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1.
Pediatr Pulmonol ; 54(2): 194-199, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30575324

RESUMO

BACKGROUND: The role of viruses in children with respiratory tract infections and humoral immunodeficiencies has hardly been studied. We have evaluated these infections in children with humoral immunodeficiencies who required immunoglobulin replacement therapy, considering their relationship with symptoms, lung function, bacterial co-infection, and outcomes. METHODS: We conducted a prospective case-control study during a 1-year period, including children with humoral immunodeficiencies receiving immunoglobulin replacement therapy. For each patient, at least one healthy family member was included. Respiratory samples for viral detection were taken every 1-3 months, and in case of respiratory tract infections. Symptoms questionnaires were filled biweekly. Spirometry and sputum culture were performed in every episode. RESULTS: Sixty-six episodes were analyzed in 14 patients (median age 12 years; IQR 7-17), identifying 18 respiratory viruses (27.3%), being rhinovirus the most frequently isolated one (12/18; 66%). Positive viral episodes were associated with clinical symptoms (89% vs 43%), more frequent antibiotic treatment (44% vs 15%) or hospital admission (22% vs 0%) than negative ones. Patients with positive viral detection showed impaired lung function, with lower FEV1 and FVC values. CONCLUSIONS: In our experience, viral respiratory tract infections can cause significant respiratory symptoms and impaired lung function, in children with HID, despite immunoglobulin replacement therapy. These patients could benefit from the monitoring of viral infections, as these may be a gateway for ongoing lung damage.


Assuntos
Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência , Infecções Respiratórias , Viroses , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/fisiopatologia , Masculino , Testes de Função Respiratória , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/fisiopatologia , Espanha/epidemiologia , Viroses/tratamento farmacológico , Viroses/epidemiologia , Viroses/fisiopatologia
2.
Orv Hetil ; 159(49): 2057-2064, 2018 Dec.
Artigo em Húngaro | MEDLINE | ID: mdl-30525879

RESUMO

The number of primary immune deficiencies exceeds 350, approximately a quarter of them having neurological implications. Severe central nervous system infections may occur in an even higher proportion. Beyond listing in a table of all diseases with a neurological impact, the author gives detailed analysis of one typical disorder. Ataxia telangiectasia is caused by biallelic mutation of the ATM gene resulting in genomic instability, increased cancer risk, immune deficiency and a predominantly cerebellar neurodegeneration. The most common classic form is characterized by gait and limb ataxia, oculomotor apraxia, choreoathetosis, disturbance of speech and swallowing, less often by other movement disorders. There is no remarkable cognitive deficit. Telangiectasia of the conjunctivae and skin usually appears after 6 years of age. Frequent, especially severe sino-pulmonary infections may indicate the immune deficiency present in 60 to 80% of patients, who are also prone to malignancies. The clinical course is sometimes atypical or has a late onset which results in diagnostic difficulties. Serum alpha-fetoprotein level is elevated in nearly all patients. Brain MRI shows progressive cerebellar atrophy starting at the age of 7-8 years. DNA testing of the ATM gene is necessary for the diagnosis. The detected biallelic pathogenic variants provide help for family planning and for possible gene therapies in the future. Ataxia telangiectasia has to be differentiated from a number of other disorders, some of which also belong to primary immune deficiencies. The disorder has no causal treatment at present, the patients live until their young adult ages. Orv Hetil. 2018; 159(49): 2057-2064.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatologia , Síndromes de Imunodeficiência/fisiopatologia , Adulto , Criança , Feminino , Humanos , Masculino
3.
Curr Opin Pediatr ; 30(6): 821-828, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30407975

