High molecular weight Non-Immunoglobulin Salivary Agglutinins (NIA) bind C1q globular heads and have the potential to activate the first complement component

Boackle, Robert J.; Connor, Michael H.; Vesely, Jana

doi:10.1016/0161-5890(93)90059-k

Cited by 56 publications

(60 citation statements)

References 26 publications

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“…Enhanced clearance of pulmonary bacteria and viruses is also achieved by DMBT1/gp340/SAG in cooperation with surfactant proteins SP-A and SP-D, involved in the innate defense of lung mucosae (Ligtenberg et al, 2001;Hartshorn et al, 2003); in this case, although gp340 can bind to SP-D/A at a site distinct from the mannan-binding site, the cooperative effect was achieved not by binding of DMBT1 to the surfactant proteins but rather by the combined effects of each protein working independently (White et al, 2005). Binding of DMBT1/gp340/SAG to the complement protein C1q activates the classic complement pathway, inducing inflammatory response (Boackle et al, 1993); DMBT1/gp340/SAG also seems to activate the lectin pathway of complement through interaction with mannosebinding lectin (A. Ligtenberg, personal communication). DMBT1/gp340/SAG has further been reported to stimulate migration of alveolar macrophages (Tino and Wright, 1999), suggesting that its protective functions exceed those that involve direct binding of pathogens.…”

Section: A Role In Epithelial Cell Differentiation and Pathogen Recomentioning

confidence: 99%

The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis

Moestrup²,

et al. 2011

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Section: A Role In Epithelial Cell Differentiation and Pathogen Recomentioning

confidence: 99%

The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis

Moestrup²,

et al. 2011

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“…Venous blood from healthy donors served as a source of complement and was prepared as previously described (Boackle et al, 1993). Human subjects gave informed consent prior to giving blood.…”

Section: Complementmentioning

confidence: 99%

“…In addition to its role within the macromolecular C1qr 2 s 2 complex, the C1q subcomponent, especially in its isolated (free, fluid phase) form, interacts with an array of non-immunoglobulin substances such as DNA (Uwatoko and Mannik, 1990), serum amyloid P (Bristow and Boackle, 1986;Ying et al, 1993), cardiolipin (Kovacsovics et al, 1985;Boackle et al, 1993), betaamyloid fibrils (Bradt et al, 1998), decorin (Krumdieck et al, 1992), membrane type-1 matrix metalloproteinases (Rozanov et al, 2004) and alpha 2 beta 1 integrins (Edelson et al, 2006). Furthermore, several C1q-receptors have been identified that upon binding to isolated C1q result in responses, such as reactive oxygen species production by neutrophils (Guan et al, 1994;Goodman et al, 1995;Ruiz et al, 1999), enhancement of phagocytosis by monocytes, macrophages (Bobak et al, 1987) and microglial cells (Webster et al, 2000), and improvement of immunoglobulin production by B-lymphocytes Young et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

Duvall

Tomlinson

Boackle

2008

Molecular Immunology

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We sought to specifically regulate the binding of human C1q, and thus the activation of the first complement component, via the construction of a single chain antibody variable binding region fragment (scFv) targeting the C1q globular heads. Here we describe details of the construction, expression and evaluation of this scFv, which was derived from a high affinity hybridoma (Qu) specific for the C1q globular heads. The scFv was comprised of the Qu variable-heavy chain domain (VH) linked to the Qu variable-light chain domain (VL) and was termed scFv-QuVHVL. When mixed with either purified C1q or with human serum as a source of C1, scFv-QuVHVL bound to C1q and competitively restricted the interaction of C1q or C1 with immobilized IgG or with IgG1 antibody-coated cells, and prevented the activation of native C1 in human serum as determined by analyses of C1-mediated C4 deposition and fluid phase C4 conversion. However scFv-QuVHVL could be manipulated to become a C1 activator when it was irreversibly immobilized onto microtiter ELISA plates, prior to contact with human serum complement. This functional dichotomy can be a useful tool in selectively elucidating, differentiating, inducing or inhibiting specific roles of human C1q and the classical complement pathway in complement-mediated physiological processes. We project that once fully humanized, fluid phase scFv-QuVHVL could become a useful therapeutic in limiting inadvertent host tissue damage elicited by the classical complement pathway.

