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4.
Int J Hematol ; 112(3): 422-426, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32342335

RESUMO

Post-transplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab is effective for PTLD; however, rituximab can produce adverse effects, including hypogammaglobulinemia. Here, we present the case of an 18-year-old female with refractory cytopenia of childhood who developed persistent selective hypogammaglobulinemia with low immunoglobulin G (IgG) 2 and IgG4 levels and monoclonal protein after rituximab therapy against probable PTLD. Despite B-cell recovery, the serum IgG levels gradually declined, reaching < 300 mg/dL at 33 months after rituximab treatment. In addition, class-switched memory (CD27 + IgD -) B cells were limited in phenotypic analysis. These findings suggest that peri-HSCT rituximab may contribute to an abnormal B-cell repertoire induced by impaired immunoglobulin class switch.


Assuntos
Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/imunologia , Switching de Imunoglobulina , Imunoglobulina G , Transtornos Linfoproliferativos/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Rituximab/efeitos adversos , Adolescente , Subpopulações de Linfócitos B , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transtornos Linfoproliferativos/etiologia , Complicações Pós-Operatórias/etiologia , Transplante Homólogo
5.
Clin Exp Immunol ; 200(2): 176-184, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31989577

RESUMO

The absence of adenosine deaminase (ADA) causes severe combined immune deficiency (SCID), which has been treated with PEGylated bovine-extracted ADA (ADAGEN). ADAGEN was recently replaced by a PEGylated recombinant bovine ADA, expressed in Escherichia coli (elapegademase, ELA-ADA). Limited information on ELA-ADA is available.  ADA enzymatic activity of ELA-ADA and ADAGEN was assessed in vitro at diverse dilutions. ADA activity and immune reconstitution in an ADA-SCID patient treated with ELA-ADA were compared with age-matched patients previously treated with ADAGEN. ADA activity and thymus reconstitution were evaluated in ADA-deficient mice following ELA-ADA or ADAGEN administered from 7 days postpartum. In vitro, ADA activity of ELA-ADA and ADAGEN were similar at all dilutions. In an ADA-SCID patient, ELA-ADA treatment led to a marked increase in trough plasma ADA activity, which was 20% higher than in a patient previously treated with ADAGEN. A marked increase in T cell numbers and generation of naive T cells was evident following 3 months of ELA-ADA treatment, while T cell numbers increased following 4 months in 3 patients previously treated with ADAGEN. T cell proliferations stimulation normalized and thymus shadow became evident following ELA-ADA treatment. ADA activity was significantly increased in the blood of ADA-deficient mice following ELA-ADA compared to ADAGEN, while both treatments improved the mice weights, the weight, number of cells in their thymus and thymocyte subpopulations. ELA-ADA has similar in- vitro and possibly better in-vivo activity than ADAGEN. Future studies will determine whether ELA-ADA results in improved long-term immune reconstitution.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia , Imunodeficiência Combinada Severa , Linfócitos T , Timo , Adenosina Desaminase/sangue , Adenosina Desaminase/efeitos dos fármacos , Adenosina Desaminase/imunologia , Adenosina Desaminase/farmacologia , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Animais , Humanos , Camundongos , Camundongos Knockout , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
6.
J Med Case Rep ; 13(1): 338, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31744540

RESUMO

BACKGROUND: Myotonic dystrophy type 1 is an autosomal dominant disorder characterized by muscle weakness, myotonia, cataracts, and cardiac conduction defects; it is associated with expansions of cytosine-thymine-guanine repeats in the myotonic dystrophy protein kinase. Hypogammaglobulinemia is a lesser known association of myotonic dystrophy type 1 and the underlying pathogenesis of immunoglobulin G depletion remains unclear. CASE PRESENTATION: Here we report a kindred of two members (a 62-year-old white woman and a 30-year-old white man; mother and son) with myotonic dystrophy type 1-associated hypogammaglobulinemia associated with altered intravenous immunoglobulin elimination kinetics and reduced half-life. There was no history of systemic immunosuppression or renal or gastrointestinal protein loss in either patient, and no underlying case for a secondary immunodeficiency could be found. One patient required fortnightly intravenous immunoglobulin to maintain adequate trough immunoglobulin G levels. CONCLUSIONS: Ongoing study of myotonic dystrophy type 1-associated hypogammaglobulinemia using contemporary tools of genomic medicine may help to further delineate the pathogenesis of this entity.


