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2.
Rev Assoc Med Bras (1992) ; 66(6): 752-756, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32696881

RESUMO

OBJECTIVE To study the profile of associated autoimmune diseases in a series of patients with systemic lupus erythematosus (SLE) and see if such associations are linked to IgA deficiency. METHODS Two hundred eighty-one patients with SLE were studied for Ig A levels by nephelometry. Levels equal to or under 0.05g/dL were considered as IgA deficiency. Epidemiological and clinical data, including the presence of associated autoimmune diseases, were extracted from the patient's charts. RESULTS Ig A deficiency was found in 6% of the patients. In 30.2% of SLE patients, there was at least one more autoimmune disease; Hashimoto thyroiditis and Sjögren's syndrome were the most common. No association between the occurrence of associated autoimmune disease with IgA deficiency was found. CONCLUSIONS There is a high prevalence of autoimmune diseases associated with SLE. IgA deficiency does not affect the presence of these associations.


Assuntos
Doenças Autoimunes , Deficiência de IgA , Lúpus Eritematoso Sistêmico , Síndrome de Sjogren , Humanos , Imunoglobulina A
3.
Am J Surg Pathol ; 44(8): 1073-1081, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32235152

RESUMO

Common variable immunodeficiency (CVID) and selective immunoglobulin A deficiency (IgAD) often cause chronic lung disease, but the pulmonary pathologic features of these systemic diseases are poorly recognized by pathologists. It has been claimed that CVID cases show a characteristic combination of noncaseating granulomas-lymphoid proliferations termed granulomatous-lymphocytic interstitial lung disease (GLILD). We present 34 surgical lung biopsy cases of CVID and 4 of IgAD. Noncaseating granulomas were seen in 23/34 (68%) CVID and 2/4 (50%) IgAD cases. A statistically identical pattern of benign lymphoid proliferation was found in CVID and IgAD whether or not granulomas were present. Organizing pneumonia, sometimes considered a part of GLILD, was seen in 25/34 (74%) CVID and 2/4 (50%) IgAD cases and did not correlate with the presence of granulomas. On follow-up, 3 CVID patients died (only 1 of pulmonary disease), while 21 others are alive at 1 to 300 months with no difference by presence or absence of granulomas. Three IgAD patients with follow-up are alive. We conclude that CVID and IgAD are indistinguishable in surgical lung biopsies and a subset of both show patterns that would qualify as GLILD, while other cases lack granulomas but have identical patterns of lymphoid infiltration and organizing pneumonia. We suggest that GLILD is neither a specific nor a useful entity, and biopsies from CVID and IgAD patients should be diagnosed simply by microscopic pattern(s) observed. The prognosis of CVID with lymphoid infiltrates with or without granulomas in this series was good, contrary to claims in the literature about GLILD.


Assuntos
Imunodeficiência de Variável Comum/patologia , Granuloma do Sistema Respiratório/patologia , Deficiência de IgA/patologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Linfócitos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Proliferação de Células , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/mortalidade , Imunodeficiência de Variável Comum/terapia , Feminino , Granuloma do Sistema Respiratório/imunologia , Granuloma do Sistema Respiratório/mortalidade , Granuloma do Sistema Respiratório/terapia , Humanos , Deficiência de IgA/imunologia , Deficiência de IgA/mortalidade , Deficiência de IgA/terapia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/terapia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , América do Norte , Valor Preditivo dos Testes , Prognóstico , Adulto Jovem
5.
Clin Immunol ; 213: 108366, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32092471

RESUMO

The nuclease Artemis is a enzyme for V(D)J recombination allowing for the creation of T and B lymphocytes as well as for the repair of radiation-induced DNA double strand breaks encoded by the DCLRE1C gene. Artemis-null mutations are a known cause of severe combined immunodeficiencies (SCIDs) with radiosensitivity. Hypomorphic mutations in Artemis have been reported to cause a "leaky SCID"" phenotype, typically with hypogammaglobulinemia. We present four patients, all harboring the same unique hypomorphic mutation in the DCLRE1C gene, an 8-base pair insertion (c.1299_1306dup, p.Cys436*) presenting with a relatively mild phenotype including pulmonary infectious EBV-related lymphoproliferative diseases, an autoimmune phenomenon. Non-typical findings of IgG hypergammaglobulinemia accompanied by IgA and IgE deficiency were recorded in all patients. The typical viral, fungal, and opportunistic infections were absent, and patients reached a relatively old age.


Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Hipergamaglobulinemia/genética , Imunoglobulina G , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Adolescente , Doenças Autoimunes/genética , Feminino , Humanos , Deficiência de IgA/genética , Imunoglobulina E/deficiência , Transtornos Linfoproliferativos/genética , Masculino , Mutação , Fenótipo , Imunodeficiência Combinada Severa/complicações
6.
Clin Rev Allergy Immunol ; 58(1): 107-133, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31267472

RESUMO

Selective immunoglobulin A deficiency (SIgAD) is the most common primary immunodeficiency, defined as an isolated deficiency of IgA (less than 0.07 g/L). Although the majority of people born with IgA deficiency lead normal lives without significant pathology, there is nonetheless a significant association of IgA deficiency with mucosal infection, increased risks of atopic disease, and a higher prevalence of autoimmune disease. To explain these phenomena, we have performed an extensive literature review to define the geoepidemiology of IgA deficiency and particularly the relative risks for developing systemic lupus erythematosus, hyperthyroidism, hypothyroidism, type 1 diabetes mellitus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and vitiligo; these diseases have strong data to support an association. We also note weaker associations with scleroderma, celiac disease, autoimmune hepatitis, immune thrombocytopenic purpura, and autoimmune hemolytic anemia. Minimal if any associations are noted with myasthenia gravis, lichen planus, and multiple sclerosis. Finally, more recent data provide clues on the possible immunologic mechanisms that lead to the association of IgA deficiency and autoimmunity; these lessons are important for understanding the etiology of autoimmune disease.


Assuntos
Autoimunidade , Deficiência de IgA/diagnóstico , Deficiência de IgA/epidemiologia , Deficiência de IgA/etiologia , Fenótipo , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Comorbidade , Suscetibilidade a Doenças/imunologia , Humanos , Deficiência de IgA/complicações , Imunoglobulina A/sangue , Qualidade de Vida , Avaliação de Sintomas
7.
J Allergy Clin Immunol ; 145(3): 982-992, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816409

RESUMO

BACKGROUND: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. OBJECTIVE: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). METHODS: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/ßGeo) mouse model and validated select findings in a patient with KS. RESULTS: Compared with wild-type littermates, Kmt2d+/ßGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/ßGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/ßGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. CONCLUSIONS: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.


Assuntos
Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/patologia , Linfócitos B/patologia , Face/anormalidades , Doenças Hematológicas/imunologia , Doenças Hematológicas/patologia , Nódulos Linfáticos Agregados/patologia , Doenças Vestibulares/imunologia , Doenças Vestibulares/patologia , Animais , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Proteínas de Ligação a DNA/genética , Face/patologia , Histona-Lisina N-Metiltransferase/genética , Humanos , Deficiência de IgA/genética , Deficiência de IgA/imunologia , Cadeias beta de Integrinas/metabolismo , Intestinos/imunologia , Camundongos , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Nódulos Linfáticos Agregados/imunologia
8.
Can Vet J ; 60(12): 1305-1311, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31814637

RESUMO

Immunoglobulin A (IgA) is widely recognized as the important antibody isotype involved in protective responses on mucosal surfaces, where it acts primarily by effectuating immune exclusion of foreign material. Selective IgA deficiency (SIgAD) is the most common immunodeficiency disease in dogs and humans and has consequences for mucosal immunity. This review is a comparative look at the biology of IgA and SIgAD with a focus on how this branch of immunology relates to vaccine selection and efficacy for canine infectious respiratory disease.


