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1.
Front Immunol ; 8: 1824, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29375547

RESUMO

Heterozygous mutations in the cytotoxic T lymphocyte antigen-4 (CTLA-4) are associated with lymphadenopathy, autoimmunity, immune dysregulation, and hypogammaglobulinemia in about 70% of the carriers. So far, the incomplete penetrance of CTLA-4 haploinsufficiency has been attributed to unknown genetic modifiers, epigenetic changes, or environmental effects. We sought to identify potential genetic modifiers in a family with differential clinical penetrance of CTLA-4 haploinsufficiency. Here, we report on a rare heterozygous gain-of-function mutation in Janus kinase-3 (JAK3) (p.R840C), which is associated with the clinical manifestation of CTLA-4 haploinsufficiency in a patient carrying a novel loss-of-function mutation in CTLA-4 (p.Y139C). While the asymptomatic parents carry either the CTLA-4 mutation or the JAK3 variant, their son has inherited both heterozygous mutations and suffers from hypogammaglobulinemia combined with autoimmunity and lymphoid hyperplasia. Although the patient's lymph node and spleen contained many hyperplastic germinal centers with follicular helper T (TFH) cells and immunoglobulin (Ig) G-positive B cells, plasma cell, and memory B cell development was impaired. CXCR5+PD-1+TIGIT+ TFH cells contributed to a large part of circulating T cells, but they produced only very low amounts of interleukin (IL)-4, IL-10, and IL-21 required for the development of memory B cells and plasma cells. We, therefore, suggest that the combination of the loss-of-function mutation in CTLA-4 with the gain-of-function mutation in JAK3 directs the differentiation of CD4 T cells into dysfunctional TFH cells supporting the development of lymphadenopathy, hypogammaglobulinemia, and immunodeficiency. Thus, the combination of rare genetic heterozygous variants that remain clinically unnoticed individually may lead to T cell hyperactivity, impaired memory B cell, and plasma cell development resulting finally in combined immunodeficiency.

2.
J Immunol ; 194(9): 4144-53, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25825446

RESUMO

The immune and the skeletal system are tightly interconnected, and B lymphocytes are uniquely endowed with osteo-interactive properties. In this context, receptor activator of NF-κB (RANK) ligand (RANKL) plays a pivotal role in lymphoid tissue formation and bone homeostasis. Although murine models lacking RANK or RANKL show defects in B cell number, the role of the RANKL-RANK axis on B physiology is still a matter of debate. In this study, we have characterized in detail B cell compartment in Rankl(-/-) mice, finding a relative expansion of marginal zone B cells, B1 cells, and plasma cells associated with increased Ig serum levels, spontaneous germinal center formation, and hyperresponse to CD40 triggering. Such abnormalities were associated with an increased frequency of regulatory B cells and augmented B cell-derived IL-10 production. Remarkably, in vivo IL-10-R blockade reduced T cell-triggered plasma cell differentiation and restrained the expansion of regulatory B cells. These data point to a novel role of the RANKL-RANK axis in the regulation of B cell homeostasis and highlight an unexpected link between IL-10 CD40 signaling and the RANKL pathway.


Assuntos
Linfócitos B/imunologia , Interleucina-10/imunologia , Ligante RANK/deficiência , Ligante RANK/imunologia , Animais , Camundongos , Camundongos Knockout
3.
J Immunol ; 194(8): 3723-34, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25762782

