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Front Immunol ; 10: 204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809226


Interleukin 26 (IL-26) is the most recently identified member of the IL-20 cytokine subfamily, and is a novel mediator of inflammation overexpressed in activated or transformed T cells. Novel properties have recently been assigned to IL-26, owing to its non-conventional cationic, and amphipathic features. IL-26 binds to DNA released from damaged cells and, as a carrier molecule for extracellular DNA, links DNA to inflammation. This observation suggests that IL-26 may act both as a driver and an effector of inflammation, leading to the establishment of a deleterious amplification loop and, ultimately, sustained inflammation. Thus, IL-26 emerges as an important mediator in local immunity/inflammation. The dysregulated expression and extracellular DNA carrier capacity of IL-26 may have profound consequences for the chronicity of inflammation. IL-26 also exhibits direct antimicrobial properties. This review summarizes recent advances on the biology of IL-26 and discusses its roles as a novel kinocidin.

Blood ; 130(12): 1456-1467, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28679735


X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

Transplante de Células-Tronco Hematopoéticas , Quinase I-kappa B/genética , Mutação/genética , Pré-Escolar , Estudos de Coortes , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Inflamação/patologia , Doenças Inflamatórias Intestinais/etiologia , NF-kappa B/metabolismo , Fenótipo , Transdução de Sinais/genética , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante , Resultado do Tratamento
J Allergy Clin Immunol ; 135(3): 818-20.e4, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25420683
Gut ; 64(9): 1466-75, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25183206


OBJECTIVE: Interleukin-26 (IL-26) is a member of the IL-10 cytokine family, first discovered based on its peculiar expression by virus-transformed T cells. IL-26 is overexpressed in chronic inflammation (rheumatoid arthritis and Crohn's disease) and induces proinflammatory cytokines by myeloid cells and some epithelial cells. We thus investigated the expression and potential role of IL-26 in chronic HCV infection, a pathology associated with chronic inflammation. DESIGN: IL-26 was quantified in a cohort of chronically HCV-infected patients, naive of treatment and its expression in the liver biopsies investigated by immunohistochemistry. We also analysed the ability of IL-26 to modulate the activity of natural killer (NK) cells, which control HCV infection. RESULTS: The serum levels of IL-26 are enhanced in chronically HCV-infected patients, mainly in those with severe liver inflammation. Immunohistochemistry reveals an intense IL-26 staining in liver lesions, mainly in infiltrating CD3+ cells. We also show that NK cells from healthy subjects and from HCV-infected patients are sensitive to IL-26. IL-26 upregulates membrane tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression on CD16- CD56(bright) NK cells, enabling them to kill HCV-infected hepatoma cells, with the same efficacy as interferon (IFN)-α-treated NK cells. IL-26 also induces the expression of the antiviral cytokines IFN-ß and IFN-γ, and of the proinflammatory cytokines IL-1ß and TNF-α by NK cells. CONCLUSIONS: This study highlights IL-26 as a new player in the inflammatory and antiviral immune responses associated with chronic HCV infection.

Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Interferon-alfa/uso terapêutico , Interleucinas/sangue , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Antivirais/uso terapêutico , Biomarcadores/sangue , Biópsia por Agulha , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/imunologia , Citocinas/metabolismo , Feminino , Hepatite C Crônica/sangue , Humanos , Imuno-Histoquímica , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Índice de Gravidade de Doença , Estatísticas não Paramétricas
Hepatology ; 60(6): 1879-90, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25066464


UNLABELLED: Chronic hepatitis C virus (HCV) infection is characterized by progressive hepatic fibrosis, a process dependent on monocyte recruitment and accumulation into the liver. The mediators expressed in chronically injured liver that control the differentiation of human monocytes into profibrotic macrophages (Mφ) remain poorly defined. We report that chronically HCV-infected patients with high fibrosis stages have higher serum levels of macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-34 than HCV-infected patients with lower fibrosis stages and healthy subjects. Immunohistochemistry reveals an intense expression of IL-34 and M-CSF by hepatocytes around liver lesions. In addition, HCV infection and inflammatory cytokines enhance the in vitro production of IL-34 and M-CSF by hepatocytes. We next analyzed the acquisition of profibrotic properties by Mφ generated with M-CSF (M-CSF-Mφ) or IL-34 (IL-34-Mφ). M-CSF and IL-34 up-regulate the expression, by differentiating monocytes, of chemokine (C-C motif) ligand (CCL)2, CCL4, C-C chemokine receptor (CCR)1, and CCR5, which are involved in monocyte recruitment/Mφ accumulation in liver lesions. M-CSF-Mφ and IL-34-Mφ also express the hepatic stellate cell (HSC) activators, platelet-derived growth factor, transforming growth factor beta, and galectin-3. IL-34-Mφ and M-CSF-Mφ induce type I collagen synthesis by HSCs, the main collagen-producing cells in liver fibrosis. IL-13, whose expression correlates with the fibrosis stage in HCV-infected patients, decreases the expression of the collagenase, matrix metalloproteinase 1, by IL-34-Mφ and M-CSF-Mφ, thereby enhancing collagen synthesis. By inhibiting the production of interferon-gamma (IFN-γ) by activated natural killer cells, IL-34-Mφ and M-CSF-Mφ prevent the IFN-γ-induced killing of HSCs. CONCLUSION: These results identify M-CSF and IL-34 as potent profibrotic factors in HCV liver fibrosis.

Hepatite C Crônica/complicações , Interleucinas/sangue , Cirrose Hepática/imunologia , Fator Estimulador de Colônias de Macrófagos/sangue , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular , Colágeno Tipo I/biossíntese , Feminino , Células Estreladas do Fígado/metabolismo , Hepatite C Crônica/metabolismo , Hepatócitos/metabolismo , Humanos , Interferon gama/metabolismo , Interleucina-13/metabolismo , Células Matadoras Naturais/metabolismo , Cirrose Hepática/metabolismo , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Pessoa de Meia-Idade