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

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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Identifying Biomarkers in the Autoimmune Lymphoproliferative Syndrome (ALPS): IL-18, TNF-á, Serum Vitamin B12, Soluble FasL, and Plasma IL-10 Levels Are Useful Adjuvant Diagnostic Tools.

Blood ◽

10.1182/blood.v114.22.1647.1647 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1647-1647

Author(s):

Iusta Caminha ◽

Thomas Fleisher ◽

Julie Niemela ◽

Ron Hornung ◽

Joie Davis ◽

...

Keyword(s):

Vitamin B12 ◽

Fas Ligand ◽

Genetic Disorder ◽

Serum Vitamin ◽

Diagnostic Tools ◽

Tnf Alpha ◽

Genetic Defects ◽

Autoimmune Lymphoproliferative Syndrome ◽

Increased Risk ◽

Lymphoproliferative Syndrome

Abstract Abstract 1647 Poster Board I-673 Introduction The autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte apoptosis. Clinical findings include lymphadenopathy, splenomegaly, multi-lineage cytopenias, hypergammaglobulinemia and an increased risk for lymphoid malignancies. Nearly 65 % of ALPS patients have a heterozygous mutation in the TNFRSF6 gene coding for the FAS protein. Recently, analysis of selected biomarkers in a smaller group of ALPS patients has been reported (Blood.2009Mar26;113(13):3027-30). However, there is currently no algorithm to predict the presence or absence of TNFRSF6 (FAS) mutations in patients with clinical symptoms of ALPS. Methods We studied 562 individuals among ALPS patients and their relatives evaluated at the NIH under an IRB approved ALPS natural history protocol. We included 166 ALPS patients with defined germline or somatic FAS mutations, 5 patients with other genetic defects affecting FAS mediated apoptosis, 92 ALPS patients with unknown genetic defects (ALPS Type III), 120 FAS mutation-bearing healthy relatives and 179 mutation-negative healthy relatives as controls. Plasma levels of 15 different cytokines and soluble FAS ligand (sFASL) were measured for all groups. In addition, peripheral blood immunophenotyping data and serum vitamin B12 (B12) results from patients and controls were reviewed. For statistical calculations we used Wilcoxon-Mann-Whitney test. We also measured likelihood ratios (LR+ = sensitivity/100-specificity; LR- = 100-sensitivity/specificity) and probabilities ((odd / 1+odd) X 100) for the relevant biomarkers. Results As compared to controls, ALPS Ia patients with either germline or somatic FAS mutations demonstrated significantly higher serum vitamin B12 (p<0.0001), sFASL (p<0.0001), IL-10 (p<0.0001), IL-18 (p<0.0001) and TNF-alpha (p<0.001) levels. Those markers were also elevated in ALPS III patients but on a much less remarkable fashion. As previously described, there were a significantly decreased percentage of memory (CD20+CD27+) B cells (p<0.0001) in all ALPS groups. Moreover, a ratio of CD20+CD27+ to CD20+ cells > 0.16 (16%) made the diagnosis of ALPS unlikely (LR=0.17). We also found that patients with a combination of DNT>4% and with IL10 >40pg/ml or B12 >1500ng/L or sFASL >300pg/ml have a 97% chance of harboring a FAS mutation. Conversely, ALPS patients with DNTs <2% combined with sFASL <200pg/ml carry only 1.7% chance of having a FAS mutation. Conclusion The combination of elevated DNT counts with increased sFASL, vitamin B12 or IL10 levels in blood is strongly linked to the presence or absence of a FAS mutation. Also, TNF-alpha and IL-18 are novel markers associated with ALPS. This enables the targeting of patients with clinical features of ALPS to have a more directed evaluation particularly in regard to DNA sequencing for FAS mutations. Disclosures No relevant conflicts of interest to declare.

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Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis

Blood ◽

10.1182/blood.2020005486 ◽

2020 ◽

Vol 136 (17) ◽

pp. 1933-1945

Author(s):

Emese Molnár ◽

Nesrine Radwan ◽

Gábor Kovács ◽

Hajnalka Andrikovics ◽

Frances Henriquez ◽

...

