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1.
J Clin Immunol ; 45(1): 23, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39384643

RESUMO

OBJECTIVE: FAS gene defects lead to autoimmune lymphoproliferative syndrome (ALPS), which is often inherited in an autosomal dominant and rarely in an autosomal recessive manner. We report a case of a newborn girl with novel compound heterozygous variants in FAS and reveal the underlying mechanism. METHODS: Whole-exome sequencing (WES) was used to identify pathogenic variants. Multiparametric flow cytometry analysis, phosflow analysis, and FAS-induced apoptosis assays were used to explore the effects of the variants on FAS expression, apoptosis, and immunophenotype. The HEK293T cells were used to assess the impact of the variants on protein expression and FAS-induced apoptosis. RESULTS: The patient was born with hepatosplenomegaly, anemia, and thrombocytopenia. She also experienced COVID-19, rotavirus infection, herpes simplex virus infection, and severe pneumonia. The proportion of double-negative T cells (DNTs) was significantly elevated. Novel FAS compound heterozygous variants c.310T > A (p.C104S) and c.702_704del (p.T235del) were identified. The apoptotic ability of T cells was defective, and FAS expression on the surface of T cells was deficient. The T235del variant decreased FAS expression, and the C104S protein remained in the endoplasmic reticulum (ER) and could not translocate to the cell surface. Both mutations resulted in loss-of-function in terms of FAS-induced apoptosis in HEK293T cells. The DNTs were mainly terminally differentiated T (TEMRA) and CD45RA+HLA-DR+, with high expression of CD85j, PD-1, and CD57. The percentage of Th1, Tfh, and autoreactive B cells were significantly increased in the patient. The abnormal immunophenotyping was partially attenuated by sirolimus treatment. CONCLUSIONS: We identified two variants that significantly affect FAS expression or localization, leading to early disease onset of in the fetus. Abnormalities in the mTOR pathway are associated with a favorable response to sirolimus.


Assuntos
Síndrome Linfoproliferativa Autoimune , Sequenciamento do Exoma , Heterozigoto , Receptor fas , Humanos , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/imunologia , Receptor fas/genética , Feminino , Recém-Nascido , Células HEK293 , Mutação/genética , Apoptose/genética , SARS-CoV-2/fisiologia , SARS-CoV-2/imunologia , COVID-19/genética , COVID-19/imunologia , Predisposição Genética para Doença
2.
Allergol Immunopathol (Madr) ; 52(5): 6-14, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39278845

RESUMO

BACKGROUND: Elevated level of double-negative T (DNT) cells is a historical hallmark of autoimmune lymphoproliferative syndrome (ALPS) diagnosis. However, the peripheral blood level of DNT cells might also be compromised in autoimmune lymphoproliferative immunodeficiencies (ALPID) other than ALPS, inattention to which would increase the delay in diagnosis of the underlying genetic defect and hinder disease-specific treatment. MATERIALS AND METHODS: This cross-sectional study recruited patients suffering from ALPID (exclusion of ALPS) with established genetic diagnosis. Following thorough history taking, immunophenotyping for lymphocyte subsets was performed using BD FACS CaliburTM flowcytometry. RESULTS: Fifteen non-ALPS ALPID patients (60% male and 40% female) at a median (interquartile range: IQR) age of 14.0 (7.6-21.8) years were enrolled. Parental consanguinity and family history of immunodeficiency were present in 8 (53.3%) patients. The median (IQR) age at first presentation, clinical and molecular diagnosis were 18 (4-36) months, 8.0 (4.0-17.0) years, and 9.5 (5.0-20.9) years, respectively. Molecular defects were observed in these genes: LRBA (3, 20%), CTLA-4 (2, 13.3%), BACH2 (2, 13.3%), AIRE (2, 13.3%), and FOXP3, IL2Rß, DEF6, RASGRP1, PIK3CD, and PIK3R1 each in one patient (6.7%). The most common manifestations were infections (14, 93.3%), autoimmunity (12, 80%), and lymphoproliferation (10, 66.7%). The median (IQR) count of white blood cells (WBCs) and lymphocytes were 7160 (3690-12,600) and 3266 (2257-5370) cells/mm3, respectively. The median (IQR) absolute counts of CD3+ T lymphocytes and DNTs were 2085 (1487-4222) and 18 (11-36) cells/mm3, respectively. Low lymphocytes and low CD3+ T cells were observed in 3 (20%) patients compared to normal age ranges. Only one patient with FOXP3 mutation had DNT cells higher than the normal range for age. CONCLUSIONS: Most non-ALPS ALPID patients manifested normal DNT cell count. For a small subgroup of patients with high DNT cells, defects in other IEI genes may explain the phenotype and should be included in the diagnostic genetic panel.


