Low CD4 + T cell count is related to specific anti-nuclear antibodies, IFNα protein positivity and disease activity in systemic lupus erythematosus pregnancy.

BACKGROUND: Lymphopenia, autoantibodies and activation of the type I interferon (IFN) system are common features in systemic lupus erythematosus (SLE). We speculate whether lymphocyte subset counts are affected by pregnancy and if they relate to autoantibody profiles and/or IFNα protein in SLE pregnancy. METHODS: Repeated blood samples were collected during pregnancy from 80 women with SLE and 51 healthy controls (HC). Late postpartum samples were obtained from 19 of the women with SLE. Counts of CD4 + and CD8 + T cells, B cells and NK cells were measured by flow cytometry. Positivity for anti-nuclear antibodies (ANA) fine specificities (double-stranded DNA [dsDNA], Smith [Sm], ribonucleoprotein [RNP], chromatin, Sjögren's syndrome antigen A [SSA] and B [SSB]) and anti-phospholipid antibodies (cardiolipin [CL] and ß2 glycoprotein I [ß2GPI]) was assessed with multiplexed bead assay. IFNα protein concentration was quantified with Single molecule array (Simoa) immune assay. Clinical data were retrieved from medical records. RESULTS: Women with SLE had lower counts of all lymphocyte subsets compared to HC throughout pregnancy, but counts did not differ during pregnancy compared to postpartum. Principal component analysis revealed that low lymphocyte subset counts differentially related to autoantibody profiles, cluster one (anti-dsDNA/anti-Sm/anti-RNP/anti-Sm/RNP/anti-chromatin), cluster two (anti-SSA/anti-SSB) and cluster three (anti-CL/anti-ß2GPI), IFNα protein levels and disease activity. CD4 + T cell counts were lower in women positive to all ANA fine specificities in cluster one compared to those who were negative, and B cell numbers were lower in women positive for anti-dsDNA and anti-Sm compared to negative women. Moreover, CD4 + T cell and B cell counts were lower in women with moderate/high compared to no/low disease activity, and CD4 + T cell count was lower in IFNα protein positive relative to negative women. Finally, CD4 + T cell count was unrelated to treatment. CONCLUSION: Lymphocyte subset counts are lower in SLE compared to healthy pregnancies, which seems to be a feature of the disease per se and not affected by pregnancy. Our results also indicate that low lymphocyte subset counts relate differentially to autoantibody profiles, IFNα protein levels and disease activity, which could be due to divergent disease pathways.

Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia.

BACKGROUNDIdiopathic CD4 lymphopenia (ICL) is defined by persistently low CD4+ cell counts (<300 cells/µL) in the absence of a causal infection or immune deficiency and can manifest with opportunistic infections. Approximately 30% of ICL patients develop autoimmune disease. The prevalence and breadth of their autoantibodies, however, and their potential contribution to pathogenesis of ICL remain unclear.METHODSWe hybridized 34 and 51 ICL patients' sera to a 9,000-human-proteome array and to a 128-known-autoantigen array, respectively. Using a flow-based method, we characterized the presence of anti-lymphocyte Abs in the whole cohort of 72 patients, as well as the Ab functional capability of inducing Ab-dependent cell-mediated cytotoxicity (ADCC), complement deposition, and complement-dependent cytotoxicity (CDC). We tested ex vivo the activation of the classical complement pathway on ICL CD4+ T cells.RESULTSAll ICL patients had a multitude of autoantibodies mostly directed against private (not shared) targets and unrelated quantitatively or qualitatively to the patients' autoimmune disease status. The targets included lymphocyte intracellular and membrane antigens, confirmed by the detection by flow of IgM and IgG (mostly IgG1 and IgG4) anti-CD4+ cell Abs in 50% of the patients, with half of these cases triggering lysis of CD4+ T cells. We also detected in vivo classical complement activation on CD4+ T cells in 14% of the whole cohort.CONCLUSIONOur data demonstrate that a high prevalence of autoantibodies in ICL, some of which are specific for CD4+ T cells, may contribute to pathogenesis, and may represent a potentially novel therapeutic target.TRIAL REGISTRATIONClinicalTrials.gov NCT00867269.FUNDINGNIAID and National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH.

