RESUMO
Psoriasis is a chronic inflammatory skin disease arising from poorly defined pathological cross-talk between keratinocytes and the immune system. BCL10 (B cell lymphoma/leukemia 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) are ubiquitously expressed inflammatory signaling proteins that can interact with the psoriasis susceptibility factor CARD14, but their functions in psoriasis are insufficiently understood. We report that although keratinocyte-intrinsic BCL10/MALT1 deletions completely rescue inflammatory skin pathology triggered by germline Card14 gain-of-function mutation in mice, the BCL10/MALT1 signalosome is unexpectedly not involved in the CARD14-dependent interleukin-17 receptor (IL-17R) proximal pathway. Instead, it plays a more pleiotropic role by amplifying keratinocyte responses to a series of inflammatory cytokines, including IL-17A, IL-1ß, and TNF. Moreover, selective keratinocyte-intrinsic activation of BCL10/MALT1 signaling with an artificial engager molecule is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation, and aberrant BCL10/MALT1 activity is frequently detected in the skin of human sporadic psoriasis. Together, these results establish that BCL10/MALT1 signalosomes can act as initiators and crucial amplifiers of psoriatic skin inflammation and indicate a critical function for this complex in sporadic psoriasis.
Assuntos
Proteína 10 de Linfoma CCL de Células B/imunologia , Inflamação/imunologia , Queratinócitos/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Psoríase/imunologia , Pele/imunologia , Animais , Proteína 10 de Linfoma CCL de Células B/deficiência , Proteína 10 de Linfoma CCL de Células B/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genéticaRESUMO
Mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1)-deficiency is a rare combined immunodeficiency characterized by recurrent infections, dermatitis and enteropathy. We herein investigate the immunological profiles of our patient and previously reported children with MALT1-deficiency. A mutation analysis was performed by targeted panel sequencing for primary immunodeficiency. Lymphocyte subset, activation and B cell differentiation were analyzed by flow cytometry and t-distributed stochastic neighbor embedding. Pneumocystis pneumonia developed in a 6-month-old Japanese infant with atopic dermatitis, enteritis and growth restriction. This infant showed agammaglobulinemia without lymphopenia. At 8 years of age, the genetic diagnosis of MALT1-deficiency was confirmed on a novel homozygous mutation of c.1102G>T, p.E368X. T cell stimulation tests showed impairments in the production of interleukin-2, phosphorylation of nuclear factor kappa B (NF-κB) p65 and differentiation of B cells. In combination with the literature data, we found that the number of circulatory B cells, but not T cells, were inversely correlated with the age of patients. The hematopoietic cell transplantation (HCT) successfully reconstituted the differentiation of mature B cells and T cells. These data conceptualize that patients with complete MALT1-deficiency show aberrant differentiation and depletion of B cells. The early diagnosis and HCT lead to a cure of the disease phenotype associated with the loss-of-function mutations in human CARD11.
Assuntos
Linfócitos B/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Guanilato Ciclase/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Imunodeficiência Combinada Severa/genética , Linfócitos T/imunologia , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Linfócitos B/citologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Análise Mutacional de DNA , Humanos , Interleucina-2/biossíntese , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Linfopenia/diagnóstico , Linfopenia/genética , Masculino , NF-kappa B/metabolismoRESUMO
Human germline MALT1 deficiency is an inborn error of immunity characterized by recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. The number of identified MALT1-deficient patients have greatly increased in the past two years, which has significantly improved our understanding of the clinical features of this disorder. Patients frequently experience infections affecting the respiratory, skin, gastrointestinal, and blood systems. The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus. Enhanced susceptibility to S. aureus and C. albicans is likely due to impaired Th17 immunity, similar to STAT3 and IL-17 pathway deficiencies.
Assuntos
Predisposição Genética para Doença , Infecções/etiologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Alelos , Animais , Citocinas/metabolismo , Genótipo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Infecções/diagnóstico , Infecções/metabolismo , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Mutação , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
MALT1 plays an important role in innate and adaptive immune signaling by acting as a scaffold protein that mediates NF-κB signaling. In addition, MALT1 is a cysteine protease that further fine tunes proinflammatory signaling by cleaving specific substrates. Deregulated MALT1 activity has been associated with immunodeficiency, autoimmunity, and cancer in mice and humans. Genetically engineered mice expressing catalytically inactive MALT1, still exerting its scaffold function, were previously shown to spontaneously develop autoimmunity due to a decrease in Tregs associated with increased effector T cell activation. In contrast, complete absence of MALT1 does not lead to autoimmunity, which has been explained by the impaired effector T cell activation due to the absence of MALT1-mediated signaling. However, here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4.
