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Evaluation of cellular and humoral autoimmunity before the development of type 1 diabetes in a patient with idiopathic CD4 lymphocytopenia.

ABSTRACT: A 64-year-old woman developed type 1 diabetes 23 years after the diagnosis of idiopathic CD4 lymphocytopenia. To investigate the etiological interaction between idiopathic CD4 lymphocytopenia and type 1 diabetes, we carried out a longitudinal analysis related to islet-specific autoimmunity. Anti-glutamic acid decarboxylase antibody had been already weakly positive for at least 16 years and started rising at 6 months before the onset of type 1 diabetes. The seroconversion of anti-insulinoma-associated antigen-2 antibody and insulin autoantibody occurred at the time of onset. The ratio of CD8/CD4 had been gradually increasing for 8 years before type 1 diabetes onset. Notably, islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD8⁺ T cells were detected at type 1 diabetes onset, and the frequency was higher than that in 15 non-diabetic controls (6.75% vs 0.49 ± 0.78%, mean ± SD). The present type 1 diabetes patient, presented with idiopathic CD4 lymphocytopenia and showed an elevated number of CD8⁺ T cells, including the islet antigen-specific CD8⁺ T cells that might contribute to autoimmune destruction of pancreatic β-cells.

SUBMITTER: Maruyama K

PROVIDER: S-EPMC6626996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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[Lymphocytopenia: aetiology and diagnosis, when to think about idiopathic CD4(+) lymphocytopenia?].

Project description:Lymphocytopenia is defined by a lymphocyte count less than 1500/mm(3) in adults and less than 4500/mm(3) in children before the age of 8 months. Lymphocytopenia can be global or selectively affect a peculiar lymphocyte subpopulation. The patient's age, the context as well as the associated clinical manifestations and treatment prescribed must be taken into account in order to identify the etiology of lymphocytopenia. In adults, lymphocytopenia can be caused by: (1) insufficient thymic output (primary immune deficiencies, corticosteroid treatment, zinc deficiency, etc.), (2) increased lymphocyte catabolism (radiotherapy, chemotherapy, immunosuppressant, HIV infection, systemic lupus, etc.), (3) modified lymphocyte distribution (viral infections, septic shock, extensive burns, splenomegaly, granulomatosis, etc.), (4) multifactorial or unknown etiology (end-stage renal disease, lymphoid malignancies, solid tumor, ethnicity, etc.). In children, in addition to these etiologies, other immune deficiencies may be responsible for severe lymphocytopenia (thymocytes apoptosis, cytokine deficiencies, altered B-cell and T-cell receptor synthesis, signal transduction and cellular interactions deficiencies). Idiopathic CD4(+) lymphocytopenia is a rare disorder. It is defined by a persisting lymphocyte CD4(+) count less or equal to 300/mm(3) or less or equal to 20% of total lymphocytes in the absence of alternative diagnosis. Clinical symptoms can be absent or include opportunistic infections, auto-immune manifestations, lymphoma or solid tumors. Treatment is similar to that of HIV-infected patients and sometimes relies on specific immunotherapy even though clinical benefit has not been evaluated.

| S-EPMC7115373 | biostudies-literature

Osteomyelitis due to multiple rare infections in a patient with idiopathic CD4 lymphocytopenia.

Project description:A 26-year-old male patient presented with features suggestive of osteomyelitis involving the entire left femur, hip joint and knee joint. Culture from the debrided tissue grew Acinetobacter spp. and he was treated with sensitivity based antibiotics but the symptoms did not resolve. The synovial biopsy showed multinucleated giant cells and acid fast bacilli on Ziehl Neelsen stain. Cartridge based nucleic acid amplification test (GeneXpert) was negative. The Mycobacteria growth indicator tube culture was found to be positive for Mycobacterium abscessus. The patient was started on imipenem, amikacin and macrolide based therapy. There was partial response initially but the patient worsened again. A girdle stone arthroplasty with cemented nail (with tobramycin) insertion after debridement of the infected tissue was done. Potassium hydroxide (KOH) mount from the debridement sample was found to be positive for aseptate hyphae suggestive of mucormycosis. He was treated with liposomal amphotericin B. He was evaluated for immunodeficiency in view of multiple atypical infections and was found to have a low CD4 count. The patient was discharged on amikacin, azithromycin, trimethoprim-sulfamethoxazole and posaconazole. Follow up showed considerable resolution both clinically and radiologically. To our knowledge, this is the first reported case of osteomyelitis with co-infection of Acinetobacter spp., M. abscessus and mucormycetes. We report this case to highlight the possibility of multiple rare infections in patients with immunodeficiency. Also, atypical complicated bone infections, such as Mycobacterium abscessus and mucormycetes might require combined medical and surgical treatment.

| S-EPMC5608932 | biostudies-literature

Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors.

Project description: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).

| S-EPMC2442741 | biostudies-literature

Administration of interleukin-7 increases CD4 T cells in idiopathic CD4 lymphocytopenia.

