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To evaluate a novel candidate disease gene, we engaged international collaborators and identified rare, biallelic, specifically homozygous, loss of function variants in SENP7 in 4 children from 3 unrelated families presenting with neurodevelopmental abnormalities, dysmorphism, and immunodeficiency. Their clinical presentations were characterized by hypogammaglobulinemia, intermittent neutropenia, and ultimately death in infancy for all 4 patients. SENP7 is a sentrin-specific protease involved in posttranslational modification of proteins essential for cell regulation, via a process referred to as deSUMOylation. We propose that deficiency of deSUMOylation may represent a novel mechanism of primary immunodeficiency.
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BACKGROUND: Chylothorax is a very rare form of pleural effusion in children, especially after the neonatal period, and predominantly occurs secondary to cardiothoracic surgery. It can lead to significant respiratory distress, immunodeficiency, and malnutrition. Effective treatment strategies are therefore required to reduce morbidity. CASE PRESENTATION: A previously healthy two-year old boy was admitted with history of heavy coughing followed by progressive dyspnea. The chest X-ray showed an extensive opacification of the right lung. Ultrasound studies revealed a large pleural effusion of the right hemithorax. Pleural fluid analysis delivered the unusual diagnosis of chylothorax, most likely induced by preceded excessive coughing. After an unsuccessful treatment attempt with a fat-free diet and continuous pleural drainage for two weeks, therapy with octreotide was initiated. This led to complete and permanent resolution of his pleural effusion within 15 days, without any side effects. CONCLUSIONS: Severe cough may be a rare cause of chylothorax in young children. Octreotide seems to be an effective and safe treatment of spontaneous or traumatic chylothorax in children. There is, however, a lack of comprehensive studies for chylothorax in children and many issues concerning diagnostic strategies and treatment algorithms remain.
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Quilotórax , Derrame Pleural , Masculino , Criança , Recém-Nascido , Humanos , Pré-Escolar , Quilotórax/etiologia , Quilotórax/terapia , Tosse/etiologia , Octreotida/uso terapêutico , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/etiologia , Derrame Pleural/terapia , Algoritmos , DispneiaRESUMO
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells of myeloid origin. MDSC are functionally defined by their capacity to suppress T, NK, and B cell responses and henceforth altering the disease outcome in various pathological conditions. MDSC are further subdivided into three distinct subsets: monocytic (M-) MDSC, neutrophilic or polymorphonuclear (PMN-) MDSC, and early-stage (e-) MDSC. However, since surface markers utilized to define MDSC are expressed on other myeloid cells too, it is mandatory to functionally assess the suppressive activity for characterizing these cells. Here, we provide a protocol for generation of PMN-MDSC in vitro from freshly isolated human peripheral blood mononuclear cells. These MDSC can be used further to perform functional assays to determine their immunosuppressive potential or test their activities in various biological conditions, for instance in infection and cancer.
