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1.
Immunol Invest ; : 1-14, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31762358

RESUMO

Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency and cancer predisposition, caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The clinical and immunological manifestations of A-T are very heterogeneous, especially at an early age, leading to frequent misdiagnosis. Cutaneous granulomas with unknown pathogenesis occur uncommonly in a minority of A-T patients. We herein report an unusual case of a 13-year-old girl with A-T who presented severe clinical manifestations, including multiple granulomatous lesions of the skin and a class switch defect phenotype. This patient is the first Iranian A-T case with cutaneous granulomatosis and immunodeficiency. In addition, the literature on skin granulomas in all previously reported A-T patients is reviewed indicating an increased frequency of elevated IgM level and female dominancy in this selected group of patients.

2.
Immunol Lett ; 216: 70-78, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31589898

RESUMO

BACKGROUND: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency disorders that is characterized by impaired early T lymphocyte differentiation and is variably associated with abnormal development of other lymphocyte lineages. SCID can be caused by mutations in more than 20 different genes. Molecular diagnosis in SCID patients contributes to genetic counseling, prenatal diagnosis, treatment modalities, and overall prognosis. In this cohort, the clinical, laboratory and genetic data related to Iranian SCID patients were comprehensively evaluated and efficiency of stepwise sequencing methods approach based on immunophenotype grouping was investigated METHODS: Clinical and laboratory data from 242 patients with SCID phenotype were evaluated. Molecular genetic analysis methods including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 62 patients. RESULTS: Mortality rate was 78.9% in the cohort with a median follow-up of four months. The majority of the patients had a phenotype of T-NK-B+ (34.3%) and the most severe clinical manifestation and highest mortality rate were observed in T-NK-B- SCID cases. Genetic mutations were confirmed in 50 patients (80.6%), of which defects in recombination-activating genes (RAG1 and RAG2) were found in 16 patients (32.0%). The lowest level of CD4+ and CD8+ cells were observed in patients with ADA deficiency (p = 0.026) and IL2RG deficiency (p = 0.019), respectively. CONCLUSION: Current findings suggest that candidate gene approach based on patient's immunophenotype might accelerate molecular diagnosis of SCID patients. Candidate gene selection should be done according to the frequency of disease-causing genes in different populations. Targeted gene panel, WES and WGS methods can be used for the cases which are not diagnosed using this method.

3.
Expert Rev Clin Immunol ; 15(11): 1225-1233, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31592698

RESUMO

Objectives: Common variable immunodeficiency is a primary immunodeficiency disease characterized by hypogammaglobulinemia and heterogeneous clinical features. Neutropenia is a rare complication among CVID patients leading to a higher rate of infections and morbidity. Multiple factors (e.g. autoimmunity, infections, drugs and etc.) are found to underlie this complication.Methods: In the present study, demographic, clinical and laboratory data were compared between two groups of CVID patients with and without neutropenia.Results: Frequency of neutropenia was 8.1%. Infectious complications were the most prevalent clinical manifestations regardless of presence of neutropenia. However, candida infection and septicemia were significantly higher in neutropenic patients (p = 0.001 and p = 0.01, respectively). The most prominent clinical phenotypes of CVID patients with neutropenia were polyclonal lymphocytic infiltration and autoimmunity, both being considerably higher compared to the non-neutropenic group (p = 0.04 and p = 0.009, respectively). The mortality rate in neutropenic patients was higher than in patients without neutropenia (61.1 vs. 25.2%, p = 0.004).Conclusion: Although neutropenia is a rare complication among CVID patients, it is associated with frequent and severe clinical complications, including autoimmunity and lymphoproliferative conditions. Also, its accompaniment with higher mortality frequency in CVID patients indicates a need for more precise attention and consideration regarding specific treatment in neutropenic patients.

