Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy

AbstractThe ongoing COVID-19 pandemic has caused significant morbidity and mortality worldwide, as well as profound effects on society. COVID-19 patients have an increased risk of thromboembolic (TE) complications, which develop despite pharmacological thromboprophylaxis. The mechanism behind COVID-19-associated coagulopathy remains unclear. Mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, has been suggested as a potential amplifier of blood coagulation during thromboinflammation. Here we describe data from a cohort of critically ill COVID-19 patients (n = 65) treated at a tertiary hospital center intensive care unit (ICU). A subset of patients had strongly elevated MBL plasma levels, and activity upon ICU admission, and patients who developed symptomatic TE (14%) had significantly higher MBL levels than patients without TE. MBL was strongly correlated to plasma D-dimer levels, a marker of COVID-19 coagulopathy, but showed no relationship to degree of inflammation or other organ dysfunction. In conclusion, we have identified complement activation through the MBL pathway as a novel amplification mechanism that contributes to pathological thrombosis in critically ill COVID-19 patients. Pharmacological targeting of the MBL pathway could be a novel treatment option for thrombosis in COVID-19. Laboratory testing of MBL levels could be of value for identifying COVID-19 patients at risk for TE events.

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C4b-Binding protein and mannose binding lectin interactions with β2-glycoprotein I: Association of complement activation and antiphospholipid antibodies

Immunopharmacology ◽

10.1016/s0162-3109(00)80238-6 ◽

2000 ◽

Vol 49 (1-2) ◽

pp. 83

Author(s):

Derek S. Sim ◽

Steffen Thiel ◽

Dana V. Devine

Keyword(s):

Complement Activation ◽

Antiphospholipid Antibodies ◽

Binding Protein ◽

Mannose Binding Lectin ◽

Glycoprotein I ◽

Mannose Binding ◽

Binding Lectin

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Interactions between mannose-binding lectin and MASPs during complement activation by the lectin pathway

Immunobiology ◽

10.1016/j.imbio.2006.11.004 ◽

2007 ◽

Vol 212 (4-5) ◽

pp. 289-299 ◽

Cited By ~ 68

Author(s):

Russell Wallis

Keyword(s):

Complement Activation ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

Mannose Binding ◽

Binding Lectin

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Complement-Mediated Neutralization of Dengue Virus Requires Mannose-Binding Lectin

mBio ◽

10.1128/mbio.00276-11 ◽

2011 ◽

Vol 2 (6) ◽

Cited By ~ 45

Author(s):

Panisadee Avirutnan ◽

Richard E. Hauhart ◽

Mary A. Marovich ◽

Peter Garred ◽

John P. Atkinson ◽

...

Keyword(s):

Dengue Virus ◽

Human Serum ◽

Complement Activation ◽

Insect Cell ◽

Denv Infection ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

Denv Serotypes ◽

Mannose Binding ◽

Binding Lectin

ABSTRACTMannose-binding lectin (MBL) is a key soluble pathogen recognition protein of the innate immune system that binds specific mannose-containing glycans on the surfaces of microbial agents and initiates complement activation via the lectin pathway. Prior studies showed that MBL-dependent activation of the complement cascade neutralized insect cell-derived West Nile virus (WNV) in cell culture and restricted pathogenesis in mice. Here, we investigated the antiviral activity of MBL in infection by dengue virus (DENV), a related flavivirus. Using a panel of naïve sera from mouse strains deficient in different complement components, we showed that inhibition of infection by insect cell- and mammalian cell-derived DENV was primarily dependent on the lectin pathway. Human MBL also bound to DENV and neutralized infection of all four DENV serotypes through complement activation-dependent and -independent pathways. Experiments with human serum from naïve individuals with inherent variation in the levels of MBL in blood showed a direct correlation between the concentration of MBL and neutralization of DENV; samples with high levels of MBL in blood neutralized DENV more efficiently than those with lower levels. Our studies suggest that allelic variation of MBL in humans may impact complement-dependent control of DENV pathogenesis.IMPORTANCEDengue virus (DENV) is a mosquito-transmitted virus that causes a spectrum of clinical disease in humans ranging from subclinical infection to dengue hemorrhagic fever and dengue shock syndrome. Four serotypes of DENV exist, and severe illness is usually associated with secondary infection by a different serotype. Here, we show that mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, neutralized infection of all four DENV serotypes through complement activation-dependent and -independent pathways. Moreover, we observed a direct correlation with the concentration of MBL in human serum and neutralization of DENV infection. Our studies suggest that common genetic polymorphisms that result in disparate levels and function of MBL in humans may impact DENV infection, pathogenesis, and disease severity.

