epiglucan and Vasculitis

Kawasaki disease (KD) is an inflammatory disease that was identified by Professor Tomisaku Kawasaki in 1961. Candida albicans-derived substances, such as C. albicans water-soluble fraction (CAWS) , induce coronary arteritis similar to KD in mice. CAWS functions as a pathogen-associated molecular pattern (PAMP) by acting as a ligand for dectin-2. A gut-associated immunological system has developed specifically to segregate advantageous and detrimental stimuli, and the microbial flora has been found to markedly affect the development and severity of diseases. We herein investigated whether diet affects the onset and progression of CAWS vasculitis in mice. A standard diet, CE-2, and chemically defined diet, AIN93G, which is free of β-glucan, were used. Although all mice administered with CAWS died, the mean number of survival days was smaller in the AIN93G group because vasculitis was induced earlier than in the CE-2 group. Bacteroides, which are inflammatory flora, were enriched in the microbial flora of the AIN93G group. The results of the present study suggest that diet quality affects not only microbial flora changes, but also the progression of systemic disease.

Topics: Animals; Bacteroides; beta-Glucans; Candida albicans; Diet; Disease Progression; Food; Gastrointestinal Microbiome; Gastrointestinal Tract; Lectins, C-Type; Ligands; Male; Mice, Inbred DBA; Mucocutaneous Lymph Node Syndrome; Solubility; Subcellular Fractions; Vasculitis; Water

Candida albicans water-soluble fraction (CAWS), a mannoprotein-β-glucan complex obtained from the culture supernatant of C. albicans NBRC1385, causes CAWS-mediated vasculitis (CAWS-vasculitis) in B6 and DBA/2 mice with mild and lethal symptoms, respectively. Why CAWS is lethal only in DBA/2 mice remains unknown.. We performed DNA microarray analyses using mRNA obtained from peripheral blood mononuclear cells (PBMCs) of B6 and DBA/2 mice and compared their respective transcriptomes. We found that the mRNA levels of interferon-γ (Ifng) and several genes that regulate the complement system, such as C3, C4, Cfb, Cfh, and Fcna, were increased dramatically only in DBA/2 mice at 4 and 8 weeks after CAWS administration. The dramatic increase was confirmed by quantitative real-time polymerase chain reactions (qRT-PCR). Moreover, mRNA levels of immune-related genes, such as Irf1, Irf7, Irf9, Cebpb, Ccl4, Itgam, Icam1, and IL-12rb1, whose expression levels are known to be increased by Ifng, were also increased, but only in DBA/2 mice. By contrast, the mRNA level of Dectin-2, the critical receptor for the α-mannans of CAWS, was increased slightly and similarly in both B6 and DBA/2 mice after CAWS administration.. Taken together, our results suggest that CAWS administration induces Dectin-2 mediated CAWS-vasculitis in both B6 and DBA/2 mice and the expression of Ifng, but only in DBA/2 mice, which led to increased expression of C3, C4, Cfb, Cfh, and Fcna and an associated increase in lethality in these mice. This model may contribute to our understanding of the pathogenesis of severe human vasculitis.

Topics: Animals; beta-Glucans; Candida albicans; Cluster Analysis; Complement System Proteins; Gene Regulatory Networks; Interferon-gamma; Leukocytes, Mononuclear; Male; Membrane Glycoproteins; Mice; Mice, Inbred DBA; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Severity of Illness Index; Solubility; Transcriptome; Vasculitis; Water