Assuntos
Agamaglobulinemia/diagnóstico , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas/uso terapêutico , Mães , Distrofia Miotônica/diagnóstico , Núcleo Familiar , Adulto , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Feminino , Predisposição Genética para Doença , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/imunologia , Distrofia Miotônica/terapia
7.
PLoS One ; 14(10): e0223861, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31613907

RESUMO

Patients with primary or secondary antibody deficiency (PAD or SAD) are at increased risk of recurrent infections that can be alleviated by immunoglobulin replacement therapy (IRT). In addition to replenishing antibody levels, IRT has been suggested to modulate immune response in patients with antibody deficiency. Although both commonly treated with IRT, the underlying causes of PAD and SAD vary greatly, suggesting differential modulation of T-cell function that may lead to different responses to IRT. To explore this, peripheral blood mononuclear cells (PBMCs) were sampled from 17 PAD and 14 SAD patients before and 2-10 months after initiation of IRT, and analyzed for changes in T-cell phenotype and function. Proportions of CD4, CD8, Treg, or memory T-cells did not significantly change post-IRT compared to pre-IRT. However, we report distinct modulation in T-cell function between PAD and SAD patients post-IRT. Upon α-CD3/CD28 stimulation, proportion of IFN-γ+ CD4 and CD8 T-cells increased in SAD (p = 0.005) but not PAD patients post-IRT compared to baseline. Interestingly, total T-cell proliferation was reduced post-IRT in both PAD and SAD patients, although the reduction in proliferation was primarily due to reduced CD4 T-cell proliferation in PAD (p = 0.025) in contrast to CD8 T-cells in SAD (p = 0.042). In summary, even though IRT provides patients with passive humoral immunity-mediated protection in PAD and SAD, our findings suggest that IRT immunomodulation of T-cells is different in T-cell subsets depending on underlying immunodeficiency.


Assuntos
Agamaglobulinemia/terapia , Imunização Passiva/métodos , Doenças da Imunodeficiência Primária/terapia , Linfócitos T/metabolismo , Administração Intravenosa , Agamaglobulinemia/imunologia , Idoso , Proliferação de Células , Citocinas/metabolismo , Feminino , Humanos , Injeções Subcutâneas , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária/imunologia , Linfócitos T/citologia , Resultado do Tratamento
8.
Transpl Infect Dis ; 21(6): e13188, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587457

RESUMO

Hypogammaglobulinemia (HGG) frequently occurs in recipients after types of (SOT). The incidence and significance of HGG in HIV+ recipients of SOT are just being explored. We reported that 12% of the recipients in the SOT in multi-center HIV-TR (HIV-TR) Study developed moderate or severe HGG at 1 year. In LT recipients, this was associated with serious infections and death. We have now further characterized the decreased antibodies in HIV+ SOT recipients who developed HGG. We measured the levels of pathogen-specific antibodies and poly-specific self-reactive antibodies (PSA) in relation to total IgG levels from serial serum samples for 20 HIV+ SOT recipients who developed moderate to severe HGG following SOT. Serum antibody levels to measles, tetanus toxoid, and HIV-1 were determined by EIA. Levels of PSAs were determined by incubating control lymphocytes with patient serum, staining with anti-human IgG Fab-FITC, and analysis by flow cytometry. Levels of PSA were higher compared to healthy, HIV-uninfected controls at pre-transplant baseline and increased by weeks 12 and 26, but the changes were not significant. Likewise, anti-HIV antibody levels remained unchanged over time. In contrast, antibody levels against measles and tetanus were significantly reduced from baseline by week 12, and did not return to baseline, even after 2 years. For HIV patients who develop moderate to severe HGG after transplant, the reduction in IgG levels is associated with a significant decrease in pathogen-specific antibody titers, while PSA levels and anti-HIV antibodies are unchanged. This may contribute to infectious complications and other clinical endpoints.


Assuntos
Agamaglobulinemia/epidemiologia , Anticorpos Antivirais/sangue , Soropositividade para HIV/complicações , Imunoglobulina G/sangue , Transplante de Órgãos/efeitos adversos , Adulto , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Anticorpos Antivirais/imunologia , Feminino , Soropositividade para HIV/sangue , Soropositividade para HIV/imunologia , Humanos , Imunoglobulina G/imunologia , Incidência , Masculino , Vírus do Sarampo/imunologia , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Estudos Prospectivos , Fatores de Risco , Toxoide Tetânico/imunologia
9.
Int Arch Allergy Immunol ; 180(3): 221-232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509832