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Secondary Cell Wall Polymers ofEnterococcus faecalisAre Critical for Resistance to Complement Activation via Mannose-binding Lectin

Journal of Biological Chemistry ◽

10.1074/jbc.m112.358283 ◽

2012 ◽

Vol 287 (45) ◽

pp. 37769-37777 ◽

Cited By ~ 25

Author(s):

Stefan Geiss-Liebisch ◽

Suzan H. M. Rooijakkers ◽

Agnieszka Beczala ◽

Patricia Sanchez-Carballo ◽

Karolina Kruszynska ◽

...

Keyword(s):

Cell Wall ◽

Complement Activation ◽

Secondary Cell Wall ◽

Mannose Binding Lectin ◽

Cell Wall Polymers ◽

Mannose Binding ◽

Binding Lectin

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Human Mannose-binding Lectin in Immunity

Journal of Experimental Medicine ◽

10.1084/jem.20040537 ◽

2004 ◽

Vol 199 (10) ◽

pp. 1295-1299 ◽

Cited By ~ 79

Author(s):

Jean-Laurent Casanova ◽

Laurent Abel

Keyword(s):

Complement Activation ◽

Prospective Studies ◽

Protective Immunity ◽

Mannose Binding Lectin ◽

Counter Selection ◽

Wide Range ◽

Mannose Binding ◽

Severe Infections ◽

Binding Lectin

Human mannose-binding lectin (MBL) recognizes a wide range of microorganisms and triggers the most ancient pathway of complement activation. However, ∼5% of individuals lack functional serum MBL and have not been found to be prone to severe infections in prospective studies. These data suggest that human MBL is largely redundant for protective immunity and may even have been subject to counter selection because of a deleterious impact.

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Myocardial ischemia and reperfusion injury is dependent on both IgM and mannose-binding lectin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00049.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. H1853-H1859 ◽

Cited By ~ 71

Author(s):

Marc N. Busche ◽

Vasile Pavlov ◽

Kazue Takahashi ◽

Gregory L. Stahl

Keyword(s):

Myocardial Ischemia ◽

Complement Activation ◽

Tissue Injury ◽

Left Ventricular ◽

Mannose Binding Lectin ◽

Left Ventricular Ejection ◽

Ischemia And Reperfusion ◽

Myocardial Ischemia And Reperfusion ◽

Mannose Binding ◽

Binding Lectin

Complement activation has been shown to play an important role in the inflammation and tissue injury following myocardial ischemia and reperfusion (MI/R). Several recent studies from our laboratory demonstrated the importance of mannose-binding lectin (MBL) as the initiation pathway for complement activation and the resulting pathological effects following MI/R. However, other studies from the past suggest an important role of the classical pathway and perhaps natural antibodies. In the present study, we used newly generated genetically modified mice that lack secreted IgM (sIgM), MBL-A, and MBL-C (sIgM/MBL null) in a plasma reconstitution mouse model of MI/R. Following 30 min of ischemia and 4 h of reperfusion, left ventricular ejection fractions were significantly higher in sIgM/MBL null mice reconstituted with MBL null or sIgM/MBL null plasma compared with reconstitution with wild-type (WT) plasma or WT mice reconstituted with WT plasma following MI/R. Serum troponin I concentration, myocardial polymorphonuclear leukocyte infiltration, and C3 deposition were dependent on the combined presence of sIgM and MBL. These results demonstrate that MI/R-induced complement activation, inflammation, and subsequent tissue injury require both IgM and MBL. Thus MBL-dependent activation of the lectin pathway may not be completely antibody independent in I/R models.

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