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Técnicas de Cultura de Células/métodos , Células Supressoras Mieloides/citologia , Neutrófilos/citologia , Células Cultivadas , Citometria de Fluxo , Humanos , Coloração e RotulagemRESUMO
BACKGROUND: Rare autoinflammatory diseases (AIDs) including Cryopyrin-Associated Periodic Syndrome (CAPS), Tumor Necrosis Receptor-Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency Syndrome (MKD)/ Hyper-IgD Syndrome (HIDS) are genetically defined and characterized by recurrent fever episodes and inflammatory organ manifestations. Early diagnosis and early start of effective therapies control the inflammation and prevent organ damage. The PRO-KIND initiative of the German Society of Pediatric Rheumatology (GKJR) aims to harmonize the diagnosis and management of children with rheumatic diseases nationally. The task of the PRO-KIND CAPS/TRAPS/MKD/HIDS working group was to develop evidence-based, consensus diagnosis and management protocols including the first AID treat-to-target strategies. METHODS: The national CAPS/TRAPS/MKD/HIDS expert working group was established, defined its aims and conducted a comprehensive literature review synthesising the recent (2013 to 2018) published evidence including all available recommendations for diagnosis and management. General and disease-specific statements were anchored in the 2015 SHARE recommendations. An iterative expert review process discussed, adapted and refined these statements. Ultimately the GKJR membership vetted the proposed consensus statements, agreement of 80% was mandatory for inclusion. The approved statements were integrated into three disease specific consensus treatment plans (CTPs). These were developed to enable the implementation of evidence-based, standardized care into clinical practice. RESULTS: The CAPS/TRAPS/MKD/HIDS expert working group of 12 German and Austrian paediatric rheumatologists completed the evidence synthesis and modified a total of 38 statements based on the SHARE recommendation framework. In iterative reviews 36 reached the mandatory agreement threshold of 80% in the final GKJR member survey. These included 9 overarching principles and 27 disease-specific statements (7 for CAPS, 11 TRAPS, 9 MKD/HIDS). A diagnostic algorithm was established based on the synthesized evidence. Statements were integrated into diagnosis- and disease activity specific treat-to-target CTPs for CAPS, TRAPS and MKD/HIDS. CONCLUSIONS: The PRO-KIND CAPS/TRAPS/MKD/HIDS working group established the first evidence-based, actionable treat-to-target consensus treatment plans for three rare hereditary autoinflammatory diseases. These provide a path to a rapid evaluation, effective control of disease activity and tailored adjustment of therapies. Their implementation will decrease variation in care and optimize health outcomes for children with AID.
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Antirreumáticos/uso terapêutico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Planejamento de Assistência ao Paciente , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Etanercepte/uso terapêutico , Medicina Baseada em Evidências , Alemanha , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/tratamento farmacológico , ReumatologiaRESUMO
Myeloid-derived suppressor cells (MDSCs) are key regulators of immunity that initially have been defined by their ability to potently suppress T-cell responses. Recent studies collectively demonstrate that the suppressive activity of MDSCs is not limited to T cells, but rather affects a broad range of immune cell subsets. However, relatively few studies have assessed the impact of MDSCs on B cells, particularly in the human context. Here, we report that human monocytic MDSCs (M-MDSCs) significantly interfere with human B-cell proliferation and function in vitro. We further show that the inhibition occurs independent of direct cell-contact and involves the expression of suppressive mediators such as indoleamine 2, 3-dioxygenase (IDO), arginase-1 (Arg1), and nitric oxide (NO). In addition, our studies demonstrate that the suppression of B cells by M-MDSCs is paralleled by a skewing in B-cell phenotype and gene expression signatures. M-MDSCs induced the downregulation of key surface markers on activated B cells, including IgM, HLA-DR, CD80, CD86, TACI, and CD95. Concurrently, M-MDSCs but not conventional monocytes elicited alterations in the transcription of genes involved in apoptosis induction, class-switch regulation, and B-cell differentiation and function. In summary, this study expands our understanding of the regulatory role of M-MDSCs for human B-cell responses.