Assuntos
Deficiência de IgA/veterinária , Vacinas , Animais , Doenças do Cão , Cães , Humanos , Imunização/veterinária , Imunoglobulina A , Vacinação/veterinária
9.
Stem Cell Res ; 41: 101613, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31689593

RESUMO

Selective immunoglobulin-A deficiency (IgAD) is the most common primary immunodeficiency (PID) in the Western world and results in higher susceptibility to infections, autoimmune disorders and malignancies. We generated human induced pluripotent stem cell lines from two patients with selective IgAD, PHAi001 and PHAi002. Patient samples were reprogrammed using non-integrative based methods. Pluripotency of the PHAi001 and PHAi002 cell lines was confirmed by their expression of stem cell markers and capacity to differentiate into cells of the three germ layers. The PHAi001 and PHAi002 lines are a unique resource for experimental modeling of selective IgAD and associated disorders.


Assuntos
Técnicas de Cultura de Células/métodos , Linhagem Celular/patologia , Deficiência de IgA/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Adulto , Feminino , Humanos
10.
Clin Immunol ; 209: 108293, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31678364

RESUMO

Immunoglobulin A (IgA) is the principal antibody in secretions that bathe the gastrointestinal and respiratory mucosal surfaces and acts as an important first line of defense against invasion of pathogenic micro-organisms. The reported prevalence rate of complete IgA deficiency in healthy children ranges from 1:170 to 1:400, and as a solitary condition, it is often considered of limited clinical importance. However, patients with IgA deficiency can develop recurrent respiratory and gastrointestinal infections, as well as allergic and autoimmune diseases. In children referred for recurrent respiratory tract infections, the observed prevalence rate increases more than tenfold. This review discusses several aspects of IgA deficiency in children, including immunologic and microbiome changes in early childhood and the potential consequences of this condition in later life. It illustrates the importance of early identification of children with impaired IgA production who deserve appropriate clinical care and follow-up.


Assuntos
Deficiência de IgA/imunologia , Imunoglobulina A/imunologia , Animais , Doenças Autoimunes/imunologia , Criança , Humanos , Prevalência , Infecções Respiratórias/imunologia
12.
Scand J Immunol ; 90(6): e12828, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31520490

RESUMO

BACKGROUND: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency. Although most people with selective IgAD (sIgAD) are asymptomatic, many patients often suffer from recurrent respiratory infections and different allergic disorders. Our aim was to investigate connection between subtypes of sIgAD and incidence of respiratory and allergic disorders, as well as connection with lung function changes in children. METHODS: Children with IgAD where divided into two groups; severe IgAD in patients was defined as serum IgA level <7 mg/dL, while partial IgA deficiency diagnosis was made when serum IgA levels was higher than 7 mg/dL but at least two standard deviations (SD) below mean normal concentrations for their age. All patients were evaluated by their clinical and laboratory investigation parameters and compared to control group of children. RESULTS: Group of children with IgAD, severe as well as partial, showed higher prevalence of allergic diseases and total number of infections, compared to controls. There was a statistically significant difference in lung function for peak expiratory flow (PEF), the maximal expiratory flow at 50% of the forced vital capacity (MEF50) and fraction of exhaled nitric oxide (FENO) between group of patients with severe as well as partial IgAD and control group, where children with IgAD showed reduced lung function. CONCLUSIONS: Children with sIgAD are at increased risk for higher number of respiratory infections and developing allergic diseases, resulting in significantly lower pulmonary function which is related with the severity of sIgAD.


Assuntos
Hipersensibilidade/etiologia , Deficiência de IgA/complicações , Doenças Respiratórias/etiologia , Adolescente , Fatores Etários , Biomarcadores , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/diagnóstico , Deficiência de IgA/diagnóstico , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Masculino , Testes de Função Respiratória , Doenças Respiratórias/diagnóstico , Índice de Gravidade de Doença
13.
J Allergy Clin Immunol ; 144(6): 1660-1673, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31445098

RESUMO

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Imunodeficiência de Variável Comum/imunologia , Endotoxemia/imunologia , Deficiência de IgA/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Linfócitos B/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/patologia , Endotoxemia/patologia , Feminino , Humanos , Deficiência de IgA/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/patologia
15.
Medicina (Kaunas) ; 55(7)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311098