RESUMO

The paracaspase MALT1 plays an important role in immune receptor-driven signaling pathways leading to NF-κB activation. MALT1 promotes signaling by acting as a scaffold, recruiting downstream signaling proteins, as well as by proteolytic cleavage of multiple substrates. However, the relative contributions of these two different activities to T and B cell function are not well understood. To investigate how MALT1 proteolytic activity contributes to overall immune cell regulation, we generated MALT1 protease-deficient mice (Malt1(PD/PD)) and compared their phenotype with that of MALT1 knockout animals (Malt1(-/-)). Malt1(PD/PD) mice displayed defects in multiple cell types including marginal zone B cells, B1 B cells, IL-10-producing B cells, regulatory T cells, and mature T and B cells. In general, immune defects were more pronounced in Malt1(-/-) animals. Both mouse lines showed abrogated B cell responses upon immunization with T-dependent and T-independent Ags. In vitro, inactivation of MALT1 protease activity caused reduced stimulation-induced T cell proliferation, impaired IL-2 and TNF-α production, as well as defective Th17 differentiation. Consequently, Malt1(PD/PD) mice were protected in a Th17-dependent experimental autoimmune encephalomyelitis model. Surprisingly, Malt1(PD/PD) animals developed a multiorgan inflammatory pathology, characterized by Th1 and Th2/0 responses and enhanced IgG1 and IgE levels, which was delayed by wild-type regulatory T cell reconstitution. We therefore propose that the pathology characterizing Malt1(PD/PD) animals arises from an immune imbalance featuring pathogenic Th1- and Th2/0-skewed effector responses and reduced immunosuppressive compartments. These data uncover a previously unappreciated key function of MALT1 protease activity in immune homeostasis and underline its relevance in human health and disease.


Assuntos
Linfócitos B Reguladores/imunologia , Caspases/imunologia , Diferenciação Celular/imunologia , Proliferação de Células , Encefalomielite Autoimune Experimental/imunologia , Proteínas de Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos B Reguladores/patologia , Caspases/genética , Diferenciação Celular/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Humanos , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Camundongos , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/genética , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/patologia
4.
J Virol ; 89(9): 4748-59, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25673724

RESUMO

UNLABELLED: The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections. IMPORTANCE: Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.


Assuntos
Infecções por Arenaviridae/imunologia , Macrófagos/química , Macrófagos/imunologia , Receptores de Interleucina-4/deficiência , Infecções por Rhabdoviridae/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/análise , Imunidade Adaptativa , Animais , Imunidade Inata , Interferon Tipo I/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos Knockout , Transdução de Sinais , Vesiculovirus/imunologia
5.
Nat Commun ; 5: 5360, 2014 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-25406581

RESUMO

Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling. Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in NIK can cause multiple aberrations of lymphoid immunity.


Assuntos
Agamaglobulinemia/genética , Linfopenia/genética , Proteínas Serina-Treonina Quinases/genética , Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Infecções Bacterianas/imunologia , Pré-Escolar , Simulação por Computador , Criptosporidiose/imunologia , Feminino , Humanos , Switching de Imunoglobulina , Síndromes de Imunodeficiência/genética , Memória Imunológica , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Lactente , Células Matadoras Naturais/imunologia , Contagem de Leucócitos , Contagem de Linfócitos , Linfopenia/imunologia , Mutação , Linhagem , Recidiva , Linfócitos T Auxiliares-Indutores/imunologia , Viroses/imunologia
6.
PLoS One ; 9(6): e100328, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24945754

RESUMO

Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.


Assuntos
Diferenciação Celular , Plasmócitos/citologia , Plasmócitos/metabolismo , Fatores de Transcrição SOXD/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXD/genética
7.
J Allergy Clin Immunol ; 134(2): 420-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24679343

RESUMO

BACKGROUND: Five different G protein-coupled sphingosine-1-phosphate (S1P) receptors (S1P1-S1P5) regulate a variety of physiologic and pathophysiologic processes, including lymphocyte circulation, multiple sclerosis (MS), and cancer. Although B-lymphocyte circulation plays an important role in these processes and is essential for normal immune responses, little is known about S1P receptors in human B cells. OBJECTIVE: To explore their function and signaling, we studied B-cell lines and primary B cells from control subjects, patients with leukemia, patients with S1P receptor inhibitor-treated MS, and patients with primary immunodeficiencies. METHODS: S1P receptor expression was analyzed by using multicolor immunofluorescence microscopy and quantitative PCR. Transwell assays were used to study cell migration. S1P receptor internalization was visualized by means of time-lapse imaging with fluorescent S1P receptor fusion proteins expressed by using lentiviral gene transfer. B-lymphocyte subsets were characterized by means of flow cytometry and immunofluorescence microscopy. RESULTS: Showing that different B-cell populations express different combinations of S1P receptors, we found that S1P1 promotes migration, whereas S1P4 modulates and S1P2 inhibits S1P1 signals. Expression of CD69 in activated B lymphocytes and B cells from patients with chronic lymphocytic leukemia inhibited S1P-induced migration. Studying B-cell lines, normal B lymphocytes, and B cells from patients with primary immunodeficiencies, we identified Bruton tyrosine kinase, ß-arrestin 2, LPS-responsive beige-like anchor protein, dedicator of cytokinesis 8, and Wiskott-Aldrich syndrome protein as critical signaling components downstream of S1P1. CONCLUSION: Thus S1P receptor signaling regulates human B-cell circulation and might be a factor contributing to the pathology of MS, chronic lymphocytic leukemia, and primary immunodeficiencies.