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Linfócitos B/imunologia , Células Supressoras Mieloides/imunologia , Linfócitos B/metabolismo , Proliferação de Células/fisiologia , Células Cultivadas , Humanos , Ativação Linfocitária/imunologia , Células Supressoras Mieloides/metabolismo , FenótipoRESUMO
Introduction: The accelerating threat of multidrug-resistant bacteria (MRB) forces health care providers to use antibiotics more rationally. Antibiotic stewardship programs (ASP) are a proven and safe way to achieve that goal. They have been comprehensively studied in adults but data from secondary care pediatric hospitals are lacking. Material and Methods: In our study an ASP with standard operating procedures (SOPs), audits, a weekly ward round with experts in pediatric infectious diseases and an antibiotic pocket-card for selected infectious diseases was established in July 2017 in a Munich municipal secondary care children's hospital. All antibiotic prescriptions on general pediatric wards were reviewed each in the first quarter of 2017 and 2018. The primary outcome was adherence to treatment guidelines. Secondary outcomes were substance consumption, duration of therapy and death. Results: After the ASP was implemented guideline adherence increased significantly from 33 to 63%. The consumption of cephalosporins decreased significantly (-60%), whereas aminopenicillin use increased accordingly (+120%). Neither in the pre- nor in the post-intervention group deaths occurred. Discussion: Data on ASP in pediatric secondary care hospitals are scarce. Most previous studies have been performed at tertiary care/university children's hospitals. We demonstrate a significant improvement in guideline adherence regarding antibiotic treatments after the implementation of an ASP. Cephalosporin consumption decreased which might be relevant for the selection of MRB (e.g., vancomycin-resistant enterococci). Results are limited by the single-center design and the short observation period. The study encourages the implementation of ASPs in secondary care children's hospitals.
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Staphylococcus aureus is one of the major human bacterial pathogens causing a broad spectrum of serious infections. Myeloid-derived suppressor cells (MDSC) represent an innate immune cell subset capable of regulating host-pathogen interactions, yet their role in the pathogenesis of S. aureus infections remains incompletely defined. The aim of this study was to determine the influence of different S. aureus strains and associated virulence factors on human MDSC generation. Using an in vitro MDSC generation assay we demonstrate that low concentrations of supernatants of different S. aureus strains led to an induction of functional MDSC, whereas increased concentrations, conversely, reduced MDSC numbers. The concentration-dependent reduction of MDSC correlated with T cell proliferation and cytotoxicity. Several findings supported a role for staphylococcal enterotoxins in modulating MDSC generation. Staphylococcal enterotoxins recapitulated concentration-dependent MDSC induction and inhibition, T cell proliferation and cytotoxicity, while an enterotoxin-deficient S. aureus strain largely failed to alter MDSC. Taken together, we identified staphylococcal enterotoxins as main modulators of MDSC generation. The inhibition of MDSC generation by staphylococcal enterotoxins might represent a novel therapeutic target in S. aureus infections and beyond in non-infectious conditions, such as cancer.
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Proliferação de Células/efeitos dos fármacos , Enterotoxinas/imunologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Staphylococcus aureus/imunologia , Células Cultivadas , Enterotoxinas/metabolismo , Humanos , Evasão da Resposta Imune , Tolerância Imunológica , Modelos Teóricos , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/metabolismoRESUMO
Myeloid-derived suppressor cells (MDSC) represent an innate immune cell subset capable of suppressing T-cell responses in cancer and chronic inflammation. While the effect of MDSC on T cells has been defined thoroughly, the reciprocal impact of T cells on MDSC homeostasis remains poorly understood. Therefore, we comprehensively analyzed the effect of different T-cell subsets on the generation and survival of human MDSC. Using an in vitro MDSC generation assay, we demonstrate that unstimulated CD4+, but not CD8+ T cells, induce polymorphonuclear MDSC (PMN-MDSC) from CD33+ myeloid cells. This effect was dependent on direct cell-cell contact and required TNF-α signaling. Soluble TNF-α was dispensable for PMN-MDSC generation, suggesting that transmembrane TNF-α is involved in that trans-cellular process. Stimulated human CD3+ T cells delayed the apoptosis of PMN-MDSC, which was independent of TNF-α signaling or direct cell-cell contact, but was recapitulated by IL-2. Taken together, our study shows that human T cells modulate MDSC generation and survival through two distinct mechanisms and thereby fine-tune the homeostasis of human MDSC in a regulated manner.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Mieloides/imunologia , Células Supressoras Mieloides/imunologia , Fator de Necrose Tumoral alfa/imunologia , Apoptose/imunologia , Células Cultivadas , Homeostase/imunologia , Humanos , Interleucina-2/imunologia , Neoplasias/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Transdução de Sinais/imunologiaRESUMO
BACKGROUND: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany. METHODS: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements. RESULTS: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy. CONCLUSIONS: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.