RESUMO

BACKGROUND: Immunoglobulin (Ig) therapy is highly effective in reducing the frequency and severity of infections. However, a subset of patients does not respond adequately. OBJECTIVE: To determine in adult patients with primary hypogammaglobulinemia (a) if failure to reconstitute IgG subclass(es) is associated with inadequate clinical response, (b) whether reconstitution of IgG subclasses differs between routes of Ig administration, (c) which subclasses contribute to low total IgG, and (d) what are the most commonly impaired Streptococcus pneumoniae serotypes. METHODS: A retrospective review of the records of patients with primary hypogammaglobulinemia followed up at the Immunology Clinic between 2010 and 2018 was conducted. Demographic, clinical, and laboratory data were collected. RESULTS: Seventy-one patients with primary hypogammaglobulinemia were included. All subclasses were reconstituted in 85% of the patients. IgG3 and IgG4 were most commonly not reconstituted. Reconstitution occurred in 85% of the patients on intravenous Ig (IVIG), 81% of the patients on conventional subcutaneous Ig (SCIG), and 100% of the patients on enzyme-facilitated subcutaneous Ig (fSCIG). The annual infection rate was 0.87 with IVIG, 0.88 with conventional SCIG, and 0.6 with fSCIG. IgG subclasses contributing to low total IgG included IgG1 (61%), IgG2 (49%), IgG3 (23%), and IgG4 (28%). In patients with concomitant specific antibody deficiency (n = 47), the most commonly impaired antibody responses were against pneumococcal serotypes 3, 4, 6b, 12f, and 23f. CONCLUSIONS: Failure to reconstitute subclasses does not correlate with an inadequate clinical response to immunoglobulin therapy in primary hypogammaglobulinemia. Full reconstitution of IgG subclasses was observed with fSCIG. A smaller panel of pneumococcal antibody responses may be used to define specific antibody deficiency.


Assuntos
Agamaglobulinemia/terapia , Isotipos de Imunoglobulinas/biossíntese , Imunoglobulinas Intravenosas/uso terapêutico , Imunoterapia/métodos , Infecções Pneumocócicas/epidemiologia , Streptococcus pneumoniae/fisiologia , Adolescente , Adulto , Agamaglobulinemia/epidemiologia , Agamaglobulinemia/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/sangue , Autorrenovação Celular , Feminino , Homeostase , Humanos , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos , Adulto Jovem
10.
Pediatr Clin North Am ; 66(5): 897-903, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31466679

RESUMO

The most common primary immune deficiencies are those of the humoral immune system, and most of these present in childhood. The severity of these disorders ranges from transient deficiencies to deficiencies that are associated with a complete loss of ability to make adequate or functional antibodies, and have infectious as well as noninfectious complications. This article reviews, in a case-based discussion, the most common of the humoral immune deficiencies; their presentations, diagnoses, treatments; and, when known, the genetic defects.


Assuntos
Imunidade Humoral , Imunoglobulinas/deficiência , Síndromes de Imunodeficiência/imunologia , Agamaglobulinemia/imunologia , Formação de Anticorpos/imunologia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido
11.
Rheumatol Int ; 39(10): 1829-1838, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31312887

RESUMO

Kawasaki disease (KD) has features that appear supporting an infectious cause with a secondary deranged inflammatory/autoimmune response. The association of KD in adults with human immunodeficiency virus infection and the presence of KD in patients with immunodeficiency disorders support the infectious theory. We present four KD patients associated with immunodeficiencies: one with X-linked agammaglobulinemia, one with HIV infection, and two with leukemia; one of these patients also had Down syndrome. We did a literature search to find out all reported cases of immunodeficiency with KD in children. In immunodeficiency disorders, the inability of the immune system to eradicate the pathogens coupled to an exaggerated inflammatory response, especially in chronic granulomatous disease, may lead to the development of KD. The study of patients with immunodeficiencies complicated with KD may shed light into the etiopathogenesis of the disease.


Assuntos
Agamaglobulinemia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Infecções por HIV/imunologia , Hospedeiro Imunocomprometido , Leucemia/imunologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Corticosteroides/uso terapêutico , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Síndrome de Down/complicações , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Leucemia/complicações , Leucemia/diagnóstico , Leucemia/tratamento farmacológico , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Fatores de Risco , Resultado do Tratamento
12.
Proc Natl Acad Sci U S A ; 116(26): 12952-12957, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31189594

RESUMO

T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton's tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+ plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Agamaglobulinemia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Imunidade Humoral , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ácido Fítico/imunologia , Tirosina Quinase da Agamaglobulinemia/imunologia , Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Modelos Animais de Doenças , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Camundongos , Camundongos Transgênicos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Ácido Fítico/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/imunologia
13.
Arthritis Rheumatol ; 71(11): 1812-1823, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31131994

