Paradoxical CD4 Lymphopenia in Autoimmune Lymphoproliferative Syndrome (ALPS)

Lisco, Andrea; Wong, Chun-Shu; Price, Susan; Ye, Peiying; Niemela, Julie E.; Anderson, Megan; Richards, Elizabeth; Manion, Maura; Mystakelis, Harry; Similuk, Morgan; Lo, Bernice; Stoddard, Jennifer; Rosenzweig, Sergio D.; Vanpouille, Christophe; Rupert, Adam; Marić, Irina; Pérez-Díez, Ainhoa; Parenti, David M.; Burbelo, Peter D.; Rao, V. Koneti; Sereti, Irini

doi:10.3389/fimmu.2019.01193

Cited by 19 publications

(6 citation statements)

References 32 publications

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“…Additional detailed patient clinical and laboratory characteristics are shown in Supplemental Table 1 (supplemental material available online with this article; https:// doi.org/10.1172/JCI136254DS1). Although at the outset of this project a total of 77 patients were included, 5 patients were excluded in final analyses due to diagnoses that could explain their CD4 + T cell lymphopenia, specifically Crohn's disease (patient experienced CD4 + recovery to >400 cells/μL after treatment with anti-TNF-α antibody), and mutations in FAS (16), PI3KCD, NF-κB1, or DOCK-8 unveiled after sequencing.…”

Section: Resultsmentioning

confidence: 99%

“…Lymphopenia is a predictor of systemic lupus erythematosus (SLE) flares (12,13), development of autoantibodies in primary Sjögren's syndrome (14), and dermatomyositis (5). Previously, studies have shown that autoantibodies are present in other conditions with CD4 lymphopenia (15,16), suggesting an association between lymphopenia and anti-lymphocyte Abs. Moreover, it has been shown that primary immunodeficiencies (PIDs) are associated with a higher risk of autoimmune complications than the general population (17), with the greatest risk linked to T cell PIDs and common variable immunodeficiency.…”

Section: Resultsmentioning

confidence: 99%

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Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia

Pérez-Díez¹,

Wong²,

Liu³

et al. 2020

Journal of Clinical Investigation

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METHODS.We 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. RESULTS.All 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 IgG 1 and IgG 4 ) 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. CONCLUSION.Our 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 REGISTRATION. ClinicalTrials.gov NCT00867269.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia

Pérez-Díez¹,

Wong²,

Liu³

et al. 2020

Journal of Clinical Investigation

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“…Though more research is definitely necessary, it would be prudent to examine the consequences of mutations within this particular gene on lymphocytes and other cells, as has been done with FAS genes. A better understanding of the CD4 gene could lead to a new classification of lymphocytopenia rather than a placement under the umbrella term of ICL, similar to the creation of autoimmune lymphoproliferative syndrome as a result of loss-of-function mutations in FAS [ 13 ]. To remain aware of any potentially deleterious CD4 mutations, we recommend that the CD4 gene be added to primary immunodeficiency panels in cases where the cause of immunodeficiency remains unknown or difficult to discern.…”

Section: Discussionmentioning

confidence: 99%

Idiopathic CD4+ Lymphocytopenia Due to Homozygous Loss of the CD4 Start Codon

Sama

Challa

Patel³

et al. 2021

Cureus

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Idiopathic CD4+ lymphocytopenia (ICL) is an extremely rare condition characterized by low numbers of CD4+ cells (<0.3 K/μL) without human immunodeficiency virus (HIV) infection or any other cause of immunodeficiency. In this case report, we report a case of idiopathic CD4+ lymphocytopenia in a 22-year-old woman initially presenting with insomnia, fatigue, and a sore throat. However, this rapidly progressed to shortness of breath and chest pain, ultimately leading to acute respiratory distress syndrome (ARDS) over the span of a few days. Broad-spectrum antimicrobials were administered, resulting in prompt recovery. Serological studies were negative for malignancy and severe infections, including HIV1 and HIV2. Flow cytometry revealed an absence of CD4+ cells and an increase in double-negative T-cells. Further genetic workup revealed that in the second exon of the CD4 gene, the patient had a homozygous c.1ATG>GTG (p.Met1Val; p.M1V) mutation. Family screening showed that the patient’s mother, father, and brother all had a single p.M1V mutation, allowing for deleterious effects to be partially offset by the normal copy of the gene. We have provided an organized analysis of the existing literature in addition to a concise overview of this case, with the intention of identifying patterns in presentation, clinical course, and outcomes. This case discusses the effects of the loss of the CD4+ start codon in the patient. Although this specific form of lymphocytopenia is very uncommon, it illustrates the importance of genetic testing and the integral nature of laboratory testing in therapy charting.

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“…In the case of HIV infection, as well as in other immunodeficiencies (e.g. common variable immunodeficiency -CVID and autoimmune lymphoproliferative syndrome -ALPS), loss of immunological tolerance is essential [49][50][51].…”

Section: Pathogenesis Of Aihamentioning

confidence: 99%

Autoimmune hemolytic anemia: current knowledge and perspectives

et al. 2020

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Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases which includes warm AIHA, cold agglutinin disease (CAD), mixed AIHA, paroxysmal cold hemoglobinuria and atypical AIHA. Currently CAD is defined as a chronic, clonal lymphoproliferative disorder, while the presence of cold agglutinins underlying other diseases is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies directed against red blood cells (RBCs) causing premature erythrocyte destruction. The pathogenesis of AIHA is complex and still not fully understood. Recent studies indicate the involvement of T and B cell dysregulation, reduced CD4+ and CD25+ Tregs, increased clonal expansions of CD8 + T cells, imbalance of Th17/Tregs and Tfh/Tfr, and impaired lymphocyte apoptosis. Changes in some RBC membrane structures, under the influence of mechanical stimuli or oxidative stress, may promote autohemolysis. The clinical presentation and treatment of AIHA are influenced by many factors, including the type of AIHA, degree of hemolysis, underlying diseases, presence of concomitant comorbidities, bone marrow compensatory abilities and the presence of fibrosis and dyserthropoiesis. The main treatment for AIHA is based on the inhibition of autoantibody production by mono- or combination therapy using GKS and/or rituximab and, rarely, immunosuppressive drugs or immunomodulators. Reduction of erythrocyte destruction via splenectomy is currently the third line of treatment for warm AIHA. Supportive treatment including vitamin supplementation, recombinant erythropoietin, thrombosis prophylaxis and the prevention and treatment of infections is essential. New groups of drugs that inhibit immune responses at various levels are being developed intensively, including inhibition of antibody-mediated RBCs phagocytosis, inhibition of B cell and plasma cell frequency and activity, inhibition of IgG recycling, immunomodulation of T lymphocytes function, and complement cascade inhibition. Recent studies have brought about changes in classification and progress in understanding the pathogenesis and treatment of AIHA, although there are still many issues to be resolved, particularly concerning the impact of age-associated changes to immunity.

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Paradoxical CD4 Lymphopenia in Autoimmune Lymphoproliferative Syndrome (ALPS)

Cited by 19 publications

References 32 publications

Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia

Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia

Idiopathic CD4+ Lymphocytopenia Due to Homozygous Loss of the CD4 Start Codon

Autoimmune hemolytic anemia: current knowledge and perspectives

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