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Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Among the most studied CLRs are Dectin-1 (Group V, Ca++-independent) and Dectin-2 (Group II, Ca++-dependent). Dectin-1 plays a key role in antifungal immunity by initiating signals that lead to phagocytosis and killing of fungi. Expressed on macrophages, monocytes, DCs, neutrophils, microglia, and eosinophils, Dectin-1 binds β-glycans, a major cell-wall component of nearly all fungi. Deficiencies in Dectin-1 or CARD9 in mice and humans result in increased susceptibility to fungal infections. In mice, for example, Dectin-1 deficiency causes increased mortality in response to infection by fungal pathogens such as Candida albicans, Aspergillus fumigatus, and Coccoidiodes podasii. Some patients with familial chronic mucocutaneous candidiasis have a nonsense mutation in the Dectin-1 gene. Dectin-1 also appears to contribute to mucosal myeloid cell sensing of enteric commensal fungi, thereby contributing to the maintenance of “mucosal homeostasis.” For example, mice with Dectin-1 deficiency (Clec7a-/-) show an increased mucosal inflammatory response to commensal fungi in dextran sodium sulfate-induced colitis. Further, a single nucleotide polymorphism in the human Dectin-1 CLEC7A gene in patients with ulcerative colitis is associated with medically refractory disease.
Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
CARD9 deficiency results in predisposition to invasive fungal infection and deep dermatophytoses. In contrast, increased susceptibility to mycobacterial disease is seen in complete interferon-γ receptor deficiency, manifest by disseminated mycobacterial infection in soft tissue, bone, lung, skin, and lymphoid tissues. Similar clinical phenotypes are seen with IL-12 deficiency and STAT 1 loss of function mutations. Susceptibility to viral infections, particularly human papillomaviruses is seen in WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis) due to an autosomal-dominant gain of function mutation in CXCR4.
Epidemiology of fungal infections: What, where, and when
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Frederic Lamoth, Sylvia F. Costa, Barbara D. Alexander
Environmental contamination of products has been implicated in E. dermatitidis infections, including peritonitis in patients undergoing CAPD and meningitis from contaminated compounded injectable steroids [246,255,256]. Similarly, E. jeanselmei fungemia has been associated with contaminated water products in immunocompromised patients [257]. An outbreak of E. jeanselmei fungemia over a 10-month period was ultimately related to contaminated deionized water from a hospital pharmacy. Over half the patients presenting with fungemia had malignancy, mostly hematologic, while the other patients had AIDS, agranulocytosis, and systemic lupus erythematosus (SLE) with thrombotic thrombocytopenic purpura. Invasive Exophiala infections also have been recently reported in patients with inherited CARD9 deficiency [258]. The most common presenting clinical sign associated with Exophilala infections is fever [257].
Genetics of Uveitis
Published in Ocular Immunology and Inflammation, 2021
Emmett T. Cunningham, Francesco Pichi, Vinit B. Mahajan, James T. Rosenbaum, Manfred Zierhut
Li et al29 examined six known single nucleotide polymorphisms (SNPs) in the Caspase Recruitment Domain Family Member 9 (CARD9) gene from 480 subjects with BD, 1151 with acute anterior uveitis (AAU), and 1440 healthy controls in China. The authors chose CARD9 as it is known to play a key role in the regulation of both innate and adaptive immunity, and alterations in the CARD9 gene have been linked to both primary immunodeficiencies and inflammatory disorders in humans.43 While none of the six individual SNPs showed an association with either BD or AAU, a haplotype analysis did reveal a significant decrease in a specific 5-SNP CARD9 gene haplotype in BD compared to healthy controls (p = .012; OR = 0.59, 95% CI = 0.41 to 0.84), leading the authors to suggest that this particular haplotype might be protective for BD in their Han population. No haplotype combinations were associated with AAU.
The mycobiota of the human body: a spark can start a prairie fire
Published in Gut Microbes, 2020
Di Zhang, Ying Wang, Sunan Shen, Yayi Hou, Yugen Chen, Tingting Wang
Th17 cells are the main force of specific immunity against fungal infection in organisms. Th17 cells can receive stimulatory signals from multiple cytokines (IL-23, IL-6, and IL-1β), with an article highlighting the role of IL-6 produced by the Langerhans cell combined with CLRs.155 The upstream events may lead back to a few signaling pathways that were previously discussed; the well-known mechanism is combined with Card9, which is the center of anti-fungal immunity.157,158 For example, in the response to Aspergillus fumigatus infection, researchers found that Card9 accepts the signal from dectin-1 and impels CD4 + T cells toward the direction of Th17 cell differentiation, which is based on the inhibition of Th1 cell formation.159 After activation, Th17 cells can produce cytokines based on IL-22 and IL-17. Accumulating evidence has shown that IL-17 predominates the protective response160 with the second role of IL-22 when the body encounters OPC and RVVC. It suggests that Th17 cells have a role in the immunity of mucosal fungal infection specifically.79
CARD9 deficiency promotes pancreatic cancer growth by blocking dendritic cell maturation via SLC6A8-mediated creatine transport
Published in OncoImmunology, 2023
Cheng Tian, Huimin Yuan, Yi Lu, Henghui He, Qing Li, Senlin Li, Jian Yang, Mengheng Wang, Ruochen Xu, Qian Liu, Ming Xiang
Caspase-recruitment domain-containing protein 9 (CARD9) is chiefly expressed in innate immune cells, especially macrophages and DCs13. As an imperative integrator of the innate immunity, CARD9 mediates signaling from multiple pattern recognition receptors (PRRs) by forming a CARD9/B cell lymphoma/leukemia 10 (BCL10)/mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex. Therefore, CARD9 exerts a regulatory effect on a variety of disorders, including infection, cancer, cardiovascular pathologies, inflammatory diseases, and metabolic disorders14–17. Although CARD9 is involved in tumorigenesis, development, or metastasis of numerous cancers such as lung and colon cancers18,19, its exact role in PC remains undefined.