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Nat Immunol ; 19(9): 973-985, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30127434


Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.

Sci Immunol ; 3(24)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691


Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

Pan Afr Med J ; 26: 212, 2017.
Artigo em Francês | MEDLINE | ID: mdl-28690727


Hyper IgM syndrome is a well known genetic (primary) immunodeficiency disorder which was first described in 1961. It is caused by B lymphocyte deficiency characterized by normal or elevated serum IgM levels and low or zero levels of IgG, IgA, IgE resulting from isotype-switching deficiency. Clinical manifestations are dominated by recurrent infections, especially involving the digestive tube of the ENT sphere and the lungs. This syndrome is caused by B-cell immunoglobulin class switch deficiency and decreased capacity to induce proliferation of T lymphocytes. The net result of these deficiencies is reflected in increased susceptibility to Pneumocystis jiroveci, Cryptosporidium spp and other intracellular organisms as well as high rate of bacterial and viral infections. This study aimed to illustrate the importance of understanding the pathophysiological mechanisms associated with this increased susceptibility to infections in order to allow a better diagnosis and therapy in patients with Hyper IgM syndrome (HIM).

Linfócitos B/imunologia , Síndrome de Imunodeficiência com Hiper-IgM/fisiopatologia , Infecções Oportunistas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Imunoglobulina M/sangue , Lactente , Masculino , Marrocos , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/microbiologia , Linfócitos T/imunologia
J Clin Immunol ; 33(1): 1-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22847546


PURPOSE: Primary immunodeficiency diseases (PIDs) comprise at least 176 hereditary disorders that are thought to be individually and collectively rare. The actual prevalence and incidence of PIDs remains unclear, but recent epidemiologic studies have suggested that PIDs are more common than generally thought. Based on these studies, we attempted to estimate the worldwide prevalence and incidence of PIDs. METHODS: Using data from registries and two recent epidemiologic surveys estimating the frequencies of PIDs, we extrapolated the frequencies reported for certain countries to the populations of continents and of the world. RESULTS: Our upper estimates suggest that six million people may be living with a PID worldwide, whereas only 27,000-60,000 have been identified to date (all national registries and the Jeffrey Modell Centers Network, respectively). For Europe, our upper estimate was 638,000 cases, and 15,052 cases are currently registered (2.27 %). In Africa, up to 902,631 people may have a PID, whereas only 1,016 cases are currently registered. We also found that PIDs were prevalent not only in children, but also in adults, who were strongly underrepresented in registries. CONCLUSION: Specific, dedicated epidemiologic studies are required, to obtain more realistic statistics for PIDs and to increase the awareness of physicians and public health systems about these diseases. Furthermore, the field of PIDs is continually growing, and this is likely to lead to a revision of the definition of these conditions, potentially increasing estimates of their impact on both adults and children, at the population level.

Imunodeficiência de Variável Comum/epidemiologia , Imunodeficiência de Variável Comum/imunologia , Adolescente , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/terapia , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Qualidade de Vida , Inquéritos e Questionários