Before continuing with the discussion of the complement cascade at the point of C3 cleavage by convertase, we turn our attention to the other two complement-activating pathways: the lectin pathway (LP) and the alternative pathway (AP). What will become evident is that all of these pathways converge at C3.

The LP is a relatively recently described pathway for complement activation. MBL, similar to C1q, is a triple helical structure with collagen-like arms coupled to C-type lectin globular domains, which form carbohydrate recognition domains (CRDs) that bind repeating polysaccharides present on the surfaces of many microorganisms. Most commonly MBL circulates as an oligomer of three or four collagenous stem-associated subunits, where each subunit consists of a homotrimer of MBL chains. The MBL CRDs attach to the termini of polymeric carbohydrate chains in the following order: mannose > GlcNAc > fucose > glucose. The greatest avidity appears to be for repeating mannose-based structural patterns typical of microbial surfaces. On vertebrate cells, these sugars are not as dense as on microbial surfaces, thus decreasing the avidity of the MBL-binding interaction, and furthermore, they often are covered by sialic acid residues, thus limiting recognition by MBL. The MBL- associated serine proteases MASP-1 and MASP-2, whose domain architecture is simi lar to C1r and C1s, predominantly bind as homodimeric zymogens to separate MBL oligomers. Upon MBL binding to polysaccharides on a pathogen surface, MASP-1 and MASP-2 become activated. The mechanism of activation has recently been clarified and is distinctly different from the conformational distortion-based intracomplex mechanism described above for the C1 activation. Although it had originally been thought that MASP-2 was capable of autoactivating itself when MBL bound to its target, and that MASP-1 played a non-essential and ill-defined augmentary role, under physiological conditions autoactivated MASP-1 has now been firmly established to be the obligatory activator of MASP2.  Although the relationship between MASP-1 and MASP-2 parallels that of C1r to C1s in the C1 activation mechanism, what is decidedly different is that MASP-1 autoactivation is intercomplex, as is MASP-2 activation by autoacti vated MASP-1. Specifically, it is the juxtaposition through clustering of the MBL–MASP-1 and MBL–MASP-2 complexes brought about by MBL binding to the target surface that leads to the inter complex autoactivation of MASP-1, and the subsequent cleavage of MASP-2 by autoactivated MASP-1 that is on a neighboring com plex. Activated MASP-2 acts similar to C1s, cleaving C4 and C2 and thereby forming a C3 convertase, C4b2a, as found in the CP. Besides its role in cleaving zymogen MASP-2, activated MASP-1 also cleaves C2, but not C4. Nevertheless, given the approximately 24-fold higher serum concentration of MASP-1 relative to MASP-2, this would ensure the efficiency of C2 activation on C4b deposited near an MBL-MASP2 complex.

While MBL was the microbial pattern recognition molecule initially identified in the LP, collectin-10 (also known as collectin-liver 1, CL-L1), collectin-11 (also known as collectin-kidney 1, CL-K1), and the ficolins M, L, and H (also known as ficolins-1, -2, -3) are collagen triple helix-containing paralogues of MBL in serum, which also associate with MASP-1 and MASP-2  and which undergo activation in a similar manner to the MBL-MASP complexes.  CL-L1 and CL-K1, like its collectin family member MBL, have C-type lectin CRDs, and have a carbohydrate binding spectrum that largely overlaps that of MBL. However, unlike the homotrimeric subunit composition of MBL, CL-K1 and CL-L1 mostly circulate as heteromeric subunit complexes, referred to as CL-LK, with each arm consisting of CL-K1 and CL-L1 in a 2:1 ratio. In contrast to the collectins, the globular regions of the respective ficolin chains bear a fibrinogen-like domain fold and they recognize acetyl groups, be they on carbohydrate (e.g., N-acetylglucosamine) or non-carbohydrate entities (e.g., N-acetyl glycine or acetylcholine).

MBL serum concentration can differ by up to 1000-fold among individuals, with those having low circulating MBL apparently more vulnerable to infections. MBL insufficiency appears to be a particular risk factor for infections in infants and individuals undergoing chemotherapy or immunosuppression treatment.

Gene-targeted knock-out mouse models deficient in MBL com ponents have been described. In general, in pathogenic microbe infection models, such as Candida albicans or Staphylococcus aureus, MBL knock-out mice showed increased susceptibility to systemic infection and relatively much higher mortality compared to wild type.

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المزيد

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المزيد

مواضيع ذات صلة

B-Lymphocyte Coreceptors

The Complement System : Alternative Pathway

The Complement System: Classical Pathway

Secondary Lymphoid Tissue

The Hematopoietic Microenvironment

The Pro-B- and Pre-B-Cell Checkpoints

Immunoglobulin Gene Rearrangement : Heavy Chain Gene Rearrangement

Transcriptional Regulation of B-Cell Development

Stages of B-Cell development

Genetic Engineering of Natural Killer Cells

The role of Natural Killer Cells in Human Disease

Natural Killer Cells and Hematopoietic Cell Transplantation