Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

Chandrakasan, Shanmuganathan; Chandra, Sharat; Saldaña, Blachy J. Dávila; Torgerson, Troy R.; Buchbinder, David

doi:10.1002/pbc.27619

Cited by 28 publications

(16 citation statements)

References 74 publications

(182 reference statements)

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“…The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines ( 34 ). Clinical ALPS-like criteria were immune dysregulation defined as autoimmunity and lymphoproliferation ( 17 , 29 , 35 ). The genes in which genetic defects gave rise to an ALPS-like phenotype, excluding those already described in the Fas-FasL pathway, were selected based on the IUIS classification ( 1 , 2 ) and a literature search in MEDLINE (pubmed), Google scholar databases, Web Of Science (WOS) and congress communications.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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“…Primary immune dysregulation diseases are a group of monogenic disorders characterized by defective immune regulatory pathways (1)(2)(3). Their clinical presentation mainly comprises organ-specific autoimmunity, hyperinflammation, and nonmalignant lymphoproliferation.…”

Section: Introductionmentioning

confidence: 99%

“…Their clinical presentation mainly comprises organ-specific autoimmunity, hyperinflammation, and nonmalignant lymphoproliferation. New sequencing technologies have improved the understanding of this ever-expanding group of disorders but they still often pose a diagnostic challenge because of their variable and complex phenotypic expressions and the overlap of symptoms between different entities ( 1 , 4 ). Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and autoimmune lymphoproliferative syndrome (ALPS) are archetypes of inborn errors of immunity (IEI) with immune dysregulation and have gained attention as models of monogenic autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Case Report: FOXP3 Mutation in a Patient Presenting With ALPS

et al. 2021

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ALPS and IPEX are two well-characterized inborn errors of immunity with immune dysregulation, considered as two master models of monogenic auto-immune diseases. Thus, with autoimmunity as their primary clinical manifestation, these two entities may show clinical overlap. Traditionally, immunological biomarkers are used to establish an accurate differential diagnosis. Herein, we describe a patient who presented with clinical features and biomarkers fulfilling the diagnostic criteria of ALPS. Severe apoptotic defect was also shown in the patient’s cell lines and PHA-activated peripheral blood lymphocytes. Sanger sequencing of the FAS gene did not reveal any causal mutation. NGS screening revealed a novel deleterious variant located in the N terminal repressor domain of FOXP3 but no mutations in the FAS pathway-related genes. TEMRA cells (terminally differentiated effector memory cells re-expressing CD45RA) and PD1 expression were increased arguing in favor of T-cell exhaustion, which could be induced by unrestrained activation of T effector cells because of Treg deficiency. Moreover, defective FOXP3 observed in the patient could intrinsically induce increased proliferation and resistance to apoptosis in T effector cells. This observation expands the spectrum of FOXP3 deficiency and underscores the role of NGS in detecting mutations that induce overlapping phenotypes among inborn errors of immunity with immune dysregulation. In addition, these findings suggest a potential link between FOXP3 and FAS pathways.

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“…Primary Immune Regulation Disorders (PIRD)s lead to defects in the immune homeostasis that cause a defective or exacerbated immune response that usually produce autoimmunity, allergy, and/ or inflammation (1)(2)(3)(4)(5)(6). These diseases constitute an expanding group of primary immunodeficiencies (PID) listed in the last IUIS Phenotypic Classification of PID (7).…”

Section: Introductionmentioning

confidence: 99%

Immune Monitoring of Patients With Primary Immune Regulation Disorders Unravels Higher Frequencies of Follicular T Cells With Different Profiles That Associate With Alterations in B Cell Subsets

et al. 2020

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Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

Cited by 28 publications

References 74 publications

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

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

Case Report: FOXP3 Mutation in a Patient Presenting With ALPS

Immune Monitoring of Patients With Primary Immune Regulation Disorders Unravels Higher Frequencies of Follicular T Cells With Different Profiles That Associate With Alterations in B Cell Subsets

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