4.
Emerg Infect Dis ; 25(11): 2005-2012, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31625840

RESUMO

Patients with immunodeficiency-associated vaccine-derived poliovirus (iVDPV) are potential poliovirus reservoirs in the posteradication era that might reintroduce polioviruses into the community. We update the iVDPV registry in Iran by reporting 9 new patients. In addition to national acute flaccid paralysis surveillance, cases were identified by screening nonparalyzed primary immunodeficiency (PID) patients. Overall, 23 iVDPV patients have been identified since 1995. Seven patients (30%) never had paralysis. Poliovirus screening accelerated the iVDPV detection rate in Iran after 2014.The iVDPV infection rate among nonparalyzed patients with adaptive PID was 3.1% (7/224), several folds higher than previous estimates. Severe combined immunodeficiency patients had the highest risk for asymptomatic infection (28.6%) compared with other PIDs. iVDPV2 emergence has decreased after the switch from trivalent to bivalent oral poliovirus vaccine in 2016. However, emergence of iVDPV1 and iVDPV3 continued. Poliovirus screening in PID patients is an essential step in the endgame of polio eradication.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31456526

RESUMO

BACKGROUND AND OBJECTIVE: Primary immunodeficiency diseases (PIDs) are a group of more than 350 disorders affecting distinct components of the innate and adaptive immune systems. In this review, the classic and advanced stepwise approach towards the diagnosis of PIDs are simplified and explained in detail. RESULTS: Susceptibility to recurrent infections is the main hallmark of almost all PIDs. However, non-infectious complications attributable to immune dysregulation presenting with lymphoproliferative and/or autoimmune disorders are not uncommon. Moreover, PIDs could be associated with misleading presentations including allergic manifestations, enteropathies, and malignancies. CONCLUSIONS: Timely diagnosis is the most essential element in improving outcome and reducing the morbidity and mortality in PIDs. This wouldn't be possible unless the physicians keep the diagnosis of PID in mind and be sufficiently aware of the approach to these patients.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31389321

RESUMO

BACKGROUND/OBJECTIVE: LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency and immune dysregulation. The authors present a case report of LPS-responsive beige-like anchor protein (LRBA) deficiency with the history of autoimmunity, enteropathy and visceral leishmaniasis. Sirolimus therapy was started for autoimmunity and enteropathy but was discontinued due to recurrent leishmaniasis. Therefore, a common side-effect of many immunosuppressive drugs in patients with LRBA deficiency is increased susceptibility to infections. METHODS: Whole exome sequencing was performed to detect the underlying genetic mutation and Leishmania DNA was detected by the PCR technique in this patient. RESULTS: Whole exome sequencing of the patient reported a homozygous frameshift deletion mutation in the LRBA gene (NM_006726: exon29: c.4638delC, p. S1546fs). Leishmania DNA PCR was positive in this case. CONCLUSION: Parasite infections manifestations report in LRBA deficiency. Leishmania infections in patients with chronic diarrhea and autoimmunity should be considered for immunodeficiency.

7.
Immunol Lett ; 215: 48-59, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442542

RESUMO

Regulatory B cells (Bregs) are immune-modulating cells that affect the immune system by producing cytokines or cellular interactions. These cells have immunomodulatory effects on the immune system by cytokine production. The abnormalities in Bregs could be involved in various disorders such as autoimmunity, chronic infectious disease, malignancies, allergies, and primary immunodeficiencies are immune-related scenarios. Ongoing investigation could disclose the biology and the exact phenotype of these cells and also the assigned mechanisms of action of each subset, as a result, potential therapeutic strategies for treating immune-related anomalies. In this review, we collect the findings of human and mouse Bregs and the therapeutic efforts to change the pathogenicity of these cells in diverse disease.

