Idiopathic CD4+ lymphocytopenia and systemic vasculitis

The syndrome defined as 'idiopathic CD4 lymphocytopenia' (ICL) is a rare disease of unknown aetiology, often associated with severe depression of immune defences and the occurrence of opportunistic infections. A case is reported wherein a severe immunodeficiency syndrome with persistent idiopathic CD4+ lymphopenia developed in a woman suffering from systemic microscopic polyarteritis; no signs of HIV 1/2 or HTLV I/II infection were evident. The patient died of widespread opportunistic infections. The association of ICL with vasculitis has never been reported until now. A link between the two diseases cannot be ruled out.     

Idiopathic CD4+ lymphocytopenia and juvenile laryngeal papillomatosis

We report on an association of idiopathic CD4+ lymphocytopenia (ICL) and juvenile laryngeal papillomatosis (JLP) in a pediatric-aged patient. Because of a past medical history of recurrent lung infections and severe chickenpox in infancy, immunologic investigations were done at age 6 years. On several occasions, a CD4+lymphocyte count of <300 cells/mm3 was detected, supporting the diagnosis of ICL. During follow-up, both medical (interferon-alpha) and surgical treatments of JLP were only partially efficient. Our patient developed disseminated infection with Mycobacterium avium and died at 10 years of age. Human papillomavirus is an important pathogen in pediatric and adult patients with ICL. In pediatric patients with JLP who develop other unusually severe viral or opportunistic infections, immunological investigations should be considered.     

Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors

Idiopathic CD4(+) lymphocytopenia (ICL) is a rare non-HIV-related syndrome with unclear natural history and prognosis. This prospective natural history cohort study describes the clinical course, CD4 T lymphocyte kinetics, outcome, and prognostic factors of ICL. Thirty-nine patients (17 men, 22 women) 25 to 85 years old with ICL were evaluated between 1992 and 2006, and 36 were followed for a median of 49.5 months. Cryptococcal and nontuberculous mycobacterial infections were the major presenting opportunistic infections. Seven patients presented with no infection. In 32, CD4 T-cell counts remained less than 300/mm(3) throughout the study period and in 7 normalized after an average of 31 months. Overall, 15 (41.6%) developed an opportunistic infection in follow-up, 5 (13.8%) of which were "AIDS-defining clinical conditions," and 4 (11.1%) developed autoimmune diseases. Seven patients died, 4 from ICL-related opportunistic infections, within 42 months after diagnosis. Immunologic analyses revealed increased activation and turnover in CD4 but not CD8 T lymphocytes. CD8 T lymphocytopenia (< 180/mm(3)) and the degree of CD4 T cell activation (measured by HLA-DR expression) at presentation were associated with adverse outcome (opportunistic infection-related death; P = .003 and .02, respectively).     

Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7

Idiopathic CD4+ T lymphocytopenia (ICL) is a rare heterogeneous disorder defined by CD4+ T-cell counts below 300 cells/muL in the absence of human immunodeficiency virus (HIV) infection or other known immune deficiency disorders. Here, we report the expansion of immature/transitional B cells in patients with ICL, which is associated with elevated serum levels of IL-7. Both the percentage of immature/transitional B cells and levels of IL-7 were inversely correlated with levels of CD4+ T-cell counts and directly correlated to each other. Further analyses of B cells indicated that, in contrast to the activating effects of HIV disease on mature B cells, the expansion of immature/transitional B cells in patients with ICL occurred at the expense of memory B cells. These findings extend previous reports on primary immunodeficiencies as well as HIV disease by suggesting that CD4+ T-cell lymphopenia has an impact on human B-cell development either directly or indirectly via the associated elevation of IL-7 levels.     

Restriction of T-cell receptor repertoires in idiopathic CD4+ lymphocytopenia

We report that alpha/beta and gamma/delta T-cell repertoires of three patients with idiopathic CD4+ 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+ 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.     

Overexpression of Fas/CD95 and Fas-induced apoptosis in a patient with idiopathic CD4+ T lymphocytopenia.

The mechanisms of apoptosis have become better understood, in part with the discovery of Fas/CD95. We report the case of a patient characterized by a decreased CD4+ T cell count and an overexpression of Fas/CD95 resulting in apoptosis. A 54-year-old man presented with disseminated Mycobacterium xenopi infection. Analysis showed CD4+ T lymphopenia. Tests for human immunodeficiency virus (HIV) types 1 and 2 were negative. We compared the patient with eight healthy controls and five HIV-infected patients in terms of the expression of Fas/CD95 and Fas-mediated apoptosis of peripheral T lymphocytes. The percent of CD95+ cells in lymphocytes was 98% for the patient, and the mean percent of CD95+ cells in lymphocytes +/- SD for HIV-infected patients and healthy controls was 75% +/- 16% and 36% +/- 26%, respectively. The patient had a high level of spontaneous apoptosis, and apoptotic cells were all identified as being CD4+ T cells. Monoclonal antibodies to CD95 dramatically increased apoptosis of CD4+ T cells exclusively. CD4+ T lymphopenia observed in our patient correlated with an overexpression of Fas together with spontaneous and Fas-induced apoptosis.     