RESUMO

OBJECTIVE: To evaluate predictors of serious infection events (SIEs) during rituximab (RTX) therapy and effects of hypogammaglobulinemia on SIE rates, and humoral response and its persistence after discontinuation of RTX in the treatment of rheumatic and musculoskeletal diseases (RMDs). METHODS: A retrospective longitudinal study of 700 RMD patients treated with RTX in a single center was conducted. Immunoglobulin levels were measured at baseline and at 4-6 months after each treatment cycle. Baseline predictors of SIEs were assessed using multivariable logistic regression; for RTX cycles 2-4, a mixed-effects logistic regression model was used. RESULTS: A total of 507 patients (72%) had rheumatoid arthritis, 94 (13%) had systemic lupus erythematosus, 49 (7%) had antineutrophil cytoplasmic antibody-associated vasculitis, and 50 (7%) had other RMDs. The number of SIEs recorded was 281 in 176 patients (9.8 per 100 person-years). Predictors of SIEs included non-RTX-specific comorbidities (previous history of SIE, cancer, chronic lung disease, diabetes mellitus, and heart failure), higher corticosteroid dose, and RTX-specific factors, including low IgG (<6 gm/liter) both at baseline and during treatment, RTX-associated neutropenia, higher IgM, and longer time to RTX re-treatment, but not B cell count or depletion status. Of 110 patients with low IgG, SIE rates were higher in those with low IgG at baseline (16.4 per 100 person-years) and in those who acquired low IgG during or after RTX treatment (21.3 per 100 person-years) versus those with normal IgG (9.7 per 100 person-years). Five of 8 patients (63%) had impaired humoral response to pneumococcus and hemophilus following vaccination challenge, and only 4 of 11 patients (36%) had IgG normalized after switching biologic disease-modifying antirheumatic drugs. CONCLUSION: Immunoglobulin levels should be monitored at baseline and before each RTX cycle to identify patients at risk of SIEs. Individualized risk-benefit assessment should be undertaken in those with lower IgG as this is a consistent SIE predictor and may increase infection profiles when RTX is switched to different therapies.


Assuntos
Agamaglobulinemia/induzido quimicamente , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Infecções/epidemiologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Rituximab/efeitos adversos , Adulto , Agamaglobulinemia/imunologia , Idoso , Comorbidade , Doenças do Tecido Conjuntivo/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Feminino , Glucocorticoides/administração & dosagem , Insuficiência Cardíaca/epidemiologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Infecções/imunologia , Estudos Longitudinais , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Miosite/tratamento farmacológico , Neoplasias/epidemiologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Estudos Retrospectivos , Doenças Reumáticas/tratamento farmacológico , Medição de Risco , Fatores de Risco , Escleroderma Sistêmico/tratamento farmacológico , Índice de Gravidade de Doença , Síndrome de Sjogren/tratamento farmacológico , Fatores de Tempo
14.
Immunol Lett ; 210: 55-62, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31059734

RESUMO

Common Variable Immunodeficiency (CVID) and agammaglobulinemia are two of the main types of symptomatic primary antibody deficiencies. The pathogenic origins of these two diseases are different; agammaglobulinemia is a group of inherited disorders that usually are caused by mutations in the gene encoding Bruton Tyrosine Kinase (BTK) protein while CVID is a heterogeneous disorder mainly without monogenic cause. However, both diseases share a characteristic of frequent bacterial infections, a decline in serum immunoglobulin levels, and abnormality in antibody responses. The demographics and immunologic parameters, clinical manifestation, and mortality statistics from 297 patients with CVID and agammaglobulinemia followed up over 2 decades in the Children's Medical Center of Iran. Age at onset of symptom in agammaglobulinemia was earlier than CVID but the course of disease in CVID patients was longer than agammaglobulinemia patients. Pulmonary infections were the most prevalent clinical manifestations in both groups of patients. Lymphadenopathy, hepatomegaly, and splenomegaly were significantly higher in CVID patients than agammaglobulinemia patients and there was a significant association between these complications and mortality in CVID patients. Among 297 patients, 128 patients (88 CVID and 40 agammaglobulinemia) deceased. The predominant causes of death in CVID patients were infections, chronic lung disease, and malignancy while in agammaglobulinemia patients were infections and respiratory failure. Infections, especially respiratory infections were the most common complication and cause of death in both CVID and agammaglobulinemia groups and recent treatment advances even Immunoglobulin replacement cannot completely control these complications. Thus prompt recognition and specific management of these complications are worthwhile.


