. This is probably the first childhood-onset ICL case in which the trigger event for the development was known together with the patient's autoimmune background.

2010

Down syndrome (DS) is known for increased incidence of respiratory infections and autoimmune diseases, indicating impaired immunity. Until now, attention has been mainly focused on T lymphocytes. Therefore, we determined B-lymphocyte subpopulations in 95 children with DS compared with 33 age-matched control (AMC) children. DS serum immunoglobulin levels were compared with 962 non-DS children with recurrent infections. The results were combined with clinical data. Transitional and naive B lymphocytes are profoundly decreased in the children with DS. This could be caused by an intrinsic B-lymphocyte defect resulting in (partial) failure of B-lymphocyte generation, decreased antigen-induced proliferation and/or increased apoptosis, or by decreased proliferation due to deficient T-lymphocyte help, or a combination of these. The decreased CD27 ϩ , CD21 high , and CD23 ϩ cells are reminiscent of common variable immunodeficiency and suggestive of disturbed peripheral B-lymphocyte maturation. Immunoglobulin levels in DS are abnormal-as has been described before-and different from non-DS children with recurrent infections. We conclude that the humoral immune system is abnormal in DS, but could not find a relation between B-lymphocyte subsets, immunoglobulins and clinical features of the children with DS in our cohort, nor could we answer the question whether DS lymphocytes are truly intrinsically deficient, or could all findings be explained by deficient Tlymphocyte help. (Pediatr Res 67: 563-569, 2010) D own syndrome (DS) is associated with recurrent-mainly respiratory-infections (1,2), decreased responses to vaccination (3-8), a higher frequency of hepatitis B surface antigen carriers (3), and autoimmune diseases such as celiac disease and hypothyroidism (9-11). These features are suggestive of immunodeficiency. Until now, medical attention has been mainly focused on the thymic alterations and decreased absolute numbers of T lymphocytes in peripheral blood (12,13). We recently showed that a striking B lymphocytopenia is present from the very beginning in patients with DS (14). This B lymphocytopenia could be due to an intrinsic B-lymphocyte defect, a deficient T-lymphocyte help, or a combination of these. An intrinsic B-lymphocyte defect could be due to (partial) failure of B-lymphocyte generation, decreased antigen-induced proliferation, and/or increased apoptosis. Deficient T-lymphocyte help could lead to disturbed B-lymphocyte activation and proliferation. Despite the B lym-phocytopenia, a considerable hypergammaglobulinemia of IgA and IgG after the age of 5 y, with high levels of IgG 1 and IgG 3 and low levels of IgG 2 and IgG 4 , is described (3,15,16). This combination of profound B lymphocytopenia and hypergammaglobulinemia favors a disturbance in T-lymphocyte help, with the possibility that immunoglobulins are oligoclonal in DS, and specific T-cell-dependent antibody responses inadequate. The latter has indeed been described (3,15). However, the T-cell-independent antibody response to pneumococcal polysaccharide antigen is also decreased in DS (4), suggesting an intrinsic B-lymphocyte defect is also present. We studied B-lymphocyte subpopulations in relation to relevant clinical features in 95 children with DS, to further unravel this question. METHODS Study population. From 95 noninstitutionalized children with DS (49 boys; Fig. 1), either visiting the Jeroen Bosch Hospital, 's-Hertogenbosch or the Rijnstate Hospital, Arnhem, the Netherlands, an extra 3 mL of EDTA and 7 mL of blood without additive was drawn during routine follow-up of thyroid function after parental informed consent. All children were otherwise healthy at the time of sampling. Leftover EDTA blood from 33 healthy age-matched control (AMC) children who underwent venipuncture, e.g. preoperative screening for minor surgery, was used as control. We retrospectively collected the titers of serum IgG, IgA, and IgM that were determined for diagnostic purposes in 962 non-DS patients suffering from recurrent infections (younger than 21 y) between January 2006 and July 2008 in the Jeroen Bosch Hospital, 's-Hertogenbosch, and the Bernhoven Hospital, Oss/Veghel, The Netherlands. In 285 of the 962 patients, IgGsubclasses were also determined. The study was approved by the local Medical Ethics Committees of both hospitals. Immunophenotyping. Three-color flow cytometric immunophenotyping was performed to determine B-lymphocyte subpopulations in children with both DS and AMC using the lysed whole-blood method. FITC, phycoerythrin (PE), and PE-cyanine 5 (PE-Cy5)-conjugated antibodies were used with the following antigen specificity:

Frontiers in Pediatrics, 2017

Newborn screening for severe combined immunodeficiency has proven successful in identifying infants with T-cell deficiencies before they become severely ill. Additionally, the newborn screen can detect subtle early phenotypes that may become severe later in life. We present the case of siblings with features suggestive of T-cell lymphopenia identified as having low T-cell receptor excision circles counts by newborn screening. Expanded immune testing showed robust lymphocyte mitogen and antigen responses with normal vaccine responses and immunoglobulin levels for both boys over time. Genetic analysis revealed an Xq13.1 duplication in each child not found in the mother. The variant is downstream of the IL2RG gene with potential regulatory significance, suggesting a mechanism for the T-cell lymphopenia. The newborn screen provided these patients heightened surveillance and patient-specific management, including delayed live vaccines and Pneumocystis jiroveci pneumonia prophylaxis. Fortunately, the brothers have not suffered invasive or opportunistic infections and are well at ages 3 and 4 years. In this report, we illustrate the challenges of managing seemingly asymptomatic immunodeficient patients without a definitive genetic diagnosis and show how unbiased genetic analysis can expand understanding about primary immunodeficiency phenotypes.