Treatment of post-pneumonic empyema thoracis

OBJECTIVE: The present study evaluates the management of 65 consecutive patients with post-pneumonic empyema thoracis (PET) treated in our department during the last ten years. MATERIALS: There were 51 male (78.5 %) and 14 female (21.5 %) aged 23 - 82 years. The initial cause of PET was pneumonia (postoperative and posttraumatic empyemas were excluded). In 2 cases, a bronchopleural fistula coexisted. Diagnosis was based on clinical, radiological and pleural fluid culture findings. Pneumonococci and staphylococci were the predominant bacterial isolates in our series. RESULTS: Tube thoracostomy drainage (TS) was performed in all our patients. Forty-nine patients (75.4 %) were successfully treated with TS alone. The other 16 patients were submitted to thoracotomy: lung decortication (n = 14) along with segmentectomy in two cases and the Eloesser procedure, also in two cases. The mortality rate reached 9.2 % (n = 6). Septic shock, multiple organ failure, cardiac insufficiency, and end-stage renal failure were the causes. CONCLUSIONS: 1. Complete drainage and full lung expansion by tube thoracostomy with suction are essential in the management of post-pneumonic empyema thoracis. Surgery should only be carried out right away if these conditions are not achieved. 2. Despite clinical experience and the major strategies and procedures available, the mortality remains high.     

Cryptococcosis and idiopathic CD4 lymphocytopenia

We reviewed the cases of 11 patients with cryptococcosis and idiopathic CD4 lymphocytopenia (ICL) referred to our institution in the previous 12 years, as well as 42 similar cases reported in the literature, to assess the characteristics of the infection in this population. Cryptococcosis in 53 patients with ICL had features in common with cryptococcosis in previously normal patients. ICL patients had a slight male predominance (1.2:1) and a median age of presentation of 41 years (range, 4.5-85 yr). Initial cerebrospinal fluid findings showed glucose below 40 mg/dL in 60% of the patients, a median pleocytosis of 59 white blood cells/mm (range, 0-884), and protein of 156 mg/dL (range, 25-402 mg/dL). The median CD4 count at diagnosis of ICL and at the last available measurement was 82 (range, 7-292) and 132 (range, 13-892) cells/mm, respectively, for an average follow-up of 32 months in 46 patients. Unlike previously normal patients with cryptococcosis, those with ICL had an excess incidence of dermatomal zoster (7 episodes in 46 ICL cases). Pneumocystis pneumonia was rare (1 case), casting doubt on the need for prophylaxis in patients with ICL. A favorable outcome (cured or improved) may be more common in ICL patients than in previously normal patients with cryptococcal meningitis and no predisposing factors. Identification of ICL in patients who were apparently normal before the onset of cryptococcosis appears to be useful because it predicts a favorable outcome. Patients with cryptococcal infection and ICL have an increased likelihood of developing dermatomal zoster. The long-term follow-up of these patients offers some reassurance regarding favorable prognosis.     

Outcome of pediatric empyema thoracis managed by tube thoracostomy

The proper management of empyema thoracis in children continues to be a source of debate. This study assessed the clinical profile and outcome of patients managed by tube thoracostomy. Chart review was performed in 31 patients managed from January 1989 to December 2003. Outcome measures were duration and outcome of thoracostomy, number of days to radiologic lung re-expansion, length of hospitalization, and microbiologic flora involved. The mean age was 9 years (male/female, 2:1) and the most commonly affected group were those aged 1 year and below. Staphylococcus aureus was the most frequent infecting organism. A few (6%) achieved lung re-expansion 1 week postoperatively, but 64% did not achieve full lung re-expansion even after 3 weeks. Most (71%) of the thoracostomies were converted to open drainage. Half (52%) of the patients were hospitalized for at least 5 weeks. There were 3 recurrences and 3 deaths, 2 of which were most likely associated with empyema. Empyema managed by tube thoracostomy alone showed evidence of delayed lung re-expansion, prolonged drainage and hospitalization, and unfavorable outcome.     

