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1.
Blood ; 134(1): 9-21, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-30940614

RESUMO

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.


Assuntos
Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/imunologia , Trombocitopenia/genética , Trombocitopenia/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mutação , Adulto Jovem
2.
Pediatr Blood Cancer ; 66(4): e27569, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30537439

RESUMO

Autoimmune cytopenias (AIC) post-hematopoietic stem cell transplant (HSCT) are rare but exceptionally challenging complication. We conducted a comprehensive literature review and identified a pooled incidence of post-HSCT autoimmune hemolytic anemia and/or immune thrombocytopenia of 2.66% (SE = 0.27) in pediatric patients. Nonmalignant disease, unrelated donor transplant, peripheral or cord blood stem cell source, conditioning regimen without total body irradiation, and presence of chronic graft-versus-host disease were prominent risk factors. Treatment was highly variable, and cytopenias were commonly refractory. AIC represent a significant post-HSCT complication. We report here the incidence, risk factors, and possible biology behind the development of AIC in pediatric post-HSCT patients.


Assuntos
Anemia Hemolítica Autoimune/epidemiologia , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Púrpura Trombocitopênica Idiopática/epidemiologia , Condicionamento Pré-Transplante , Adolescente , Anemia Hemolítica Autoimune/genética , Criança , Feminino , Humanos , Incidência , Masculino , Púrpura Trombocitopênica Idiopática/etiologia , Fatores de Risco , Transplante Homólogo , Doadores não Relacionados
4.
Clin Immunol ; 188: 52-57, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29330115

RESUMO

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Anemia Hemolítica Autoimune/genética , Antígeno CTLA-4/genética , Mutação , Trombocitopenia/genética , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/patologia , Criança , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/patologia , Trombocitopenia/diagnóstico
7.
J Allergy Clin Immunol ; 139(5): 1629-1640.e2, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28139313

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations in the human signal transducer and activator of transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired TH17 cell differentiation and exaggerated responsiveness to type I and II interferons. Allogeneic bone marrow transplantation has been attempted in severely affected patients, but outcomes have been poor. OBJECTIVE: We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations. METHODS: We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1-mutated patient cells. RESULTS: We report a child with a novel mutation in the linker domain of STAT1 who had life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naive lymphocytes from the affected patient displayed increased TH1 and follicular T helper cell and suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reduced hyperresponsiveness to type I and II interferons, normalized TH1 and follicular T helper cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis, and maintained remission of immune-mediated cytopenias. CONCLUSIONS: Autoimmunity and infection caused by STAT1 GOF mutations are the result of dysregulated T helper cell responses. Janus kinase inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.


Assuntos
Anemia Hemolítica Autoimune/genética , Inibidores de Proteínas Quinases/farmacologia , Púrpura Trombocitopênica Idiopática/genética , Pirazóis/farmacologia , Fator de Transcrição STAT1/genética , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Anemia Hemolítica Autoimune/imunologia , Autoimunidade/efeitos dos fármacos , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Criança , Citocinas/imunologia , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Mutação , Púrpura Trombocitopênica Idiopática/imunologia , Fator de Transcrição STAT1/imunologia , Células Th1/imunologia , Células Th17/imunologia
9.
Hematology Am Soc Hematol Educ Program ; 2016(1): 690-697, 2016 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-27913548

RESUMO

Autoimmune hemolytic anemia (AIHA) is a rare and heterogeneous disease that affects 1 to 3/100 000 patients per year. AIHA caused by warm autoantibodies (w-AIHA), ie, antibodies that react with their antigens on the red blood cell optimally at 37°C, is the most common type, comprising ∼70% to 80% of all adult cases and ∼50% of pediatric cases. About half of the w-AIHA cases are called primary because no specific etiology can be found, whereas the rest are secondary to other recognizable underlying disorders. This review will focus on the postulated immunopathogenetic mechanisms in idiopathic and secondary w-AIHA and report on the rare cases of direct antiglobulin test-negative AIHA, which are even more likely to be fatal because of inherent characteristics of the causative antibodies, as well as because of delays in diagnosis and initiation of appropriate treatment. Then, the characteristics of w-AIHA associated with genetically defined immune dysregulation disorders and special considerations on its management will be discussed. Finally, the standard treatment options and newer therapeutic approaches for this chronic autoimmune blood disorder will be reviewed.