8.
Expert Rev Clin Immunol ; 15(10): 1105-1113, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31452405

RESUMO

Background: Common variable immunodeficiency (CVID) is the most common clinically significant primary immunodeficiency (PID) disorder characterized by variable clinical manifestations including recurrent infections, autoimmune disorders, enteropathy, lymphoproliferative disorders, and malignancy. The aim of this study is to estimate the overall prevalence of malignancy in patients with CVID. Methods: PubMed, Web of Science and Scopus were searched systemically to find eligible studies from the earliest available date to March 2019 with standard keywords. Pooled estimates of the malignancy prevalence and the corresponding 95% confidence intervals (CI) were calculated using random effects models. Results: Forty-eight studies with a total of 8123 CVID patients met the inclusion criteria and were finally included in the meta-analysis. Overall prevalence of malignancy was 8.6% (95% CI: 7.1-10.0; I2 = 79.2%). The prevalence of lymphoma, gastric cancer, and breast cancer in CVID patients were 4.1% (95% CI: 3.3-4.9; I2 = 62.6%), 1.5% (95% CI: 0.78-2.2; I2 = 68.9%), and 1.3% (95% CI: 0.64-1.9; I2 = 54.9%), respectively. Moreover, autoimmunity and malabsorption were more frequent in patients with malignancy than those without malignancy. Conclusion: The prevalence of malignancy has increased in CVID patients due to recent improvement in survival rate and the lymphoma is the most common type. This research highlighted the significance of malignancy screening and management in CVID patients.

9.
J Clin Immunol ; 39(6): 557-568, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31183658

RESUMO

PURPOSE: Hyper Immunoglobulin M (HIgM) syndrome is a heterogeneous group of primary immunodeficiency disorders, characterized by recurrent infections and associated with decreased serum IgG and IgA, but normal or increased IgM. The aim of the present study was to evaluate respiratory manifestations in patients with HIgM syndrome. METHODS: A total number of 62 patients, including 46 males and 16 females were included in the present study. To investigate the respiratory complications among HIgM patients, we evaluated the clinical hospital records, immunologic and molecular diagnostic assays, pulmonary function tests (PFT), and high-resolution computed tomography (HRCT) scans. RESULTS: Pneumonia was the most common respiratory manifestation (n = 35, 56.4%), followed by otitis media (45.1%), sinusitis (33.8%), and bronchiectasis (14.5%). 52.1% of the patients had abnormal PFT results, with a predominant restrictive pattern of changes. HRCT scans demonstrated abnormal findings in 85.7% of patients with found mutations. Ten cases had hilar lymphadenopathy and para-hilar infiltrates in their HRCT findings. Genetic diagnosis was confirmed in 29 HIgM patients (72.4% CD40 ligand (CD40L) and 24.1% activation-induced cytidine deaminase (AICDA/AID) deficiencies). Majority of patients with CD40L (71.4%) and AID (57.1%) deficiencies had missense mutations. Pneumonia and abnormal high-resolution computed tomography (HRCT) findings were more frequent among patients with CD40L mutation. Respiratory failure constituted the major cause of mortality (37.5%) with majority of cases occurring in CD40L-deficient patients (50%). CONCLUSIONS: Respiratory complications are common in patients with HIgM syndrome. A proper awareness of respiratory manifestations in patients with HIgM may result in improved management, reduced morbidity and mortality, and an improvement in the quality of life of the patients.

10.
Immunol Invest ; 48(8): 860-874, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31185757

RESUMO

Toll-like receptors (TLRs) are inevitable elements for immunity development and antibody production. TLRs are in close interaction with Bruton's tyrosine kinase which has been found mutated and malfunctioned in the prototype antibody deficiency disease named X-linked agammaglobulinemia (XLA). TLRs' ability was evaluated to induce transcription of TLR-negative regulators, including suppressor of cytokine signaling 1 (SOCS1), interleukin-1 receptor-associated kinase 3 (IRAK-M), tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20), and Ring finger protein 216 (RNF216), and Tumor necrosis factor-α (TNF-α) and Interferon-α (IFN-α) production via Lipopolysaccharides (LPS) and CpG-A oligodeoxynucleotides (CpG-A ODN). Measured by TaqMan real-time polymerase chain reaction (PCR), meaningfully increased transcripts of SOCS1 and RNF216 were found in XLA peripheral blood mononuclear cells (PBMCs). Also, TLR inductions of XLA have led to similar downregulations in the regulator's transcription which was different from that in healthy donors. Cytokine measurement by enzyme-linked immunosorbent assay (ELISA) revealed a significant lower TNF-α production both before and after LPS. By selected molecules in this study, TLRs' potential defectiveness range expands TLRs expression, downstream signaling, and cytokine production. The results show new potential elements that could play a part in TLRs defect and pathogenesis of agammaglobulinemia as well.