CD25+CD4+ T cells contribute to the control of memory CD8+ T cells

Previously we demonstrated that IL-15 and IL-2 control the number of memory CD8+ T cells in mice. IL-15 induces, and IL-2 suppresses the division of these cells. Here we show that CD25+CD4+ regulatory T cells play an important role in the IL-2-mediated control of memory phenotype CD8+ T cell number. In animals, the numbers of CD25+CD4+ T cells were inversely correlated with the numbers of memory phenotype CD8+ T cells with age. Treatment with anti-IL-2 caused CD25+CD4+ T cells to disappear and, concurrently, increased the numbers of memory phenotype CD8+ T cells. This increase in the numbers of CD8+ memory phenotype T cells was not manifest in animals lacking CD4+ cells. Importantly, adoptive transfer of CD25+CD4+ T cells significantly reduced division of memory phenotype CD8+ T cells. Thus, we conclude that CD25+CD4+ T cells are involved in the IL-2-mediated inhibition of memory CD8+ T cell division and that IL-2 controls memory phenotype CD8+ T cell numbers at least in part through maintenance of the CD25+CD4+ T cell population.     

Detection of CD4(+) T-cell antibodies in a patient with idiopathic CD4 T lymphocytopenia and cryptococcal meningitis

Idiopathic CD4(+) T lymphocytopenia (ICL) is defined as a CD4(+) T-cell count <0.3 x 10(9)/l or <20% of the total T-cell count on two occasions in the absence of any immunodeficiency disorder or therapy associated with reduced CD4(+) T-cell count. Although several mechanisms of ICL have been reported, the pathophysiology is still largely unknown. This case report describes a patient who presented with cryptococcal meningitis and was subsequently discovered to meet the criteria for ICL. Flow cytometric analysis of the patient's peripheral blood mononuclear cells revealed antibodies coating a much larger proportion of his CD4(+) T cells (33.61%) than the CD4(+) T cells of normal donors (3.94 +/- 1.77%). The reasons behind the development of these autoantibodies are explored.     

Non-myeloablative hematopoietic stem cell transplantation in the treatment of severe idiopathic CD4+ lymphocytopenia

A 40‐year‐old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunistic infections was successfully treated with non‐myeloablative allogeneic hematopoietic stem cell transplantation. After conditioning with fludarabine plus low dose of total‐body irradiation, CD34+ peripheral blood stem cells obtained by leukapheresis from his HLA‐identical sister were infused. T cell and myeloid complete chimerism was achieved at day +28 and remained stable during the follow‐up period. The patient did not develop infectious complications during the procedure. At 35 months of follow‐up, his CD4+ T cell count was 1019 cells per microliter. Non‐myeloablative allogeneic hematopoietic stem cell transplantation should be considered a treatment option for patients with severe forms of idiopathic CD4+ lymphocytopenia.     

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

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-Vβ repertoire was polyclonal with a very low content of T-cell receptor excision circles (TRECs). Kappa-deleting recombination excision circles (KRECs) were also abnormal in the B cells. Both reflect extensive in vivo proliferation. Patient-derived CD34+ hematopoietic stem cells could not repopulate RAG2(-/-)IL2Rγc(-/-) mice, indicating the lymphoid origin of the defect. We identified 2 novel missense mutations in RAG1 (p.Arg474Cys and p.Leu506Phe) resulting in reduced RAG activity. This report gives the first genetic clue for ICL and extends the clinical spectrum of RAG mutations from severe immune defects to an almost normal condition.     

支气管哮喘大鼠CD4+CD25+T细胞的变化及地塞米松干预作用的研究

目的 研究支气管哮喘(简称哮喘)大鼠模型支气管肺泡灌洗液(BALF)、血液、脾脏CD4+CD25+T细胞的变化,及地塞米松对CD4+CD25+T细胞的影响.方法 50只SD大鼠随机分为5组,空白对照(A)组,哮喘(B)组,地塞米松1(C)组、地塞米松2(D)组,地塞米松3(E)组.A组第l天给予腹腔注射生理盐水l ml,第15～21天每天给予生理盐水雾化.B、C、D、E组用卵蛋白建立哮喘大鼠模型,第1天,每只大鼠腹腔注射抗原l ml(卵蛋白1 mg+灭活百日咳杆菌9×106个+氢氧化铝干粉100 mg)混悬液,第15～21天给予1%的卵蛋白雾化30 min,C、D、E组于雾化后分别给予腹腔注射地塞米松0.2 mg/kg、1 mg/kg、2 mg/kg.采用流式细胞仪检测的方法 ,观察大鼠体内BALF、外周血、脾脏CD4+CD25+T细胞的变化及使用不同剂量地塞米松后对其的影响.结果 B组BALF、外周血、脾脏CD4+CD25+T细胞表达占CD4+T细胞的百分比分别是(42.21±5.62)%、(12.69±2.70)%、(11.15±1.05)%,A组结果 分别是(18.76±5.85)%、(6.21±1.73)%、(7.85±2.13)%.B组与A组比较,差异均具有统计学意义(P＜0.01,P＜0.01,P＜0.05);C组、D组、E组BALF中CD4+CD25+T细胞占CD4+T细胞的百分比表达分别是(10.49±4.03)%、(13.28±5.12)%、(7.51±5.39)%,显著低于A组和B组,(P＜0.05,P＜0.01);外周血中,C组(6.03±1.43)%、D组(4.88±0.95)%与A组(6.21±1.73)%比较,差异无统计学意义,E组(3.49±0.62)%与C组、A组比较,差异有统计学意义(P＜0.05).脾脏中,C组(7.25±1.82)%、D组(8.63±3.18)%与A组(7.85±2.13)%比较,差异无统计学意义,E组(3.38±1.37)%与C组、D组、A组比较,差异有统计学意义(P＜0.05).结论 CD4+CD25+T细胞在哮喘大鼠体内有明显的优势表达,可能是哮喘发病的机制之一.地塞米松可以抑制CD4+CD25+T细胞的表达.BALF内CD4+CD25+T细胞的变化与外周血和脾脏的变化具有一致性,监测外周血或脾脏CD4+CD25+T细胞变化可了解肺部情况.     