Assuntos
Anemia Hemolítica Autoimune , Adulto , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/imunologia , Anemia Hemolítica Autoimune/terapia , Feminino , Humanos , Masculino
10.
Ann Hematol ; 95(10): 1595-601, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27465156

RESUMO

Aquaporin-1 (AQP1) is the membrane water channel responsible for changes in erythrocyte volume in response to the tonicity of the medium. As the aberrant distribution of proteins in hereditary spherocytosis (HS) generates deficiencies of proteins other than those codified by the mutated gene, we postulated that AQP1 expression might be impaired in spherocytes. AQP1 expression was evaluated through flow cytometry in 5 normal controls, 1 autoimmune hemolytic anemia, 10 HS (2 mild, 3 moderate, 2 severe, and 3 splenectomized), and 3 silent carriers. The effect of AQP1 inhibitors was evaluated through water flow-based tests: osmotic fragility and hypertonic cryohemolysis. Serum osmolality was measured in 20 normal controls and 13 HS. The effect of erythropoietin (Epo) on AQP1 expression was determined in cultures of erythroleukemia UT-7 cells, dependent on Epo to survive. Independent of erythrocyte size, HS patients showed a lower content of AQP1 in erythrocyte membranes which correlated with the severity of the disease. Accordingly, red blood cells from HS subjects were less sensitive to cryohemolysis than normal erythrocytes after inhibition of the AQP1 water channel. A lower serum osmolality in HS with respect to normal controls suggests alterations during reticulocyte remodeling. The decreased AQP1 expression could contribute to explain variable degrees of anemia in hereditary spherocytosis. The finding of AQP1 expression induced by Epo in a model of erythroid cells may be interpreted as a mechanism to restore the balance of red cell water fluxes.


Assuntos
Aquaporina 1/biossíntese , Eritrócitos/metabolismo , Regulação da Expressão Gênica , Esferocitose Hereditária/sangue , Adolescente , Adulto , Anemia Hemolítica Autoimune/sangue , Anemia Hemolítica Autoimune/genética , Aquaporina 1/sangue , Aquaporina 1/genética , Transporte Biológico , Água Corporal , Linhagem Celular , Criança , Pré-Escolar , Membrana Eritrocítica/metabolismo , Eritrócitos/patologia , Eritropoetina/farmacologia , Hemólise , Heterozigoto , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Pessoa de Meia-Idade , Concentração Osmolar , Fragilidade Osmótica , Esferocitose Hereditária/genética , Esferocitose Hereditária/cirurgia , Esplenectomia
11.
Transfus Med Rev ; 30(4): 197-201, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27345938

RESUMO

Since the discovery of the ABO blood group in the early 20th century, more than 300 blood group antigens have been categorized among 35 blood group systems. The molecular basis for most blood group antigens has been determined and demonstrates tremendous genetic diversity, particularly in the ABO and Rh systems. Several blood group genotyping assays have been developed, and 1 platform has been approved by the Food and Drug Administration as a "test of record," such that no phenotype confirmation with antisera is required. DNA-based red blood cell (RBC) phenotyping can overcome certain limitations of hemagglutination assays and is beneficial in many transfusion settings. Genotyping can be used to determine RBC antigen phenotypes in patients recently transfused or with interfering allo- or autoantibodies, to resolve discrepant serologic typing, and/or when typing antisera are not readily available. Molecular RBC antigen typing can facilitate complex antibody evaluations and guide RBC selection for patients with sickle cell disease (SCD), thalassemia, and autoimmune hemolytic anemia. High-resolution RH genotyping can identify variant RHD and RHCE in patients with SCD, which have been associated with alloimmunization. In the future, broader access to cost-efficient, high-resolution RBC genotyping technology for both patient and donor populations may be transformative for the field of transfusion medicine.