RESUMO

PURPOSE OF REVIEW: A comparative description of dysregulatory syndromes with mutations in signal transducer and activator of transcription (STAT) genes. RECENT FINDINGS: STAT 1, 3 and 5b loss of function (LOF) and gain of function (GOF) mutations are a heterogeneous group of genetic disorders that range from immunodeficiency (ID) to autoimmune disease (AID), depending on the underlying signalling pathway defect. Between them, there are clear overlapping and differences in clinical presentation and laboratory findings. SUMMARY: Dysregulatory syndromes due to LOF and GOF mutations in STAT1, 3 and 5b are a particular group of primary immunodeficiencies (PIDs) in which AID may be the predominant finding in addition to infections susceptibility. STAT1 GOF mutations were described as the major cause of chronic mucocutaneous candidiasis, while activating STAT3 mutations result in early-onset multiorgan autoimmunity and ID. Human STAT5b deficiency is a rare disease that also involves ID and severe growth failure. In recent years, the identification of the genes involved in these disorders allowed to differentiate these overlapping syndromes in order to choose the most effective therapeutic options.


Assuntos
Autoimunidade/genética , Mutação com Ganho de Função/fisiologia , Síndromes de Imunodeficiência/genética , Mutação/fisiologia , Fatores de Transcrição STAT/fisiologia , Criança , Análise Mutacional de DNA , Mutação com Ganho de Função/genética , Predisposição Genética para Doença , Humanos , Síndromes de Imunodeficiência/fisiopatologia , Mutação/genética , Fenótipo , Prognóstico , Fatores de Risco , Fatores de Transcrição STAT/genética , Transdução de Sinais
4.
Curr Opin Pediatr ; 30(6): 848-854, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30407976

RESUMO

PURPOSE OF REVIEW: The mechanisms underlying the overlap of, and relationship between, atopy and immunodeficiency are just beginning to be recognized, through the identification of novel genetic conditions and the reexamination of well known primary immunodeficiencies. The present review seeks both to frame the topic and to highlight the most recent literature combining allergy in the context of immunodeficiency. RECENT FINDINGS: The true prevalence of atopic disorders in the setting of primary immunodeficiency as a whole is difficult to pinpoint, however there have been recent attempts to measure prevalence. Individual immunodeficiency disorders have been more carefully dissected for atopic disease and the mechanisms underlying the atopic phenotypic, whereas several newly described immune deficiencies because of single gene mutations are highly associated with atopic phenotypes. Finally, a number of novel genetic conditions with atopy being the primary feature, even in the absence of overt immune deficiency, have been described, providing instrumental clues into the diagnostic dilemmas these syndromes create. SUMMARY: Defining and examining diseases with primary features of atopy and infection allow for a better understanding of the interplay between the two in rare disease, and hopefully sheds light on fundamental pathways involved in atopy and host defense in the general population.


Assuntos
Predisposição Genética para Doença/epidemiologia , Hipersensibilidade/imunologia , Síndromes de Imunodeficiência/imunologia , Criança , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/genética , Hipersensibilidade/fisiopatologia , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/fisiopatologia , Mutação/genética , Prevalência
5.
Colomb Med (Cali) ; 49(3): 236-243, 2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30410199

RESUMO

Bi-allelic mutations in LRBA (from Lipopolysaccharide-responsive and beige-like anchor protein) result in a primary immunodeficiency with clinical features ranging from hypogammaglobulinemia and lymphoproliferative syndrome to inflammatory bowel disease and heterogeneous autoimmune manifestations. LRBA deficiency has been shown to affect vesicular trafficking, autophagy and apoptosis, which may lead to alterations of several molecules and processes that play key roles for immunity. In this review, we will discuss the relationship of LRBA with the endovesicular system in the context of receptor trafficking, autophagy and apoptosis. Since these mechanisms of homeostasis are inherent to all living cells and not only limited to the immune system and also, because they are involved in physiological as well as pathological processes such as embryogenesis or tumoral transformation, we envisage advancing in the identification of potential pharmacological agents to manipulate these processes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Membrana Celular/metabolismo , Síndromes de Imunodeficiência/genética , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Mutação
6.
Graefes Arch Clin Exp Ophthalmol ; 256(11): 2113-2125, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30215097

