Decreased Ficolin-3-mediated Complement Lectin Pathway Activation and Alternative Pathway Amplification During Bacterial Infections in Patients With Type 2 Diabetes Mellitus

Abstract

Bacterial infections are frequent and severe in patients with diabetes mellitus. Whether diabetes per se induces functional alterations in the complement system hampering activation during infection is unknown. We investigated key elements of the complement system during bacterial infections in patients with type 2 diabetes mellitus (T2DM) and compared them to non-diabetic (ND) individuals. Using a prospective design, we included 197 T2DM, and 196 ND subjects, all with clinical diagnosis of acute community-acquired bacterial infections. Functional activities of the ficolin-3-mediated lectin (F3-LP), mannose binding lectin-mediated lectin- (MBL-LP), classical (CP), and alternative pathways (AP), as well as concentrations of complement activation products C4d and sC5b-9 were determined. Functional in vitro activities of F3-LP and AP were significantly higher in T2DM than in ND subjects, (median 64% vs. 45%, p = 0.0354 and 75 vs. 28%, p = 0.0013, respectively), indicating a decreased in vivo activation and lack of consumption of F3-LP and AP in T2DM patients, whereas no difference in functional capacities of CP and MBL-LP were observed between T2DM and ND subjects. Diminished F3-LP and AP activation was most pronounced in diabetic patients with urinary tract infections with positive microbiological culture results for Escherichia coli bacteria. In the T2DM group 3-months mortality significantly associated with diminished F3-LP and AP, but not with CP activation. Concentrations of C4d and sC5b-9 were significantly lower in the T2DM than in ND patients. In conclusion, we found impaired F3-LP activation and lack of AP amplification during bacterial infections in patients with type 2 diabetes, compared to non-diabetic subjects, suggesting a diminished complement mediated protection to bacterial infections in T2DM.

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

“…Ficolin-3 was furthermore identified to be deiminated in whole alligator plasma only and is a sugar pattern recognition molecule, which forms part of mammalian immune systems (132). Ficolin-3 can activate the complement system via the lectin pathway (133), plays roles in bacterial defenses (134,135) and autoimmunity (136,137) and is modulated in viral infections including HIV (138). Ficolin-3 has been associated with metabolic diseases including gestational, prediabetes, and type 2 diabetes (139,140), and identified as biomarkers in axial spondyloarthritis (141) and as a prognostic biomarker for esophageal cancer (142).…”

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System

“…Nevertheless, Barkai et al did not find significant differences in the function of classical or MBL pathways between T2DM and healthy individuals (130). However, significantly decreased activity of ficolin-3-mediated lectin and alternative pathways, as well as decreased levels of C4d and soluble complement C5b-9 (sC5b-9) were seen in diabetic patients with Escherichia coli-mediated urinary tract infections (130). This may be linked to a reduced ability of diabetics to protect themselves against bacterial infections.…”

“…Reduced binding of MBL in the presence of high levels of sugar causes a significant reduction in the lectin pathway activity, but does not influence classical or alternative pathway activity (129). Nevertheless, Barkai et al did not find significant differences in the function of classical or MBL pathways between T2DM and healthy individuals (130). However, significantly decreased activity of ficolin-3-mediated lectin and alternative pathways, as well as decreased levels of C4d and soluble complement C5b-9 (sC5b-9) were seen in diabetic patients with Escherichia coli-mediated urinary tract infections (130).…”

Transcriptome Signatures Reveal Candidate Key Genes in the Peripheral Blood Mononuclear Cells of Patients With Coronary Artery Disease

“…Enriched genes such as CCR2 [56], CCL19 [57], CX3CL1 [58], CXCL12 [59], IL20 [60], epidermal growth factor receptor (EGFR) [61], ERBB3 [62], adrenomedullin (ADM) [63], SCUBE1 [64], LMAN1L [65] and EGFL7 [66] were responsible for pathogenesis of CAD. Enriched genes such as CXCL6 [67], BMP7 [68], RXFP2 [69], BRS3 [70], FFAR3 [71], neuropeptide B (NPB) [72], SPON2 [73], FCN3 [74], REG3A [75] and ornithine carbamoyltransferase (OTC) [76] were culpable for pathogenesis of diabetes, but these genes may be involved in development of CAD. Enriched genes such as COL18A1 [77], cortistatin (CORT) [78], guanine nucleotide binding protein (G protein) [79] and MUC2 [80] were involved in development of obesity, but these genes may be associated with pathogenesis of CAD.…”