Dissection of C1q Capability of Interacting with IgG

Kaul, Marcus; Loos, Michael

doi:10.1074/jbc.272.52.33234

Cited by 38 publications

(6 citation statements)

References 37 publications

(34 reference statements)

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“…The classical complement pathway is typically activated when hexameric C1q proteins bind to the fragment crystallisable (FC) CH2-domains of antigen-bound IgM and/or IgG immune complexes ( 10 – 12 ). The binding affinity of C1q to IgG is dependent on the IgG isotype with the greatest affinity for IgG-3, then IgG-1, a weak association with IgG-2, and no interaction with IgG-4 ( 13 ). However, for downstream activation and complement lysis activity, the response is more efficient following IgG1-C1q interactions rather than IgG3-C1q interactions ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

et al. 2020

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The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.

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Section: Introductionmentioning

confidence: 99%

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

et al. 2020

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“…Because of this structural organization, C1q is often pictured as a bunch of six flowers. The interaction of C1q with immune complexes takes place at the globular region [17,18], but C1q is known to also bind through its collagen‐like region (CLR) several nonimmune molecules [19], with consequences which remain unclear. Actually the binding of the C‐reactive protein [20], of the serum amyloid protein [21] and of DNA [22] to C1q leads to an activation of Complement.…”

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confidence: 99%

Interaction of the C1 complex of Complement with sulfated polysaccharide and DNA probed by single molecule fluorescence microscopy

Tissot¹,

Daniel²,

Place

2003

European Journal of Biochemistry

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The complex C1 triggers the activation of the Complement classical pathway through the recognition and binding of antigen-antibody complex by its subunit C1q. The globular region of C1q is responsible for C1 binding to the immune complex. C1q can also bind nonimmune molecules such as DNA and sulfated polysaccharides, leading either to the activation or inhibition of Complement. The binding site of these nonimmune ligands is debated in the literature, and it has been proposed to be located either in the globular region or in the collagen-like region of C1q, or in both. Using single molecule fluorescence microscopy and DNA molecular combing as reporters of interactions, we have probed the C1q binding properties of T4 DNA and of fucoidan, an algal sulfated fucose-based polysaccharide endowed with potent anticomplementary activity. We have been able to visualize the binding of C1q as well as of C1 and of the isolated collagen-like region to individual DNA strands, indicating that the collagen-like region is the main binding site of DNA. From binding assays with C1r, one of the protease components of C1, we concluded that the DNA binding site on the collagen-like region is located within the stalk part. Competition experiments between fucoidan and DNA for the binding of C1q showed that fucoidan binds also to the collagen-like region part of C1q. Unlike DNA, the binding of fucoidan to collagen-like region involves interactions with the hinge region that accommodate the catalytic tetramer C1r 2 -C1s 2 of C1. This binding property of fucoidan to C1q provides a mechanistic basis for the anticomplementary activity of the sulfated polysaccharide.

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“…Utilizing an established tosyl-activated magnetic bead-based purification method, we isolated MUC16-eluted IgG from each animal. This high-affinity Fc-mediated interaction is reminiscent of C1q binding to IgG, where there is a small subset of antibodies that bind very tightly and are not dissociated under standard dissociation conditions, such as 3 M NaCl, 5 M urea, or betamercaptoethanol (36). Under the conditions of this experiment, the bound IgG could be eluted only by denaturation with 6 M guanidine hydrochloride (GuHCl) followed by a refolding step where GuHCl is removed by buffer exchange into phosphate-buffered saline (PBS).…”

Section: Resultsmentioning

confidence: 99%

A MUC16 IgG Binding Activity Selects for a Restricted Subset of IgG Enriched for Certain Simian Immunodeficiency Virus Epitope Specificities

Schneider

Shen

Orlandi

et al. 2020

J Virol

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We have recently shown that MUC16, a component of the glycocalyx of some mucosal barriers, has elevated binding to the G0 glycoform of the Fc portion of IgG. Therefore, IgG from patients chronically infected with human immunodeficiency virus (HIV), who typically exhibit increased amounts of G0 glycoforms, showed increased MUC16 binding compared to uninfected controls. Using the rhesus macaque simian immunodeficiency virus SIVmac251 model, we can compare plasma antibodies before and after chronic infection. We find increased binding of IgG to MUC16 after chronic SIV infection. Antibodies isolated for tight association with MUC16 (MUC16-eluted antibodies) show reduced FcγR engagement and antibody-dependent cellular cytotoxicity (ADCC) activity. The glycosylation profile of these IgGs was consistent with a decrease in FcγR engagement and subsequent ADCC effector function, as they contain a decrease in afucosylated bisecting glycoforms that preferentially bind FcγRs. Testing of the SIV antigen specificity of IgG from SIV-infected macaques revealed that the MUC16-eluted antibodies were enriched for certain specific epitopes, including regions of gp41 and gp120. This enrichment of specific antigen responses for fucosylated bisecting glycoforms and the subsequent association with MUC16 suggests that the immune response has the potential to direct specific epitope responses to localize to the glycocalyx through interaction with this specific mucin. IMPORTANCE Understanding how antibodies are distributed in the mucosal environment is valuable for developing a vaccine to block HIV infection. Here, we study an IgG binding activity in MUC16, potentially representing a new IgG effector function that would concentrate certain antibodies within the glycocalyx to trap pathogens before they can reach the underlying columnar epithelial barriers. These studies reveal that rhesus macaque IgG responses during chronic SIV infection generate increased antibodies that bind MUC16, and interestingly, these MUC16-tethered antibodies are enriched for binding to certain antigens. Therefore, it may be possible to direct HIV vaccine-generated responses to associate with MUC16 and enhance the antibody’s ability to mediate immune exclusion by trapping virions within the glycocalyx and preventing the virus from reaching immune target cells within the mucosa. This concept will ultimately have to be tested in the rhesus macaque model, which is shown here to have MUC16-targeted antigen responses.

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Dissection of C1q Capability of Interacting with IgG

Cited by 38 publications

References 37 publications

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

Interaction of the C1 complex of Complement with sulfated polysaccharide and DNA probed by single molecule fluorescence microscopy

A MUC16 IgG Binding Activity Selects for a Restricted Subset of IgG Enriched for Certain Simian Immunodeficiency Virus Epitope Specificities

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