支气管哮喘大鼠CD4^＋CD25^＋T细胞的变化及地塞米松干预作用的研究

目的研究支气管哮喘（简称哮喘）大鼠模型支气管肺泡灌洗液（BALF）、血液、脾脏CD4^＋CD25^＋T细胞的变化,及地塞米松对CD4^＋CD25^＋T细胞的影响。方法50只SD大鼠随机分为5组,空白对照（A）组,哮喘（B）组,地塞米松1（C）组、地塞米松2（D）组,地塞米松3（E）组。A组第1天给予腹腔注射生理盐水1ml,第15～21天每天给予生理盐水雾化。B、C、D、E组用卵蛋白建立哮喘大鼠模型,第1天,每只大鼠腹腔注射抗原1ml（卵蛋白1mg＋灭活百日咳杆菌9×10。个＋氢氧化铝干粉100mg）混悬液,第15～21天给予1％的卵蛋白雾化30min,C、D、E组于雾化后分别给予腹腔注射地塞米松0．2mg／kg、1mg／kg、2mg／kg。采用流式细胞仪检测的方法,观察大鼠体内BALF、外周血、脾脏CD4^＋CD25^＋T细胞的变化及使用不同剂量地塞米松后对其的影响。结果B组BALF、外周血、脾脏CD4^＋CD25^＋T细胞表达占CD4^＋T细胞的百分比分别是（42．21±5．62）％、（12．69±2．70）％、（11．15±1．05）％,A组结果分别是（18．76±5．85）％、（6．21±1．73）％、（7．85±2．13）％。B组与A组比较,差异均具有统计学意义（P〈0．01,P〈0．01,P〈0．05）;C组、D组、E组BALF中CD4^＋CD25^＋T细胞占CD4^＋T细胞的百分比表达分别是（10．49±4．03）oA、（13．28±5．12）％、（7．51±5．39）％,显著低于A组和B组,（P〈0．05,P〈0．01）;外周血中,C组（6．03±1．43）％、D组（4．88±0．95）％与A组（6．21±1．73）％比较,差异无统计学意义,E组（3．49士0．62）％与C组、A组比较,差异有统计学意义（P〈0．05）。脾脏中,c组（7．25±1．82）%、D组（8．63±3．18）％与A组（7．85±2．13）％比较,差异无统计学意义,E组（3．38±1．37）％与C组、D组、A组比较,差异有统计学意义（P〈0．05）。结论CD4^＋CD25^＋T细胞在哮喘大鼠体内有明显的优势表达,可能是哮喘发病的机制之一。地塞米松可以抑制CD4^＋CD25^＋T细胞的表达。BALF内CD4^＋CD25^＋T细胞的变化与外周血和脾脏的变化具有一致性,监测外周血或脾脏CD4^＋CD25^＋T细胞变化可了解肺部情况。     

CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients

A proportion of cancer patients naturally develop CD4+ T-helper type 1 (Th1) cell responses to NY-ESO-1 that correlate with anti-NY-ESO-1 serum antibodies. To address the role of T-cell regulation in the control of spontaneous tumor immunity, we analyzed NY-ESO-1-specific Th1 cell induction before or after depletion of CD4+CD25+ T cells in vitro. While Th1 cells were generated in the presence of CD25+ T cells in cancer patients seropositive for NY-ESO-1, seronegative cancer patients and healthy donors required CD25+ T-cell depletion for in vitro induction of NY-ESO-1-specific Th1 cells. In vitro, newly generated NY-ESO-1-specific Th1 cells were derived from naive precursors, whereas preexisting memory populations were detectable exclusively in patients with NY-ESO-1 antibody. Memory populations were less sensitive than naive populations to CD4+CD25+ regulatory T cells. We propose that CD4+CD25+ regulatory T cells are involved in the generation and regulation of NY-ESO-1-specific antitumor immunity.