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 community-acquired 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.

Keywords: MASP-2; MBL; collectin; complement; ficolin-3; lectin pathway; primary immunodeficiency.

Fig. 1

The lectin pathway (LP) initiates after binding of pattern recognition molecules (PRMs) to surfaces displaying various arrays of carbohydrates or acetyl groups in PAMPs (pathogen-associated molecular patterns) or DAMPs (damage-associated molecular patterns). Several PRM of the LP have been identified so far: mannose-binding lectin; ficolin-1, ficolin-2, and ficolin-3; and collectin (CL)-10 and CL-11. CL-10 and CL-11 were found to circulate as heteromeric complexes (CL-LK) of one CL-L1 and two CL-K1 polypeptide chains, able to activate the LP. The serine proteases that initiate the proteolytic cascade of the LP are the MBL-associated serine proteases (MASPs), which circulate in complex with the PRM. When the PRMs of the LP bind to the target surface, zymogen MASP-1 autoactivates first and then activates zymogen MASP-2. Both activated MASP-1 and MASP-2 can cleave C2, but C4 is cleaved only by MASP-2. In the absence of MASP-1 or MASP-2, the classical C3 convertase C4bC2a cannot be generated through the LP, and no LP activation is observed. MASP-3 is the primary physiological activator of pro-factor D under resting conditions in human blood, inducing the activation of the alternative pathway, which serves as an amplification loop for the classical and the lectin pathways. Activation of MASP-3 by MASP-1 and MASP-2 has been also proposed. In addition, it was recently shown that MASP-2 can directly cleave C3 in the absence of C4 and/or C2 on LP-activating surfaces [–5]. PAMPs pathogen-associated molecular patterns, DAMPs damage-associated molecular patterns, PRM pattern recognition molecules, MASP MBL-associated serine proteases, MBL mannose-binding lectin, FCN-1 ficolin-1 (also commonly termed M-ficolin), FCN-2 ficolin-2 (initially identified as L-ficolin), FCN-3 ficolin-3 (initially identified as H-ficolin), CL-10 collectin-10 (also known as collectin liver 1, CL-L1), CL-11 collectin-11 (also known as collectin kidney 1, CL-K1), FD factor D, MAC membrane attack complex