RESUMO

Celiac disease (CD) is a systemic autoimmune disease driven by gluten-ingestion in genetically predisposed individuals. Although it primarily affects the small bowel, CD can also involve other organs and manifest as an extraintestinal disease. Among the extraintestinal features of CD, hematologic ones are rather frequent and consist of anemia, thrombocytosis (thrombocytopenia also, but rare), thrombotic or hemorrhagic events, IgA deficiency, hyposplenism, and lymphoma. These hematologic alterations can be the sole manifestation of the disease and should prompt for CD testing in a suggestive clinical scenario. Recognition of these atypical, extraintestinal presentations, including hematologic ones, could represent a great opportunity to increase the diagnostic rate of CD, which is currently one of the most underdiagnosed chronic digestive disorders worldwide. In this review, we summarize recent evidence regarding the hematological manifestations of CD, with focus on practical recommendations for clinicians.


Assuntos
Doença Celíaca/complicações , Doenças Hematológicas/etiologia , Anemia/etiologia , Anemia/fisiopatologia , Doença Celíaca/fisiopatologia , Doenças Hematológicas/fisiopatologia , Humanos , Deficiência de IgA/etiologia , Deficiência de IgA/fisiopatologia , Linfoma/etiologia , Linfoma/fisiopatologia
16.
Clin Exp Immunol ; 198(2): 224-232, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31260083

RESUMO

Transient hypogammaglobulinaemia of infancy (THI) is a relatively rare disorder where there is an exaggeration of the physiological nadir of immunoglobulin (Ig)G between loss of transplacentally acquired maternal IgG and production by the infant. Patients may be vulnerable to infections during the period of hypogammaglobulinaemia. The precise time to recovery in all infants is currently unknown. We sought to determine the clinical features and time-course of recovery for patients with THI. We reviewed our experience with THI over the last three decades in order to describe clinical and laboratory features, as well as the time-course of recovery. Forty-seven patients were identified with THI. Only thirty-seven per cent remitted by 4 years of age, while some patients did not recover until the third or fourth decade. In keeping with previous studies, the majority (25 of 47) presented with recurrent infections, nine had a family history of immunodeficiency and 13 had adverse reactions to food as their dominant clinical manifestation. Chronic tonsillitis developed in 10 patients and symptoms improved following surgery. The group with food allergies recovered sooner than those presenting with infections or with a family history immunodeficiency. Eight patients failed to respond to at least one routine childhood vaccine. Two have IgA deficiency and four individuals recovering in adolescence and adulthood continue to have borderline/low IgG levels. None have progressed to common variable immunodeficiency disorders (CVID). THI is a misnomer, as the majority do not recover in infancy. Recovery from THI can extend into adulthood. THI must be considered in the differential diagnosis of adolescents or young adults presenting with primary hypogammaglobulinemia.


Assuntos
Agamaglobulinemia/imunologia , Deficiência de IgA/imunologia , Adolescente , Adulto , Agamaglobulinemia/patologia , Agamaglobulinemia/terapia , Pré-Escolar , Feminino , Humanos , Deficiência de IgA/patologia , Deficiência de IgA/terapia , Lactente , Masculino
17.
J Clin Immunol ; 39(5): 470-475, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31129864

RESUMO

PURPOSE: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. METHODS: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. RESULTS: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). CONCLUSIONS: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.


Assuntos
Deficiência de IgA/epidemiologia , Adolescente , Doença Celíaca/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Hipersensibilidade/epidemiologia , Deficiência de IgA/diagnóstico , Itália , Estudos Longitudinais , Masculino , Infecções Respiratórias/epidemiologia
18.
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
19.
Front Immunol ; 10: 777, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057537

