The Lectin Pathway of Complement as a Sentinel for Nutritional and Metabolic Status: From Molecular Immunomodulation...

The lectin pathway (LP) of complement activation functions as a crucial effector of innate immunity and a homeostatic sensor operating at the intersection of systemic metabolism, nutritional status, and endothelial integrity. This review provides a comprehensive synthesis of current molecular, clinical, and epidemiological literature regarding the environmental and metabolic regulation of this pathway. First, we summarize the biophysical, structural, and stoichiometric requirements for divalent cations in fluid-phase activation and macromolecular assembly, integrating the contrasting roles of calcium (Ca²⁺) and zinc (Zn²⁺) into an explanatory Dual-Cation Dichotomy Framework. Second, we evaluate the transcriptomic mechanisms of nutrigenetic licensing, reviewing how fat-soluble vitamins sustain endoplasmic reticulum chaperone networks and mucosal barrier competence. We discuss how these micronutrient-driven axes interact with host genetic diversity, presenting a Nutrigenetic Rescue Framework to contextualize the environmental modulation of low-expressing MBL2 alleles. Third, the LP responds to metabolic and endocrine shifts, focusing on its biomarker value in gestational diabetes and its clinical patterns in type 1 diabetes. These connections to metabolic disease and related microvascular complications are further integrated into a broader Somatotropic-Gestational Sentinel Hypothesis. Fourth, we connect these metabolic profiles with public health challenges, reviewing LP hyperactivation in viral infections and discussing localized surface plasmon resonance (LSPR) biosensors, at present a conceptual, preclinical technology, as a candidate approach for future point-of-care population screening. In conclusion, bridging nutritional biochemistry with metabolic endocrinology and diagnostic technologies that remain largely preclinical outlines a potential shift from empiric management toward biomarker-driven, point-of-care stratification, which could help mitigate both infectious thromboinflammation and chronic microvascular failure once these technologies undergo further mechanistic and clinical validation.