Candida albicans water-soluble fraction (CAWS) has microbial pathogen-associated molecular patterns (PAMPs). It is a mannoprotein-β glucan complex obtained from the culture supernatant of Candida albicans NBRC1385 and exhibits vasculitis-inducing activity (CAWS vasculitis) in mice. The sensitivity to CAWS vasculitis varies greatly among mouse strains. This study examined the factors contributing to or inhibiting CAWS vasculitis using CAWS-vasculitis-resistant CBA/J mice and Bruton's tyrosine kinase (Btk)-deficient CBA/N mice, which is a CAWS-vasculitis-sensitive strain having the same origin as CBA/J mice. After stimulation with various kinds of pathogen-associated molecular patterns (PAMPs), the production of inflammatory cytokines IL-6 and IFN-γwas induced in CBA/N mice, whereas that of immunosuppressive IL-10 was induced in CAWS-vasculitis-resistant CBA/J mice. The production of TIMP1, an endogenous matrix metalloproteinase (MMP) inhibitor, was observed in CBA/J mice. Furthermore, the induction of CAWS-vasculitis was inhibited by gene therapy using plasmid (pCAGGS-mIL-10). The results strongly suggest that the difference in the production of these cytokines is closely linked to the development of CAWS vasculitis.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; beta-Glucans; Candida albicans; Genetic Therapy; Interferon-gamma; Interleukin-10; Interleukin-6; Male; Membrane Glycoproteins; Mice; Mice, Inbred CBA; Plasmids; Protein Binding; Protein-Tyrosine Kinases; Solubility; Tissue Inhibitor of Metalloproteinase-1; Vasculitis; Water

Deep mycosis (aspergillus pneumonia (AsP)) and carinii pneumonitis (PCP) are complications of immunosuppressive treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The objective was to clarify the clinical significance of plasma titer of antibody against beta-glucans (anti-BG antibody) as a predictor of complications such as AsP or PCP and the prognosis of patients. Enzyme-linked immunosorbent assay was used to measure the plasma titer of antibodies against beta-glucans (BG) from Candida albicans in 22 healthy subjects and 52 patients with various stages of AAV. The mean plasma titer of the anti-BG antibody was 2,677 +/- 1,686 U in healthy subjects, 691 +/- 522 U in patients with untreated active vasculitis (n = 14), and 547 +/- 416 U in patients soon after immunosuppressive treatment (n = 24). Healthy subjects had significantly higher antibody titers than the other two groups (P < 0.05). Repeated measurements over the clinical course of AAV revealed an increase during remission to 1,180 +/- 130 U (n = 11), while there was a significant rapid decrease to 369 +/- 441 U (P < 0.01) concomitantly with elevation in plasma C-reactive protein and BG levels in patients with AAV that had AsP or PCP infection. Antifungal therapy resulted in a rapid rise of anti-BG antibody titer. Experiments in mice suggested that the anti-BG antibody neutralizes BG. Rapid decrease of the anti-BG antibody titer may be a useful indicator for diagnosis of the presence of AsP or PCP and for estimating the prognosis of patients with these opportunistic infections during immunosuppressive treatment of AAV.

Topics: Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antifungal Agents; Aspergillus; beta-Glucans; Candida albicans; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycoses; Pneumonia; Remission Induction; Reproducibility of Results; Vasculitis

Candida albicans water soluble fraction (CAWS) is a water-soluble extracellular mannoprotein-beta-glucan complex obtained from the culture supernatant of Candida albicans, which grows in a chemically defined medium. CAWS induced toxic reactions, such as acute anaphylactoid reaction, by intravenous administration and coronary arteritis by intraperitoneal administration. To clarify the structure responsible for these toxic reactions, C. albicans was cultured in pH- and temperature-controlled conditions and prepared with CAWS with or without the beta-1,2-linked mannosyl segment (BM). The structure of CAWS was assessed by immunochemical and spectroscopic methodologies, and we found that CAWS prepared under the natural culture conditions contained only small amounts of BM and CAWS prepared at neutral conditions at 27 degrees C contained a significantly higher percentage of BM. Both the acute lethal toxicity and coronary arteritis induction was significantly more severe in the absence of BM. Activation of a complement pathway, the lectin pathway, by CAWS was significantly stronger in the absence of BM. These facts strongly suggest that BM linkages in CAWS negatively modulate acute and chronic toxicity of CAWS, and may be strongly related to the lectin pathway of the complement activation.

Topics: Anaphylaxis; Animals; beta-Glucans; Candida albicans; Complement Activation; Magnetic Resonance Spectroscopy; Male; Mannose; Mannose-Binding Lectin; Membrane Glycoproteins; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Vasculitis