Idiopathic CD4 Lymphocytopenia Patients Research Articles

Preserved MAIT cell numbers and function in idiopathic CD4 lymphocytopenia.

Mucosal-associated invariant T (MAIT) cells constitute a subset of unconventional, MR1-restricted T-cells involved in antimicrobial responses as well as inflammatory, allergic and autoimmune diseases. Chronic infection and inflammatory disorders as well as immunodeficiencies are often associated with decline and/or dysfunction of MAIT cells. Herein, we investigate the MAIT cells in patients with idiopathic CD4 + lymphocytopenia (ICL), a syndrome characterized by consistently low CD4 T-cell counts (<300 cell/µL) in the absence of HIV infection or other known immunodeficiency, and by susceptibility to certain opportunistic infections. The numbers, phenotype and function of MAIT cells in peripheral blood were preserved in ICL patients compared to healthy controls. Furthermore, administration of IL-7 to ICL patients expanded the CD8 + MAIT cell subset, with maintained responsiveness and effector functions after IL-7 treatment. In conclusion, ICL patients maintain normal levels and function of MAIT cells preserving some antibacterial responses despite the deficiency in CD4 + T cells.

Prominent antibody mediated auto-immune response in idiopathic CD4 lymphopenic patients

Abstract Patients with Idiopathic CD4 Lymphocytopenia (ICL) have low circulating CD4 T cell numbers, accompanied sometimes by low numbers of CD8, B and/or NK cells, making them susceptible to opportunistic infections. The etiology is unknown and there is no familiar linkage. In spite of their immune deficiency 32% of ICL patients have clinically defined auto-immune disease. To analyze the presence of auto-antibodies in these patients we hybridized sera from 34 patients and 15 healthy control (HC) to a 9,000 proteins human array. When identifying positive targets as the ones with Z score ≥4 we found that all 34 ICL patients, unrelated to their autoimmune disease manifestations, had IgG antibodies against tens of proteins while the HC had none. There was considerable variability in both numbers and identities of targets. We next evaluated whether some of these antigens might be displayed on the T cell membrane. Using a flow-based assay we tested sera from 72 ICL patients and found that 50% of them had either IgG, mostly but not exclusively IgG1 and/or IgG4 isotypes, or IgM antibodies against T cell membrane proteins. Functionally, 50% of the plasma with IgG1 or IgG3 antibodies induced antibody dependent cell mediated cytotoxicity against healthy T-lymphocytes. In addition, sera from 20% of the patients with anti-lymphocyte antibodies induced complement deposition on healthy CD3 T cells and some of them induced complement dependent cytotoxicity. Furthermore, we observed complement deposition (C1q, C4c and C3b) on CD4 T cells in 14% of the 72 ICL patients when analyzed directly ex vivo. Our data support a high prevalence and pathogenicity of autoantibodies in ICL, which offers a potential therapeutic target.

Idiopathic lymphocytopenia.

Idiopathic CD4⁺ lymphocytopenia (ICL) is defined by the reduction of the main lymphocyte subtype in peripheral blood and CD4⁺ T cells below 300/μl in the absence of any secondary known causes of lymphopenia, including viral causes. The present review aims to state the latest available data on clinical, pathological and therapeutic aspects related to ICL, published from 1990 to 2014. The last observed clinical presentation and complications of ICL patients are described. The latest findings and possible mechanisms involved in the development of ICL features are included in the present review; however, pathogenesis of ICL has remained mainly obscured. Finally, recent therapeutic efforts considered in ICL patients are discussed. In spite of the serious complications ICL has on the patients' quality of life, data on clinical, etiopathological and therapeutic behavior for ICL are very limited. On one side, an abnormal blood cell count may be the sole presentation; however, occurrence of disseminated malignant tumors is not uncommon in patients. Recent findings highlight the role of cytokines, especially interleukin-2, on features such as phenotype severity and responsiveness of the condition to therapy. In addition, some studies have suggested that a defect in hematopoietic stem cells may be involved in disease progression, an idea that is supported by the success of bone marrow transplantation in acquiring persistent remissions in ICL patients. ICL is a hematologic condition of increasing importance due to its diverse clinical and pathological spectrum. Molecular studies have shown the presence of mutations involved in lymphocyte development as potential factors that may contribute to ICL occurrence. ICL patients could present either with common infections or really serious malignant conditions. The role of cytokines, especially interleukin-2, has emerged as one of the main possible mechanisms involved in clinical and pathological behavior of ICL. Today, the main therapeutic approaches are controlling life-threatening infections and underlying disorders along with efforts to cure ICL through rising CD4⁺ cell counts using cytokine interventions and transplantation.