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“…Immobilization of immunoglobulins (most notably IgA1 myeloma preparations) directly to plastic may lead to atypical complement-activating conformations (Russell and Mansa, 1989), which can activate complement when incubated with diluted serum. Less than 10% serum reduces the critical rate-limiting level C1-inhibitor allowing exacerbated complement activation (Boackle et al, 1993;Dillman et al, 1995;. The purified human IgG1 was from Sigma and the myeloma IgA1 was a gift from Dr. A.C. Wang.…”

Section: Microtiter-kinetic-elisamentioning

confidence: 99%

“…Fresh normal human serum (NHS) served as a source of human complement and was prepared as previously described (Boackle et al, 1993). Human subjects donating blood provided signed a human consent form approved by the Institutional Review Board of the Medical University of South Carolina.…”

Section: Human Serum Complementmentioning

confidence: 99%

Complement-coated antibody-transfer (CCAT); serum IgA1 antibodies intercept and transport C4 and C3 fragments and preserve IgG1 deployment (PGD)

Boackle

Nguyen

Leite

et al. 2006

Molecular Immunology

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In periodontal disease, IgG1 and IgA1 antibodies produced in situ deposit on antigens in the affected tissues. Thus, there is an interest in the effect of co-deposited IgA1 antibodies on complement activation by IgG1-immune complexes. In the present study, we first analyzed the effect of IgA1-immune complexes on complement using human IgA1 antibodies to dansyl (with dansylated human serum albumin serving as the immobilized antigen). It was observed that these IgA1-immune complexes when incubated for prolonged times with 33% human serum as a source of complement received C4b and C3b deposition. As C4b and C3b deposited on the IgA1 antibodies and on the antigenic surface, the complement-coated IgA1 antibodies departed. These fluid-phase complementcoated IgA1 antibodies were transferred to antigen-coated microtiter-ELISA plates, where they became bound to the antigens. Thus, the complement-coated IgA1 antibodies retained their antigenbinding function, especially as a proportion of their covalently bound C3b progressively degraded to iC3b and C3d. Genetically engineered carbohydrate-deficient mutant human IgA1 antibodies were used to assess the role of carbohydrate in accepting the C4b and C3b depositions, and these studies indicated that the carbohydrate on the Fc-region of IgA1 played a positive role. Another interesting finding generated by this study was that when IgA1 was co-deposited with IgG1 antibodies, and serum complement was added, the IgG1 antibodies tended to remain on the antigenic surface. The co-deposited IgA1 antibodies not only controlled (reduced) the rate of the consumption of the first component of complement (C1) and of classical complement pathway activation by IgG1-immune complexes (and therein reduced the rate of complement-mediated dissolution of the IgG1-immune complexes), but also the co-deposited IgA1 antibodies simultaneously intercepted/accepted C4b and C3b, then departed, as complement began to cover the antigenic surfaces. The process in which complement-coated IgA1 antibodies transferred to non-complement-coated antigens is termed complement-coated antibody-transfer/transport (CCAT). In this way, IgA1 antibodies extended the efficiency of the complement system by insuring the specific IgA1 antibody-mediated transport of the captured biologically active complement fragments to those antigens stimulating the IgA1 antibody response but not yet neutralized (completely coated) with complement. Simultaneously by impeding the rate of C1 consumption and by intercepting C4b and C3b, IgA1 antibodies slowed C4b and C3b deposition on the antigenic surface and on the co-deposited IgG1 antibodies. Thus, in the presence of ongoing complement activation, the deposition of serum IgA1 antibodies enabled the † Portions of this work were presented in abstract form at

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High molecular weight Non-Immunoglobulin Salivary Agglutinins (NIA) bind C1q globular heads and have the potential to activate the first complement component

Cited by 56 publications

References 26 publications

The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis

The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

Complement-coated antibody-transfer (CCAT); serum IgA1 antibodies intercept and transport C4 and C3 fragments and preserve IgG1 deployment (PGD)

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