RESUMO

PURPOSE: To create new immunodeficient Royal College of Surgeons (RCS) rats by introducing the defective MerTK gene into athymic nude rats. METHODS: Female homozygous RCS (RCS-p+/RCS-p+) and male nude rats (Hsd:RH-Foxn1mu, mutation in the foxn1 gene; no T cells) were crossed to produce heterozygous F1 progeny. Double homozygous F2 progeny obtained by crossing the F1 heterozygotes was identified phenotypically (hair loss) and genotypically (RCS-p+ gene determined by PCR). Retinal degenerative status was confirmed by optical coherence tomography (OCT) imaging, electroretinography (ERG), optokinetic (OKN) testing, superior colliculus (SC) electrophysiology, and by histology. The effect of xenografts was assessed by transplantation of human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) and human-induced pluripotent stem cell-derived RPE (iPS-RPE) into the eye. Morphological analysis was conducted based on hematoxylin and eosin (H&E) and immunostaining. Age-matched pigmented athymic nude rats were used as control. RESULTS: Approximately 6% of the F2 pups (11/172) were homozygous for RCS-p+ gene and Foxn1mu gene. Homozygous males crossed with heterozygous females resulted in 50% homozygous progeny for experimentation. OCT imaging demonstrated significant loss of retinal thickness in homozygous rats. H&E staining showed photoreceptor thickness reduced to 1-3 layers at 12 weeks of age. Progressive loss of visual function was evidenced by OKN testing, ERG, and SC electrophysiology. Transplantation experiments demonstrated survival of human-derived cells and absence of apparent immune rejection. CONCLUSIONS: This new rat animal model developed by crossing RCS rats and athymic nude rats is suitable for conducting retinal transplantation experiments involving xenografts.


Assuntos
Modelos Animais de Doenças , Células-Tronco Embrionárias Humanas/transplante , Síndromes de Imunodeficiência/terapia , Células-Tronco Pluripotentes Induzidas/transplante , Distrofias Retinianas/terapia , Epitélio Pigmentado da Retina/transplante , Animais , Sobrevivência Celular , Eletrorretinografia , Feminino , Técnicas de Genotipagem , Sobrevivência de Enxerto/fisiologia , Células-Tronco Embrionárias Humanas/fisiologia , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/fisiopatologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Masculino , Fenótipo , Ratos , Ratos Nus , Retina/fisiopatologia , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/fisiopatologia , Epitélio Pigmentado da Retina/fisiologia , Tomografia de Coerência Óptica , c-Mer Tirosina Quinase/genética
7.
Curr Opin Pediatr ; 30(6): 855-863, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30124581

RESUMO

PURPOSE OF REVIEW: The risk of cancer is higher, and its outcome is worse in patients with primary immunodeficiency (PID) than in members of the general population. Thus, the inter-relationship of malignant diseases with PIDs requires more study. RECENT FINDINGS: Large genetic screens identified a vast number of germline mutations in childhood cancer patient samples. Although TP53 was the most frequent single gene identified as mutated, many PID disorders like DNA repair defects are among the inborn causes of childhood cancer. We provide a comprehensive analysis of compiled data from seven recent studies that focused on germline genetic landscapes and preexisting conditions in pediatric oncology. As potentially causal germline variants were identified in ≈8% of malignancies in children and adolescents, we visualized this proportion as the 'tips of the icebergs'. The results of additional network analyses showed the shared patterns of germline mutations in various malignancies and yielded a spatial distribution of the 'icebergs'. SUMMARY: The 'iceberg map of germline mutations in childhood cancers' was created to increase the awareness of the inborn genetic underpinnings of childhood malignancies and their relationships with immunodeficiencies. Needs and perspectives of clinical immunologists and pediatric oncologists to both improve patient care and guide research at this critical interface are discussed. VIDEO ABSTRACT.