Assuntos
Síndrome Linfoproliferativa Autoimune , Humanos , Feminino , Masculino , Estudos Transversais , Criança , Adolescente , Síndrome Linfoproliferativa Autoimune/imunologia , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Adulto Jovem , Pré-Escolar , Imunofenotipagem , Lactente , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/genética , Subpopulações de Linfócitos T/imunologia , Adulto
4.
J Clin Immunol ; 44(7): 166, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39060684

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children's Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options.


Assuntos
Síndrome Linfoproliferativa Autoimune , Testes Genéticos , Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Testes Genéticos/métodos , Feminino , Masculino , Criança , Pré-Escolar , Lactente , Adolescente , Receptor fas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Predisposição Genética para Doença , Hospitais Pediátricos , Mutação/genética
5.
Br J Haematol ; 205(3): 819-822, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38797558

RESUMO

Distinguishing RALD from JMML can be difficult. This review discusses the clinical features, genetic aetiology and the treatments that are common and distinct between the two diagnoses.


Assuntos
Síndrome Linfoproliferativa Autoimune , Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/diagnóstico , Diagnóstico Diferencial , Proteínas ras/genética , Doenças Autoimunes/genética , Doenças Autoimunes/diagnóstico
6.
Pediatr Allergy Immunol ; 35(5): e14135, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38700373

RESUMO

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder caused by defect of the extrinsic apoptotic pathway. The current diagnostic criteria combine clinical features and typical biomarkers but have not been the object of clear international consensus. METHODS: We conducted a retrospective study on pediatric patients who were investigated for autoimmune cytopenia and/or lymphoproliferation at the CHU Sainte-Justine Hospital over 10 years. Patients were screened using the combination of TCRαß+ CD4- CD8- "double negative" (DN) T cells and soluble plasmatic FAS ligand (sFASL). RESULTS: Among the 398 tested patients, the median sFASL and DN T cells were 200 ng/mL and 1.8% of TCRαß+ T cells, respectively. sFASL was highly correlated with vitamin B12 levels. We identified five patients diagnosed with ALPS for whose sFASL and vitamin B12 levels were the more discriminating biomarkers. While ALPS diagnostic criteria had high sensibility, their predictive value remained low. CONCLUSION: sFASL level can efficiently discriminate patients with ALPS when using the appropriate thresholds. Our study highlights the need for an international consensus to redefine the place and threshold of biological biomarkers for ALPS diagnosis.


Assuntos
Síndrome Linfoproliferativa Autoimune , Biomarcadores , Proteína Ligante Fas , Humanos , Biomarcadores/sangue , Masculino , Feminino , Estudos Retrospectivos , Criança , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/sangue , Pré-Escolar , Lactente , Proteína Ligante Fas/sangue , Adolescente , Vitamina B 12/sangue
7.
Cell Death Dis ; 15(5): 315, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38704374

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS, FASLG, and FADD, all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute's genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.


Assuntos
Apoptose , Síndrome Linfoproliferativa Autoimune , Caspase 10 , Mutação , Receptor fas , Humanos , Caspase 10/genética , Caspase 10/metabolismo , Síndrome Linfoproliferativa Autoimune/genética , Masculino , Feminino , Mutação/genética , Apoptose/genética , Receptor fas/genética , Receptor fas/metabolismo , Adulto , Criança , Adolescente , Pessoa de Meia-Idade
8.
J Pediatr Hematol Oncol ; 46(5): e331-e333, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38652075

RESUMO

Multiple myeloma is a rare disease in pediatrics, where about 30 cases are described under 15 years old. It is even rarer when atypical multiple myeloma occurs in the context of autoimmunity. This case describes a 9-year-old female with autoimmune lymphoproliferative-like disease and combined immune deficiency that developed acute kidney failure with monoclonal peak associated with RAC2 and TNFRSF9 variants. An adapted protocol from the backbone adult multiple myeloma standard of care with the addition of an allogeneic hematopoietic stem cell transplant was used. The patient, now nearly a year posttransplant, shows 100% chimerism with no sign of relapse.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Humanos , Feminino , Criança , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Síndrome Linfoproliferativa Autoimune/complicações , Síndrome Linfoproliferativa Autoimune/patologia , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética
10.
Lancet Haematol ; 11(2): e114-e126, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38302222

RESUMO

BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. FINDINGS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. INTERPRETATION: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. FUNDING: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.


