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

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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Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study

Blood ◽

10.1182/blood-2009-08-239525 ◽

2010 ◽

Vol 115 (11) ◽

pp. 2142-2145 ◽

Cited By ~ 54

Author(s):

Alix E. Seif ◽

Catherine S. Manno ◽

Cecilia Sheen ◽

Stephan A. Grupp ◽

David T. Teachey

Keyword(s):

Strong Predictor ◽

Clinical Manifestations ◽

High Rate ◽

Autoimmune Lymphoproliferative Syndrome ◽

Evans Syndrome ◽

Apoptotic Pathway ◽

Abnormal Lymphocyte ◽

Lymphoproliferative Syndrome ◽

Autoimmune Cytopenias ◽

Immunoglobulin Levels

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and lymphadenopathy. These findings overlap with Evans syndrome (ES), defined by presence of at least 2 autoimmune cytopenias. We hypothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measuring peripheral blood double-negative T cells (DNTs) and Fas-mediated apoptosis. ALPS was diagnosed in 47% of patients tested. Markedly elevated DNTs (≥ 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patients with DNTs less than 2.5% had ALPS on apoptosis testing. Severity of cytopenias and elevated immunoglobulin levels also predicted ALPS. This is the largest published series describing children with ES and documents a high rate of ALPS among pediatric ES patients. These data suggest that children with ES should be screened for ALPS with DNTs.

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Gadd45β and Gadd45γ are critical for regulating autoimmunity

Journal of Experimental Medicine ◽

10.1084/jem.20051359 ◽

2005 ◽

Vol 202 (10) ◽

pp. 1341-1348 ◽

Cited By ~ 35

Author(s):

Lin Liu ◽

Elise Tran ◽

Yani Zhao ◽

Yuchen Huang ◽

Richard Flavell ◽

...

Keyword(s):

T Cells ◽

Lupus Erythematosus ◽

Growth Arrest ◽

Effector T Cells ◽

Autoimmune Lymphoproliferative Syndrome ◽

Autoimmune Encephalomyelitis ◽

Disease Therapy ◽

The Central Nervous System ◽

Lymphoproliferative Syndrome ◽

Novel Target

The number of effector T cells is controlled by proliferation and programmed cell death. Loss of these controls on self-destructive effector T cells may precipitate autoimmunity. Here, we show that two members of the growth arrest and DNA damage-inducible (Gadd45) family, β and γ, are critical in the development of pathogenic effector T cells. CD4+ T cells lacking Gadd45β can rapidly expand and invade the central nervous system in response to myelin immunization, provoking an exacerbated and prolonged autoimmune encephalomyelitis in mice. Importantly, mice with compound deficiency in Gadd45β and Gadd45γ spontaneously developed signs of autoimmune lymphoproliferative syndrome and systemic lupus erythematosus. Our findings therefore identify the Gadd45β/Gadd45γ-mediated control of effector autoimmune lymphocytes as an attractive novel target for autoimmune disease therapy.

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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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A TACI Mutation in a Patient with Autoimmune Lymphoproliferative Syndrome.

Blood ◽

10.1182/blood.v108.11.3881.3881 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3881-3881

Author(s):

Maria Francesca Campagnoli ◽

Emanuela Garelli ◽

Valentina Baravalle ◽

Adriana Carando ◽

Carla Alliaudi ◽

...

Keyword(s):

Autoimmune Lymphoproliferative Syndrome ◽

Massive Splenomegaly ◽

Apoptotic Pathway ◽

Rich Domain ◽

The Alps ◽

Lymphoproliferative Syndrome ◽

Induced Apoptosis ◽

Common Variable ◽

Genetic Analyzer ◽

Cysteine Rich Domain

Abstract The autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte apoptosis caused by defects in the Fas apoptotic pathway. It is characterized by the association of chronic lymphoid accumulation and autoimmune manifestations. In a subgroup of patients the disease progresses through antibody deficiency and its clinical and laboratory features overlap those of common variable immunodeficiency (CVID). Some CVID cases are associated with mutations in gene TNFRSF13B, encoding TACI. Aim of this study was to determine whether TNFRSF13B mutations are also associated with ALPS. Methods. Genomic DNA from 31 ALPS patients was extracted from PBMCs after informed consent. Exons and intron-exon boundaries of TNFRSF13B gene were amplified by PCR and sequenced on an ABI PRISM 310 Genetic Analyzer. Results. A T>A transition at nt 275, that determined the non-conservative substitution of Isoleucine with Asparagine (I92N), was found in exon 3 from one patient. The mutation involved the second extracellular cysteine rich domain, which is critical for BAFF binding. It was not found in 100 control chromosomes. The patient showed a classical ALPS phenotype with lymphadenopathy, massive splenomegaly that required splenectomy, hepatomegaly and immune cytopenias (neutropenia and immune thrombocytopenic purpura); he had alopecia and high ANA levels. Serum immunoglobulins were normal (IgG titers at the lower level of the range); lymphocytes showed defective Fas-induced apoptosis. Discussion. TACI mutations might contribute to the ALPS phenotype in some cases. Our data confirm the relationships between ALPS and CVID and provides a possible molecular explanation for overlapping phenotypes.