Keyword(s):

Fas Ligand ◽

Molecular Genetic ◽

Group Identification ◽

Genetic Diagnosis ◽

Clinical Manifestations ◽

Functional Test ◽

Enzyme Linked Immunosorbent Assay ◽

Autoimmune Lymphoproliferative Syndrome ◽

Lymphoproliferative Syndrome

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficiency caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, CASP10). This study evaluated the clinical manifestations, laboratory findings, and molecular genetic results of 215 patients referred as possibly having ALPS. Double-negative T-cell (DNT) percentage and in vitro apoptosis functional tests were evaluated by fluorescence-activated cell sorting; interleukin 10 (IL-10) and IL-18 and soluble FAS ligand (sFASL) were measured by enzyme-linked immunosorbent assay. Genetic analysis was performed by next-generation sequencing. Clinical background data were collected from patients’ records. Patients were categorized into definite, suspected, or unlikely ALPS groups, and laboratory parameters were compared among these groups. Of 215 patients, 38 met the criteria for definite ALPS and 17 for suspected ALPS. The definite and suspected ALPS patient populations showed higher DNT percentages than unlikely ALPS and had higher rates of lymphoproliferation. Definite ALPS patients had a significantly more abnormal in vitro apoptosis function, with lower annexin, than patients with suspected ALPS (P = .002) and patients not meeting ALPS criteria (P < .001). The combination of elevated DNTs and an abnormal in vitro apoptosis functional test was the most useful in identifying all types of ALPS patients; the combination of an abnormal in vitro apoptosis functional test and elevated sFASLs was a predictive marker for ALPS-FAS group identification. Lymphoproliferation, apoptosis functional test, and DNTs are the most sensitive markers; elevated IL-10 and IL-18 are additional indicators for ALPS. The combination of elevated sFASLs and abnormal apoptosis function was the most valuable prognosticator for patients with FAS mutations.

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Autoimmune Lymphoproliferative Syndrome: A Syndrome Associated with Inherited Genetic Defects That Impair Lymphocytic Apoptosis—CT and US Features

Radiology ◽

10.1148/radiology.212.1.r99jl40257 ◽

1999 ◽

Vol 212 (1) ◽

pp. 257-263 ◽

Cited By ~ 24

Author(s):

Nilo A. Avila ◽

Andrew J. Dwyer ◽

Janet K. Dale ◽

Uri A. Lopatin ◽

Michael C. Sneller ◽

...

Keyword(s):

Genetic Defects ◽

Autoimmune Lymphoproliferative Syndrome ◽

Lymphoproliferative Syndrome

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A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome

Blood ◽

10.1182/blood-2006-04-015776 ◽

2006 ◽

Vol 108 (4) ◽

pp. 1306-1312 ◽

Cited By ~ 77

Author(s):

Manuel Del-Rey ◽

Jesus Ruiz-Contreras ◽

Alberto Bosque ◽

Sara Calleja ◽

Jose Gomez-Rial ◽

...

Keyword(s):

T Cell ◽

Gene Mutation ◽

Fas Ligand ◽

Clinical Manifestations ◽

Lymphoproliferative Disease ◽

Jurkat Cells ◽

Autoimmune Lymphoproliferative Syndrome ◽

Activation Induced Cell Death ◽

Fasl Gene ◽

Lymphoproliferative Syndrome

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphoproliferation and autoimmune clinical manifestations and is generally caused by defective Fas-mediated apoptosis. This report describes the first homozygous FASL gene mutation in a woman with clinical and immunologic features of ALPS. T-cell blasts from the patient did not induce FasL-mediated apoptosis on Fas-transfected murine L1210 or on Jurkat cells, and activation-induced cell death was impaired. Furthermore, Fas-dependent cytotoxicity was drastically reduced in COS cells transfected with the mutant FasL. In addition, FasL expression on T-cell blasts from the patient was similar to that observed in a healthy control, despite its bearing the high-producer genotype –844C/C in the FASL promoter. Sequencing of the patient's FASL gene revealed a new mutation in exon 4 (A247E). The location of A247E in the FasL extracellular domain and the conservation of the protein sequence of that region recorded in 8 species different from humans support the essential role of FasL COOH terminal domain in Fas/FasL binding. These findings provide evidence that inherited nonlethal FASL abnormalities cause an uncommon apoptosis defect producing lymphoproliferative disease, and they highlight the need for a review of the current ALPS classification to include a new ALPS type Ic subgroup.

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Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (ALPS)

Critical Reviews in Clinical Laboratory Sciences ◽

10.1080/10408363.2020.1855623 ◽

2020 ◽

pp. 1-30

Author(s):

Laura Casamayor-Polo ◽

Marta López-Nevado ◽

Estela Paz-Artal ◽

Alberto Anel ◽

Frederic Rieux-Laucat ◽

...

