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1.
Allergol. immunopatol ; 48(6): 701-710, nov.-dic. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-199261

RESUMO

INTRODUCTION AND OBJECTIVES: As well as increased susceptibility to infections, autoimmune and inflammatory manifestations also eventuate due to dysregulation of immune system in a substantial proportion of patients with primary immunodeficiency (PID). Autoimmune and inflammatory manifestations can occur prior or after diagnosis of PID. This study aimed to evaluate autoimmune and inflammatory complications among all types of PID patients in childhood and to emphasize the importance of these findings as a warning sign to diagnose PIDs. METHODS: Medical records of 1036 patients with PID, followed up between 2003 and 2019, were retrospectively screened for occurrence of autoimmunity and inflammation. During this time, demographic features, autoimmune/inflammatory findings and initial time, genetic mutations, laboratory and clinical follow up findings, treatment regimens and outcomes were recorded. RESULTS: Autoimmune and inflammatory manifestations were observed in 83 patients (10.1%). The median age of autoimmunity initial time was 61.3 ± 53 months. Sixty-seven (80.7%) patients presented with autoimmune and inflammatory manifestations, and these findings had occurred during 16 patients' (19.3%) follow-up. The most common autoimmune manifestations were autoimmune hematologic (51.8%) and endocrine diseases (26.5%). Fifty patients (60.2%) had a single autoimmune/inflammatory manifestation, however 23 patients (27.7%) had two, eight patients (9.6%) had three and two patients (2.4%) had four different types of autoimmune/inflammatory manifestations. The frequency of autoimmune and inflammatory manifestations in phagocyte defects (56%), combined immune deficiencies (53%) and immune dysregulation diseases (52%) were observed higher than other forms of PIDs. During follow-up 13 (15.7%) patients died. CONCLUSION: Autoimmune/inflammatory manifestations are associated with high morbidity in patients with PIDs and may precede the diagnosis of PID in childhood. Therefore, physicians must be aware of underlying possible immune deficiency and patients with known PIDs should be evaluated for autoimmune and inflammatory complications


No disponible


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Síndromes de Imunodeficiência/epidemiologia , Doenças Autoimunes/epidemiologia , Inflamação/epidemiologia , Estudos Retrospectivos , Síndromes de Imunodeficiência/patologia , Doenças Autoimunes/patologia , Inflamação/patologia , Prevalência , Fatores Etários , Estatísticas não Paramétricas , Mutação , Seguimentos , Turquia/epidemiologia
2.
Allergol. immunopatol ; 48(6): 711-719, nov.-dic. 2020. tab
Artigo em Inglês | IBECS | ID: ibc-199262

RESUMO

BACKGROUND: Common Variable Immunodeficiency (CVID) is characterized by an impaired antibody production and a higher susceptibility to encapsulated bacterial infections. Lung disease is considered to be the most important cause of morbidity and mortality. METHODS: We analyzed clinical, radiological and functional characteristics in 80 patients with CVID assisted in the Unidad Inmunologia e Histocompatibilidad at Durand Hospital from 1982 to 2018. RESULTS: Of the 80 patients, 55 showed pathologic lung Computed Tomography (CT). Twenty of them (36.4%) showed bronchiectasis; 26 (47.3%) interstitial involvement associated with nodules and adenopathies called GLILD (granulomatous-lymphocytic interstitial lung disease); and nine patients (16.3%) showed other lesions. Nine percent of patients with lung disease showed CT progression; none of them had spirometry worsening. GLILD patients had normal and restrictive patterns in lung function tests, in equal proportions. Two patients - one with GLILD and the other one with bronchiectasis - had an increase in spirometric pattern severity without CT progression. Lung biopsy was performed in 19% of GLILD patients, all of whom had histopathologic diagnosis of Lymphoid Interstitial Pneumonia (LIP). CONCLUSIONS: GLILD is the major cause of lung disease in CVID. Computed tomography is useful for diagnosis but not necessary in follow-up, in which functional tests should have better correlation with clinical evolution, reducing radiation exposure. Biopsy should be indicated when the clinical diagnosis is unclear. Treatment should be considered whenever there is clear evidence of disease progression


No disponible


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Síndromes de Imunodeficiência/diagnóstico , Diagnóstico Tardio/estatística & dados numéricos , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/epidemiologia , Índice de Gravidade de Doença , Fatores de Risco , Estudos Transversais , Estatísticas não Paramétricas , Modelos Logísticos , Irã (Geográfico)/epidemiologia , Prevalência
3.
Mol Immunol ; 121: 28-37, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151906

RESUMO

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.