Assuntos
Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Síndromes de Imunodeficiência/genética , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Causalidade , Criança , Análise Mutacional de DNA , Gerenciamento Clínico , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Neoplasias/imunologia , Neoplasias/fisiopatologia , Pediatria , Fenótipo
8.
Autoimmun Rev ; 17(10): 1028-1039, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30107266

RESUMO

Primary immunodeficiency diseases (PIDs) consist of a large group of genetic disorders that affect distinct components of the immune system. PID patients are susceptible to infection and non-infectious complications, particularly autoimmunity. A specific group of monogenic PIDs are due to mutations in genes that are critical for the regulation of immunological tolerance and immune responses. This group of monogenic PIDs is at high risk of developing polyautoimmunity (i.e., the presence of more than one autoimmune disease in a single patient) because of their impaired immunity. In this review, we discuss the mechanisms of autoimmunity in PIDs and the characteristics of polyautoimmunity in the following PIDs: IPEX; monogenic IPEX-like syndrome; LRBA deficiency; CTLA4 deficiency; APECED; ALPS; and PKCδ deficiency.


Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Humanos , Tolerância Imunológica , Síndromes de Imunodeficiência/fisiopatologia , Mutação
9.
Pan Afr Med J ; 29: 75, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875956

RESUMO

Macrophage activation syndrome (MAS) is a severe and potentially fatal life-threatening condition associated with excessive activation and expansion of T cells with macrophages and a high expression of cytokines, resulting in an uncontrolled inflammatory response, with high levels of macrophage colony-stimulating factor and causing multiorgan damage. This syndrome is classified into primary (genetic/familial) or secondary forms to several etiologies, such as infections, neoplasias mainly hemopathies or autoimmune diseases. It is characterised clinically by unremitting high fever, pancytopaenia, hepatosplenomegaly, hepatic dysfunction, encephalopathy, coagulation abnormalities and sharply increased levels of ferritin. The pathognomonic feature of the syndrome is seen on bone marrow examination, which frequently, though not always, reveals numerous morphologically benign macrophages exhibiting haemophagocytic activity. Because MAS can follow a rapidly fatal course, prompt recognition of its clinical and laboratory features and immediate therapeutic intervention are essential. However, it is difficult to distinguish underlying disease flare, infectious complications or medication side effects from MAS. Although, the pathogenesis of MAS is unclear, the hallmark of the syndrome is an uncontrolled activation and proliferation of T lymphocytes and macrophages, leading to massive hypersecretion of pro-inflammatory cytokines. Mutations in cytolytic pathway genes are increasingly being recognised in children who develop MAS in his secondary form. We present here a case of Macrophage activation syndrome associated with Griscelli syndrome type 2 in a 3-years-old boy who had been referred due to severe sepsis with non-remitting high fever, generalized lymphoadenopathy and hepato-splenomegaly. Laboratory data revealed pancytopenia with high concentrations of triglycerides, ferritin and lactic dehydrogenase while the bone marrow revealed numerous morphologically benign macrophages with haemophagocytic activity that comforting the diagnosis of a SAM according to Ravelli and HLH-2004 criteria. Griscelli syndrome (GS) was evoked on; consanguineous family, recurrent infection, very light silvery-gray color of the hair and eyebrows, Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. The molecular biology showed mutation in RAB27A gene confirming the diagnosis of a Griscelli syndrome type 2. The first-line therapy was based on the parenteral administration of high doses of corticosteroids, associated with immunosuppressive drugs, cyclosporine A and etoposide waiting for bone marrow transplantation (BMT).