Project description:Idiopathic CD4 lymphopenia (ICL) is a rare syndrome defined by low CD4 T-cell counts (<300/µL) without evidence of HIV infection or other known cause of immunodeficiency. ICL confers an increased risk of opportunistic infections and has no established treatment. Interleukin-7 (IL-7) is fundamental for thymopoiesis, T-cell homeostasis, and survival of mature T cells, which provides a rationale for its potential use as an immunotherapeutic agent for ICL. We performed an open-label phase 1/2A dose-escalation trial of 3 subcutaneous doses of recombinant human IL-7 (rhIL-7) per week in patients with ICL who were at risk of disease progression. The primary objectives of the study were to assess safety and the immunomodulatory effects of rhIL-7 in ICL patients. Injection site reactions were the most frequently reported adverse events. One patient experienced a hypersensitivity reaction and developed non-neutralizing anti-IL-7 antibodies. Patients with autoimmune diseases that required systemic therapy at screening were excluded from the study; however, 1 participant developed systemic lupus erythematosus while on study and was excluded from further rhIL-7 dosing. Quantitatively, rhIL-7 led to an increase in the number of circulating CD4 and CD8 T cells and tissue-resident CD3 T cells in the gut mucosa and bone marrow. Functionally, these T cells were capable of producing cytokines after mitogenic stimulation. rhIL-7 was well tolerated at biologically active doses and may represent a promising therapeutic intervention in ICL. This trial was registered at www.clinicaltrials.gov as #NCT00839436.

| S-EPMC4768432 | biostudies-literature

Altered responses to homeostatic cytokines in patients with idiopathic CD4 lymphocytopenia.

Project description: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-7R? 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 ?c cytokine responses.

| S-EPMC3559496 | biostudies-literature

Humanized mouse models reveal an immunologic classification of idiopathic CD4 lymphocytopenia subtypes.

Project description:Idiopathic CD4 lymphocytopenia (ICL) is a clinically heterogeneous immunodeficiency disorder defined by low numbers of circulating CD4+ T cells and increased susceptibility to opportunistic infections. CD8+ T cells, NK, and/or B cells may also be deficient in some patients. To delineate possible pathogenic cellular mechanisms in ICL, we compared immune system development and function in NOD-RAGKO-γcKO (NRG) mice transplanted with hematopoietic stem cells from patients with ICL or healthy controls. CD34+ hematopoietic stem cells from healthy controls and patients with ICL reconstituted NRG mice equally well. In contrast, PBMC transfers into NRG mice identified 2 ICL engraftment phenotypes, reconstituting and nonreconstituting (NR), based on the absence or presence of donor lymphopenia. For patients in the NR group, the distribution of lymphocyte subsets was similar in the peripheral blood of both the patient and the corresponding humanized mice. The NR-ICL group could be further divided into individuals whose CD3+ T cells had defects in proliferation or survival. Thus, ICL cellular pathogenesis might be classified by humanized mouse models into 3 distinct subtypes: (a) T cell extrinsic, (b) T cell intrinsic affecting proliferation, and (c) T cell intrinsic affecting survival. Humanized mouse models of ICL help to delineate etiology and ultimately to guide development of individualized therapeutic strategies.

| S-EPMC6675561 | biostudies-literature

Preserved Mucosal-Associated Invariant T-Cell Numbers and Function in Idiopathic CD4 Lymphocytopenia.

Project description:BackgroundMucosal-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.MethodsWe investigated 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.ResultsThe numbers, phenotype, and function of MAIT cells in peripheral blood were preserved in ICL patients compared to healthy controls. Administration of interleukin-7 (IL-7) to ICL patients expanded the CD8+ MAIT-cell subset, with maintained responsiveness and effector functions after IL-7 treatment.ConclusionsICL patients maintain normal levels and function of MAIT cells, preserving some antibacterial responses despite the deficiency in CD4+ T cells.Clinical trials registrationNCT00867269.

| S-EPMC8366440 | biostudies-literature

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

Project description:IntroductionWhen 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 presentationA 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).ConclusionsThe 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.

| S-EPMC5415924 | biostudies-literature

Gene-expression profiling on a HPV-related head and neck cancer patient with idiopathic CD4 lymphocytopenia and complete remission to checkpoint inhibitors

Project description:PD-L1 immunohistochemical staining has been not always enough reliable to accurately predict the response to immunotherapy; thus, and other biomarkers are required. In this context qualitative and quantitative multiparametric analyses seems promising. Data on the activity of nivolumab in challenging populations (e.g patients with autoimmune disorders; post-organ transplant; chronic viral infections; ongoing immunosuppressant use; elderly) are scant, mainly due to their underrepresentation in clinical trials. Nonetheless, it has been demonstrated that the use of ICI is safe and effective in HIV oncologic patients. Herein, we analyzed a metastatic HNSCC patient with an idiopathic CD4 lymphocytopenia who, after a recovery from a progressive multifocal leukoencephalopaty received 10 courses of nivolumab and obtained a complete remission maintaining the response two years after PD-1 blockade withdrawn.

2021-12-31 | GSE161785 | GEO

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

Project description: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.

| S-EPMC1801046 | biostudies-literature

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