Assuntos
Autoimunidade/genética , Contratura/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Síndromes de Imunodeficiência/genética , Proteínas de Transporte de Nucleosídeos/genética , Adolescente , Contratura/tratamento farmacológico , Contratura/imunologia , Contratura/patologia , Glucocorticoides/uso terapêutico , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Histiocitose/tratamento farmacológico , Histiocitose/imunologia , Histiocitose/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Inflamassomos/imunologia , Lisossomos/imunologia , Lisossomos/patologia , Masculino , Mitocôndrias/imunologia , Mitocôndrias/patologia , Resultado do Tratamento
4.
J Clin Pathol ; 73(9): 587-592, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32094276

RESUMO

AIMS: An association between antibody deficiency and clozapine use in individuals with schizophrenia has recently been reported. We hypothesised that if clozapine-associated hypogammaglobulinaemia was clinically relevant this would manifest in referral patterns. METHODS: Retrospective case note review of patients referred and assessed by Immunology Centre for Wales (ICW) between January 2005 and July 2018 with extraction of clinical and immunological features for individuals with diagnosis of schizophrenia-like illness. RESULTS: 1791 adult patients were assessed at ICW during this period; 23 patients had a psychiatric diagnosis of schizophrenia or schizoaffective disorder. Principal indications for referral were findings of low calculated globulin and immunoglobulins. Clozapine was the single most commonly prescribed antipsychotic (17/23), disproportionately increased relative to reported use in the general schizophrenia population (OR 6.48, 95% CI: 1.79 to 23.5). Clozapine therapy was noted in 6/7 (86%) of patients subsequently requiring immunoglobulin replacement therapy (IgRT). Marked reduction of class-switched memory B cells (CSMB) and plasmablasts were observed in clozapine-treated individuals relative to healthy age-matched controls. Clozapine duration is associated with CSMB decline. One patient discontinued clozapine, with gradual recovery of IgG levels without use of IgRT. CONCLUSIONS: Our findings are consistent with enrichment of clozapine-treatment within schizophrenic individuals referred for ICW assessment over the last 13 years. These individuals displayed clinical patterns closely resembling the primary immunodeficiency common variable immunodeficiency, however appears reversible on drug cessation. This has diagnostic, monitoring and treatment implications for psychiatry and immunology teams and directs prospective studies to address causality and the wider implications for this patient group.


Assuntos
Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Síndromes de Imunodeficiência/patologia , Esquizofrenia/patologia , Linfócitos B/patologia , Imunodeficiência de Variável Comum , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/tratamento farmacológico , Estudos Retrospectivos , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico
5.
J Leukoc Biol ; 107(6): 907-915, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31749173

RESUMO

The TNFR superfamily of receptors, the major focus of the recent TNFR Superfamily Conference held in June 2019, employ the TNFR-associated factor (TRAF) family of adaptor proteins in key aspects of their signaling pathways. Although many early studies investigated TRAF functions via exogenous overexpression in nonhematopoietic cell lines, it has subsequently become clear that whereas TRAFs share some overlap in function, each also plays unique biologic roles, that can be highly context dependent. This brief review summarizes the current state of knowledge of functions of each of the TRAF molecules that mediate important functions in T lymphocytes: TRAFs 1, 2, 3, 5, and 6. Due to our current appreciation of the contextual nature of TRAF function, our focus is upon findings made specifically in T lymphocytes. Key T cell functions for each TRAF are detailed, as well as future knowledge gaps of interest and importance.