Assuntos
Anemia Hemolítica Autoimune/genética , Anemia Falciforme/genética , Antígenos de Grupos Sanguíneos/genética , Transfusão de Sangue/métodos , Eritrócitos/química , Talassemia/genética , Anemia Hemolítica Autoimune/terapia , Anemia Falciforme/terapia , Autoanticorpos/sangue , Incompatibilidade de Grupos Sanguíneos/genética , Tipagem e Reações Cruzadas Sanguíneas , Feminino , Variação Genética , Genótipo , Hematologia/métodos , Hematologia/tendências , Hemoglobinopatias/sangue , Humanos , Isoanticorpos/sangue , Fenótipo , Gravidez , Sistema do Grupo Sanguíneo Rh-Hr/genética , Análise de Sequência de DNA , Talassemia/terapia , Reação Transfusional , Resultado do Tratamento
12.
J Clin Immunol ; 36(5): 480-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27146671

RESUMO

PURPOSE: Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical, immunological, and genetic features of a patient with severe autoimmune manifestations. METHODS: Whole exome sequencing was performed to establish a molecular diagnosis. Evaluation of lymphocyte subsets was performed for immunological characterization. Medical files were reviewed to collect clinical and immunological data. RESULTS: A 7-year-old boy, born to consanguineous parents, presented with autoimmune hemolytic anemia, hepatosplenomegaly, autoimmune thyroiditis, and severe autoimmune gastrointestinal manifestations. Immunological investigations revealed low immunoglobulin levels and low numbers of B and NK cells. Treatment included immunoglobulin replacement and immunosuppressive therapy. Seven years after disease onset, the patient developed severe neurological symptoms resembling acute disseminated encephalomyelitis, prompting allogeneic hematopoietic stem cell transplantation (HSCT) with the HLA-identical mother as donor. Whole exome sequencing of the patient uncovered a homozygous 1 bp deletion in LRBA (c.7162delA:p.T2388Pfs*7). Importantly, during 2 years of follow-up post-HSCT, marked clinical improvement and recovery of immune function was observed. CONCLUSIONS: Our data suggest a beneficial effect of HSCT in patients with LRBA deficiency.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Anemia Hemolítica Autoimune/terapia , Linfócitos B/imunologia , Imunodeficiência de Variável Comum/terapia , Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais/imunologia , Deleção de Sequência/genética , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/genética , Autoimunidade , Criança , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/genética , Consanguinidade , Análise Mutacional de DNA , Antígenos HLA/imunologia , Histocompatibilidade , Humanos , Imunoglobulinas/sangue , Masculino , Resultado do Tratamento
14.
Autoimmunity ; 49(3): 147-54, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26829107

RESUMO

Autoimmune hemolytic anemia (AIHA) is a rare blood disease associated with the production of auto-antibodies and autoimmune hemolysis. A critical role of B-cells in the development of AIHA has been demonstrated before. Here, we present the analysis of the clonal T-cell populations in patients with AIHA. Thirty-three patients with AIHA were included in this study. Thirteen patients with other anemias, 14 patients with other autoimmune conditions (SLE - 6, RA - 8) and 20 healthy donors were included in the study as a control group. The clonality of T-cell was evaluated by the assessment of the T-cell receptor gamma and beta chain gene rearrangements (TCRG and TCRB). The incidence of T-cell monoclonality detected in patients with AIHA was significantly higher compared to the control group. The persistence of T-cell clones did not correlate with the level of hemoglobin and other signs of remission or relapse and did not disappear after the therapy and clinical improvement (observation period was between 1 and 10 years). There was no correlation between the T-cell clonality and the gender, age, splenectomy, duration or severity of the disease. Fractionation of T-lymphocytes (CD4+, CD8+, CD4+25+) revealed that the monoclonal T-cells belonged to the CD8+ sub-population. We assume that besides a possible causative role of the T-cell clones in AIHA to autoimmune process, these clones do not directly participate in the development and maintenance of hemolysis. Most of the AIHA patients (48.5%) demonstrated a T-cell monoclonality, which requires monitoring and should be distinguished from T-cell tumors.


