Classical and lectin complement pathways and markers of inflammation for investigation of susceptibility to infections among healthy older adults

Abstract

Background: There is increasing recognition of the significance of chronic, low-level inflammation in older adults, or "inflammaging." Innate immune responses and host-bacterial interactions are recognized as key factors in inflammaging. Inflammatory cytokine IL-6, and complement protein C1q have been identified as biomarkers for the development of frailty and aging-related diseases. Older adults are also susceptible to infections with serotypes of Streptococcus pneumoniae that bind ficolin-2, a component of the lectin complement pathway, and low ficolin-2 levels could possibly be involved in such susceptibility. Methods: The aim of our study was to evaluate complement pathway components and biomarkers for inflammaging among older adults in order to investigate potential innate immune mechanisms that may account for susceptibility to infections in this population. We compared inflammatory markers, as well as components/activity of the classical and lectin complement pathways between healthy older and younger adults. We hypothesized that older adults would have higher levels of inflammatory markers and C1q, and lower levels of lectin pathway components. Older (≥70 years old) and younger (19-54 years old) adults without significant smoking history or chronic medical conditions were eligible for participation. Inflammatory markers (IL-6, TNF-α, CRP), classical complement pathway activity (CH50) and protein levels (C1q, C3, C4), and lectin pathway (MBL levels/activity, CL-L1, MASP-1/2/3, MAp44, MAp19, and H/M/Lficolin) were compared between groups. Results: Older adults had significantly higher mean levels of IL-6 and TNF-α. There were no significant differences in lectin pathway components between older and younger adults. Unexpectedly, mean C1q was significantly higher in the younger group in both unadjusted and adjusted analyses. There was also a significant association between race and C1q levels, but this association did not completely account for the observed differences between age groups.

Plasma Lectin Pathway Complement Proteins in Patients With COVID-19 and Renal Disease

“…Our COVID-19 patient population had a median age of 72 years (range 28-88 years), which was significantly older than dialysis control (62 years, p=0.01) and healthy control (49 years, p<0.0001) cohorts ( Table 1 ). We did not consider this to be a limitation because lectin protein levels do not differ significantly between older and younger adults ( 17 ). The mean estimated glomerular filtration rates (eGFR) at presentation of the patients not established on maintenance dialysis were 11ml/min/1.73m2 in the CKD patients and 23 ml/min/1.73m2 (range 12-36ml/min/1.73m2) in the kidney transplant recipients.…”

“…Increased H-ficolin and decreased MBL and MASP-3 levels have been demonstrated in serial plasma samples from patients with sepsis ( 15 , 16 ). In contrast, no significant differences have been detected in lectin pathway protein levels between young and old healthy adults ( 17 ). The potential for lectin pathway PRMs to interact with coronavirus is demonstrated by in vitro binding of MBL to SARS-CoV proteins ( 18 ).…”

Complement Inhibition in Coronavirus Disease (COVID)-19: A Neglected Therapeutic Option

“…The complement lectin pathway is activated when a pattern recognition receptor, such as mannose binding lectin (MBL), binds to pathogen-associated molecular patterns expressed on the surface of invading microorganisms ( 29 ). The complement cascade is then initiated by MBL forming complexes with MBL-associated serine proteases 1 and 2 (MASP-1 and MASP-2, respectively) in a similar fashion that C1 is activated through the classical pathway, leading to C4 and C2 cleavage and assembly of the C3 convertase ( 30 ). A historic case-control study on 569 SARS patients demonstrated a role of MBL gene polymorphisms in contributing to the susceptibility of viral invasion, and implied that the complement lectin pathway represents the “first line of defense” against SARS-CoV infection ( 31 , 32 ).…”

Drug delivery systems as immunomodulators for therapy of infectious disease: Relevance to COVID-19

“…The classical pathway recognises immune complexes, comprising of either IgG or IgM coupled with a pathogen or non-self-antigen, triggering a conformational change in complement component (C)1q, which sequentially leads to activation of C1r along with C1s and cleaving of C2 and C4 [98] . The same outcome is shared by the lectin pathway, which relies upon a multi-protein complex containing mannan-binding lectin and two protease zymogens (MASP-1 and MASP-2) to be activated, and recognises carbohydrate ligands upon cell surfaces [99] , [100] . The third and final route of activation, known as the alternative pathway, does not lead to the creation of the C4bC2a configuration C3 convertase.…”