Assuntos
Síndromes de Imunodeficiência/complicações , Linfo-Histiocitose Hemofagocítica/complicações , Síndrome de Ativação Macrofágica/etiologia , Piebaldismo/complicações , Proteínas rab27 de Ligação ao GTP/genética , Corticosteroides/uso terapêutico , Pré-Escolar , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/fisiopatologia , Imunossupressores/uso terapêutico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/fisiopatologia , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/fisiopatologia , Masculino , Mutação , Piebaldismo/diagnóstico , Piebaldismo/fisiopatologia , Sepse/etiologia
10.
Orv Hetil ; 159(23): 908-918, 2018 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-29860882

RESUMO

Primary immunodeficiencies consist of a group of genetically heterogeneous immune disorders affecting distinct elements of the innate and adaptive immune system. Patients with primary immunodeficiency are more prone to develop not only recurrent infections, but non-infectious complications, like inflammatory or granulomatous conditions, lymphoproliferative and solid malignancies, autoinflammatory disorders, and a broad spectrum of autoimmune diseases. The concomitant appearance of primary immunodeficiency and autoimmunity appears to be rather paradoxical, therefore making the diagnosis of immunodeficiency patients with autoimmune complications challenging. Mutations of one or more genes playing a fundamental role in immunoregulation and/or immune tolerance network are thought to be responsible for primary immunodeficiencies. The diverse immunological abnomalities along with the compensatory and excessive sustained inflammatory response result in tissue damage and finally in manifestation of organ-, cell-specific or systemic autoimmune diseases. Several forms of primary immunodeficiency disorders are characterized by a variety of specific autoimmune phenomena. This overview addresses the spectrum of autoimmune diseases associated with primary immunodeficiencies, and explores the molecular and cellular mechanisms underlying abnormalities of the immune system. The case presented finally highlights that both the recognition of autoimmune diseases in association with immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging. Orv Hetil. 2018; 159(23): 908-918.


Assuntos
Doenças Autoimunes/complicações , Doenças Autoimunes/fisiopatologia , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/fisiopatologia , Autoimunidade/imunologia , Humanos
11.
Curr Hypertens Rep ; 20(5): 40, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29717384

RESUMO

PURPOSE OF REVIEW: Significant and intricate immune adaptations are essential for the establishment and maintenance of normal pregnancy. Preeclampsia is a morbid, potentially life-threatening disease for both mother and neonate that occurs uniquely in pregnancy, at least in part, due to maternal immune maladaptation. We aim to review the literature that focuses on case reports, diagnostic approaches, and treatment strategies for disorders of the complement alternative pathway (CAP) as related to preeclampsia. RECENT FINDINGS: There is evidence of complement dysregulation in preeclampsia and HELLP syndrome, similar to that observed in a few rare types of thrombotic microangiopathies. Complement dysregulation may be identified with functional laboratory testing as well as genetic testing. Increased utilization of a standardized diagnostic approach to establish whether persistent and/or severe cases of preeclampsia and HELLP syndrome are complement-mediated may lead to development of future treatment strategies, such as complement-targeted therapy.


Assuntos
Via Alternativa do Complemento/imunologia , Tolerância Imunológica/imunologia , Pré-Eclâmpsia/fisiopatologia , Adulto , Via Alternativa do Complemento/fisiologia , Proteínas do Sistema Complemento/imunologia , Feminino , Síndrome HELLP/genética , Síndrome HELLP/imunologia , Síndrome HELLP/fisiopatologia , Síndrome HELLP/terapia , Humanos , Tolerância Imunológica/fisiologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Recém-Nascido , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/imunologia , Pré-Eclâmpsia/terapia , Gravidez , Microangiopatias Trombóticas/imunologia , Microangiopatias Trombóticas/fisiopatologia
12.
J Clin Lab Anal ; 32(7): e22460, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29682788

RESUMO

BACKGROUND: Being able to detect the presence of autoantibodies to interferon (IFN)-γ in serum is essential for evaluating patients with suspected adult-onset immunodeficiency (AOID) with unusual intracellular infections. Most reported patients with AOID have been Asian, although the exact prevalence of this illness is unknown. To date, no standard assay exists to detect autoantibodies to IFN-γ. An easy-to-use, low-cost assay that can be performed in any laboratory would be a valuable tool for clinical management of AOID, as well as better reveal its prevalence. METHODS: Our experimental study exploited a dot enzyme-linked immunosorbent assay (Dot-ELISA) strip to detect autoantibodies to IFN-γ. Sera from 66 HIV-negative patients having autoantibodies to IFN-γ as determined by indirect ELISA were tested. RESULTS: Dot enzyme-linked immunosorbent assay was sensitive (100%) and specific (94.5%), with a positive predictive value of 97.6% and a negative predictive value of 100%. CONCLUSION: This simple method provides prompt qualitative results that can be read visually and used in facilities with limited testing capabilities.