Idiopathic CD4+ T-lymphocytopenia with cryptococcal meningitis: first case report from Cambodia.

We report on a patient with cryptococcal meningitis with CD4+ T-lymphocytopenia and no evidence of HIV infection.

Pneumocystis Pneumonia Secondary to Idiopathic CD4+ T-lymphocytopenia: A Comparison of AIDS and Non-AIDS Patients.

A 67-year-old man was admitted to our hospital complaining of dry cough. Chest computed tomography showed diffuse infiltrates and ground-glass opacities in the bilateral lung fields. Transbronchial lung biopsy specimens showed alveoli filled with yeast-like fungi. With a diagnosis of pneumocystis pneumonia (PCP), he was given oral sulfamethoxazole/trimethoprim, to which he responded well. However, seven months later, PCP relapsed. Analyses revealed a low bronchoalveolar lavage fluid CD4/CD8 ratio of 0.04 and CD4+ lymphocytopenia (250/µL). Despite intensive work-up, we were unable to detect the underlying cause of CD4+ lymphocytopenia; therefore, a final diagnosis of idiopathic CD4+ T-lymphocytopenia was made.

Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia.

Progressive loss of CD4+ T lymphocytes, accompanied by opportunistic infections characteristic of the acquired immune deficiency syndrome, ahs been reported in the absence of any known etiology. The pathogenesis of this syndrome, a subset of idiopathic CD4+ T lymphocytopenia (ICL), is uncertain. We report that CD4+ T cells from seven of eight ICL patients underwent accelerated programmed cell death, a process facilitated by T cell receptor cross-linking. Apoptosis was associated with enhanced expression of Fas and Fas ligand in unstimulated cell populations, and partially inhibited by soluble anti-Fas mAb. In addition, apoptosis was suppressed by aurintricarboxylic acid, an inhibitor of calcium-dependent endonucleases and proteases, in cells from four of seven patients, The in vivo significance of these findings was supported by three factors: the absence of accelerated apoptosis in persons with stable, physiologic CD4 lymphopenia without clinical immune deficiency; detection of serum antihistone H2B autoantibodies, one consequence of DNA fragmentation, in some patients; and its selectivity, with apoptosis limited to the CD4 population in some, and occurring among CD8+ T cells predominantly in those individuals with marked depletion of both CD4+ T lymphocytes linked to clinical immune suppression have evidence for accelerated T cell apoptosis in vitro that may be pathophysiologic and amenable to therapy with apoptosis inhibitors.

CD4+ T lymphocytopenia in children: lack of evidence for a new acquired immunodeficiency syndrome agent.

We investigated children with CD4+ T lymphocytopenia to determine the magnitude and public health impact of this condition and to investigate possible causes. Children < 13 years old with CD4+ T lymphocyte counts below age-adjusted cutoffs (age < 24 months, 1000 cells/microliters; age > or = 24 months, 300 cells/microliters) or < 20% on 2 separate measurements were considered to have CD4+ T lymphocytopenia. We solicited information from clinicians and public health departments on these children and their families and collected blood for immunologic and retroviral testing. We identified 18 children (10 boys; 14 African-Americans) with a median age of 10 months at their first low CD4+ T lymphocyte measurement. Three children had had opportunistic infections and two still had low CD4+ T lymphocyte counts 5 and 7 years later. Of the 11 children born to human immunodeficiency virus (HIV)-infected mothers 7 were asymptomatic. Specimens from all children were negative for HIV and human T lymphotropic virus antibodies and negative for HIV by culture or polymerase chain reaction. Among 12 families interviewed no other HIV-seronegative family or household member had illnesses suggestive of immunosuppression. We conclude that negative retroviral tests and lack of illness among their family members do not support the hypothesis that a retrovirus causes CD4+ T lymphocytopenia among these children.(ABSTRACT TRUNCATED AT 250 WORDS)

CD4+ lymphocytopenia due to common variable immunodeficiency mimicking AIDS.