Assuntos
Dermatite Atópica/etiologia , Suscetibilidade a Doenças , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Fatores Etários , Animais , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Citocinas/sangue , Dermatite Atópica/sangue , Dermatite Atópica/diagnóstico , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Predisposição Genética para Doença , Imunoglobulina E/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Pele/imunologia , Pele/metabolismo , Pele/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
The paracaspase Malt1 is a key regulator of canonical NF-κB activation downstream of multiple receptors in both immune and nonimmune cells. Genetic disruption of Malt1 protease function in mice and MALT1 mutations in humans results in reduced regulatory T cells and a progressive multiorgan inflammatory pathology. In this study, we evaluated the altered immune homeostasis and autoimmune disease in Malt1 protease-deficient (Malt1PD) mice and the Ags driving disease manifestations. Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis. Conversely, the disease was driven by a polyclonal T cell population directed against self-antigens. Characterization of the Malt1PD T cell compartment revealed expansion of T effector memory cells and concomitant loss of a CD4+ T cell population that phenotypically resembles anergic T cells. Therefore, we propose that the compromised regulatory T cell compartment in Malt1PD animals prevents the efficient maintenance of anergy and supports the progressive expansion of pathogenic, IFN-γ-producing T cells. Overall, our data revealed a crucial role of the Malt1 protease for the maintenance of intestinal and systemic immune homeostasis, which might provide insights into the mechanisms underlying IPEX-related diseases associated with mutations in MALT1.
Assuntos
Autoimunidade/imunologia , Homeostase/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Linfócitos T Reguladores/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genéticaRESUMO
This study tested the hypothesis that mucosa associated lymphoid tissue 1 (Malt1) deficiency causes osteoporosis in mice by increasing osteoclastogenesis and osteoclast activity. A patient with combined immunodeficiency (CID) caused by MALT1 deficiency had low bone mineral density resulting in multiple low impact fractures that was corrected by hematopoietic stem cell transplant (HSCT). We have reported that Malt1 deficient MÏs, another myeloid cell type, are hyper-responsive to inflammatory stimuli. Our objectives were to determine whether Malt1 deficient mice develop an osteoporosis-like phenotype and whether it was caused by Malt1 deficiency in osteoclasts. We found that Malt1 deficient mice had low bone volume by 12 weeks of age, which was primarily associated with reduced trabecular bone. Malt1 protein is expressed and active in osteoclasts and is induced by receptor activator of NF-κB ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro. However, Malt1 deficient (Malt1-/- ) mice had more osteoclasts in vivo and had lower levels of serum osteoprotegerin (OPG), an endogenous inhibitor of osteoclastogenesis. Inhibition of Malt1 activity in MÏs induced MCSF production, required for osteoclastogenesis, and decreased OPG production in response to inflammatory stimuli. In vitro, MCSF increased and OPG inhibited osteoclastogenesis, but effects were not enhanced in Malt1 deficient osteoclasts. These data support the hypothesis that Malt1 deficient mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, but suggest that this is caused by inflammation rather than an effect of Malt1 deficiency in osteoclasts.
Assuntos
Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose/metabolismo , Osteoporose/patologia , Animais , Densidade Óssea/efeitos dos fármacos , Transplante de Medula Óssea , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Diferenciação Celular/efeitos dos fármacos , Humanos , Fator Estimulador de Colônias de Macrófagos/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Tamanho do Órgão , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/diagnóstico por imagem , Osteoprotegerina/metabolismo , Ligante RANK/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Imunidade Inata , Monócitos/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , PPAR gama/imunologia , Fatores de Transcrição/imunologia , Adulto , Proteína 10 de Linfoma CCL de Células B/deficiência , Proteína 10 de Linfoma CCL de Células B/genética , Proteína 10 de Linfoma CCL de Células B/imunologia , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Candida albicans/imunologia , Candida parapsilosis/imunologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Interleucinas/deficiência , Interleucinas/genética , Interleucinas/imunologia , Lectinas Tipo C/deficiência , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Lipopolissacarídeos/farmacologia , Análise em Microsséries , Monócitos/citologia , Monócitos/efeitos dos fármacos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , PPAR gama/deficiência , PPAR gama/genética , Cultura Primária de Células , Biossíntese de Proteínas/imunologia , Serina-Treonina Quinases TOR/deficiência , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transcriptoma/imunologia , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
This study tested the hypothesis that Malt1 deficiency in macrophages contributes to dextran sodium sulfate (DSS)-induced intestinal inflammation in Malt1-deficient mice. In people, combined immunodeficiency caused by a homozygous mutation in the MALT1 gene is associated with increased susceptibility to bacterial infections and chronic inflammation, including severe inflammation along the gastrointestinal tract. The consequences of Malt1 deficiency have largely been attributed to its role in lymphocytes, but Malt1 is also expressed in macrophages, where it is activated downstream of TLR4 and dectin-1. The effect of Malt1 deficiency in murine macrophages and its contribution to DSS-induced colitis have not been investigated. Our objectives were to compare the susceptibility of Malt1+/+ and Malt1-/- mice to DSS-induced colitis, to determine the contribution of macrophages to DSS-induced colitis in Malt1-/- mice, and to assess the effect of innate immune stimuli on Malt1-/- macrophage inflammatory responses. We found that Malt1 deficiency exacerbates DSS-induced colitis in mice, accompanied by higher levels of IL-1ß, and that macrophages and IL-1 signaling contribute to pathology in Malt1-/- mice. Malt1-/- macrophages produce more IL-1ß in response to either TLR4 or dectin-1 ligation, whereas inhibition of Malt1 proteolytic (paracaspase) activity blocked IL-1ß production. TLR4 or dectin-1 stimulation induced Malt1 protein levels but decreased its paracaspase activity. Taken together, these data support the hypothesis that Malt1-/- macrophages contribute to increased susceptibility of Malt1-/- mice to DSS-induced colitis, which is dependent on IL-1 signaling. Increased IL-1ß production by MALT1-deficient macrophages may also contribute to chronic inflammation in people deficient in MALT1.