Assuntos
Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Síndromes de Imunodeficiência/diagnóstico , Interferon gama/imunologia , Adulto , Autoanticorpos/imunologia , Humanos , Immunoblotting , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Valor Preditivo dos Testes
13.
Hum Mol Genet ; 27(14): 2409-2424, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29659838

RESUMO

Alterations of DNA methylation landscapes and machinery are a hallmark of many human diseases. A prominent case is the ICF syndrome, a rare autosomal recessive immunological/neurological disorder diagnosed by the loss of DNA methylation at (peri)centromeric repeats and its associated chromosomal instability. It is caused by mutations in the de novo DNA methyltransferase DNMT3B in about half of the patients (ICF1). In the remainder, the striking identification of mutations in factors devoid of DNA methyltransferase activity, ZBTB24 (ICF2), CDCA7 (ICF3) or HELLS (ICF4), raised key questions about common or distinguishing DNA methylation alterations downstream of these mutations and hence, about the functional link between the four factors. Here, we established the first comparative methylation profiling in ICF patients with all four genotypes and we provide evidence that, despite unifying hypomethylation of pericentromeric repeats and a few common loci, methylation profiling clearly distinguished ICF1 from ICF2, 3 and 4 patients. Using available genomic and epigenomic annotations to characterize regions prone to loss of DNA methylation downstream of ICF mutations, we found that ZBTB24, CDCA7 and HELLS mutations affect CpG-poor regions with heterochromatin features. Among these, we identified clusters of coding and non-coding genes mostly expressed in a monoallelic manner and implicated in neuronal development, consistent with the clinical spectrum of these patients' subgroups. Hence, beyond providing blood-based biomarkers of dysfunction of ICF factors, our comparative study unveiled new players to consider at certain heterochromatin regions of the human genome.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , DNA Helicases/genética , Síndromes de Imunodeficiência/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Instabilidade Cromossômica/genética , Metilação de DNA/genética , Feminino , Genoma Humano/genética , Genótipo , Heterocromatina/genética , Humanos , Síndromes de Imunodeficiência/fisiopatologia , Masculino , Mutação , Neurogênese/genética
15.
J Child Neurol ; 33(5): 320-328, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29421957

RESUMO

The nervous system may be affected in primary immune deficiency (PID) syndromes through infectious, autoimmune, neoplastic mechanisms, or as a primary feature of the syndrome. However certain neurologic problems do not conform to these etiopathogenetic groups. We retrospectively examined PID patients seen in neurology consultation between 2014 and 2017 in order to determine the spectrum of nervous system involvement. Among patients with confirmed neurologic problems (n = 35), common manifestations were encephalopathy and global developmental/cognitive delay. In 13 (37%) instances, the neurologic signs had no apparent relation with a treatment-related, infectious, or vascular complication and were considered as primary findings: acquired microcephaly, central nervous system malformation, or peripheral neuropathy. The diagnosis of PID was made after, and based on, the neurologic manifestation in 6 of 35 (17%) patients. Neurologic presentation may constitute the initial manifestation in some types of primary immune deficiency.