Assuntos
Síndromes de Imunodeficiência/genética , Receptores do Fator de Necrose Tumoral/genética , Transdução de Sinais/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Memória Imunológica , Camundongos , Camundongos Knockout , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/deficiência , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/imunologia
8.
Am J Dermatopathol ; 42(1): e11-e15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31313695

RESUMO

The development of T-cell lymphomas, granulomatous reactions, and autoimmunity has been observed in immunodeficiency due to milder forms of recombination activating gene (RAG) deficiency. A few cases of cutaneous clonal papulonodular CD8 lymphocytic infiltrates and cutaneous CD8 granulomatous T-cell lymphoma have been described in association with common variable immunodeficiency, and with X-linked agammaglobulinemia. We describe a 15-year-old girl with several autoimmune disorders and recurrent infections that presented with several nodules on her cheek. Histopathological studies demonstrate histological, immunohistochemical, and molecular findings compatible with a primary cutaneous clonal CD8 T-cell lymphoproliferative disorder. Vacuolar interface changes were also seen in the involved skin, reminiscent of cutaneous lupus erythematosus. Molecular genetic analysis revealed a germline novel homozygous missense mutation in RAG1 (T1003>C). The parents were heterozygous carriers. The facial cutaneous lesions recurred despite local radiation therapy. Because of recurrent life-threatening systemic infections, allogeneic bone marrow transplantation was performed. The pathogenesis of this primary cutaneous clonal CD8 T-cell lymphoproliferative disorder may have been related to a chronic stimulation of autoreactive T cells in the involved skin paired with reduced RAG1 activity.


Assuntos
Linfócitos T CD8-Positivos/patologia , Proteínas de Homeodomínio/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Adolescente , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia
9.
J Clin Exp Hematop ; 59(4): 196-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31866621

RESUMO

Gamma heavy chain disease (γ-HCD) is a rare B-cell neoplasm that produces a truncated immunoglobulin γ-heavy chain lacking the light chain. The clinical features of γ-HCD are heterogeneous, resembling different types of B-cell lymphomas. Although rheumatoid arthritis (RA) is one of the common underlying diseases of γ-HCD, the therapeutic modality for RA has changed greatly in recent years; therefore, γ-HCD as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) should be taken into consideration. Here, we report such a γ-HCD case. A 69-year-old female was admitted because of fever, multiple lymph node swelling in the abdominal cavity, and peritoneal effusion. She had been treated using methotrexate for RA for 14 years, and using infliximab and adalimumab for Crohn's disease for one year. The serum concentration of IgG was 3,525 mg/dL, which was revealed to be monoclonal IgG lacking the light chain by rocket immunoselection assay. CD19+/CD20-/smκ-/smλ- large abnormal lymphocytes were observed in the peritoneal fluid, which were demonstrated to be clonal B-cells by PCR examination. Discontinuation of methotrexate did not improve her condition and she died of pneumonia. Many abnormal lymphocytes positive for IgG and EBER but negative for the light chain were found on immunohistological examination of necropsy specimens from the spleen and bone marrow.


Assuntos
Artrite Reumatoide , Neoplasias Hematológicas , Cadeias gama de Imunoglobulina/metabolismo , Síndromes de Imunodeficiência , Linfoma de Células B , Metotrexato/efeitos adversos , Proteínas de Neoplasias/metabolismo , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Evolução Fatal , Feminino , Neoplasias Hematológicas/induzido quimicamente , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Síndromes de Imunodeficiência/induzido quimicamente , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Linfoma de Células B/induzido quimicamente , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Metotrexato/administração & dosagem , Pessoa de Meia-Idade
10.
Front Immunol ; 10: 2134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572362