Assuntos
Anemia Hemolítica Autoimune , Síndrome Linfoproliferativa Autoimune , Imunodeficiência de Variável Comum , Trombocitopenia , Masculino , Feminino , Criança , Humanos , Pré-Escolar , Adolescente , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/terapia , Estudos Prospectivos , Biomarcadores , Proteínas Adaptadoras de Transdução de Sinal/genética
11.
J Allergy Clin Immunol ; 153(1): 67-76, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37977527

RESUMO

Chronic nonmalignant lymphoproliferation and autoimmune cytopenia are relevant manifestations of immunohematologic diseases of childhood. Their diagnostic classification is challenging but important for therapy. Autoimmune lymphoproliferative syndrome (ALPS) is a genetically defined inborn error of immunity combining these manifestations, but it can explain only a small proportion of cases. Diagnostic categories such as ALPS-like disease, common variable immunodeficiency, or Evans syndrome have therefore been used. Advances in genetics and increasing availablity of targeted therapies call for more therapy-oriented disease classification. Moreover, recent discoveries in the (re)analysis of genetic conditions affecting FAS signaling ask for a more precise definition of ALPS. In this review, we propose the term autoimmune lymphoproliferative immunodeficiencies for a disease phenotype that is enriched for patients with genetic diseases for which targeted therapies are available. For patients without a current molecular diagnosis, this term defines a subgroup of immune dysregulatory disorders for further studies. Within the concept of autoimmune lymphoproliferative immunodeficiencies, we propose a revision of the ALPS classification, restricting use of this term to conditions with clear evidence of perturbation of FAS signaling and resulting specific biologic and clinical consequences. This proposed approach to redefining ALPS and other lymphoproliferative conditions provides a framework for disease classification and diagnosis that is relevant for the many specialists confronted with these diseases.


Assuntos
Anemia Hemolítica Autoimune , Doenças Autoimunes , Síndrome Linfoproliferativa Autoimune , Imunodeficiência de Variável Comum , Doenças do Sistema Imunitário , Transtornos Linfoproliferativos , Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/terapia , Fenótipo , Receptor fas/genética , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/terapia
13.
J Allergy Clin Immunol ; 153(1): 203-215, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37793571

RESUMO

BACKGROUND: The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated. OBJECTIVE: We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent. METHODS: We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4+ or DN T cells. RESULTS: We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations. CONCLUSIONS: The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.


Assuntos
Síndrome Linfoproliferativa Autoimune , Proteína de Domínio de Morte Associada a Fas , Humanos , Apoptose/genética , Doenças Autoimunes/genética , Síndrome Linfoproliferativa Autoimune/genética , Hibridização Genômica Comparativa , DNA , Receptor fas/genética , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Células Germinativas/patologia , Mutação
15.
J Allergy Clin Immunol ; 153(1): 297-308.e12, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37979702

RESUMO

BACKGROUND: Elevated TCRαß+CD4-CD8- double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U). OBJECTIVE: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases. METHODS: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway-related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH). RESULTS: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH. CONCLUSION: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing.


Assuntos
Síndrome Linfoproliferativa Autoimune , Receptor fas , Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Biomarcadores , Variações do Número de Cópias de DNA , Sequenciamento do Exoma , Receptor fas/genética , Proteína de Domínio de Morte Associada a Fas/genética , Mutação
16.
Rheum Dis Clin North Am ; 49(4): 841-860, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37821199

RESUMO

As a disorder of immune dysregulation, autoimmune lymphoproliferative syndrome (ALPS) stems from pathogenic variants in the first apoptosis signal-mediated apoptosis (Fas) and Fas-ligand pathway that result in elevations of CD3+ TCRαß+ CD4- CD8- T cells along with chronic lymphoproliferation, a heightened risk for malignancy, and importantly for the rheumatologist, increased risk of autoimmunity. While immune cytopenias are the most encountered autoimmune phenomena, there is increasing appreciation for ocular, musculoskeletal, pulmonary and renal inflammatory manifestations similar to more common rheumatology diseases. Additionally, ALPS-like conditions that share similar clinical features and opportunities for targeted therapy are increasingly recognized via genetic testing, highlighting the need for rheumatologists to be facile in the recognition and diagnosis of this spectrum of disorders. This review will focus on clinical and laboratory features of both ALPS and ALPS-like disorders with the intent to provide a framework for rheumatologists to understand the pathophysiologic drivers and discriminate between diagnoses.


Assuntos
Doenças Autoimunes , Síndrome Linfoproliferativa Autoimune , Neoplasias , Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Receptor fas/genética , Autoimunidade
17.
J Clin Immunol ; 43(8): 1692-1705, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37794137

RESUMO

PURPOSE: Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome-related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency. METHODS: Literature review was performed using MEDLINE. RESULTS: Twenty cases have been described in the literature with significant heterogeneity. CONCLUSION: The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.