Severe Pneumocystis jirovecii pneumonia in an idiopathic CD4+ lymphocytopenia patient: case report and review of the literature.

Introduction:When diagnosing Pneumocystis jirovecii pneumonia (PJP), the clinical suspicion must be confirmed by laboratory tests. PJP is rarely described in patients with idiopathic CD4+ lymphocytopenia (ICL), a rare T-cell deficiency of unknown origin with persistently low levels of CD4+ T-cells (<300 µl−1 or <20 % of total lymphocytes) but repeated negative human immunodeficiency virus (HIV) tests. We retrospectively analysed a case of an ICL patient with severe PJP associated with multiple opportunistic infections (OIs). We also reviewed the literature since 1986.Case presentation:A laboratory-confirmed case of PJP associated with invasive candidiasis and cytomegalovirus infection was reported in an ICL patient. Despite early treatment, the patient died of respiratory failure under polymicrobial pneumonia. According to the literature, the mortality rate of ICL patients is 10.4 % (33/316). In ICL patients, the risk of OI is 83.2 % (263/316), with viral infections being the most prevalent (58.2 %, 184/316), followed by fungal infections (52.2 %, 165/316) and mycobacterial infections (15.5 %, 49/316). Dysimmunity is reported in 15.5 % (49/316) of ICL patients. Among the fungal infections, cryptococcal infections are the most prevalent (24.1 %, 76/316), followed by candidiasis (15.5 %, 49/316) and PJP (7.9 %, 25/316).Conclusions:The high risk of OIs underlines the importance of more vigorous preventative actions in hospitals. The response to therapy and the detection of early relapse of PJP may be monitored by several laboratory tests including quantitative PCR. It is essential to treat the ICL and to follow the guidelines concerning therapy and prophylaxis of OIs as given to HIV patients.

Use of humanized mouse models for the study of idiopathic CD4 lymphocytopenia (HUM7P.313)

Abstract Patients with Idiopathic CD4 Lymphocytopenia (ICL) have low circulating CD4 T-cell counts and develop opportunistic diseases and papillomavirus-related dysplasia. The etiology of ICL is unknown but the low numbers of CD4 T-cells could be explained by decreased thymic production, increased cell death, and/or increased migration or retention of the T cells in secondary lymphoid organs or tissues. To distinguish between these three possibilities we set up a humanized mouse model by transferring either peripheral blood mononuclear cells (PBMC), or Hematopoietic Stem Cells (HSC) from ICL patients or healthy controls (HC) into immune-compromised mice. First, we transferred HC cells into three different strains of mice to identify the most efficient and reproducible host for the human cells. We found that NOD-RAGKO-γcKO (NRG) mice represented the best model, as one to four weeks after transferring PBMC into NRG mice, we reproducibly found human T cells in blood, spleen, lymph node and bone marrow with no graft versus host disease. We next transferred PBMC from either HC or ICL patients into NRG mice to compare survival, expansion, phenotype and migration properties of the human cells. Preliminary results show that mice that received ICL cells developed lymphocytopenia comparable to ICL patients. These data encourage further use of this humanized mouse model to identify the etiology and pathogenesis of ICL and perhaps other human immune-deficiencies that affect T-cell homeostasis.

Evidence of T cell lymphopenia in the colonic mucosa in idiopathic CD4 lymphocytopenia patients (HEM4P.250)

Abstract Idiopathic CD4 lymphocytopenia (ICL) is a syndrome of unknown etiology characterized by low peripheral CD4 T cell counts and susceptibility to opportunistic infections. One hypothesis for its etiology is trapping of T cells in effector sites. 11 ICL patients and 16 healthy controls (HC) underwent colonic biopsies for CD3, CD4, and CD8 T cell enumeration by flow cytometry (FC) and immunohistochemistry (IHC) in lamia propria (LP). Mucosal IL17+ CD4 T cells were assessed after PMA/ionomycin stimulation. Plasma levels of LPS (for microbial translocation), I-FABP (for gut epithelial integrity), sCD14 (for monocyte activation), D-dimer (for coagulation) and CRP, IL-6 and TNFalpha (for inflammation) were tested in 33 ICL patients and 44 HC. ICL patients had fewer CD3 (2.84-fold, P=0.0080), CD4 (3.04-fold, P=0.013) and CD8 (2.28-fold, P=0.043) T cells in the colonic mucosa compared to HC by FC and fewer CD3 (2.31-fold, P=0.036) and CD4 (3.81-fold, P=0.0003) T cells in LP by IHC. The proportion of IL-17+ CD4 T cells was higher in ICL compared to HC (6.04 vs 3.35%, P=0.013). Levels of sCD14 levels were slightly higher in ICL than in HC (1.42 vs 1.21 µg/ml, P=0.003). Levels of LPS, I-FABP, IL-6, TNFalpha, D-Dimer, and CRP levels were not significantly different between ICL and HC (all P&amp;gt;0.05). These data suggest that colonic mucosal lymphopenia accompanies peripheral T cell lymphopenia in ICL, albeit with preserved gut epithelial integrity and a lack of systemic inflammation.