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Artrite Juvenil/diagnóstico , Padrões de Prática Médica/estatística & dados numéricos , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Criança , Pré-Escolar , Consenso , Bases de Dados Factuais , Alemanha , Glucocorticoides/uso terapêutico , Humanos , Sistema de RegistrosRESUMO
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population expanded in cancer, infection and autoimmunity capable of suppressing T-cell functions. Checkpoint inhibitors have emerged as a key therapeutic strategy in immune-oncology. While checkpoint molecules were initially associated with T cell functions, recent evidence suggests a broader expression and function in innate myeloid cells. Previous studies provided first evidence for a potential role for checkpoints on MDSCs, yet the human relevance remained poorly understood. Therefore, we investigated the expression and functional relevance of checkpoint molecules in human MDSC-T-cell interactions. Our studies demonstrate that programmed death-ligand 1 (PD-L1) is expressed on granulocytic MDSCs upon co-culture with T cells. Transwell experiments showed that cell-to-cell contact was required for MDSC-T-cell interactions and antibody blocking studies showed that targeting PD-L1 partially impaired MDSC-mediated T-cell suppression. Collectively, these studies suggest a role for PD-L1 in human MDSC function and thereby expand the functionality of this checkpoint beyond T cells, which could pave the way for further understanding and therapeutic targeting of PD-1/PD-L1 in innate immune-mediated diseases.
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Antígeno B7-H1/metabolismo , Imunoterapia/métodos , Células Supressoras Mieloides/imunologia , Linfócitos T/imunologia , Anticorpos Bloqueadores/farmacologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Comunicação Celular , Células Cultivadas , Técnicas de Cocultura , Humanos , Tolerância Imunológica , Imunidade Inata , Terapia de Alvo MolecularRESUMO
Myeloid-derived suppressor cells (MDSCs) are key regulators of adaptive immunity by suppressing T-cell functions. However, their potential action on or interaction with B cells remained poorly understood. Here we demonstrate that human polymorphonuclear MDSCs differentially modulate B-cell function by suppressing B-cell proliferation and antibody production. We further demonstrate that this MDSC-mediated effect is cell contact dependent and involves established mediators such as arginase-1, nitric oxide (NO), reactive oxygen species (ROS) as well as B-cell death. Collectively, our studies provide novel evidence that human MDSCs modulate B cells, which could have future implications for immunotherapy approaches.
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Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular/imunologia , Imunomodulação , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Formação de Anticorpos/imunologia , Arginase/metabolismo , Biomarcadores , Células Cultivadas , Humanos , Imunoglobulina M/imunologia , Ativação Linfocitária/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: The Nod-like receptor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) and Bruton tyrosine kinase (BTK) are protagonists in innate and adaptive immunity, respectively. NLRP3 senses exogenous and endogenous insults, leading to inflammasome activation, which occurs spontaneously in patients with Muckle-Wells syndrome; BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia (XLA). However, to date, few proteins that regulate NLRP3 inflammasome activity in human primary immune cells have been identified, and clinically promising pharmacologic targeting strategies remain elusive. OBJECTIVE: We sought to identify novel regulators of the NLRP3 inflammasome in human cells with a view to exploring interference with inflammasome activity at the level of such regulators. METHODS: After proteome-wide phosphoproteomics, the identified novel regulator BTK was studied in human and murine cells by using pharmacologic and genetic BTK ablation. RESULTS: Here we show that BTK is a critical regulator of NLRP3 inflammasome activation: pharmacologic (using the US Food and Drug Administration-approved inhibitor ibrutinib) and genetic (in patients with XLA and Btk knockout mice) BTK ablation in primary immune cells led to reduced IL-1ß processing and secretion in response to nigericin and the Staphylococcus aureus toxin leukocidin AB (LukAB). BTK affected apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and caspase-1 cleavage and interacted with NLRP3 and ASC. S aureus infection control in vivo and IL-1ß release from cells of patients with Muckle-Wells syndrome were impaired by ibrutinib. Notably, IL-1ß processing and release from immune cells isolated from patients with cancer receiving ibrutinib therapy were reduced. CONCLUSION: Our data suggest that XLA might result in part from genetic inflammasome deficiency and that NLRP3 inflammasome-linked inflammation could potentially be targeted pharmacologically through BTK.
