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

Blood ◽  
2010 ◽  
Vol 115 (11) ◽  
pp. 2142-2145 ◽  
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.

Using the Genetics of the Autoimmune Lymphoproliferative Syndrome to Guide Therapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-7-SCI-7
Author(s):  
David T. Teachey
Keyword(s):  
Mycophenolate Mofetil ◽  
T Cell ◽  
Autoimmune Disease ◽  
Mtor Signaling ◽  
Cell Phenotype ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Second Line ◽  
Evans Syndrome ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias

Abstract Abstract SCI-7 Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis. Patients with ALPS may present with lymphoproliferation (lymphadenopathy and hepatosplenomegaly), autoimmune disease (most commonly autoimmune cytopenias), and secondary malignancies (typically EBER+ non-Hodgkin lymphoma). Eighty percent of ALPS patients have an identifiable genetic mutation in FAS (TNFRSF6), FASL (TNFSF6), or CASP10. These mutations can be germline or somatic with localization to the double negative T cell (DNT) compartment. DNTs (cell phenotype TCRα/β+, CD3+, CD4−, CD8−) are an atypical T cell population found in elevated quantities in peripheral blood and lymphoid tissue in ALPS patients. The diagnostic criteria for ALPS were modified in 2010 based on the results of an international consensus conference and include meeting a constellation of clinical findings, elevated DNTs, abnormal biomarkers (elevated vitamin B12, IL-10, and sFasL), in vitro evidence of defective Fas-mediated apoptosis, and mutations (somatic or germline) in Fas pathway genes. Patients with idiopathic autoimmune cytopenia syndromes (ITP, AIHA, and Evans Syndrome) and rheumatologic conditions (SLE) may have similar clinical presentations as ALPS. Our group demonstrated that approximately 45% of children diagnosed with Evans syndrome may in fact have a forme fruste of ALPS as confirmed by genetic and functional testing. Diagnosing ALPS with genetic confirmation is extremely important, because patients with idiopathic immune cytopenias should receive different treatment than ALPS patients. While first line therapy for both uses IVIgG and corticosteroids, two second-line treatments routinely used for refractory and/or chronic idiopathic autoimmune cytopenias are relatively contradicted in ALPS patients. Splenectomy has been associated with pneumococcal sepsis despite appropriate vaccination and antibiotic prophylaxis in ALPS patients. It is hypothesized that ALPS patients have increased difficulty fighting encapsulated organisms and splenectomy should be avoided. Rituximab (anti-CD20 monoclonal antibody) has been shown to cause profound and potentially life-long hypogammaglobulinemia similar to common variable immunodeficiency when used in ALPS patients and should also be avoided. In contrast, other agents used less commonly in idiopathic autoimmune cytopenias have demonstrated remarkable success in ALPS. Mycophenolate mofetil (MMF) improves autoimmune cytopenias in some refractory ALPS patients and is often used as second line treatment. Recently, we demonstrated that the mTOR inhibitor sirolimus (rapamycin) is extremely effective in ALPS both in preclinical models and in children. We have found complete responses in most patients treated with sirolimus to date. Unlike other agents, we found that sirolimus improved both autoimmune disease and lymphoproliferation, as well as specifically targeting the abnormal DNTs. No other agent, including corticosteroids, has been demonstrated to eliminate DNTs. Our preliminary data suggest that the DNTs have intrinsic abnormalities in mTOR signaling, potentially driving the autoimmune disease; and, therefore, we have a possible biologic explanation for the profound effects. Ongoing work will determine if the mTOR signaling abnormalities are specific to FAS-mutant ALPS or whether they are also found in other genetic ALPS variants that result in abnormal Fas-mediated apoptosis. Disclosures: Off Label Use: Sirolimus and mycophenolate mofetil are medications used to treat refractory autoimmune disease in patients with ALPS.

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

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.

scholarly journals Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1928 ◽  
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.

scholarly journals Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis

Blood ◽  
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.

A TACI Mutation in a Patient with Autoimmune Lymphoproliferative Syndrome.

Blood ◽  
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.

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

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.

scholarly journals Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 1965-1971 ◽  
Author(s):  
David T. Teachey ◽  
Dana A. Obzut ◽  
Kelly Axsom ◽  
John K. Choi ◽  
Kelly C. Goldsmith ◽  
...  
Keyword(s):  
Treatment Options ◽  
Three Dimensional ◽  
Mitochondrial Pathway ◽  
Lymphoproliferative Disease ◽  
Enzyme Linked Immunosorbent Assay ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Double Stranded Dna ◽  
Abnormal Lymphocyte ◽  
Lymphoproliferative Syndrome ◽  
Induced Apoptosis

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti–double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.

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

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1306-1312 ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document