Assuntos
Subpopulações de Linfócitos B/metabolismo , Imunodeficiência de Variável Comum/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Esclerose Múltipla/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Tirosina Quinase da Agamaglobulinemia , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Arrestinas/genética , Arrestinas/imunologia , Arrestinas/metabolismo , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Linhagem Celular , Movimento Celular , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Cultura Primária de Células , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Proteínas Tirosina Quinases/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/imunologia , Transdução de Sinais , Imagem com Lapso de Tempo , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/imunologia , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , beta-Arrestina 2 , beta-Arrestinas
8.
J Allergy Clin Immunol ; 133(6): 1651-9.e12, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24746753

RESUMO

BACKGROUND: Alterations of immune homeostasis in the gut can result in development of inflammatory bowel disease (IBD). Recently, Mendelian forms of IBD have been discovered, as exemplified by deficiency of IL-10 or its receptor subunits. In addition, other types of primary immunodeficiency disorders might be associated with intestinal inflammation as one of their leading clinical presentations. OBJECTIVE: We investigated a large consanguineous family with 3 children who presented with early-onset IBD within the first year of life, leading to death in infancy in 2 of them. METHODS: Homozygosity mapping combined with exome sequencing was performed to identify the molecular cause of the disorder. Functional experiments were performed to assess the effect of IL-21 on the immune system. RESULTS: A homozygous mutation in IL21 was discovered that showed perfect segregation with the disease. Deficiency of IL-21 resulted in reduced numbers of circulating CD19(+) B cells, including IgM(+) naive and class-switched IgG memory B cells, with a concomitant increase in transitional B-cell numbers. In vitro assays demonstrated that mutant IL-21(Leu49Pro) did not induce signal transducer and activator of transcription 3 phosphorylation and immunoglobulin class-switch recombination. CONCLUSION: Our study uncovers IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development similar to those found in patients with common variable immunodeficiency. IBD might mask an underlying primary immunodeficiency, as illustrated here with IL-21 deficiency.


Assuntos
Imunodeficiência de Variável Comum/genética , Doenças Inflamatórias Intestinais/genética , Interleucinas/deficiência , Interleucinas/genética , Idade de Início , Sequência de Aminoácidos , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/metabolismo , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Switching de Imunoglobulina , Isotipos de Imunoglobulinas/sangue , Isotipos de Imunoglobulinas/imunologia , Imunofenotipagem , Lactente , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Interleucinas/química , Ativação Linfocitária , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Linhagem , Conformação Proteica , Receptores de Interleucina-21/metabolismo , Alinhamento de Sequência , Transdução de Sinais
9.
Curr Allergy Asthma Rep ; 14(5): 434, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24633618

RESUMO

In this review we summarize recent insights into the development of human B cells primarily by studying immunodeficiencies. Development and differentiation of B cells can be considered as a paradigm for many other developmental processes in cell biology. However, it differs from the development of many other cell types by phases of extremely rapid cell division and by defined series of somatic recombination and mutation events required to assemble and refine the B cell antigen receptors. Both somatic DNA alteration and proliferation phases take place in defined sites but in different organs. Thus, cell migration and timely arrival at defined sites are additional features of B cell development. By comparing experimental mouse models with insights gained from studying defined genetic defects leading to primary immunodeficiencies and hypogammaglobulinemia, we address important features that are characteristic for human B cells. We also summarize recent advances made by developing improved in vitro and in vivo systems allowing the development of human B cells from hematopoietic stem cells. Combined with genetic and functional studies of immunodeficiencies, these models will contribute not only to a better understanding of disease affecting the B lymphocyte compartment, but also to designing better and safer novel B cell-targeted therapies in autoimmunity and allergy.