Keyword(s):

Genetic Defects ◽

Autoimmune Lymphoproliferative Syndrome ◽

Lymphoproliferative Syndrome

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Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD

International Journal of Immunopathology and Pharmacology ◽

10.1177/20587384211025934 ◽

2021 ◽

Vol 35 ◽

pp. 205873842110259

Author(s):

Hao Gu ◽

Zhenping Chen ◽

Jie Ma ◽

Jing Wang ◽

Rui Zhang ◽

...

Keyword(s):

T Cells ◽

Clinical Manifestations ◽

Autoimmune Lymphoproliferative Syndrome ◽

Apoptotic Pathway ◽

Type Iii ◽

Safety Mechanism ◽

Kinase C ◽

Clinical Control ◽

Immature B Cells ◽

Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) usually presents in childhood with fever, nonmalignant splenomegaly, and lymphadenopathy along with cytopenia, which is caused by mutations in the FAS apoptotic pathway. The TCRαβ + CD4/CD8 double-negative T cells (DNT), one of required criteria of ALPS, will rise markedly in ALPS. Human Protein kinase C delta (PRKCD) deficiency (OMIM # 615559) was recently identified to be causative for an ALPS-type III with significant B-cell proliferation particularly of immature B cells. We report a pedigree homozygous variation of PRKCD gene (c.36T>G, p. Y12X) which presented with refractory cytopenia, splenomegaly, and polarization of DNT/regulatory T cells (Treg) axis. After repeated recurrence, the patient was treated with mTOR inhibitor sirolimus, which had a safety mechanism and specifically rebalance the DNT/Treg axis. The patient’s hemoglobin and clinical condition improved gradually by the application of sirolimus (1.5 mg/m2, actual blood concentration 4.27–10.3 ng/l). Homozygous variation in PRKCD may lead to typical ALPS clinical manifestations. Targeting DNT/Treg axis, use of sirolimus in such patients may help to achieve good clinical control.

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Next Generation Sequencing for Detecting Somatic FAS Mutations in Patients With Autoimmune Lymphoproliferative Syndrome

Frontiers in Immunology ◽

10.3389/fimmu.2021.656356 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marta López-Nevado ◽

Jorge Docampo-Cordeiro ◽

José T. Ramos ◽

Rebeca Rodríguez-Pena ◽

Celia Gil-López ◽

...

Keyword(s):

Somatic Mutations ◽

Genetic Defect ◽

Autoimmune Lymphoproliferative Syndrome ◽

Apoptotic Pathway ◽

Somatic Variant ◽

Panel Testing ◽

Increased Risk ◽

Lymphoproliferative Syndrome ◽

Generation Sequencing ◽

Blood Data

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder clinically defined by chronic and benign lymphoproliferation, autoimmunity and an increased risk of lymphoma due to a genetic defect in the FAS-FASL apoptotic pathway. Genetic defects associated with ALPS are germinal and somatic mutations in FAS gene, in addition to germinal mutations in FASLG, FADD, CASP8 and CASP10 genes. The accumulation of CD3+TCRαβ+CD4-CD8- double negative T-cells (DNT) is a hallmark of the disease and 20-25% of ALPS patients show heterozygous somatic mutations restricted to DNT in the FAS gene (ALPS-sFAS patients). Nowadays, somatic mutations in the FAS gene are detected through Sanger sequencing in isolated DNT. In this study, we report an ALPS-sFAS patient fulfilling clinical and laboratory ALPS criteria, who was diagnosed through NGS with a targeted gene panel using DNA from whole blood. Data analysis was carried out with Torrent Suite Software and variant detection was performed by both germinal and somatic variant caller plugin. The somatic variant caller correctly detected other six ALPS-sFAS patients previously diagnosed in the authors’ laboratories. In summary, this approach allows the detection of both germline and somatic mutations related to ALPS by NGS, avoiding the isolation of DNT as the first step. The reads of the somatic variants could be detected even in patients with DNT in the cut off limit. Thus, custom-designed NGS panel testing may be a faster and more reliable method for the diagnosis of new ALPS patients, including those with somatic FAS mutations (ALPS-sFAS).