Assuntos
Colite/imunologia , Interleucina-1beta/biossíntese , Macrófagos/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Animais , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Feminino , Inflamação/induzido quimicamente , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiênciaAssuntos
Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Dano ao DNA , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , NF-kappa B/metabolismo , Animais , Antineoplásicos/farmacologia , Proteína 10 de Linfoma CCL de Células B/deficiência , Proteínas Adaptadoras de Sinalização CARD/deficiência , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiênciaRESUMO
Regulatory T cells (Tregs) are crucial for the maintenance of immunological self-tolerance and their absence or dysfunction can lead to autoimmunity. However, the molecular pathways that govern Treg biology remain obscure. In this study, we show that the nuclear factor-κB signalling mediator mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important novel regulator of both Tregs originating in the thymus ('natural' or nTregs) and Tregs induced to differentiate from naive thymocyte helper (Th) cells in the periphery ('induced' or iTregs). Our examination of mice deficient for MALT1 revealed that these mutants have a reduced number of total Tregs. In young Malt1-/- mice, nTregs are totally absent and iTreg are diminished in the periphery. Interestingly, total Treg numbers increase in older Malt1-/- mice as well as in Malt1-/- mice subjected to experimentally induced inflammation. iTregs isolated from WT and Malt1-/- mice were indistinguishable with respect to their ability to suppress the activities of effector T cells, but Malt1-/- iTregs expressed higher levels of Toll-like receptor (TLR) 2. Treatment of WT and Malt1-/- Th cells in vitro with the TLR2 ligand Pam3Cys strongly enhanced the induction and proliferation of Malt1-/- iTregs. Our data suggest that MALT1 supports nTreg development in the thymus but suppresses iTreg induction in the periphery during inflammation. Our data position MALT1 as a key molecule that contributes to immune tolerance at steady-state while facilitating immune reactivity under stress conditions.
Assuntos
Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Inflamação/patologia , Camundongos Endogâmicos C57BL , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Receptor 2 Toll-Like/metabolismoRESUMO
OBJECTIVE: Early-onset inflammatory bowel diseases can result from a wide spectrum of rare mendelian disorders. Early molecular diagnosis is crucial in defining treatment and in improving life expectancy. Herein we aimed at defining the mechanism of an immunodeficiency-polyendrocrinopathy and enteropathy-X-linked (IPEX)-like disease combined with a severe immunodeficiency in 2 siblings born from distantly related parents. METHODS: Whole exome sequencing was performed on blood-extracted genomic DNA from the 2 affected children and their parents on the genomic platform of Institut IMAGINE. Candidate gene mutation was identified using the in-house software PolyWeb and confirmed by Sanger sequencing. Protein expression was determined by western blot. Flow cytometry was used to assess consequences of the mutation on lymphocyte phenotype and nuclear factor-kappa B (NF-κB) activation at diagnosis and after treatment by hematopoietic stem cell transplantation. RESULTS: We identified a homozygous missense mutation in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1), which precluded protein expression. In keeping with the known function of MALT1, NF-κB-dependent lymphocyte activation was severely impaired. Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype. Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery. Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency. CONCLUSIONS: Along with FOXP3, interleukin 2 receptor alpha chain (IL2RA), and cytotoxic T-lymphocyte protein 4 precursor (CTLA-4) mutations, MALT1 deficiency should now be considered as a possible cause of IPEX-like syndrome associated with immunodeficiency that can be cured by hematopoietic stem cell transplantation.