RESUMO

Genetic primary immunodeficiency diseases are increasingly recognized, with pathogenic mutations changing the composition of circulating leukocyte subsets measured by flow cytometry (FCM). Discerning changes in multiple subpopulations is challenging, and subtle trends might be missed if traditional reference ranges derived from a control population are applied. We developed an algorithm where centiles were allocated using non-parametric comparison to controls, generating multiparameter heat maps to simultaneously represent all leukocyte subpopulations for inspection of trends within a cohort or segregation with a putative genetic mutation. To illustrate this method, we analyzed patients with Primary Antibody Deficiency (PAD) and kindreds harboring mutations in TNFRSF13B (encoding TACI), CTLA4, and CARD11. In PAD, loss of switched memory B cells (B-SM) was readily demonstrated, but as a continuous, not dichotomous, variable. Expansion of CXCR5+/CD45RA- CD4+ T cells (X5-Th cells) was a prominent feature in PAD, particularly in TACI mutants, and patients with expansion in CD21-lo B cells or transitional B cells were readily apparent. We observed differences between unaffected and affected TACI mutants (increased B cells and CD8+ T-effector memory cells, loss of B-SM cells and non-classical monocytes), cellular signatures that distinguished CTLA4 haploinsufficiency itself (expansion of plasmablasts, activated CD4+ T cells, regulatory T cells, and X5-Th cells) from its clinical expression (B-cell depletion), and those that were associated with CARD11 gain-of-function mutation (decreased CD8+ T effector memory cells, B cells, CD21-lo B cells, B-SM cells, and NK cells). Co-efficients of variation exceeded 30% for 36/54 FCM parameters, but by comparing inter-assay variation with disease-related variation, we ranked each parameter in terms of laboratory precision vs. disease variability, identifying X5-Th cells (and derivatives), naïve, activated, and central memory CD8+ T cells, transitional B cells, memory and SM-B cells, plasmablasts, activated CD4 cells, and total T cells as the 10 most useful cellular parameters. Applying these to cluster analysis of our PAD cohort, we could detect subgroups with the potential to reflect underlying genotypes. Heat mapping of normalized FCM data reveals cellular trends missed by standard reference ranges, identifies changes associating with a phenotype or genotype, and could inform hypotheses regarding pathogenesis of genetic immunodeficiency.


Assuntos
Citometria de Fluxo , Doenças Genéticas Inatas/imunologia , Temperatura Alta , Síndromes de Imunodeficiência/imunologia , Mutação , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia
11.
Autoimmunity ; 52(5-6): 192-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31476899

RESUMO

Immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is a rare autosomal recessive disorder, which is characteristic of a severe impairment of immunity. In the genetic aspect, ICF is featured with mutations primarily located in the specific genes (DNMT3B for ICF1, ZBTB24 for ICF2, CDCA7 for ICF3, and HELLS for ICF4). The subtelomeric region is defined as 500 kb at the terminal of each autosomal arm. And subtelomeric DNA fragments can partially regulate key biological activities, including chromosome movement and localization in the nucleus. In this review, we updated and summarized gene mutations in ICF based on the previous review. In addition, we focused on the correlation between subtelomeric DNA methylation and ICF. The relationship between subtelomeric methylation and telomere length in ICF was also summarized.


Assuntos
Centrômero , Instabilidade Cromossômica , Metilação de DNA , Face/anormalidades , Síndromes de Imunodeficiência , Mutação , Centrômero/genética , Centrômero/metabolismo , Centrômero/patologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia
12.
Cells ; 8(8)2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349725

RESUMO

Aging is a risk factor for adipose tissue dysfunction, which is associated with inflammatory innate immune mechanisms. Since the adipose tissue/liver axis contributes to hepatosteatosis, we sought to determine age-related adipose tissue dysfunction in the context of the activation of the innate immune system fostering fatty liver phenotypes. Using wildtype and immune-deficient mice, we compared visceral adipose tissue and liver mass as well as hepatic lipid storage in young (ca. 14 weeks) and adult (ca. 30 weeks) mice. Adipocyte size was determined as an indicator of adipocyte function and liver steatosis was quantified by hepatic lipid content. Further, lipid storage was investigated under normal and steatosis-inducing culture conditions in isolated hepatocytes. The physiological age-related increase in body weight was associated with a disproportionate increase in adipose tissue mass in immune-deficient mice, which coincided with higher triglyceride storage in the liver. Lipid storage was similar in isolated hepatocytes from wildtype and immune-deficient mice under normal culture conditions but was significantly higher in immune-deficient than in wildtype hepatocytes under steatosis-inducing culture conditions. Immune-deficient mice also displayed increased inflammatory, adipogenic, and lipogenic markers in serum and adipose tissue. Thus, the age-related increase in body weight coincided with an increase in adipose tissue mass and hepatic steatosis. In association with a (pro-)inflammatory milieu, aging thus promotes hepatosteatosis, especially in immune-deficient mice.


