Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management

López-Nevado, Marta; González‐Granado, Luis Ignacio; Ruiz‐García, Raquel; Pleguezuelo, Daniel; Cabrera-Marante, Óscar; Salmón, Nerea; Lobo, Pilar Blanco; Domínguez‐Pinilla, Nerea; Rodríguez-Pena, Rebeca; Sebastián, Elena; Cruz-Rojo, Jaime; Olbrich, Peter; Ruiz–Contreras, Jesús; Paz‐Artal, Estela; Neth, Olaf; Allende, Luis M.

doi:10.3389/fimmu.2021.671755

Cited by 50 publications

(30 citation statements)

References 106 publications

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“…For example, in the condition ALPS Fas- mediated death is disrupted, so the FFL drives to terminal effector differentiation without apoptosis, reversing the sign of the outcome ( 2 , 21 ). As such, we can contextualize the autoimmune toxicity to peripheral tissues and lymphoproliferation and see the physiological utility of the coherent FFL as opposed to an incoherent FFL in the Fas/Akt Differentiation and Death feed-forward system ( 2 , 5 , 12 , 37 , 50 , 51 ).…”

Section: Discussionmentioning

confidence: 99%

Understanding the Effects of Age and T-Cell Differentiation on COVID-19 Severity: Implicating a Fas/FasL-mediated Feed-Forward Controller of T-Cell Differentiation

Leonardi

Argyropoulos

Hamdy³

et al. 2022

Front. Immunol.

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Section: Discussionmentioning

confidence: 99%

Understanding the Effects of Age and T-Cell Differentiation on COVID-19 Severity: Implicating a Fas/FasL-mediated Feed-Forward Controller of T-Cell Differentiation

Leonardi

Argyropoulos

Hamdy³

et al. 2022

Front. Immunol.

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“…While each IEI is a unique genetic disease, variants in different genes can converge in multiple IEIs with similar impacts on shared signaling pathways. This could potentially yield shared dysfunctional states and similar clinical phenotypes ( 58 ). For example, within IEIs, this could be anticipated to take place in PIRDs that amplify TCR signaling and/or inflammatory cytokine signaling.…”

Section: Relationship Between Inborn Errors Of Immunity and T-cell Ex...mentioning

confidence: 99%

Defining and targeting patterns of T cell dysfunction in inborn errors of immunity

Campos

Henrickson

2022

Front. Immunol.

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Inborn errors of immunity (IEIs) are a group of more than 450 monogenic disorders that impair immune development and function. A subset of IEIs blend increased susceptibility to infection, autoimmunity, and malignancy and are known collectively as primary immune regulatory disorders (PIRDs). While many aspects of immune function are altered in PIRDs, one key impact is on T-cell function. By their nature, PIRDs provide unique insights into human T-cell signaling; alterations in individual signaling molecules tune downstream signaling pathways and effector function. Quantifying T-cell dysfunction in PIRDs and the underlying causative mechanisms is critical to identifying existing therapies and potential novel therapeutic targets to treat our rare patients and gain deeper insight into the basic mechanisms of T-cell function. Though there are many types of T-cell dysfunction, here we will focus on T-cell exhaustion, a key pathophysiological state. Exhaustion has been described in both human and mouse models of disease, where the chronic presence of antigen and inflammation (e.g., chronic infection or malignancy) induces a state of altered immune profile, transcriptional and epigenetic states, as well as impaired T-cell function. Since a subset of PIRDs amplify T-cell receptor (TCR) signaling and/or inflammatory cytokine signaling cascades, it is possible that they could induce T-cell exhaustion by genetically mimicking chronic infection. Here, we review the fundamentals of T-cell exhaustion and its possible role in IEIs in which genetic mutations mimic prolonged or amplified T-cell receptor and/or cytokine signaling. Given the potential insight from the many forms of PIRDs in understanding T-cell function and the challenges in obtaining primary cells from these rare disorders, we also discuss advances in CRISPR-Cas9 genome-editing technologies and potential applications to edit healthy donor T cells that could facilitate further study of mechanisms of immune dysfunctions in PIRDs. Editing T cells to match PIRD patient genetic variants will allow investigations into the mechanisms underpinning states of dysregulated T-cell function, including T-cell exhaustion.

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“…Immunodeficiency, particularly impaired T-cell production, as a secondary consequence of diminished or lost thymic function affects up to 75% of pediatric DGS patients ( 4 , 5 ). As one of the important features of immune dysregulation, increased TCRαβ + CD4 − CD8 − double-negative T (DNT) cells and immune cytopenias are frequently seen in disorders with autoimmune lymphoproliferative syndrome (ALPS)-like phenotypes ( 6 ). Sirolimus is considered as an effective and safe therapeutic option for multilineage immune cytopenias with ALPS-like phenotypes ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Case report: Effectiveness of sirolimus in treating partial DiGeorge Syndrome with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features

Mou

Chen

et al. 2023

Front. Pediatr.

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BackgroundDiGeorge Syndrome (DGS) is a rare disease associated with 22q11.2 chromosomal microdeletion, also known as a velocardiofacial syndrome, based on the frequent involvements of the palate, facial, and heart problems. Hematologic autoimmunity is rare in DGS but presents with a refractory course and poor prognosis. Herein, we report a case of partial DGS in a patient with refractory immune cytopenia and autoimmune lymphoproliferative syndrome (ALPS)-like manifestations.Case descriptionA 10-year-old boy with growth retardation presented initially with a ventricular septal defect at 7 months old, which had been repaired soon after. The patient suffered from thrombocytopenia and progressed into chronic refractory immune thrombocytopenia (ITP) at 30 months old. One year later, the patient developed multilineage cytopenias including thrombocytopenia, neutropenia, and anemia. First-line treatment of ITP, like high-dose dexamethasone and intravenous immunoglobulin, had little or short-term effect on controlling symptoms. Whole-exome sequencing revealed the presence of a de novo heterozygous 2.520 Mb deletion on chromosome 22q11.21. Moreover, decreased proportion of naive T cells and elevated double-negative T cells were found. The patient was given sirolimus therapy (1.5 mg/m2, actual blood concentration range: 4.0–5.2 ng/ml) without adding other immunosuppressive agents. The whole blood cell count was gradually restored after a month, and the disease severity was soothed with less frequency of infections and bleeding events. Decreased spleen size and restrained lymph node expansion were achieved after 3-month sirolimus monotherapy.ConclusionsThis case is the first description on the efficacy of sirolimus monotherapy to treat refractory multilineage cytopenias of DGS presented with ALPS-like features.

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Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management

Cited by 50 publications

References 106 publications

Understanding the Effects of Age and T-Cell Differentiation on COVID-19 Severity: Implicating a Fas/FasL-mediated Feed-Forward Controller of T-Cell Differentiation

Understanding the Effects of Age and T-Cell Differentiation on COVID-19 Severity: Implicating a Fas/FasL-mediated Feed-Forward Controller of T-Cell Differentiation

Defining and targeting patterns of T cell dysfunction in inborn errors of immunity

Case report: Effectiveness of sirolimus in treating partial DiGeorge Syndrome with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features

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