Autoimmune regulator (AIRE) contributes to Dectin-1–induced TNF-α production and complexes with caspase recruitment domain–containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1

Pedroza, Luis Alberto; Kumar, Vipul; Sanborn, Keri B.; Mace, Emily M.; Niinikoski, Harri; Nadeau, Kari; Vasconcelos, Dewton de Moraes; Perez, Elena E.; Jyonouchi, Soma; Jyonouchi, Harumi; Banerjee, Pinaki P.; Ruuskanen, Olli; Condino‐Neto, Antônio; Orange, Jordan S.

doi:10.1016/j.jaci.2011.08.027

Cited by 24 publications

(25 citation statements)

References 38 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Kisand et al 44 also observed that IL-17 and IL-22 production was markedly decreased from Candida-stimulated blood cells derived from APECED patients with CMC disease, perhaps due to autoimmune destruction of IL-17+ and IL-22+ T cells. Interestingly, Pedroza et al 45 observed that the AIRE protein can also function as a signaling effector downstream of Dectin-1 in blood cells and a monocytic cell line (Fig. 1).…”

Section: Cmc Disease As Part Of a Syndromementioning

confidence: 99%

TH17 deficiency in human disease

McDonald

2012

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

The differentiation of naïve T cells into distinct subsets of effector T cells is critical for effective immunity against a wide variety of infectious agents in the environment. Activation of innate immune responses by Candida through pattern recognition receptors directs the subsequent development of naïve T cells into Th17 cells, which are essential for effective mucosal immunity against fungi. Thorough analyses of cohorts of patients with unusual susceptibility to chronic mucocutaneous candidiasis (CMC) resulting from Th17 deficiency has confirmed the role of Th17 cells and Th17 cytokines in human host defense against Candida and has provided valuable insight into the complex process of Th17 cell development.

show abstract

Section: Cmc Disease As Part Of a Syndromementioning

confidence: 99%

TH17 deficiency in human disease

McDonald

2012

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

show abstract

“…Practically all patients have neutralizing Abs against type I IFNs (14), which are often the earliest manifestation of the disease, and autoantibodies targeting other cytokines are also found, of which anti-IL-17 and -IL-22 Abs have been linked to impaired defense against Candida (2,15,16). A more recent study reported that AIRE interacts with Dectin-1, an inflammasome-activating pathway linked to antifungal immunity (17). A substantial fraction of the patients also exhibit gastrointestinal manifestations, including chronic obstipation, diarrhea, gastritis, and hepatitis (1,7,18).…”

mentioning

confidence: 99%

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Hetemäki

Jarva

Kluger

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the AIRE gene. Although mainly an endocrine disease, a substantial fraction of patients have gastrointestinal manifestations. In this study, we have examined the role of anticommensal responses and their regulation. APECED patients had increased levels of Abs against Saccharomyces cerevisiae (p < 0.0001) and against several species of commensal gut bacteria, but not against species predominantly associated with other locations. The anticommensal Ab levels did not correlate with gastrointestinal autoantibodies, neutralizing anti–IL-17 or –IL-22 Abs, or gastrointestinal symptoms, although scarcity of the available clinical data suggests that further study is required. However, the anti–S. cerevisiae Ab levels showed a significant inverse correlation with FOXP3 expression levels in regulatory T cells (Treg), previously shown to be dysfunctional in APECED. The correlation was strongest in the activated CD45RO+ population (ρ = −0.706; p < 0.01). APECED patients also had decreased numbers of FOXP3+ cells in gut biopsies. These results show that APECED patients develop early and sustained responses to gut microbial Ags in a pattern reminiscent of Crohn’s disease. This abnormal immune recognition of gut commensals is linked to a systemic Treg defect, which is also reflected as a local decrease of gut-associated Treg. To our knowledge, these data are the first to show dysregulated responses to non-self commensal Ags in APECED and indicate that AIRE contributes to the regulation of gut homeostasis, at least indirectly. The data also raise the possibility of persistent microbial stimulation as a contributing factor in the pathogenesis of APECED.

show abstract

“…Surprisingly, increased CARD9-mediated NF-κB translocation did not result in increased production of TNFα or IL6, both of which are known transcriptional targets of NF-κB. There have been a handful of studies implicating CARD9 in increased TNFα production in models of fungal pathogenesis, and no reports connecting CARD9 signaling and IL-6 production to date (42–44). The studies examining CARD9 mediated TNFα production all required dectin-1 ligation.…”

Section: Discussionmentioning

confidence: 99%

Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcγR Cooperation and Is Dependent on CARD9

Rhoads

Lukens

Wilhelm

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Oxidized LDL (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells (DCs). Interestingly, much of the oxLDL in circulation is complexed to antibodies and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory disease such as atherosclerosis, Type-2 diabetes, systemic lupus erythematosus and rheumatoid arthritis. Levels of oxLDL-ICs often correlate with disease severity, and past studies have demonstrated that oxLDL-ICs elicit potent inflammatory responses in macrophages. Here we show that bone marrow-derived dendritic cells (BMDCs) incubated with oxLDL-ICs for 24 hrs secrete significantly more IL-1β compared to BMDCs treated with free oxLDL, while there was no difference in levels of TNFα or IL-6. Treatment of BMDCs with oxLDL-ICs increased expression of inflammasome-related genes Il1a, Il1b, and Nlrp3; and pre-treatment with a caspase 1 inhibitor decreased IL-1β secretion in response to oxLDL-ICs. This inflammasome priming was due to oxLDL-IC signaling via multiple receptors as inhibition of CD36, TLR4 and FcγR significantly decreased IL-1β secretion in response to oxLDL-ICs. Signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9-Bcl10-MALT1 signalosome complex involved in NF-κB translocation. Finally, oxLDL-IC-mediated IL-1β production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data demonstrate that oxLDL-ICs induce inflammasome activation through a separate and more robust mechanism than oxLDL alone, and that these ICs may be immunomodulatory in chronic disease and not just biomarkers of severity.

show abstract

Autoimmune regulator (AIRE) contributes to Dectin-1–induced TNF-α production and complexes with caspase recruitment domain–containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1

Cited by 24 publications

References 38 publications

TH17 deficiency in human disease

TH17 deficiency in human disease

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and FcγR Cooperation and Is Dependent on CARD9

Contact Info

Product

Resources

About