RESUMO

Primary immunodeficiencies and immune dysregulatory disorders (PIDDs; now referred to as inborn errors in immunity) are rare disorders with a prevalence of 41. 4 or 50.5 per 100,000 persons (1). The incidence of malignancy in PIDD patents is the second-highest cause of death in children as well as adults, after infection, and is higher in certain PIDDs compared to others. We performed a systematic review of the literature to identify reports of B cell and T cell neoplasias in PIDDs and clustered them based on their classification in the IUIS schema. As would be expected, higher susceptibility to malignancies are typically reported in patients with Common Variable Immunodeficiency (CVID), combined immunodeficiencies affecting cellular immunity, in particular, DNA repair defects, or in the context of impaired immune regulatory control. There is not much evidence of increased risk for cancer in patients with innate immune defects, indicating that not all types of infection or genetic susceptibility predispose equally to cancer risk. Viral infections, in particular EBV, HHV and HPV, have been shown to increase susceptibility to developing cancer, but also patients with defects in immune regulation, such as Autoimmune Lymphoproliferative Syndrome (ALPS), activated p110delta syndrome (APDS type 1) and IL-10 receptor deficiency among others have a higher incidence of neoplastic disease, particularly lymphomas. In fact, lymphomas account for two-thirds of all malignancies reported in PIDD patients (2), with either a combined immunodeficiency or DNA repair defect predominating as the underlying immune defect in one registry, or antibody deficiencies in another (3). The vast majority of lymphomas reported in the context of PIDDs are B cell lymphomas, though T cell lymphomas have been reported in a few studies, and tend to largely be associated with chromosomal breakage disorders (4) or Cartilage Hair Hypoplasia (5). There appears to be a much higher prevalence of T cell lymphomas in patients with secondary immunodeficiencies (6), though this could reflect treatment bias. We reviewed the literature and summarized the reports of B and T cell lymphoma in PIDD patients to survey the current state of knowledge in this area.


Assuntos
Doenças do Sistema Imunitário/complicações , Linfoma de Células B/etiologia , Linfoma de Células T/etiologia , Doenças da Imunodeficiência Primária/complicações , Predisposição Genética para Doença , Humanos , Deficiência de IgA/imunologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfoma de Células T/genética , Linfoma de Células T/imunologia , Linfoma de Células T/terapia , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia
20.
Front Immunol ; 10: 403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936864

RESUMO

Objectives: It has recently been shown that individuals with selective IgA deficiency (sIgAD) have defective B cell responses both to T cell dependent and independent mimicking stimulations. The complex intracellular signaling pathways from different stimuli leading to IgA isotype switching have not been fully elucidated. Thus, the main objective of this study was to delineate these pathways and their potential role in the immunopathology linked to sIgAD. Materials and Methods: PBMCs from 10 individuals with sIgAD and 10 healthy controls (HC) were activated in vitro via either a T cell dependent or independent mimicking stimulation. Intracellular phosphorylation of pSTAT3, pSTAT5, pSTAT6, and as pERK1/2 was evaluated in T and B cells using phosphoflow cytometry. Results: By evaluating T cell dependent cytokine driven pathways linked to IgA isotype induction we identified a defect involving an IL-21 driven STAT3 activation isolated to B cells in sIgAD individuals. However, all other signaling pathways studied were found to be normal compared to HC. In T cell dependent cytokine driven stimulations linked to IgA isotype induction the following patterns emerged: (i) IL-10 led to significant STAT3 activation in both T- and B cells; (ii) IL-4 stimulation was predominantly confined to STAT6 activation in both T- and B cells, with some effects on STAT3 activation in T-cells; (iii) as expected, of tested stimuli, IL-2 alone activated STAT5 and some STAT3 activation though in both cases only in T-cells; (iv) IL-21 induced significant activation of STAT3 in both T- and B cells, with some effects on STAT5 activation in T-cells; and finally (v) synergistic effects were noted of IL-4+IL-10 on STAT5 activation in T-cells, and possibly STAT6 in both T- and B cells. On the other hand, CPG induced T cell independent activation was confined to ERK1/2 activation in B cells. Conclusion: Our results indicate a diminished STAT3 phosphorylation following IL-21 stimulation solely in B cells from sIgAD individuals. This can represent aberrant germinal center reactions or developmental halt. Thus, our work provides further insight into the unraveling of the previously hypothesized role of IL-21 to reconstitute immunoglobulin production in primary antibody deficiencies.


Assuntos
Linfócitos B/imunologia , Deficiência de IgA/imunologia , Interleucinas/imunologia , Ativação Linfocitária/imunologia , Fator de Transcrição STAT3/imunologia , Linfócitos B/metabolismo , Humanos , Deficiência de IgA/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
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