Assuntos
Síndromes de Imunodeficiência/fisiopatologia , Sistema Nervoso/fisiopatologia , Adolescente , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/diagnóstico , Lactente , Masculino , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/fisiopatologia , Estudos Retrospectivos , Adulto Jovem
17.
Endocr Metab Immune Disord Drug Targets ; 18(2): 175-183, 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-29119939

RESUMO

BACKGROUND: Primary immunodeficiencies (PIDs) are inherited disorders in which one or several components of the immune system are defective. Immunoglobulin replacement therapy is the mainstay of treatment for patients with impaired antibody production. However, recurrent infections would continue to occur in some patients due to the other high frequent concomitant defects, such as mannose-binding lectin (MBL) deficiency. METHODS: A total of 51 PID patients participated in this cross-sectional study. A detailed questionnaire was completed by interviewing patients in order to record demographic, clinical and laboratory data. The levels of MBL were determined in the serums of patients by a sandwich enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: MBL deficiency was found in 29.4% of cases; 11.8% patients had mild, 3.9% patients had moderate and 13.7% patients had severe MBL deficiency. In patients with MBL deficiency, the rate of meningitis, sepsis, pneumonia, and otitis media was higher than patients with normal MBL levels. Immunoglobulin replacement therapy reduced the rate of infectious complications in PID patients; however, these reductions were more apparent in patients with normal MBL levels than patients with MBL deficiency. CONCLUSION: Antibody deficient patients with a concomitant immune defect in MBL production have higher rates of recurrent infections despite receiving Immunoglobulin replacement therapy.


Assuntos
Doenças Genéticas Inatas/complicações , Hospedeiro Imunocomprometido , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/terapia , Lectinas Tipo C/deficiência , Lectinas de Ligação a Manose/deficiência , Infecções Oportunistas/complicações , Adolescente , Adulto , Antígenos CD , Criança , Estudos Transversais , Feminino , Seguimentos , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/fisiopatologia , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/fisiopatologia , Masculino , Herança Multifatorial , Infecções Oportunistas/imunologia , Infecções Oportunistas/prevenção & controle , Prevalência , Recidiva , Risco , Índice de Gravidade de Doença , Adulto Jovem
18.
Am J Med Genet A ; 176(2): 465-469, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29265708

RESUMO

RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias with microcephalic osteodysplastic primordial dwarfism, type 1 having a more severe phenotype than Roifman syndrome. Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. The features also overlap with Lowry Wood syndrome, another rare but well-defined skeletal dysplasia for which the genetic etiology has not been identified. Characteristic features include multiple epiphyseal dysplasia and microcephaly. Here, we describe three patients with Lowry Wood syndrome with biallelic RNU4ATAC pathogenic variants. This report expands the phenotypic spectrum for biallelic RNU4ATAC disorder causing variants and is the first to establish the genetic cause for Lowry Wood syndrome.


Assuntos
Cardiomiopatias/genética , Nanismo/genética , Transtornos do Crescimento/genética , Síndromes de Imunodeficiência/genética , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Microcefalia/genética , Osteocondrodisplasias/genética , RNA Nuclear Pequeno/genética , Doenças Retinianas/genética , Adolescente , Cardiomiopatias/fisiopatologia , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Nanismo/fisiopatologia , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/fisiopatologia , Transtornos do Crescimento/fisiopatologia , Humanos , Síndromes de Imunodeficiência/fisiopatologia , Deficiência Intelectual/fisiopatologia , Masculino , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Microcefalia/fisiopatologia , Mutação , Osteocondrodisplasias/fisiopatologia , Fenótipo , Doenças Retinianas/fisiopatologia
19.
Leuk Lymphoma ; 59(5): 1127-1132, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28792255

RESUMO

Host-related immunodeficiency is known to play a role in the development of multiple myeloma (MM) from its precursor conditions (monoclonal gammopathy of undetermined significance, MGUS, smoldering multiple myeloma, SMM). In order to understand the underlying immune changes in this process, we characterized immune patterns from MGUS to SMM to MM. We further sought to identify potential novel immune biomarkers that may predict progression of SMM to MM. We characterized patterns of circulating lymphocytes in 181 patients using multiparametric flow cytometry. We found decreased B- (p = .0003), increased T- (p = .037) and unaltered NK cell proportions from MGUS to SMM to MM. To gain insights into functional variability, we further characterized immunophenotypic lymphocyte subsets, which uncovered differences in CD57 subsets. Specifically, we found that SMM patients who eventually progressed to MM showed decreased proportions of CD57-CD56 + (p = .0061) and CD57-CD16 + (p = .035) lymphocyte subsets. We thus report novel data characterizing the nature of host-related immunodeficiency in the development of MM. We show sequential changes in lymphocyte subsets from MGUS to SMM to MM. We further suggest that CD57 subsets may serve as potential markers of progression from SMM to MM. Our findings support the study of lymphocyte subsets in the search for immune biomarkers. Such markers could provide clinical guidance in managing myeloma precursor disease.


