Abstract
Antibody effector functions, such as antibody-dependent cellular cytotoxicity, complement deposition, and antibody-dependent phagocytosis, play a critical role in immunity against multiple pathogens, particularly in the absence of neutralizing activity. Two modifications to the IgG constant domain (Fc domain) regulate antibody functionality: changes in antibody subclass and changes in a single N-linked glycan located in the CH2 domain of the IgG Fc. Together, these modifications provide a specific set of instructions to the innate immune system to direct the elimination of antibody-bound antigens. While it is clear that subclass selection is actively regulated during the course of natural infection, it is unclear whether antibody glycosylation can be tuned, in a signal-specific or pathogen-specific manner. Here, we show that antibody glycosylation is determined in an antigen- and pathogen-specific manner during HIV infection. Moreover, while dramatic differences exist in bulk IgG glycosylation among individuals in distinct geographical locations, immunization is able to overcome these differences and elicit antigen-specific antibodies with similar antibody glycosylation patterns. Additionally, distinct vaccine regimens induced different antigen-specific IgG glycosylation profiles, suggesting that antibody glycosylation is not only programmable but can be manipulated via the delivery of distinct inflammatory signals during B cell priming. These data strongly suggest that the immune system naturally drives antibody glycosylation in an antigen-specific manner and highlights a promising means by which next-generation therapeutics and vaccines can harness the antiviral activity of the innate immune system via directed alterations in antibody glycosylation in vivo.
Highlights
IntroductionMounting evidence points to a critical role for non-neutralizing antibody effector function, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC), in protection against [1], and control of HIV [2], influenza [3], Ebola virus [4], and bacterial infections [5]
Non-neutralizing antibody function is controlled by antibody constant domain interactions with Fc receptors, which itself is regulated via changes in antibody subclass/isotype selection or antibody glycosylation
Because different vaccines drive unique glycosylation profiles, future studies that define the specific signals that control antibody glycosylation may lead to the generation of next-generation therapeutic interventions that can leverage and direct the killing activity of the innate immune system, targeting HIV and beyond
Summary
Mounting evidence points to a critical role for non-neutralizing antibody effector function, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC), in protection against [1], and control of HIV [2], influenza [3], Ebola virus [4], and bacterial infections [5]. While emerging data suggest that the co-selection of additional antibody subclasses, such as the most functional subclass, IgG3, may collaborate to direct more effective immune complex–based activity [8], IgG3 is cleared rapidly from the systemic circulation [9], arguing that sustained levels of some, but not other IgG1 antibodies may represent the critical determinant of protective immunity against HIV. Every IgG antibody is glycosylated at a single asparagine residue within the CH2 domain of the constant region (in the crystallizable fragment, Fc), and data from the monoclonal therapeutic community suggest that these changes potently alter the inflammatory profile and effector functions of the antibody [10]. Changes in fucose and the b-GlcNAc play a critical role in modulating monoclonal therapeutic antibody effector function, where a lack of fucose [12], the addition of the b-GlcNAc [13], and elevated sialic acid [14] increases ADCC activity. The presence of higher levels of galactose provides the scaffold for the addition of terminal sialic acid groups, that are thought to drive antiinflammatory activity through binding to lectin-like receptors [19], though there is some controversy in the field as to whether IVIG’s anti-inflammatory effect is due to sialylation alone [20,21,22]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
