Linnea Lindelöf: Functional and clinical studies of the lectin pathway of complement in humans

Abstract

The complement system plays a vital role in protecting against and removing pathogens and damaged cells in humans. It is initiated by three pathways, of which the lectin pathway is the least studied. This thesis aimed to further characterize the roles and functions of lectin pathway components in humans.

In Paper I, we analyzed the pattern-recognition molecule (PRM) ficolin-3's ability to bind proteins with different post-translational modifications. We showed that, at physiological pH, ficolin-3 binds acetylated proteins with high specificity. However, at pH 6.0, the ficolin-3 binding is enhanced and broadened to include carbamylated proteins.

In Paper II, we analyzed ficolin-3 activity in sera/plasma from two Swedish cohorts comprising 786 Systemic Lupus Erythematosus (SLE) patients and 566 controls, as well as genetic data from 985 SLE patients and 1026 controls. Ficolin-3 activity was significantly elevated in SLE patients, and an acquired ficolin-3 deficiency was observed in a subset of patients. Ficolin-3 was also found to associate with the autoantibody profile and hematological disease manifestations in SLE patients.

In Paper III, we studied MASP-2 and MASP-3, two of the lectin pathway serine proteases, and MAP-1, a non-enzymatic splice variant, in 519 Swedish SLE patients and 322 controls to evaluate their role in SLE pathogenesis. This study provided further evidence of associations between lectin pathway components, hematological disease manifestations, and the autoantibody profile. MAP-1 was also found to be type I interferon-regulated.

In Paper IV, we measured ficolin-3 activity in a Sudanese cohort of 92 SLE patients and 100 controls to determine whether there are geographical differences in ficolin-3's role in SLE pathogenesis. Here, ficolin-3 was found to associate with anti-Sm and antiphospholipid antibodies.

In Paper V, we investigated the role of the PRM MBL in critically ill COVID-19 patients by analyzing MBL activity in plasma and genetic data from 426 COVID-19 patients admitted to the intensive care unit in Sweden. We found that genetic variants that determine plasma MBL activity are not risk factors for hospitalization or organ failure in patients with critical COVID-19. Patients with MBL2 haplotypes associated with intermediate MBL activity were protected against thrombotic complications. 

Taken together, these studies emphasize the role of the lectin pathway in systemic inflammatory diseases and underscore the need not to overlook its components when evaluating the complement system in human diseases.