Mechanisms of mannose-binding lectin-associated serine proteases-1/3 activation of the alternative pathway of complement

Banda, Nirmal K.; Takahashi, Minoru; Takahashi, Kazue; Stahl, Gregory L.; Hyatt, Stephanie; Glogowska, Magdalena J.; Wiles, Timothy A.; Endo, Yuichi; Fujita, Teizo; Holers, V. Michael; Arend, William P.

doi:10.1016/j.molimm.2011.08.021

Cited by 21 publications

(21 citation statements)

References 47 publications

(79 reference statements)

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“…Instead, the results herein are consistent with our previous findings that properdin of the AP does not initiate C3 convertase assembly but serves mainly as a convertase stabilizer (11). It is now becoming apparent from this and other recent studies (44)(45)(46)(47) that the LP triggers the initial complement activation and the AP serves to amplify the LP activity in many disease models. These results also suggest a more careful reexamination of the role of properdin and the AP in the pathogenesis of many disease processes (48) and the evaluation of properdin and other AP proteins as therapeutic targets.…”

Section: Discussionsupporting

confidence: 92%

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Zhou

Yan

Bertram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression. Using an elastase-induced AAA mouse model that recapitulates key features of human AAA, we previously reported that a natural IgG antibody directs alternative pathway complement activation and initiates the inflammatory process that culminates in aneurysmal development. The target of this natural antibody, however, was unknown. Herein we identify a natural IgG that binds to fibrinogen deposited in elastaseperfused aortic tissues, activates the complement lectin pathway (LP), and induces AAA. Moreover, we establish that alterations in the glycosylation patterns of this antibody critically affect its ability to activate the LP in vivo. We find that LP activation precedes the alternative pathway and absence of the LP complement protein mannan-binding lectin abrogates elastase-induced AAA. In human AAA tissues the mouse anti-fibrinogen antibody recognizes epitopes that localize to the same areas that stain positively for mannan-binding lectin, which suggests that the complement LP is engaged in humans as well. Lastly, we demonstrate that circulating antibodies in a subset of AAA patients react against fibrinogen or fibrinogen-associated epitopes in human aneurysmal tissues. Our findings support the concept that an autoimmune process directed at aortic wall self-antigens may play a central role in the immunopathogenesis of AAA.A bdominal aortic aneurysm (AAA) is a common vascular disorder that affects ∼5% of men and ∼1.5% of women ages 65 and older (1, 2). Rupture of AAA presents a medical emergency that accounts for 15,000 deaths annually in the United States (3). Currently, surgical repair represents the only treatment option for large AAAs, whereas surgery in small AAAs offers no clear overall long-term survival advantage (4, 5). Thus, medical management, to inhibit or reverse the progression of small AAAs, has received increasing attention. Major challenges remain in the development of therapeutic agents that impede aneurysm expansion, as our understanding of the pathophysiology underlying this disease is incomplete.One of the defining characteristics of AAA is inflammation accompanied by a cellular infiltrate that is predominantly lymphocytic (6-8). The elastase-induced AAA mouse model recapitulates many key features of human AAA, including the inflammatory response (9). We previously established with this model that aneurysm development requires factor B and properdin of the complement alternative pathway (AP) (10, 11). We showed that mice deficient in B cells (and hence antibodies), called μMT mice, are protected against aneurysm formation. Reconstitution with natural IgG, but not IgM, from wild-type mice res...

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Section: Discussionsupporting

confidence: 92%

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Zhou

Yan

Bertram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast, mice having only the AP plus FCNs and CLs ( C1q −/− /MBL A/C −/ ) are highly susceptible to CAIA (6, 35, 54). Furthermore, mice in which the LP is only able to be activated through FCN-B and CLs but with a functional CP and AP ( MBL A/C −/− /FCN A −/− or MBL A/C −/− ) are fully susceptible to CAIA (35). Thus, in these previous studies, the key role of the AP was clear; however, additional roles for the LP acting through FCN-A, FCN-B and/or CLs were not able to be assessed.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse FCN B was originally found in the lysosomes of macrophages, similar to human FCN-M, which is also found in the secretary granules of monocytes and neutrophils (33, 34). We have reported that FCN-B is also present in the circulation of mice, suggesting that it is secreted from macrophages (35). …”

Section: Introductionmentioning

confidence: 99%

Deconstructing the Lectin Pathway in the Pathogenesis of Experimental Inflammatory Arthritis: Essential Role of the Lectin Ficolin B and Mannose-Binding Protein–Associated Serine Protease 2

Banda

Acharya

Scheinman

et al. 2017

The Journal of Immunology

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Complement plays an important role in the pathogenesis of rheumatoid arthritis (RA). While the alternative pathway (AP) is known to play a key pathogenic role in models of RA, the importance of the lectin pathway (LP) pattern recognition molecules such as ficolin A (FCN A), ficolin B (FCN B) and collectin-11 (CL-11) as well as the activating enzyme MBL (mannose binding lectin)-associated serine protease-2 (MASP-2) are less well understood. We show here that FCN A−/− and CL-11−/− mice are fully susceptible to collagen antibody-induced arthritis (CAIA). In contrast, FCN B−/− and MASP-2−/−/sMAp−/− mice are substantially protected, with clinical disease activity decreased significantly (p < 0.05) by 47% and 70%, respectively. Histopathology scores, C3, fD, FCN B deposition and infiltration of synovial macrophages and neutrophils were similarly decreased in FCN B−/− and MASP-2−/−/sMAp−/− mice. Our data support that FCN B plays an important role in the development of CAIA, likely through ligand recognition in the joint and MASP activation, and that MASP-2 also contributes to the development of CAIA, likely in a C4-independent manner. Decreased AP activity in the sera from FCN B−/− and MASP-2−/−/sMAp−/− mice with arthritis on adherent anti-collagen antibodies also support the hypothesis that pathogenic antibodies as well as additional inflammation-related ligands are recognized by the LP and operate in vivo to activate complement. Finally, we also speculate that the residual disease seen in our studies is driven by the AP and/or the C2/C4 bypass pathway via the direct cleavage of C3 through a LP-dependent mechanism.

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“…However, improved understanding of the mechanisms of complement activation and the recognition of complement functions beyond host defence has led to a move away from this strict separation of initiation routes. For example, antibodies can also initiate the lectin pathway via their carbohydrate portions, and proteases of the MASP family that are typically attributed to lectin pathway activation might well have a role in the alternative pathway 175–177 . Of note, however, some of the activities of MASP-1/3, such as the cleavage of pro-factor D (FD) to mature FD, might not depend on lectin pathway activation but rather be mediated in a ‘homeostatic’ manner independent of prior pattern recognition 175,176 .…”

Section: Complement In Immune Surveillancementioning

confidence: 99%

Complement in disease: a defence system turning offensive

2016

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Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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Mechanisms of mannose-binding lectin-associated serine proteases-1/3 activation of the alternative pathway of complement

Cited by 21 publications

References 47 publications

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Deconstructing the Lectin Pathway in the Pathogenesis of Experimental Inflammatory Arthritis: Essential Role of the Lectin Ficolin B and Mannose-Binding Protein–Associated Serine Protease 2

Complement in disease: a defence system turning offensive

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