Inborn errors of interferon-gamma (IFN-γ) immunity and their autoimmune phenocopies underlie mycobacterial diseases, whereas inborn errors of interleukin 17 (IL-17) and IL-22 immunity and their autoimmune phenocopies underlie chronic mucocutaneous candidiasis (CMC) in humans and mice. All other authors had no financial relationships to disclose. Alton Swennes acts as a consultant for AbbVie, Merck, and OraSure Technologies. PC1, principal coordinate 1 PC2, principal coordinate 2ĭisclosures: Joud Hajjar has relevant financial relationships with proprietary interests with The Texas Medical center Digestive Diseases Center (Research Grant includes principal investigator, collaborator or consultant and pending grants as well as grants already received), Jeffrey Modell Foundation (Research Grant includes principal investigator, collaborator or consultant and pending grants as well as grants already received), Immune Deficiency Foundation (Research Grant includes principal investigator, collaborator or consultant and pending grants as well as grants already received) Baxalta (Research Grant includes principal investigator, collaborator or consultant and pending grants as well as grants already received), Chao Physician-Scientist Foundation (Research Grant includes principal investigator, collaborator or consultant and pending grants as well as grants already received), Takeda (Consultant/Advisory Board Member), Pharming (Consultant/Advisory Board Member), Horizon: Consultant/Advisory Board Member, and Alfaisal University (ad hoc consultancy/speaker).
Axis labels indicate the percentage of variance explained by the respective principal coordinate axis. Principal coordinate analysis plots of unweighted distances of fecal microbiota generated by the 16S rRNA gene sequence analysis. D30 and D40 represent days 30 & 40 post-FMT, respectively. Germ-Free mice received h-IgG 500 mg/kg or NS 50μl, intraperitoneally (n=4/group). Human IgG significantly changes the gut microbiome beta diversity of NIC-FMT recipient GF mice. Feces were freshly collected from GF (C57Bl/6J) mice (n=8/group, all males, ages 8-12 weeks), mice housed at the Gnotobiotics Core, BCM). PC1, principal coordinate 1 PC2, principal coordinate 2.
Principal-coordinate analysis plots of Unifraction distances of fecal microbiota generated from 16S rRNA gene sequence analysis. There is a significant difference in alpha and beta gut microbiome diversity between NIC, INF, and CTL FMT recipients: Beta diversity between GF mice 30 days following FMT. Dysregulation of the same genera has been described in CVID patients. In addition, IgG-treated NIC-FMT recipients had a decrease in the relative abundance of Eggerthella, Bifidobacterium, and Ruminococcaceae genera. Compared to NS, h-IgG resulted in a significant change in gut microbiome beta diversity in NIC-FMT but not in INF or CTL-FMT recipients. We next treated 50% of the mice in each group with normal saline (NS) and 50% with a single dose of intraperitoneal human IgG (h-IgG). Furthermore, FMT recipients from all CVID donors (NIC and INF) had significantly higher serum IgG2b and IgG2c, indicating inflammation. Thirty days later, gut microbial alpha and beta diversity were significantly different between NIC, INF, and CTL-FMT recipients.
GF-mice received FMT from NIC-CVID, INF-CVID, or a healthy control (CTL). To investigate the role of dysbiosis in the immune responses in CVID, we performed fecal microbiota transplant (FMT) from CVID patients to C57Bl/6J Germ-Free (GF) mice. Studies showed associations between NIC-CVID and gut microbiome aberrations, including imbalanced microbial composition, leaky gut, and systemic inflammation. Compared to INF-CVID, NIC-CVID patients have higher morbidity and mortality rates. CVID patients have two distinct phenotypes: patients who develop infections-only (INF), and patients who develop autoimmune and inflammatory complications (noninfectious complications (NIC)). We seek to identify the role of the microbiome in immune dysregulation in Common Variable Immunodeficiency (CVID).
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