Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway

Abstract

Mannose-binding lectin (MBL)-associated serine protease-2 (MASP-2) is an indispensable enzyme for the activation of the lectin pathway of complement. Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity. In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G (p.D120G), occurs in 7 to 14/10,000 individuals. We analyzed the presence of the p.D120G mutation in adults (increasing the sample size of our previous studies) and children. Different groups of patients (1495 adults hospitalized with communityacquired pneumonia, 186 adults with systemic lupus erythematosus, 103 pediatric patients with invasive pneumococcal disease) and control individuals (1119 healthy adult volunteers, 520 adult patients without history of relevant infectious diseases, and a pediatric control group of 311 individuals) were studied. Besides our previously reported MASP-2-deficient healthy adults, we found a new p.D120G homozygous individual from the pediatric control group. We also reviewed p.D120G homozygous individuals reported so far: a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls (including our four MASP-2-deficient individuals) have been identified by chance in association studies. Individuals with complete deficiencies of several pattern recognition molecules of the lectin pathway (MBL, collectin-10 and collectin-11, and ficolin-3) as well as of MASP-1 and MASP-3 have also been reviewed. Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

“…Ficolin-3 was furthermore identified to be deiminated in whole alligator plasma only and is a sugar pattern recognition molecule, which forms part of mammalian immune systems (132). Ficolin-3 can activate the complement system via the lectin pathway (133), plays roles in bacterial defenses (134,135) and autoimmunity (136,137) and is modulated in viral infections including HIV (138). Ficolin-3 has been associated with metabolic diseases including gestational, prediabetes, and type 2 diabetes (139,140), and identified as biomarkers in axial spondyloarthritis (141) and as a prognostic biomarker for esophageal cancer (142).…”

The Clinical Value of Ficolin-3 Gene Polymorphism in Rheumatic Heart Disease. An Egyptian Adolescents Study

“…Concerning colin oligomers, they are bounded to MBL associated serine proteases (MASP-1 and MASP-2). Moreover, colin binds certain patterns of acetylated residues on the surface of pathogens or altered cells [7,14,15]. MASP-1, at this point auto-activates and trans-activates MASP-2 leading to cleavage of downstream complement constituents [15,16].…”

MASP2 levels are elevated in thrombotic microangiopathies: association with microvascular endothelial cell injury and suppression by anti-MASP2 antibody narsoplimab

“…Blockade of MASP2 should not be accompanied by a high risk of infectious or autoimmune disorders, as it appears redundant in human defenses. Even very low levels do not appear to predispose to infectious or autoimmune diseases [31]. In terms of the broad benefits of this research, it was recently shown that lung injury related to infection with SARS‐CoV‐2, the etiological agent of the novel coronavirus‐2019 (COVID‐19) pandemic, is a systemic microvascular thrombopathy, characterized by deposition of MASP2 and C5b‐9 in pulmonary as well as cutaneous microvasculature [32].…”

“…However, involvement of the LP has not been assessed in the TMAs. Cumulative evidence suggests that MASP2 is redundant in human defense, as individuals with primary MASP2 deficiency are not prone to infectious or autoimmune diseases [15]. In contrast, we hypothesized that over‐activity of MASP2 in the LP is important in three major TMAs, TTP, aHUS and ‘secondary’ aHUS‐type TMAs, occurring in the setting of infections, autoimmune disease or allogeneic hematopoietic stem cell transplantation [alloHSCT, also known as transplant‐associated TMA (TA‐TMA)].…”