Assuntos
Linfócitos B/imunologia , Animais , Antígenos/imunologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Sobrevivência Celular , Humanos , Memória Imunológica , Fatores de Transcrição/imunologia
11.
J Immunol ; 192(3): 1044-54, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24379121

RESUMO

The peripheral B cell compartment is maintained by homeostatic proliferation and through replenishment by bone marrow precursors. Because hematopoietic stem cells cycle at a slow rate, replenishment must involve replication of precursor B cells. To study proliferation of early human B cell progenitors, we established a feeder cell-free in vitro system allowing the development of B cells from CD34(+) hematopoietic stem cells up to the stage of immature IgM(+) B cells. We found that pro-B and pre-B cells generated in vitro can proliferate autonomously and persist up to 7 wk in culture in the absence of signals induced by exogenously added cytokines. Nevertheless, addition of IL-7 enhanced pre-B cell expansion and inhibited maturation into IgM(+) B cells. The B cell precursor subsets replicating in vitro were highly similar to the bone marrow B cell precursors cycling in vivo. The autonomous proliferation of B cell precursor subsets in vitro and their long-term persistence implies that proliferation during pro-B and pre-B cell stages plays an important role in the homeostasis of the peripheral B cell compartment. Our in vitro culture can be used to study defects in B cell development or in reconstitution of the B cell pool after depletion and chemotherapy.


Assuntos
Linfócitos B/citologia , Técnicas de Cultura de Células/métodos , Células-Tronco Hematopoéticas/citologia , Adulto , Animais , Medula Óssea , Divisão Celular , Linhagem da Célula , Células Cultivadas , Técnicas de Cocultura , Proteínas de Ligação a DNA/deficiência , Sangue Fetal/citologia , Sobrevivência de Enxerto , Células-Tronco Hematopoéticas/efeitos dos fármacos , Xenoenxertos , Homeostase , Humanos , Imunoglobulina M/biossíntese , Imunofenotipagem , Interleucina-7/farmacologia , Linfopoese/efeitos dos fármacos , Camundongos , Quimera por Radiação , Receptores de Interleucina-2/deficiência , Fatores de Tempo , Adulto Jovem
12.
Autoimmunity ; 46(7): 429-38, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23742274

RESUMO

B-lymphocytes play a pivotal role in ANCA-associated vasculitides (AAV). The homeostasis of peripheral human B-lymphocyte subpopulations is tightly regulated, but may be disturbed in autoimmune disease or following immunosuppressive therapies. To elucidate the effect of immunosuppression and the relevance of B-lymphocyte disturbances, the B-lymphocyte compartment was analysed in 61 AAV patients. After immunosuppressive treatment a general B-lymphocytopenia developed in AAV patients. Within the B-lymphocyte subpopulations transitional B cells are the first maturation stage found in the peripheral blood. Transitional B-lymphocytes were significantly lower in AAV patients after immunosuppressive therapy compared to healthy controls. Furthermore, marginal zone B cells--a B-lymphocyte population protecting against encapsulated bacteria--were markedly lowered after immunosuppressive therapy in AAV patients. AAV patients treated with immunosuppressants had lower numbers of naïve and memory B-lymphocytes. Numbers of marginal zone B cells, memory B cells and plasmablasts correlated with concentrations of immunoglobulins. We evaluated plasmablasts for a potential correlation with disease activity. Different from what has been reported for e.g. large vessel vasculitis, absolute numbers of plasmablasts were not increased in patients with AAV and showed no correlation to disease activity. As low transitional B cells after treatment with immunosuppressants indicated an impaired early B-lymphocyte development, seven patients treated with the B cell depleting agent rituximab (RTX) because of relapsing disease activity were analysed for their B cell repopulation kinetics. In the majority of these patients repopulation of the peripheral B cell compartment by newly formed transitional B cells after RTX treatment was constricted and delayed.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Homeostase/imunologia , Imunossupressores/administração & dosagem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Subpopulações de Linfócitos B/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Homeostase/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Leflunomida , Contagem de Linfócitos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/análogos & derivados , Rituximab
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