High glucose disrupts oligosaccharide recognition function via competitive inhibition: A potential mechanism for immune dysregulation in diabetes mellitus

Ilyas, Rebecca; Wallis, Russell; Soilleux, Elizabeth; Paul, Thierry; Zehnder, Daniel; Tan, Bee K.; Sim, Robert B.; Lehnert, Hendrik; Randeva, Harpal S.; Mitchell, Daniel A.

doi:10.1016/j.imbio.2010.06.002

Cited by 83 publications

(65 citation statements)

References 45 publications

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“…These structural changes likely contribute to the altered interaction of C3 with bacteria in hyperglycemic environments. A recent study showed that high glucose inhibited the lectin pathway by inhibiting oligosaccharide recognition, but classical and alternative complement pathway activation were not inhibited in Weislab ELISA-style complement activation assays [56]. We confirmed in CH50 and AP50 assays that serum complement-mediated hemolysis was not altered by elevated glucose (data not shown).…”

Section: Discussionsupporting

confidence: 76%

Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus

et al. 2012

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BackgroundDiabetic patients are at increased risk for bacterial infections; these studies provide new insight into the role of the host defense complement system in controlling bacterial pathogens in hyperglycemic environments.MethodsThe interactions of complement C3 with bacteria in elevated glucose were assayed for complement activation to opsonic forms, phagocytosis and bacterial killing. C3 was analyzed in euglycemic and hyperglycemic conditions by mass spectrometry to measure glycation and structural differences.ResultsElevated glucose inhibited S. aureus activation of C3 and deposition of C3b and iC3b on the bacterial surface. S. aureus-generated C5a and serum-mediated phagocytosis by neutrophils were both decreased in elevated glucose conditions. Interestingly, elevated glucose increased the binding of unactivated C3 to S. aureus, which was reversible on return to normal glucose concentrations. In a model of polymicrobial infection, S. aureus in elevated glucose conditions depleted C3 from serum resulting in decreased complement-mediated killing of E. coli. To investigate the effect of differing glucose concentration on C3 structure and glycation, purified C3 incubated with varying glucose concentrations was analyzed by mass spectrometry. Glycation was limited to the same three lysine residues in both euglycemic and hyperglycemic conditions over one hour, thus glycation could not account for observed changes between glucose conditions. However, surface labeling of C3 with sulfo-NHS-biotin showed significant changes in the surface availability of seven lysine residues in response to increasing glucose concentrations. These results suggest that the tertiary structure of C3 changes in response to hyperglycemic conditions leading to an altered interaction of C3 with bacterial pathogens.ConclusionsThese results demonstrate that hyperglycemic conditions inhibit C3-mediated complement effectors important in the immunological control of S. aureus. Mass spectrometric analysis reveals that the glycation state of C3 is the same regardless of glucose concentration over a one-hour time period. However, in conditions of elevated glucose C3 appears to undergo structural changes.

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Section: Discussionsupporting

confidence: 76%

Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus

et al. 2012

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“…This is an observation that has not been previously demonstrated in other studies presumably because of lack of power (16;19;21). Patients with poorly-controlled diabetes mellitus are presumed to be immunocompromised because of multiple hyperglycemia-related immune system impairments (35–39), and most relevantly may have decreased production of interferon-gamma and tumor necrosis factor-alpha by T-cells (40), which may result in increased risk of CMV disease.…”

Section: Discussionmentioning

confidence: 99%

Delayed-Onset Cytomegalovirus Disease Coded During Hospital Readmission After Kidney Transplantation

et al. 2014

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Background Use of prophylactic anti-CMV therapy for 3 to 6 months after kidney transplantation can result in delayed-onset CMV disease. We hypothesized that delayed-onset CMV disease (occurring ≥ 100 days post-transplant) occurs more commonly than early-onset CMV disease, and that it is associated with death. Methods We assembled a retrospective cohort of 15,848 adult kidney transplant recipients using 2004 to 2010 administrative data from the California and Florida Healthcare Cost and Utilization Project State Inpatient Databases. We identified demographic data, comorbidities, CMV disease coded during readmission and inpatient death. We used multivariate Cox proportional hazards modeling to determine risk factors for delayed-onset CMV disease and inpatient death. Results Delayed-onset CMV disease was identified in 4.0% and early-onset CMV disease was identified in 1.2% of the kidney transplant recipients. Risk factors for delayed-onset CMV disease included previous transplant failure or rejection (HR 1.4) and residence in the lowest-income ZIP codes (HR 1.2). Inpatient death was associated with CMV disease occurring 101–365 days post-transplant (HR 1.5), CMV disease occurring > 365 days post-transplant (HR 2.1), increasing age (by decade: HR 1.5), non-white race (HR 1.2), residence in the lowest-income ZIP codes (HR 1.2), transplant failure or rejection (HR 3.2), prior solid organ transplant (HR 1.7) and several comorbidities. Conclusions These data showed that delayed-onset CMV disease occurred more commonly than early-onset CMV disease, and that transplant failure or rejection is a risk factor for delayed-onset CMV disease. Further research should be done to determine if delayed-onset CMV disease is independently associated with death.

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“…Hyperglykämie hemmt die Produktion von IL-10 von myeloischen Zellen und von TNF-α und Interferon-γ von T Zellen [48]. Die Bindung von Oligosacchariden durch C-Lektin wird durch hohe Glukosekonzentrationen kompetitiv gehemmt, was sich auf viele Funktionen des Immunsystems auswirkt [49]. Für Impfungen von Bedeutung ist die Verwendung von CD20-Antikörpern wie Rituximab oder Ofatumumab, die über zumindest drei verschiedene Mechanismen gleichzeitig wirken und zu einer B-Zell-Depletion führen [56].…”

Section: Diabetes Mellitusunclassified

Impfungen bei Immundefekten/Immunsuppression – Expertenstatement und Empfehlungen

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et al. 2016

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High glucose disrupts oligosaccharide recognition function via competitive inhibition: A potential mechanism for immune dysregulation in diabetes mellitus

Cited by 83 publications

References 45 publications

Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus

Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus

Delayed-Onset Cytomegalovirus Disease Coded During Hospital Readmission After Kidney Transplantation

Impfungen bei Immundefekten/Immunsuppression – Expertenstatement und Empfehlungen

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