There are an increasing number of published reports of patients with acquired immunodeficiency without evidence of HIV infection, who have been labelled as having "idiopathic CD4+ lymphocytopenia". The case is reported here of a young man who presented with Pneumocystis carinii pneumonia (PCP), CD4+ lymphopenia, and hypogammaglobulinaemia attributable to common variable immunodeficiency (CVID). The presentation of this condition, with many of the clinical and laboratory features of AIDS, highlights CVID as a diagnosis to be considered in the differential diagnosis of CD4+ lymphocytopenia.

Idiopathic CD4+ T-lymphocytopenia and recurrent vulvar intraepithelial neoplasia.

BACKGROUND: CD4+ T-lymphocytopenia immunodeficiency without human immunodeficiency virus (HIV) infection has been reported recently. The association between immunodeficiency and anogenital neoplasia secondary to human papillomavirus infections is well documented. CASE: A woman with recurrent vulvar intraepithelial neoplasia (VIN) had idiopathic CD4+ T-lymphocytopenia without HIV infection. CONCLUSION: Human papillomavirus-related VIN may be associated with idiopathic CD4+ T-lymphocytopenia.

CD4+ T-lymphocytopenia in severe pulmonary tuberculosis without evidence of human immunodeficiency virus infection.

SETTING: A large public hospital in Buenos Aires, Argentina. OBJECTIVE: To determine the number of blood CD4 and CD8 T-lymphocytes in male human immunodeficiency virus (HIV) negative patients with severe pulmonary tuberculosis. DESIGN: Seventeen patients with severe pulmonary tuberculosis (SPT), with a mean age of 44.1 years, all HIV negative, had on admission lost 20% or more of their normal weight. Ten male HIV negative pulmonary tuberculosis patients (PT), with a mean age of 25.2 years, in good general condition, acted as a control group. Patients from both groups had a blood CD4/CD8 count before treatment. RESULTS: In the SPT patients, the CD4/CD8 count before treatment yielded a mean of 341.25 +/- 142.73/ mm3 for CD4 and 259.33 +/- 100.89/mm3 for CD8. Three patients died a few weeks after starting treatment; on admission they had 180,220 and 280 CD4/ mm3, respectively. Patients in good general condition yielded 721.40 +/- 272.20 for CD4 (P < 0.01, t = 4.216) and 416.67 for CD8. At the same time, five normal volunteers, with a mean age of 35.60 +/- 10.45 years, had mean CD4 and CD8 counts of 906 +/- 75.37 and 360 +/- 190.79, respectively. CONCLUSION: Based on the findings of this study, we feel that it is of value to measure the CD4 and CD8 T-lymphocyte counts in STP patients with a compromised general condition and with significant weight loss at the beginning of treatment. Those patients with a CD4 count of < 300/mm3 have a very poor prognosis and, in addition to the regular antituberculosis drugs, will require intensive care during the first weeks of treatment.

Undefined CD4 lymphocytopenia without clinical complications. A report of two cases.

A form of idiopathic CD4 lymphocytopenia (ICL) has been recently described. Its diagnostic criteria have been defined by the Centers for Disease Control (CDC), Atlanta. Associations of ICL with hepatitis C infection have been reported, while some ICL patients have presented abnormalities partly similar to those observed in common variable immunodeficiency (CVI). This paper illustrates the immunological pictures of two subjects with a CD4 deficiency confirmed in a series of peripheral blood lymphocyte subset determinations, but not associated with other cellular or humoral immunity abnormalities and accompanied by poorly significant clinical manifestations (no opportunistic infections). Patient one has been observed for a very long period. Her serological picture has been negative and she is free from hypergammaglobulinemia. HIV infection can thus be ruled out. Patient two has not required any specific treatment so far. The CDC's diagnostic criteria for ICL are not fully met in the two cases. Their pictures meet many, though not all of the CDC criteria for the diagnosis of ICL. It is to be hoped that a protracted follow-up will allow an assessment to be made of the natural history of the two cases.

The syndrome of idiopathic CD4+ lymphocytopenia.