Assuntos
Síndromes de Imunodeficiência/complicações , Linfócitos/imunologia , Gamopatia Monoclonal de Significância Indeterminada/etiologia , Mieloma Múltiplo/etiologia , Paraproteinemias/etiologia , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/patologia , Paraproteinemias/patologia , Prognóstico , Estudos Prospectivos
20.
J Child Adolesc Psychopharmacol ; 28(2): 92-103, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28832181

RESUMO

OBJECTIVE: The goal of this study was to investigate treatment histories and outcomes in a large community sample of youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), and, where appropriate, to examine the impact of immune deficiency on treatment outcomes. METHODS: A comprehensive internet-based survey was completed by parents or guardians of youth who had received physician diagnoses of PANS, or by young adults (age 18+) who had themselves been diagnosed by a physician (N = 698). Data regarding the treatment histories of these patients, including the variety of medical and psychological treatments employed and the caregiver- or self-reported response to each, are presented. RESULTS: The PANS patients in this study had commonly been treated with antibiotic (N = 675), anti-inflammatory (N = 437), and/or psychotropic therapy (N = 378). Response to antibiotic treatment was best when treatment was relatively aggressive, with broad-spectrum antibiotics and courses of >30 days generally producing the best results (i.e., up to 52% of patients achieving a "very effective" response). For immune-deficient patients (caregiver-reported laboratory studies below normal limits; N = 108), use of broad-spectrum antibiotics appeared to be particularly desirable. Anti-inflammatory therapies, including over-the-counter medications such as ibuprofen, were at least "somewhat effective" for most patients. Intravenous immunoglobulin (IVIG) had been used to treat PANS in 193 (28%) of the patients and was at least "somewhat effective" for 89%, although for 18% of these, the effect was not sustained. The highest rate of sustained response to IVIG treatment was seen in immune-deficient patients who received doses of at least 0.8 g/kg IVIG on a regular basis. Psychotropic medications, most commonly SSRIs (38% reported a trial), were commonly employed, but were often ineffective (e.g., 44% found SSRIs "somewhat" to "very effective"). Many patients (N = 473) had received some form of psychotherapy with some benefit, with cognitive behavioral therapy found to be at least somewhat effective in a majority of those treated with this modality. CONCLUSION: Among the PANS patients represented in this study, relatively aggressive treatment courses targeted at eradicating infection and modulating the inflammatory response appeared to provide the best caregiver-reported therapeutic results, and to be generally well tolerated. Given its relative efficacy and tolerability, treatment targeting the inflammatory response may represent an underutilized approach in this population. The results of this study should be considered in light of the limitations inherent in a self-selected and administered online survey.


Assuntos
Doenças Autoimunes/terapia , Síndromes de Imunodeficiência/terapia , Transtorno Obsessivo-Compulsivo/terapia , Psicoterapia/métodos , Infecções Estreptocócicas/terapia , Doença Aguda , Adolescente , Adulto , Antibacterianos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Doenças Autoimunes/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Síndromes de Imunodeficiência/fisiopatologia , Lactente , Masculino , Transtorno Obsessivo-Compulsivo/fisiopatologia , Psicotrópicos/administração & dosagem , Infecções Estreptocócicas/fisiopatologia , Inquéritos e Questionários , Síndrome , Resultado do Tratamento , Adulto Jovem
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