Assuntos
Síndrome Linfoproliferativa Autoimune , Lúpus Eritematoso Sistêmico , Criança , Humanos , Proteína Quinase C-delta/genética , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Síndrome Linfoproliferativa Autoimune/genética , Tolerância Imunológica , Variação Biológica da População
18.
Autoimmun Rev ; 22(11): 103442, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37683818

RESUMO

Autoimmune Lymphoproliferative Syndrome (ALPS) is an autoimmune disease that has been reported in over 2200 patients. It is a rare, genetic disease where pathogenic variants occur in the extrinsic pathway of apoptosis. Various mutations in different genes, such as FAS, FASL, and CASP10, can result in ALPS. Most commonly, pathogenic variants occur in the FAS receptor. This malfunctioning pathway allows for the abnormal accumulation of lymphocytes, namely CD3 + TCRαß+CD4 - CD8- (double negative (DN) T) cells, which are a hallmark of the disease. This disease usually presents in childhood with lymphadenopathy and splenomegaly as a result of lymphoproliferation. Over time, these patients may develop cytopenias or lymphomas because of irregularities in the immune system. Current treatments include glucocorticoids, mycophenolate mofetil, sirolimus, immunoglobulin G, and rituximab. These medications serve to manage the symptoms and there are no standardized recommendations for the management of ALPS. The only curative therapy is a bone marrow transplant, but this is rarely done because of the complications. This review serves to broaden the understanding of ALPS by discussing the mechanism of immune dysregulation, how the symptoms manifest, and the mechanisms of treatment. Additionally, we discuss the epidemiology, comorbidities, and medications relating to ALPS patients across the United States using data from Cosmos.


Assuntos
Doenças Autoimunes , Síndrome Linfoproliferativa Autoimune , Transtornos Linfoproliferativos , Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Síndrome Linfoproliferativa Autoimune/terapia , Doenças Autoimunes/tratamento farmacológico , Receptor fas/genética , Receptor fas/uso terapêutico , Esplenomegalia/tratamento farmacológico , Esplenomegalia/genética , Esplenomegalia/patologia , Mutação , Sirolimo/uso terapêutico , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia
19.
Sci Rep ; 13(1): 13530, 2023 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-37598245

RESUMO

In the northern forelands of the Alps, farmers report an increase of Jacobaea aquatica in production grasslands. Due to its toxicity, the species affects grassland productivity and calls for costly control measures. We are investigating the extent to which management practices or climatic factors are responsible for the increase of the species and how the situation will change due to climate change. We tested for effects of management intensity, fertilization, agri-environmental measures, and soil disturbance, and modeled the occurrence of the species under rcp4.5 and rcp8.5 scenarios. The main determinants of the occurrence of the species are soil type and summer rainfall. A high risk is associated with wet soils and > 400 mm of rain between June and August; an influence of the management-related factors could not be detected. Under the climate-change scenarios, the overall distribution decreases and shifts to the wetter alpine regions. Thus, the current increase is rather a shift in the occurrence of the species due to the altered precipitation situation. Under future climatic conditions, the species will decline and retreat to higher regions in the Alps. This will decrease the risk of forage contamination for production grassland in the lowlands.


Assuntos
Síndrome Linfoproliferativa Autoimune , Plantas Tóxicas , Pradaria , Chuva , Solo
20.
J Clin Immunol ; 43(8): 1992-1996, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37644277

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a disease of lymphocyte homeostasis caused by FAS-mediated apoptotic pathway dysfunction and is characterized by non-malignant lymphoproliferation with an increased number of TCRαß+CD4-CD8- double-negative T cells (αßDNTs). Conversely, RAS-associated leukoproliferative disease (RALD), which is caused by gain-of-functional somatic variants in KRAS or NRAS, is considered a group of diseases with a similar course. Herein, we present a 7-year-old Japanese female of RALD harboring NRAS variant that aggressively progressed to juvenile myelomonocytic leukemia (JMML) with increased αßDNTs. She eventually underwent hematopoietic cell transplantation due to acute respiratory distress which was caused by pulmonary infiltration of JMML blasts. In general, αßDNTs have been remarkably increased in ALPS; however, FAS pathway gene abnormalities were not observed in this case. This case with RALD had repeated shock/pre-shock episodes as the condition progressed. This shock was thought to be caused by the presence of a high number of αßDNTs. The αßDNTs observed in this case revealed high CCR4, CCR6, and CD45RO expressions, which were similar to Th17. These increased Th17-like αßDNTs have triggered the inflammation, resulting in the pathogenesis of shock, because Th17 secretes pro-inflammatory cytokines such as interleukin (IL)-17A and granulocyte-macrophage colony-stimulating factor. The presence of IL-17A-secreting αßDNTs has been reported in systemic lupus erythematosus (SLE) and Sjögren's syndrome. The present case is complicated with SLE, suggesting the involvement of Th17-like αßDNTs in the disease pathogenesis. Examining the characteristics of αßDNTs in RALD, JMML, and ALPS may reveal the pathologies in these cases.


Assuntos
Síndrome Linfoproliferativa Autoimune , Lúpus Eritematoso Sistêmico , Transtornos Linfoproliferativos , Feminino , Humanos , Criança , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Linfócitos T CD4-Positivos , Receptores de Antígenos de Linfócitos T alfa-beta/genética
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