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Agamaglobulinemia/genética , Síndromes Periódicas Associadas à Criopirina/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Tirosina Quinases/metabolismo , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Imunidade Adaptativa , Proteínas Adaptadoras de Transdução de Sinal , Tirosina Quinase da Agamaglobulinemia , Animais , Proteínas Reguladoras de Apoptose , Proteínas de Bactérias/imunologia , Células Cultivadas , Humanos , Imunidade Inata , Leucocidinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Proteínas NLR , Nigericina/imunologia , Proteínas Tirosina Quinases/genética , Proteômica , Domínio Pirina/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptor de Lamina BRESUMO
BACKGROUND: Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions. OBJECTIVES: We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. METHODS: In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. RESULTS: A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of "atypical" SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution. CONCLUSIONS: The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.
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Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Projetos de PesquisaRESUMO
Pseudomonas aeruginosa is an opportunistic pathogen that causes infections mainly in patients with cystic fibrosis (CF) lung disease. Despite innate and adaptive immune responses upon infection, P. aeruginosa is capable of efficiently escaping host defenses, but the underlying immune mechanisms remain poorly understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that are functionally characterized by their potential to suppress T- and natural killer (NK)-cell responses. Here we demonstrate, using an airway in vivo infection model, that P. aeruginosa recruits and activates neutrophilic MDSCs, which functionally suppress T-cell responses. We further show that the CF gene defect (CF transmembrane conductance regulator, CFTR) modulates the functionality, but not the recruitment or generation of neutrophilic MDSCs. Collectively, we define a mechanism by which P. aeruginosa airway infection undermines host immunity by modulating neutrophilic MDSCs in vivo.
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Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Infecções Respiratórias/imunologia , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Evasão da Resposta Imune , Tolerância Imunológica , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CFTR , Linfócitos T/imunologiaRESUMO
Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterized by their ability to suppress T-cell responses. Recently, we demonstrated that the human-pathogenic fungi Candida albicans and Aspergillus fumigatus induced a distinct subset of neutrophilic MDSCs. To dissect Candida-mediated MDSC induction in more depth, we studied the relative efficacy of different pathogenic non-albicans Candida species to induce and functionally modulate neutrophilic MDSCs, including C. glabrata, C. parapsilosis, C. dubliniensis, and C. krusei. Our data demonstrate that the extent of MDSC generation is largely dependent on the Candida species with MDSCs induced by C. krusei and C. glabrata showing a higher suppressive activity compared to MDSCs induced by C. albicans. In summary, these studies show that fungal MDSC induction is differentially regulated at the species level and differentially affects effector T-cell responses.
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Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed Aspergillus infection of the lungs. One patient had homozygous M1I CARD9 (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X CARD9 mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against Aspergillus fumigatus were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary Aspergillus infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection.