Assuntos
Anemia Hemolítica Autoimune/sangue , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/terapia , Antígenos de Superfície/metabolismo , Sequência de Bases , Linfócitos T CD8-Positivos/metabolismo , Índices de Eritrócitos , Feminino , Rearranjo Gênico do Linfócito B , Rearranjo Gênico do Linfócito T , Humanos , Imunofenotipagem , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de DNA , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
17.
J Autoimmun ; 62: 22-30, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26112660

RESUMO

Primary warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease in which red blood cells are eliminated by IgG autoantibodies. We analyzed the antibody-secreting cells in the spleen and the peripheral blood of wAIHA patients in various contexts of treatment. Plasmablasts were observed in peripheral blood of newly diagnosed wAIHA patients and, accordingly, active germinal center reactions were present in the spleen of patients receiving short-term corticosteroid therapy. Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro. In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive. By using a set of diagnostic genes that allowed us to assess the plasma cell maturation stage, we observed that these cells displayed a long-lived program, differing from the one of plasma cells from healthy donors or from wAIHA patients with various immunosuppressant treatments, and more similar to the one of normal long-lived bone-marrow plasma cells. Interestingly, an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients. These results suggest, in line with our previous report on primary immune thrombocytopenia, that the B-cell depletion induced by rituximab promoted a suitable environment for the maturation and survival of auto-immune long-lived plasma cells in the spleen.


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Anemia Hemolítica Autoimune/imunologia , Autoimunidade , Fatores Imunológicos/uso terapêutico , Plasmócitos/imunologia , Rituximab/uso terapêutico , Baço/imunologia , Adulto , Idoso , Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/cirurgia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Eritrócitos/imunologia , Feminino , Perfilação da Expressão Gênica , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Plasmócitos/metabolismo , Baço/metabolismo , Baço/patologia , Esplenectomia , Adulto Jovem
18.
J Immunol ; 195(3): 1233-41, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26116505

RESUMO

Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1ß and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1ß output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1ß in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies.


Assuntos
Anemia Hemolítica Autoimune/genética , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Inflamassomos/genética , Macrófagos/imunologia , Anemia Hemolítica Autoimune/imunologia , Animais , Anticorpos Antinucleares/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Candida albicans/imunologia , Candidíase/imunologia , Candidíase/microbiologia , Proteínas de Transporte/imunologia , Caspase 1/genética , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/imunologia , Inflamassomos/imunologia , Interleucina-1beta/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Camundongos , Camundongos Endogâmicos NZB , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais/genética , Transdução de Sinais/imunologia
19.
Neth J Med ; 73(2): 86-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25753074

RESUMO

Membrane disorders comprise an important group of inherited haemolytic anaemias. Diagnostic work-up starts with examination of the blood smear, followed by osmotic gradient ektacytometry. In special cases DNA analysis is performed to confirm the diagnosis. For this purpose a next-generation sequencing-based method has been developed. The combination of these techniques established the correct diagnosis in a case of haemolytic anaemia of unknown cause.


Assuntos
Anemia Hemolítica Autoimune/diagnóstico , Análise de Sequência de DNA/métodos , Anemia Hemolítica Autoimune/genética , Feminino , Humanos , Adulto Jovem
20.
Blood ; 125(5): 741-2, 2015 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-25634610

RESUMO

In this issue of Blood, Stepensky et al provide an astute description of immunosenescence arising from deficiency in tripeptidyl peptidase II (TPPII). Senescence of T and B lymphocytes is a striking finding, which has recently come into the limelight because it can be linked to primary immunodeficiency syndromes with autoimmunity.


Assuntos
Envelhecimento/imunologia , Aminopeptidases/imunologia , Anemia Hemolítica Autoimune/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/imunologia , Mutação da Fase de Leitura , Síndromes de Imunodeficiência/genética , Serina Endopeptidases/imunologia , Trombocitopenia/genética , Animais , Feminino , Humanos , Masculino
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