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Cell-targeting antibodies in immunity to Ebola.

Schmaljohn A, Lewis GK - Pathog Dis (2016)

Bottom Line: To be clear, many NAbs are also CTAbs, and in the case of Ebola the great majority of NAbs are likely CTAbs.Isotype, glycosylation, and other features of CTAbs are likely crucial in their capacity to mediate protection.Overall, results and analysis invite an increasingly complex view of antibody-mediated immunity to enveloped viruses.

View Article: PubMed Central - PubMed

Affiliation: Microbiology & Immunology, University of Maryland School of Medicine, USA aschmaljohn@som.umaryland.edu.

No MeSH data available.


Related in: MedlinePlus

Euler diagram of CTAb in the context of functional antibodies to an enveloped virus. (a) Within the total population virus-reactive antibodies that arise in an individual host, some can be demonstrated to protect against disease caused by the homologous virus, and a subset of these are broadly protective against related viruses. (b) Among the antibodies that can be defined as virus-neutralizing in vitro through any of several mechanisms and assays (see text), some are broadly neutralizing (BN), many but not all are protective in vivo, and neutralizing antibodies do not account for all protective antibodies. (c) Antibodies responsible for ADCC and complement-mediated cytolysis (CMC) form distinct but highly overlapping sets, and depending upon the antigen (as well as Ig isotype and other factors) may include a high proportion of neutralizing antibodies. ‘Other’ protective antibodies are described elsewhere (Schmaljohn 2013) (d) Antibodies of all types may occasionally be harmful to the host through mechanisms that include autoimmunity, antibody-dependent enhancement of viral infection, increased virus-specific immunopathology, displacing or functionally blocking otherwise-protective antibodies or creating immunosuppressive immune complexes. Some antibodies may be categorized as both protective and harmful, with outcome depending on such things as antibody concentration, timing of antibody arrival relative to viral load and host variations in inflammatory response. It can further be inferred that single antibody specificity (as defined by clonal lineage and paratope) may be protective, harmful or impotent depending upon Ig isotype and its consequences. (e) CTAb, often polyfunctional, are those that bind viral antigen on virus-infected (and sometimes uninfected but virus-sensitized) cells, potentially marking cells for damage or destruction by FcR-bearing cells before peak viral production by the antigen-bearing cells. Antibody-mediated protection in vivo is very often dependent upon Fc–FcR interactions regardless of whether antibodies are also categorized as neutralizing. Opsonization facilitated by antibodies against virion surfaces may play a role in vivo, but the larger body of virological evidence points toward CTAb mediating protection in concert with FcR-bearing cells of various types.
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fig1: Euler diagram of CTAb in the context of functional antibodies to an enveloped virus. (a) Within the total population virus-reactive antibodies that arise in an individual host, some can be demonstrated to protect against disease caused by the homologous virus, and a subset of these are broadly protective against related viruses. (b) Among the antibodies that can be defined as virus-neutralizing in vitro through any of several mechanisms and assays (see text), some are broadly neutralizing (BN), many but not all are protective in vivo, and neutralizing antibodies do not account for all protective antibodies. (c) Antibodies responsible for ADCC and complement-mediated cytolysis (CMC) form distinct but highly overlapping sets, and depending upon the antigen (as well as Ig isotype and other factors) may include a high proportion of neutralizing antibodies. ‘Other’ protective antibodies are described elsewhere (Schmaljohn 2013) (d) Antibodies of all types may occasionally be harmful to the host through mechanisms that include autoimmunity, antibody-dependent enhancement of viral infection, increased virus-specific immunopathology, displacing or functionally blocking otherwise-protective antibodies or creating immunosuppressive immune complexes. Some antibodies may be categorized as both protective and harmful, with outcome depending on such things as antibody concentration, timing of antibody arrival relative to viral load and host variations in inflammatory response. It can further be inferred that single antibody specificity (as defined by clonal lineage and paratope) may be protective, harmful or impotent depending upon Ig isotype and its consequences. (e) CTAb, often polyfunctional, are those that bind viral antigen on virus-infected (and sometimes uninfected but virus-sensitized) cells, potentially marking cells for damage or destruction by FcR-bearing cells before peak viral production by the antigen-bearing cells. Antibody-mediated protection in vivo is very often dependent upon Fc–FcR interactions regardless of whether antibodies are also categorized as neutralizing. Opsonization facilitated by antibodies against virion surfaces may play a role in vivo, but the larger body of virological evidence points toward CTAb mediating protection in concert with FcR-bearing cells of various types.