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Case Report: A Novel Pathogenic Missense Mutation in FAS: A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome

Frontiers in Pediatrics ◽

10.3389/fped.2021.624116 ◽

2021 ◽

Vol 9 ◽

Author(s):

Claudia L. Gaefke ◽

Jonathan Metts ◽

Donya Imanirad ◽

Daime Nieves ◽

Paola Terranova ◽

...

Keyword(s):

Genetic Defect ◽

Clinical Manifestations ◽

Case Series ◽

Missense Variant ◽

Autoimmune Lymphoproliferative Syndrome ◽

Generational Cohort ◽

Variant Of Uncertain Significance ◽

Uncertain Significance ◽

Exon 9 ◽

Lymphoproliferative Syndrome

Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in the FAS gene, is a disease with variable penetrance. Subjects may be asymptomatic, or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy. Prompt recognition of ALPS is needed for optimal management. We describe a multi-generational cohort presenting with clinical manifestations of ALPS, and a previously unreported heterozygous missense variant of uncertain significance in FAS (c.758G >T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort underscores the importance of genetic testing in subjects with clinical features of ALPS and should facilitate the reclassification of this variant as pathogenic.

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Case Report: Autoimmune Lymphoproliferative Syndrome vs. Chronic Active Epstein-Barr Virus Infection in Children: A Diagnostic Challenge

Frontiers in Pediatrics ◽

10.3389/fped.2021.798959 ◽

2021 ◽

Vol 9 ◽

Author(s):

Aleksandra Szczawińska-Popłonyk ◽

Elzbieta Grześk ◽

Eyal Schwartzmann ◽

Anna Materna-Kiryluk ◽

Jadwiga Małdyk

Keyword(s):

Epstein Barr Virus ◽

Autoimmune Disorders ◽

Epstein Barr Virus Infection ◽

Autoimmune Lymphoproliferative Syndrome ◽

Diagnostic Challenge ◽

Apoptosis Pathway ◽

Barr Virus ◽

Increased Risk ◽

Lymphoproliferative Syndrome ◽

Epstein Barr

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder characterized by a disruption of the lymphocyte apoptosis pathway, self-tolerance, and immune system homeostasis. Defects in genes within the first apoptosis signal (FAS)-mediated pathway cause an expansion of autoreactive double-negative T cells leading to non-malignant lymphoproliferation, autoimmune disorders, and an increased risk of lymphoma. The aim of the study was to show the diagnostic dilemmas and difficulties in the process of recognizing ALPS in the light of chronic active Epstein-Barr virus (CAEBV) infection. Clinical, immunological, flow cytometric, biomarkers, and molecular genetic approaches of a pediatric patient diagnosed with FAS-ALPS and CAEBV are presented. With the ever-expanding spectrum of molecular pathways associated with autoimmune lymphoproliferative disorders, multiple genetic defects of FAS-mediated apoptosis, primary immunodeficiencies with immune dysregulation, malignant and autoimmune disorders, and infections are included in the differential diagnosis. Further studies are needed to address the issue of the inflammatory and neoplastic role of CAEBV as a triggering and disease-modifying factor in ALPS.

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Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

F1000Research ◽

10.12688/f1000research.11545.1 ◽

2017 ◽

Vol 6 ◽

pp. 1928 ◽

Cited By ~ 26

Author(s):

Karen Bride ◽

David Teachey

Keyword(s):

Clinical Manifestations ◽

Lymphocyte Activation ◽

Autoimmune Lymphoproliferative Syndrome ◽

Regulatory Pathways ◽

Diagnosis And Management ◽

Disease Biology ◽

Autoimmune Pathology ◽

Lymphocyte Homeostasis ◽

Lymphoproliferative Syndrome ◽

Autoimmune Cytopenias

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited syndrome characterized by abnormal lymphocyte survival caused by failure of apoptotic mechanisms to maintain lymphocyte homeostasis. This failure leads to the clinical manifestations of non-infectious and non-malignant lymphadenopathy, splenomegaly, and autoimmune pathology, most commonly, autoimmune cytopenias. Since ALPS was first characterized in the early 1990s, insights in disease biology have improved both diagnosis and management of this syndrome. Sirolimus is the best-studied and most effective corticosteroid-sparing therapy for ALPS and should be considered first-line for patients in need of chronic treatment. This review highlights practical clinical considerations for the diagnosis and management of ALPS. Further studies could reveal new proteins and regulatory pathways that are critical for lymphocyte activation and apoptosis.

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