11.
Int Arch Allergy Immunol ; 180(1): 52-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31117086

RESUMO

BACKGROUND: Hyper-immunoglobulin M (HIGM) syndrome is a rare heterogeneous group of primary immunodeficiency disorders characterized by low or absent serum levels of IgG and IgA along with normal or elevated serum levels of IgM. METHODS: Clinical and immunological data were collected from the 75 patients' medical records diagnosed in Children's Medical Center affiliated to Tehran University Medical Sciences and other Universities of Medical Sciences in Iran. Among 75 selected patients, 48 patients (64%) were analyzed genetically using targeted and whole-exome sequencing. RESULTS: The ratio of male to female was 2.9:1. The median age at the onset of the disease, time of diagnosis, and diagnostic delay were 10.5, 50, and 24 months, respectively. Pneumonia and lower respiratory tract infections (61.3%) were the most common complications. Responsible genes were identified in 35 patients (72.9%) out 48 genetically analyzed patients. Cluster of differentiation 40 ligand gene was the most mutated gene observed in 24 patients (68.5%) followed by activation-induced cytidine deaminase gene in 7 patients, lipopolysaccharide-responsive and beige-like anchor (1 patient), nuclear factor-kappa-B essential modulator (1 patient), phosphoinositide-3-kinase regulatory subunit 1 (1 patient), and nuclear factor kappa B subunit 1 (1 patient) genes. Nineteen (25.3%) patients died during the study period, and pneumonia was the major cause of death occurred in 6 (31.6%) patients. CONCLUSION: Physicians in our country should carefully pay attention to respiratory tract infections and pneumonia, particularly in patients with a positive family history. Further investigations are required for detection of new genes and pathways resulting in HIGM phenotype.


Assuntos
Síndrome de Imunodeficiência com Hiper-IgM/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM/etiologia , Fenótipo , Adolescente , Adulto , Biomarcadores , Criança , Suscetibilidade a Doenças , Feminino , Testes Genéticos , Humanos , Isotipos de Imunoglobulinas/sangue , Irã (Geográfico) , Contagem de Linfócitos , Masculino , Mutação , Avaliação de Sintomas , Adulto Jovem
12.
Immunol Lett ; 210: 55-62, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31059734

RESUMO

Common Variable Immunodeficiency (CVID) and agammaglobulinemia are two of the main types of symptomatic primary antibody deficiencies. The pathogenic origins of these two diseases are different; agammaglobulinemia is a group of inherited disorders that usually are caused by mutations in the gene encoding Bruton Tyrosine Kinase (BTK) protein while CVID is a heterogeneous disorder mainly without monogenic cause. However, both diseases share a characteristic of frequent bacterial infections, a decline in serum immunoglobulin levels, and abnormality in antibody responses. The demographics and immunologic parameters, clinical manifestation, and mortality statistics from 297 patients with CVID and agammaglobulinemia followed up over 2 decades in the Children's Medical Center of Iran. Age at onset of symptom in agammaglobulinemia was earlier than CVID but the course of disease in CVID patients was longer than agammaglobulinemia patients. Pulmonary infections were the most prevalent clinical manifestations in both groups of patients. Lymphadenopathy, hepatomegaly, and splenomegaly were significantly higher in CVID patients than agammaglobulinemia patients and there was a significant association between these complications and mortality in CVID patients. Among 297 patients, 128 patients (88 CVID and 40 agammaglobulinemia) deceased. The predominant causes of death in CVID patients were infections, chronic lung disease, and malignancy while in agammaglobulinemia patients were infections and respiratory failure. Infections, especially respiratory infections were the most common complication and cause of death in both CVID and agammaglobulinemia groups and recent treatment advances even Immunoglobulin replacement cannot completely control these complications. Thus prompt recognition and specific management of these complications are worthwhile.