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Aspergilose/imunologia , Proteínas Adaptadoras de Sinalização CARD/deficiência , Infiltração de Neutrófilos , Adolescente , Adulto , Aspergilose/genética , Aspergillus fumigatus , Proteínas Adaptadoras de Sinalização CARD/genética , Criança , Homozigoto , Humanos , Pulmão , Masculino , Mutação , Neutrófilos/imunologiaRESUMO
Cryopyrin-associated periodic syndromes (CAPS) are caused by mutations in the NLRP3 gene leading to overproduction of IL-1ß and other NLRP3 inflammasome products. Myeloid-derived suppressor cells (MDSCs) represent a novel innate immune cell subset capable of suppressing T-cell responses. As inflammasome products were previously found to induce MDSCs, we hypothesized that NLRP3 inflammasome-dependent factors induce the generation of MDSCs in CAPS. We studied neutrophilic MDSCs, their clinical relevance, and MDSC-inducing factors in a unique cohort of CAPS patients under anti-IL-1 therapy. Despite anti-IL-1 therapy and low clinical disease activity, CAPS patients showed significantly elevated MDSCs compared to healthy controls. MDSCs were functionally competent, as they suppressed polyclonal T-cell proliferation, as well as Th1 and Th17 responses. In addition, MDSCs decreased monocytic IL-1ß secretion. Multiplex assays revealed a distinct pattern of MDSC-inducing cytokines, chemokines, and growth factors. Experimental analyses demonstrated that IL-1 cytokine family members and autoinflammation-associated alarmins differentially induced human MDSCs. Increased MDSCs might represent a novel autologous anti-inflammatory mechanism in autoinflammatory conditions and may serve as a future therapeutic target.
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Síndromes Periódicas Associadas à Criopirina/imunologia , Inflamassomos/metabolismo , Células Supressoras Mieloides/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adolescente , Adulto , Idoso , Alarminas/metabolismo , Autoimunidade , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Síndromes Periódicas Associadas à Criopirina/genética , Feminino , Humanos , Tolerância Imunológica , Imunidade Inata , Interleucina-1beta/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Adulto JovemRESUMO
Myeloid-derived suppressor cells (MDSCs) comprise monocytic and granulocytic innate immune cells with the capability of suppressing T- and NK-cell responses. While the role of MDSCs has been studied in depth in malignant diseases, the understanding of their regulation and function in infectious disease conditions has just begun to evolve. Here we summarize and discuss the current view how MDSCs participate in bacterial infections and how this knowledge could be exploited for potential future therapeutics.
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Infecções Bacterianas/imunologia , Células Matadoras Naturais/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Linfócitos T/imunologia , Humanos , Macrófagos/imunologiaRESUMO
Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterised by their potential to control T-cell responses and to dampen inflammation. While the role of MDSCs in cancer has been studied in depth, our understanding of their relevance for infectious and inflammatory disease conditions has just begun to evolve. Recent studies highlight an emerging and complex role for MDSCs in pulmonary diseases. In this review, we discuss the potential contribution of MDSCs as biomarkers and therapeutic targets in lung diseases, particularly lung cancer, tuberculosis, chronic obstructive pulmonary disease, asthma and cystic fibrosis.
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Pneumopatias/imunologia , Células Supressoras Mieloides/imunologia , Linfócitos T/imunologia , Asma/imunologia , Fibrose Cística/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Tuberculose/imunologiaRESUMO
Cystic fibrosis airways are frequently colonised with fungi. However, the interaction of these fungi with immune cells and the clinical relevance in cystic fibrosis lung disease are incompletely understood.We characterised granulocytes in airway fluids and peripheral blood from cystic fibrosis patients with and without fungal colonisation, non-cystic fibrosis disease controls and healthy control subjects cross-sectionally and longitudinally and correlated these findings with lung function parameters.Cystic fibrosis patients with chronic fungal colonisation by Aspergillus fumigatus were characterised by an accumulation of a distinct granulocyte subset, expressing the HIV coreceptor CXCR4. Percentages of airway CXCR4(+) granulocytes correlated with lung disease severity in patients with cystic fibrosis.These studies demonstrate that chronic fungal colonisation with A. fumigatus in cystic fibrosis patients is associated with CXCR4(+) airway granulocytes, which may serve as a potential biomarker and therapeutic target in fungal cystic fibrosis lung disease.