Assuntos
Tecido Adiposo/metabolismo , Proteínas de Ligação a DNA/deficiência , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Adipócitos , Tecido Adiposo/patologia , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Perfilação da Expressão Gênica , Hepatócitos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo
13.
J Clin Exp Hematop ; 59(2): 48-55, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257345

RESUMO

In the current revised 4th edition of the World Health Organization (WHO) classification, 'other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPDs)' is listed in the last section in the chapter on immunodeficiency-associated lymphoproliferative disorders. Oii-LPDs cover a broad spectrum from benign lesions to lymphoma, and correspond to one of the subtypes in the WHO classification for immunocompetent patients.The WHO classification does not clearly indicate the histological subtype of this disease category; however, the framework of subtype classification is similar to the classification of post-transplant lymphoproliferative disorders, and recent studies have attempted to subcategorize Oii-LPDs that fit this unique disease type. In this review, we provide an overview of B-cell-type Oii-LPDs regarding their histopathology and immunophenotype, genetics and clinical behaviors.


Assuntos
Linfócitos B/patologia , Síndromes de Imunodeficiência/patologia , Imunossupressores/efeitos adversos , Transtornos Linfoproliferativos/patologia , Animais , Linfócitos B/efeitos dos fármacos , Humanos , Doença Iatrogênica/epidemiologia , Síndromes de Imunodeficiência/induzido quimicamente , Síndromes de Imunodeficiência/classificação , Transtornos Linfoproliferativos/induzido quimicamente , Transtornos Linfoproliferativos/classificação
14.
J Clin Exp Hematop ; 59(2): 56-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257346

RESUMO

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) with a T- or NK-cell phenotype are markedly rare, with only a limited number of cases having been reported thus far. Methotrexate (MTX) is the most common agent used for OIIA-LPD patients, and 43 cases of MTX-associated T-LPDs (MTX T-LPDs) and five cases of MTX-associated NK/T-LPDs (MTX NK-LPDs) have been described. In addition to MTX T-LPDs and MTX NK/T-LPDs, T-LPD and NK/T-LPDs have been reported in patients receiving other immunosuppressive agents such as thiopurines, TNF antagonists, and cyclosporine. Hepatosplenic T-cell lymphoma (HSTL) is specifically associated with iatrogenic immunodeficiency, and 10% of HSTL cases develop in patients receiving thiopurines and/or TNF antagonists for inflammatory bowel disease (IBD). In this review, we focused on MTX T-LPD, MTX NK/T-LPD, and HSTL in patients with IBD. These T- and NK/T-cell associated OIIA-LPDs are the most common in daily medical practice.


Assuntos
Síndromes de Imunodeficiência/patologia , Transtornos Linfoproliferativos/patologia , Linfócitos T/patologia , Animais , Humanos , Doença Iatrogênica/epidemiologia , Síndromes de Imunodeficiência/induzido quimicamente , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Transtornos Linfoproliferativos/induzido quimicamente , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/patologia , Linfócitos T/efeitos dos fármacos
15.
J Clin Exp Hematop ; 59(2): 72-92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257348

RESUMO

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD), a category of immunodeficiency-associated LPD according to the World Health Organization classification, is associated with immunosuppressive drugs (ISDs). Several factors, including autoimmune disease (AID) activity, Epstein-Barr virus (EBV) infection, ISD usage, and aging, influence the development of OIIA-LPD, resulting in complicated clinical courses and outcomes. Most OIIA-LPD develops in patients with rheumatoid arthritis using methotrexate (MTX-LPD). The management of MTX-LPD is based on the clinical course, i.e., with/without regression, with/without relapse/regrowth event (RRE), LPD subtype, and ISDs for AIDs after LPD development. There are three clinical courses after ISD withdrawal: regressive LPD without relapse/regrowth (R-G), regressive LPD with RRE (R/R-G), and persistent LPD (P-G). The majority of EBV+ diffuse large B-cell lymphomas are classified in R-G, whereas classic Hodgkin lymphoma is generally classified in R/R-G. Polymorphic LPD (P-LPD) in MTX-LPD develops with heterogeneous pathological features similar to monomorphic LPD. Chemotherapy for MTX-LPD is selected according to that for de novo LPD, although the strategy for aggressive P-LPD and non-specific LPD is not well established. The absolute lymphocyte count in the peripheral blood has been suggested as a candidate marker for MTX-LPD development and RRE. Several clinical issues, including correct diagnosis among overlapping clinicopathological features in MTX-LPD and clinical management of LPD by ISDs other than MTX, require further investigation.