13.
Int Arch Allergy Immunol ; 179(3): 231-246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091523

RESUMO

Selective immunoglobulin A deficiency (SIgAD) is the most prevalent type of primary immunodeficiency disorder. The phenotypic feature of SIgAD is related to a defect in B lymphocyte differentiation into plasma cell-producing immunoglobulin A (IgA). In this review, we summarize the recent advances in this regard. Genetic (including major histocompatibility complex [MHC] and non-MHC genes), immunologic (including B and T lymphocyte subsets abnormality), cytokines/chemokines and their related receptors, apoptosis and microbiota defects are reviewed. The mechanisms leading to SIgAD are most likely multifactorial and it can be speculated that several pathways controlling B cells functions or regulating epigenetic of the IGHA gene encoding constant region of IgA heavy chain and long-term survival of IgA switched memory B cells and plasma cells may be defective in different SIgAD patients.


Assuntos
Deficiência de IgA/etiologia , Animais , Apoptose , Citocinas/imunologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Microbiota , Receptores Imunológicos/imunologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-31111319

RESUMO

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively. Patients with APDS present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation. We searched PubMed, Web of Science, and Scopus databases for APDS patients and screened for eligibility criteria. A total of 243 APDS patients were identified from 55 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Overall, 179 APDS1 and 64 APDS2 patients were identified. The most common clinical manifestations were respiratory tract infections (pneumonia (43.6%), otitis media (28.8%), and sinusitis (25.9%)), lymphoproliferation (70.4%), autoimmunity (28%), enteropathy (26.7%), failure to thrive (20.6%), and malignancy (12.8%). The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4+ T cells in 64.8% of APDS patients. The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations. The majority of APDS patients were placed on long-term immunoglobulin replacement therapy. Immunosuppressive agents such as rituximab, tacrolimus, rapamycin, and leniolisib were also administered for autoimmunity and inflammatory complications. In addition, hematopoietic stem cell transplantation (HSCT) was used in 12.8% of patients. APDS has heterogynous clinical manifestations. It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels. Moreover, HSCT should be considered in patients with severe and complicated clinical manifestations with no or insufficient response to the conventional therapies.

15.
Clin Immunol ; 205: 35-42, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31096038

RESUMO

Defects in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) are closely related to very early onset (infantile) inflammatory bowel disease (VEO-IBD). In the present study, we report a novel homozygous null mutation within interleukin-10 receptor B (IL10RB) gene in a child presenting with severe VEO-IBD. In accordance with previous reports, our patient manifested with chronic diarrhea, failure to thrive, intermittent fever and multiple anal ulcers associated with Candidiasis. Homozygous null mutation within IL10RB gene (c.92C > T, p.S31P) affecting the extracellular domain of protein was discovered in this patient. In conclusion, the diagnosis of IL-10R gene mutations should always be considered as a possible cause of refractory diarrhea and failure to thrive. Mutation analysis could help detect the genetic defects associated with these clinical manifestations and to determine the most appropriate treatment option for patients affected by this disease.

16.
J Allergy Clin Immunol Pract ; 7(7): 2379-2386.e5, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30995531

RESUMO

BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency and immune dysregulation syndrome caused by biallelic mutations in the LRBA gene. These mutations usually abrogate the protein expression of LRBA, leading to a broad spectrum of clinical phenotypes including autoimmunity, chronic diarrhea, hypogammaglobulinemia, and recurrent infections. OBJECTIVE: Our aim was to systematically collect all studies reporting on the clinical manifestations, molecular and laboratory findings, and management of patients with LRBA deficiency. METHODS: We searched in PubMed, Web of Science, and Scopus without any restrictions on study design and publication time. A total of 109 LRBA-deficient cases were identified from 45 eligible articles. For all patients, demographic information, clinical records, and immunologic and molecular data were collected. RESULTS: Of the patients with LRBA deficiency, 93 had homozygous and 16 had compound heterozygous mutations in LRBA. The most common clinical manifestations were autoimmunity (82%), enteropathy (63%), splenomegaly (57%), and pneumonia (49%). Reduction in numbers of CD4+ T cells and regulatory T cells as well as IgG levels was recorded for 21.6%, 65.6%, and 54.2% of evaluated patients, respectively. B-cell subpopulation analysis revealed low numbers of switched-memory and increased numbers of CD21low B cells in 73.5% and 77.8% of patients, respectively. Eighteen (16%) patients underwent hematopoietic stem cell transplantation due to the severity of complications and the outcomes improved in 13 of them. CONCLUSIONS: Autoimmune disorders are the main clinical manifestations of LRBA deficiency. Therefore, LRBA deficiency should be included in the list of monogenic autoimmune diseases, and screening for LRBA mutations should be routinely performed for patients with these conditions.