Arthritis Research & Therapy, 2012

Idiopathic CD4 lymphocytopenia (ICL) was described in 1992 as an immunodefi ciency syndrome characterized by opportunistic infections and low CD4 T-cell counts in the absence of HIV infection. Despite the 20 years that have elapsed, the clinical spectrum, pathogenesis, and possible treatment for ICL remain obscure. Here, we attempt to summarize the salient features of this condition on the basis of the available literature to date.

Clinical Immunology and Immunopathology, 1982

The case of an infant female with severe infections and failure to thrive is reported. Immunological workup demonstrated a severe combined immunodeficiency with normal numbers of circulating T and B lymphocytes. Studies of T-cell subsets showed an absence of T,+ cells, while the percentage of T4+ exceeded that of T3+ cells. Functional studies of the T4+ subset demonstrated lack of helper activity. When cocultured with normal T cells, B cells from the patient produced in vitro subnormal amounts of IgM, but practically no quantities of IgG and IgA. A lymph node biopsy showed a preserved T-cell-dependent area. Possible pathogenetic mechanisms are discussed.

European Journal of Case Reports in Internal Medicine, 2020

We report the case of a 23-year-old woman evaluated for asthenia and lymphocytopenia. Clinical examination was unremarkable but laboratory tests showed the presence of CD4 lymphocytopenia. Secondary causes of CD4 lymphocytopenia were ruled out and a previous diagnosis of idiopathic CD4+ T-cell lymphocytopenia was retained. CD4 lymphocytopenia has persisted for 11 years now but the patient has been clinically asymptomatic. LEARNING POINTS CD4+ T-cell lymphocytopenia needs to be meticulously evaluated and secondary causes ruled out. The patient has been clinically asymptomatic for 11 years. Measurement of CD4 subsets twice yearly seems to be appropriate.

Medicine, 2014

Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe condition with limited available data. We conducted a French multicenter study to analyze the clinical and immunologic characteristics of a cohort of patients with ICL according to the Centers for Disease Control criteria. We recruited 40 patients (24 female) of mean age 44.2 T 12.2 (19Y70) years. Patients underwent T-lymphocyte phenotyping and lymphoproliferation assay at diagnosis, and experiments related to thymic function and interferon (IFN)-F release by natural killer (NK) cell were performed. Mean follow-up was 6.9 T 6.7 (0.14Y24.3) years. Infectious, autoimmune, and neoplastic events were recorded, as were outcomes of interleukin 2 therapy. In all, 25 patients had opportunistic infections (12 with human papillomavirus infection), 14 had autoimmune symptoms, 5 had malignancies, and 8 had mild or no symptoms. At the time of diagnosis, the mean cell counts were as follows: mean CD4 cell count: 127/mm 3 (range, 4Y294); mean CD8: 236/mm 3 (range, 1Y1293); mean CD19: 113/mm 3 (range, 3Y547); and mean NK cell count: 122/mm 3 (range, 5Y416). Most patients had deficiency in CD8, CD19, and/or NK cells. Cytotoxic function of NK cells was normal, and patients with infections had a significantly lower NK cell count than those without (p = 0.01). Patients with autoimmune manifestations had increased CD8 T-cell count. Proliferation of thymic precursors, as assessed by T-cell rearrangement excision circles, was increased. Six patients died (15%). CD4 T-cell count G150/mm 3 and NK cell count G100/mm 3 were predictors of death. In conclusion, ICL is a heterogeneous disorder often associated with deficiencies in CD8, CD19, and/or NK cells. Long-term prognosis may be related to initial CD4 and NK cell deficiency.

Blood, 2011

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.

British Journal of Haematology, 2000

We report that a/b and g/d T-cell repertoires of three patients with idiopathic CD4 1 lymphocytopenia, who showed different clinical manifestations and outcomes over time, were highly restricted. The disruption of T-cell repertoires does not influence the susceptibility to infections: the first patient was unable to attain a protective response to mycobacterium, the second showed clinical improvement and the third did not develop opportunistic infections. These results indicate that idiopathic CD4 1 lymphocytopenia could give rise to mono-/ oligoclonal T-cell expansions, but the degree of repertoire disturbance is not indicative of the severity of disease progression.

Journal of Clinical and Diagnostic Research, 2017