Assuntos
Síndromes de Imunodeficiência/terapia , Transtornos Linfoproliferativos/terapia , Animais , Artrite Reumatoide/tratamento farmacológico , Gerenciamento Clínico , Humanos , Doença Iatrogênica/epidemiologia , Síndromes de Imunodeficiência/induzido quimicamente , Síndromes de Imunodeficiência/patologia , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/induzido quimicamente , Transtornos Linfoproliferativos/patologia , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico
16.
J Exp Med ; 216(9): 1986-1998, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31235509

RESUMO

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.


Assuntos
Síndromes de Imunodeficiência/patologia , Inflamação/patologia , Receptores de Interleucina-6/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Recém-Nascido , Masculino , Receptores de Interleucina-6/metabolismo
17.
Br J Haematol ; 186(3): 471-476, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31106410

RESUMO

MonoMAC is a complex primary immunodeficiency caused by mutations in the myeloid transcription factor GATA2, characterized by multilineage cytopenia with malignant complications and severe infections, including mycobacteria and herpesviruses. We describe the clinical presentation, genetics and antiviral inflammatory responses in a small case series. Two patients presented in childhood with mycobacterial infection and were diagnosed with MonoMAC germline GATA2 variants; their healthy fathers with the same mutations were also studied. Three patients were elderly individuals with acquired GATA2 mutations and malignant haematological conditions. Overall, this study demonstrates the heterogeneous clinical presentation and variation in immunodeficiency caused by GATA2 mutations.


Assuntos
Fator de Transcrição GATA2/deficiência , Herpesviridae/imunologia , Síndromes de Imunodeficiência/diagnóstico , Adulto , Criança , Feminino , Humanos , Síndromes de Imunodeficiência/patologia , Ligantes , Masculino , Adulto Jovem
19.
Indian J Pathol Microbiol ; 62(2): 279-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30971555

RESUMO

Griscelli syndrome is a rare autosomal recessive inherited disorder characterized by hypopigmentation, silver colored hair, and associated immunological deficiency, which proves fatal in the absence of timely intervention. Our patients diagnosed with Griscelli syndrome-2 presented with fever, hepatosplenomegaly, and deranged hematological and biochemical parameters. Both cases underwent detailed investigations comprising of hair mount microscopic examination, degranulation assay, and mutational studies. Our cases showed defective degranulation activity by NK cells and gene mutation analysis revealed RAB27A mutation that causes defect of cytotoxic granule exocytosis from natural killer (NK) and T-cells, manifesting clinically as hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplantation in one of the patients resulted in stable chimerism; however, the second case relapsed within a month after SCT. Stem cell transplantation is the only curative therapeutic option for GS2; thus, improvement in posttransplantation management may reduce mortality and posttransplant complications. Hence, any child who presents with partial albinism and clinical features suggestive of HLH, a peripheral blood, hair shaft mount examination along with basic immunological NK and T-cell cytotoxicity assay by flow cytometry will help clinch the diagnosis early. It can subsequently be confirmed by molecular study. Timely therapeutic intervention can prevent relapses and severe infection and improve outcome in these cases.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/terapia , Piebaldismo/genética , Piebaldismo/terapia , Pré-Escolar , Feminino , Cabelo , Humanos , Síndromes de Imunodeficiência/patologia , Células Matadoras Naturais/patologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Mutação , Piebaldismo/patologia , Doenças da Imunodeficiência Primária , Resultado do Tratamento , Proteínas rab27 de Ligação ao GTP/genética
20.
Orphanet J Rare Dis ; 14(1): 61, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819232

RESUMO

BACKGROUND: Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing. RESULTS: In order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8-51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6). CONCLUSIONS: Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.


Assuntos
Cerebelo/anormalidades , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico por imagem , Imagem por Ressonância Magnética , Transtornos Mentais/etiologia , Malformações do Sistema Nervoso/etiologia , Verrugas/complicações , Verrugas/diagnóstico por imagem , Adolescente , Adulto , Cerebelo/diagnóstico por imagem , Criança , Feminino , Mutação com Ganho de Função , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária , Receptores CXCR4/genética , Verrugas/genética , Verrugas/patologia , Adulto Jovem
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