Assuntos
Agamaglobulinemia/diagnóstico , Agamaglobulinemia/imunologia , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Adolescente , Adulto , Agamaglobulinemia/mortalidade , Biomarcadores , Criança , Imunodeficiência de Variável Comum/mortalidade , Comorbidade , Suscetibilidade a Doenças , Feminino , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Fenótipo , Prognóstico , Avaliação de Sintomas , Adulto Jovem
16.
Nat Immunol ; 20(3): 350-361, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718914

RESUMO

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.


Assuntos
Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Proteínas de Transporte de Cátions/imunologia , Zinco/imunologia , Agamaglobulinemia/genética , Agamaglobulinemia/metabolismo , Animais , Linfócitos B/metabolismo , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Pré-Escolar , Citosol/imunologia , Citosol/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Linhagem , Zinco/metabolismo
17.
Clin Immunol ; 200: 39-42, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30690192

RESUMO

Good syndrome is an immunodeficiency presenting with thymoma, hypogammaglobulinemia and almost absent B cells. To investigate the origin of the B-cell lymphopenia in these patients, we studied B cell differentiation in the bone marrow of Good syndrome patients. We found very low numbers of precursor B cells in bone marrow of Good syndrome patients and a differentiation arrest after the pro-B-cell stage; this is different from other agammaglobulinemia patients with a defect in pre B-cell receptor signaling.


Assuntos
Agamaglobulinemia/imunologia , Linfócitos B/citologia , Medula Óssea , Linfopenia/imunologia , Linfopoese/imunologia , Células Precursoras de Linfócitos B/citologia , Timoma/imunologia , Neoplasias do Timo/imunologia , Agamaglobulinemia/complicações , Agamaglobulinemia/terapia , Idoso , Anti-Infecciosos/uso terapêutico , Linfócitos B/imunologia , Feminino , Humanos , Imunoglobulinas/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Fatores Imunológicos/uso terapêutico , Linfopenia/complicações , Linfopenia/terapia , Masculino , Pessoa de Meia-Idade , Células Precursoras de Linfócitos B/imunologia , Síndrome , Timectomia , Timoma/complicações , Timoma/terapia , Neoplasias do Timo/complicações , Neoplasias do Timo/terapia
18.
Clin Immunol ; 200: 31-34, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639166

RESUMO

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.


Assuntos
Agamaglobulinemia/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Linfopenia/genética , Doenças da Imunodeficiência Primária/genética , Adulto , Agamaglobulinemia/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Mutação com Ganho de Função , Humanos , Linfopenia/imunologia , Linfopoese , Doenças da Imunodeficiência Primária/imunologia
19.
Clin Immunol ; 200: 16-18, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30630113

RESUMO

Severe combined immunodeficiency (SCID) can be caused by deleterious mutations in DCLRE1C, leading to deficient non-homologous end joining by compromising the function of the Artemis protein. This impairs the process of V(D)J recombination of the T- and B-cell receptors and typically results in radiosensitive T-, B-, NK+ SCID presenting during the first months of life. We present a case of a 3-year-old girl with two novel compound heterozygous variants in DCLRE1C (c.58G>C and c.374A>C) that were associated with marked reduced numbers of peripheral T- and B-cells and undetectable total serum IgG. Despite the severe laboratory phenotype, the patient had a normal development, albeit failure to thrive (-2.5 to -3 SD), during her first years of life including day-care attendance at preschool for 1.5 years. After being diagnosed with pneumonia the clinical picture of SCID was recognized and the girl successfully underwent hematopoietic stem-cell transplantation.


Assuntos
Agamaglobulinemia/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Imunodeficiência Combinada Severa/genética , Agamaglobulinemia/complicações , Agamaglobulinemia/imunologia , Pré-Escolar , Feminino , Heterozigoto , Humanos , Mutação , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/etiologia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/imunologia
20.
Rheumatology (Oxford) ; 58(5): 889-896, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590695

RESUMO

OBJECTIVES: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases. METHODS: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology. RESULTS: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82-100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy. CONCLUSION: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia.


Assuntos
Agamaglobulinemia/induzido quimicamente , Doenças Autoimunes/tratamento farmacológico , Linfócitos B , Imunização Passiva/efeitos adversos , Doenças Reumáticas/tratamento farmacológico , Adulto , Comitês Consultivos , Agamaglobulinemia/imunologia , Doenças Autoimunes/imunologia , Tomada de Decisão Clínica , Técnica Delfos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Reumáticas/imunologia
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