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Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression

Blood ◽

10.1182/blood.v97.10.3161 ◽

2001 ◽

Vol 97 (10) ◽

pp. 3161-3170 ◽

Cited By ~ 81

Author(s):

Uri Lopatin ◽

Xu Yao ◽

Richard K. Williams ◽

Jack J. H. Bleesing ◽

Janet K. Dale ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Messenger Rna ◽

Mononuclear Cells ◽

Population Expansion ◽

Interleukin 10 ◽

Lymphoid Tissues ◽

Autoimmune Lymphoproliferative Syndrome ◽

Peripheral Blood Mononuclear ◽

Lymphoproliferative Syndrome

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which genetic defects in proteins that mediate lymphocyte apoptosis, most often Fas, are associated with enlargement of lymph nodes and the spleen and a variety of autoimmune manifestations. Some patients with ALPS have relatives with these same apoptotic defects, however, who are clinically well. This study showed that the circulating levels of interleukin 10 (IL-10) were significantly higher (P < .001) in 21 patients with ALPS than in healthy controls. Moreover, the peripheral blood mononuclear cells (PBMCs) and lymphoid tissues of these patients with ALPS contained significantly higher levels of IL-10 messenger RNA (mRNA;P < .001 and P < .01, respectively). By fractionating PBMC populations, disproportionately high concentrations of IL-10 mRNA were found in the CD4−CD8−T-cell population, expansion of which is virtually pathognomonic for ALPS. Immunohistochemical staining showed intense IL-10 protein signals in lymph node regions known to contain CD4−CD8− T cells. Nonetheless, in vitro studies showed no influence of IL-10 on the survival of CD4−CD8− T cells. Overexpression of IL-10 in patients with inherited apoptotic defects is strongly associated with the overt manifestations of ALPS.

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Autoimmune Lymphoproliferative Syndrome Type III, an Indefinite Disorder

Leukemia & Lymphoma ◽

10.3109/10428190109060341 ◽

2001 ◽

Vol 41 (5-6) ◽

pp. 501-511 ◽

Cited By ~ 10

Author(s):

Jutte van Derwerff Ten Bosch ◽

Jacques Otten ◽

Kris Thielemans

Keyword(s):

Syndrome Type ◽

Autoimmune Lymphoproliferative Syndrome ◽

Type Iii ◽

Lymphoproliferative Syndrome

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.671755 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marta López-Nevado ◽

Luis I. González-Granado ◽

Raquel Ruiz-García ◽

Daniel Pleguezuelo ◽

Oscar Cabrera-Marante ◽

...

Keyword(s):

Correct Diagnosis ◽

Clinical Manifestations ◽

Genetic Defects ◽

Immunological Study ◽

Autoimmune Lymphoproliferative Syndrome ◽

Loss Of Function ◽

Stat3 Phosphorylation ◽

Increased Risk ◽

Lymphoproliferative Syndrome ◽

Regulatory Disorders

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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Autoimmune Lymphoproliferative Syndrome: An Overview

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2018-0190-rs ◽

2019 ◽

Vol 144 (2) ◽

pp. 245-251

Author(s):

Daniel R. Matson ◽

David T. Yang

Keyword(s):

T Cells ◽

Double Negative ◽

Autoimmune Lymphoproliferative Syndrome ◽

Test Results ◽

Pathologic Feature ◽

Laboratory Test Results ◽

Inherited Immunodeficiency ◽

Fas Signaling ◽

Lymphoproliferative Syndrome ◽

Double Negative T Cells

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited nonmalignant lymphoproliferative disorder characterized by heterozygous mutations within the first apoptosis signal receptor (FAS) signaling pathway. Defects in FAS-mediated apoptosis cause an expansion and accumulation of autoreactive CD4− and CD8− (double-negative) T cells, leading to cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and a greatly increased lifetime risk of lymphoma. The differential diagnosis of ALPS includes infection, other inherited immunodeficiency disorders, primary and secondary autoimmune syndromes, and lymphoma. The most consistent pathologic feature is a florid paracortical expansion of double-negative T cells in lymph nodes. A presumptive clinical diagnosis can be made from symptoms and a constellation of laboratory test results. However, a definitive diagnosis requires ancillary testing and enables disease subclassification. Recognition of ALPS is critical, as treatment with immunosuppressive therapies can effectively reduce or ameliorate symptoms for most patients.

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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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