Successful fludarabine‐based hematopoietic stem cell transplantation in a pediatric patient with idiopathic CD4+ lymphocytopenia

Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disease with severe CD4 T-cell depletion, leading to serious opportunistic infections. The optimal treatment of ICL has not been determined, especially in severe form of the disease. Here, we report an eight-yr-old girl with ICL who was successfully treated with fludarabine-based conditioning HSCT. To the best of our knowledge, this is the first pediatric ICL case that was treated by HSCT. Allogeneic HSCT with a reduced intensity condition (RIC) regimen may be a feasible and curative treatment option in ICL patients with recurrent life-threatening complications.

Altered Responses to Homeostatic Cytokines in Patients with Idiopathic CD4 Lymphocytopenia

Idiopathic CD4 lymphocytopenia (ICL) is a rare immune deficiency characterized by a protracted CD4+ T cell loss of unknown etiology and by the occurrence of opportunistic infections similar to those seen in AIDS. We investigated whether a defect in responses to cytokines that control CD4+ T cell homeostasis could play a role in ICL. Immunophenotype and signaling responses to interleukin-7 (IL-7), IL-2, and thymic stromal lymphopoietin (TSLP) were analyzed by flow cytometry in CD4+ T cells from 15 ICL patients and 15 healthy blood donors. The induction of phospho-STAT5 after IL-7 stimulation was decreased in memory CD4+ T cells of some ICL patients, which correlated with a decreased expression of the IL-7Rα receptor chain (R = 0.74, p<0.005) and with lower CD4+ T cell counts (R = 0.69, p<0.005). IL-2 responses were also impaired, both in the Treg and conventional memory subsets. Decreased IL-2 responses correlated with decreased IL-7 responses (R = 0.75, p<0.005), pointing to combined defects that may significantly perturb CD4+ T cell homeostasis in a subset of ICL patients. Unexpectedly, responses to the IL-7-related cytokine TSLP were increased in ICL patients, while they remained barely detectable in healthy controls. TSLP responses correlated inversely with IL-7 responses (R = −0.41; p<0.05), suggesting a cross-regulation between the two cytokine systems. In conclusion, IL-7 and IL-2 signaling are impaired in ICL, which may account for the loss of CD4+ T cell homeostasis. Increased TSLP responses point to a compensatory homeostatic mechanism that may mitigate defects in γc cytokine responses.

T.131. Disseminated Common Warts in Idiopathic CD4 Lymphocytopenia Patients: Response to Treatment with Interferon-alpha

T.131. Disseminated Common Warts in Idiopathic CD4 Lymphocytopenia Patients: Response to Treatment with Interferon-alpha

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.

Involvement of human intracisternal A‐type retroviral particles in autoimmunity

Prior studies have linked retroviruses to various arthropathies and autoimmune diseases. Sjögren's syndrome (SS), a systemic autoimmune disease, is characterized by aggressive infiltration of lymphocytes into the salivary and lacrimal glands, resulting in destruction of the glands and dry mouth and eyes (sicca syndrome). The infiltrating lymphocytes in SS may become overtly malignant, and thus, the incidence of lymphoma is greatly increased in SS patients. A human intracisternal A-type retroviral particle type I (HIAP-I) has been isolated from persons with SS. HIAP-I shares a limited number of antigenic epitopes with human immunodeficiency virus (HIV), but is distinguishable from HIV by morphological, physical, and biochemical criteria. A substantial majority of patients with SS or systemic lupus erythematosus (SLE) have serum antibodies to the proteins of this human retrovirus. Fewer than 3% of the normal blood donor population have antibodies to any HIAP-associated proteins. A second type of a human intracisternal A-type retrovirus, HIAP-II, was detected in a subset of patients with idiopathic CD4 lymphocytopenia (ICL), an AIDS-like immunodeficiency disease. Most HIAP-II positive ICL patients were also antinuclear antibody positive. Reviewed here are additional studies from several laboratories suggesting that HIAP or related viruses may be involved in SLE and other autoimmune conditions. Additionally, results of comprehensive surveys of autoimmune patients to determine seroreactivity to HIAP, and other human retroviruses, including HIV and human T-lymphotropic virus type I, are reported.