The syndrome of idiopathic CD4+ lymphocytopenia has recently been recognized and referred to as the persistent depletion of peripheral blood CD4+ T lymphocytes below 300 cells per cubic millimeter or less than 20% of total lymphocytes in the absence of either HIV infection or other known causes of immunodeficiency. The available literature indicates that neither human retroviruses (HIV-1, HIV-2, HTLV-I, HTLV-II) nor other transmissible agents play any clear-cut role in the pathogenesis. Furthermore, the epidemiologic, immunologic and clinical features of this syndrome differ substantially from those of HIV infection. The heterogeneity of both immunologic abnormalities, in addition to CD4+ depletion, and clinical course in patients with this disorder points out no common cause although in at least a subset of patients the pathogenetic pathways could be shared with common variable immunodeficiency.

[Idiopathic CD4+ T-lymphocyte deficiency: the clinical evolution of a case]. / Deficit idiopatico di linfociti T CD4+: evoluzione clinica di un caso.

The case of a patient with Salmonella arizonae sepsis, esophageal candidiasis, and a low CD4+ T lymphocyte count is presented. Follow-up continued for over 2 years after the patient was discharged from the hospital, and his clinical course and clinical-immunological examinations are described. After a period of several years during which the patient had recurrent acute infectious episodes, he improved markedly after cholecystectomy and toilette of the gingival inlets for severe parodontopathy. His CD4+ T cell count increased although it remained below normal values. This case points to possible hypothesis that chronic infective foci may further compromise the immune system when a congenital functional or numerical CD4+ T cell deficit is present.

Idiopathic CD4+ lymphocytopenia may be due to decreased bone marrow clonogenic capability.

BACKGROUND: Idiopathic CD4+ lymphocytopenia is defined by a stable decrease of CD4+ T cells in the absence of any known cause of immune deficiency. The mechanisms responsible for the immunological impairment are still unknown, but a regenerative failure of hematopoietic stem/progenitor cells has been hypothesized. METHODS: We evaluated in the bone marrow (BM) of 5 patients with idiopathic CD4+ lymphocytopenia the phenotype of BM progenitor cells, their differentiation capacity with colony-forming cells and long-term culture-initiating cell assays, in parallel with the spontaneous IL-7 production in the patient sera. RESULTS: Compared with controls, a regenerative failure of hematopoietic stem cells has been observed, both in 'committed' and in 'uncommitted' progenitor cells, despite high IL-7 serum levels. The percentage of phenotypically primitive CD34+CD38-DR+ cells (this includes the lymphoid precursor cells) was decreased, suggesting an involvement of the more primitive BM compartment in the de novo T cell generation. CONCLUSIONS: Despite the low number of patients, due to the low incidence of the disease, the decrease of primitive precursors sustains the possibility that diminished stem cell precursors might contribute to the development of CD4+ T cell depletion.

The effect of a novel immunosuppressant, FTY720, in mice without secondary lymphoid organs.

PURPOSE: FTY720 is a novel immunosuppressive agent that is thought to reduce the number of peripheral blood lymphocytes (PBL) by directing them toward secondary lymphoid organs such as the lymph nodes and Peyer's patches. We studied the effects of FTY720 on aly/aly mice that do not have either lymph nodes or Peyer's patches, as well as on splenectomized aly/aly mice. METHODS: FTY720 was orally administered by gavage (1 mg/kg) to aly/aly mice as well as to aly/+ mice with and without a splenectomy on 14 consecutive days. The number of lymphocytes was then counted using True Cell beads and flow cytometry. The number of B220-, CD3-, and CD4-positive cells was also determined. In addition, skin grafts from C3H donor mice were performed on these mice. RESULTS: FTY720 was effective in significantly reducing the total lymphocyte count as well as the B220-, CD3-, and CD4-positive subtypes in the peripheral blood of aly/+ mice as well as in aly/aly mice with and without a splenectomy. While we did observe allograft skin graft rejection in both the aly/+ mice as well as the aly/aly mice recipients and splenectomized aly/aly mice, the graft survival was prolonged in all groups. The skin allografts treated by FTY720 thus demonstrated fewer lymphocytic cells and less infiltration of CD4-positive cells. CONCLUSIONS: The administration of FTY720 to mice without lymph nodes, Peyer's patches, or spleens still results in peripheral lymphopenia. In all groups, FTY720 was found to prevent the infiltration of CD4-positive cells in skin allografts while also prolonging skin allograft survival. The fate of these lymphocytes, however, is unclear.