17.
Immunol Invest ; 48(4): 410-430, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30885031

RESUMO

Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive primary immunodeficiency disorder characterized by decreased numbers of T-cells, variable B-cell abnormalities, decreased amount of serum uric acid and PNP enzyme activity. The affected patients usually present with recurrent infections, neurological dysfunction and autoimmune phenomena. In this study, whole-exome sequencing was used to detect mutation in the case suspected of having primary immunodeficiency. We found a homozygous mutation in PNP gene in a girl who is the third case from the national Iranian registry. She had combined immunodeficiency, autoimmune hemolytic anemia and a history of recurrent infections. She developed no neurological dysfunction. She died at the age of 11 after a severe chicken pox infection. PNP deficiency should be considered in late-onset children with recurrent infections, autoimmune disorders without typical neurologic impairment.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Purina-Núcleosídeo Fosforilase/deficiência , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Anemia Hemolítica Autoimune , Varicela , Criança , Evolução Fatal , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Síndromes de Imunodeficiência/genética , Mutação de Sentido Incorreto , Purina-Núcleosídeo Fosforilase/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/genética
18.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

19.
Pediatr Allergy Immunol ; 30(4): 469-478, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30801830

RESUMO

BACKGROUND: Hyper-IgE syndromes (HIES) are distinct diseases characterized by recurrent cutaneous and lung infections, eczema, and elevated serum IgE level. METHODS: In this study, clinical manifestations, immunologic findings, and genetic studies of all patients with HIES in the Iranian national registry database were evaluated. RESULTS: A total of 129 HIES patients with a median age of 14.0 (9.0-24.0) years were followed up for a total of 307.8 patient-years. Genetic studies showed heterozygous STAT3 mutations in 19 patients and homozygous DOCK8 mutation in 16 patients. The mean of National Institutes of Health score in STAT3-deficient patients was higher than in patients with DOCK8 mutation (P = 0.001). It was shown that the presence of pneumatocele and hematologic complication were significantly frequent in STAT3-deficient cases compared to patients with DOCK8 deficiency (P = 0.001 and P = 0.002, respectively). Moreover, the median IgE serum levels were higher in patients with STAT3 gene mutation than in patients with DOCK8 gene mutation (P = 0.02). The eosinophils' count was enhanced in patients with DOCK8 deficiency than in patients with STAT3 gene defects (P = 0.02). CONCLUSION: Specific molecular study of STAT3 and DOCK8 mutations in patients with HIES clinical phenotype could help the physician to definitively characterize the disease. Since HIES showed the highest rate of unsolved combined immunodeficiency, investigation of other genetic and environmental factors could also help in understanding the mechanism of remaining patients as well as providing strategy into therapeutic modalities.

20.
Int J Radiat Biol ; 95(6): 680-690, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30714845

RESUMO

Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is an autosomal recessive primary immunodeficiency disease characterized by a CVID-like phenotype, particularly severe autoimmunity and inflammatory bowel disease. This study was undertaken to evaluate radiation sensitivity in 11 LRBA-deficient patients. Therefore, stimulated lymphocytes of the studied subjects were exposed to a low dose γ-radiation (100 cGy) in the G2 phase of the cell cycle and chromosomal aberrations were scored. Lymphocytes of age-sex matched healthy individuals used in the same way as controls. Based on the G2-assay, six (54.5%) of the patients had higher radiosensitivity score comparing to the healthy control group, forming the radiosensitive LRBA-deficient patients. This chromosomal radiosensitivity showed that these patients are predisposed to autoimmunity and/or malignancy, and should be protected from unnecessary diagnostic and therapeutic procedures using ionizing radiation and exposure to other DNA damaging agents.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Cromossomos Humanos/efeitos da radiação , Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Tolerância a Radiação/genética , Adolescente , Adulto , Criança , Cromossomos Humanos/metabolismo , Reparo do DNA/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Raios gama , Humanos , Masculino , Adulto Jovem
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