Mentions: In reporting findings with monoclonal antibodies (MAbs) some 34 years ago (Schmaljohn et al.1982), the term ‘non-neutralizing’ seemed helpful to emphasize that NAbs are not solely responsible for antibody-mediated protection against viruses, and that other Abs (lacking in demonstrable neutralizing activity) are also important for many viruses. Today, the distinction between neutralizing and non-neutralizing Abs serves mostly to create a false dichotomy in which devout adherents of a notional in vitro phenomenon called ‘neutralization’ endeavor to dismiss CTAbs. The time has surely arrived to retire the term ‘non-neutralizing antibodies’ as a negative descriptor, which for the sake of precise language must be regularly distinguished as either protective or non-protective. There is common ground in the data. NAbs are important, and so are CTAbs, and foremost in this regard, many NAbs are CTAbs (Schmaljohn 2013). If the term CTAb describes an expansive set of antibodies that generally includes NAbs (Fig 1), does it matter if research efforts (and funding) revolve almost exclusively around NAbs? Yes, insofar as NAbs are potentially polyfunctional in vivo, either preventing viral entry into cells or alternatively acting at a later step in viral replication, perhaps in concert with Fc receptor-bearing cells or complement. For the latter mechanisms, the Fc portion of the Ab molecule may be decisive in the quality of antiviral effect observed in vivo, partially or wholly independent of the neutralization activity observed in vitro (Hessell et al.2007; Boesch, Brown and Ackerman 2015; Chung et al.2015). Even more obviously—and where unhelpful battle lines are sometimes drawn—there exist antibodies that protect wholly as CTAbs despite lacking neutralization activity and sometimes lacking even the capacity to bind virion surfaces (Schmaljohn 2013).


Cell-targeting antibodies in immunity to Ebola.

Schmaljohn A, Lewis GK - Pathog Dis (2016)

Euler diagram of CTAb in the context of functional antibodies to an enveloped virus. (a) Within the total population virus-reactive antibodies that arise in an individual host, some can be demonstrated to protect against disease caused by the homologous virus, and a subset of these are broadly protective against related viruses. (b) Among the antibodies that can be defined as virus-neutralizing in vitro through any of several mechanisms and assays (see text), some are broadly neutralizing (BN), many but not all are protective in vivo, and neutralizing antibodies do not account for all protective antibodies. (c) Antibodies responsible for ADCC and complement-mediated cytolysis (CMC) form distinct but highly overlapping sets, and depending upon the antigen (as well as Ig isotype and other factors) may include a high proportion of neutralizing antibodies. ‘Other’ protective antibodies are described elsewhere (Schmaljohn 2013) (d) Antibodies of all types may occasionally be harmful to the host through mechanisms that include autoimmunity, antibody-dependent enhancement of viral infection, increased virus-specific immunopathology, displacing or functionally blocking otherwise-protective antibodies or creating immunosuppressive immune complexes. Some antibodies may be categorized as both protective and harmful, with outcome depending on such things as antibody concentration, timing of antibody arrival relative to viral load and host variations in inflammatory response. It can further be inferred that single antibody specificity (as defined by clonal lineage and paratope) may be protective, harmful or impotent depending upon Ig isotype and its consequences. (e) CTAb, often polyfunctional, are those that bind viral antigen on virus-infected (and sometimes uninfected but virus-sensitized) cells, potentially marking cells for damage or destruction by FcR-bearing cells before peak viral production by the antigen-bearing cells. Antibody-mediated protection in vivo is very often dependent upon Fc–FcR interactions regardless of whether antibodies are also categorized as neutralizing. Opsonization facilitated by antibodies against virion surfaces may play a role in vivo, but the larger body of virological evidence points toward CTAb mediating protection in concert with FcR-bearing cells of various types.
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fig1: Euler diagram of CTAb in the context of functional antibodies to an enveloped virus. (a) Within the total population virus-reactive antibodies that arise in an individual host, some can be demonstrated to protect against disease caused by the homologous virus, and a subset of these are broadly protective against related viruses. (b) Among the antibodies that can be defined as virus-neutralizing in vitro through any of several mechanisms and assays (see text), some are broadly neutralizing (BN), many but not all are protective in vivo, and neutralizing antibodies do not account for all protective antibodies. (c) Antibodies responsible for ADCC and complement-mediated cytolysis (CMC) form distinct but highly overlapping sets, and depending upon the antigen (as well as Ig isotype and other factors) may include a high proportion of neutralizing antibodies. ‘Other’ protective antibodies are described elsewhere (Schmaljohn 2013) (d) Antibodies of all types may occasionally be harmful to the host through mechanisms that include autoimmunity, antibody-dependent enhancement of viral infection, increased virus-specific immunopathology, displacing or functionally blocking otherwise-protective antibodies or creating immunosuppressive immune complexes. Some antibodies may be categorized as both protective and harmful, with outcome depending on such things as antibody concentration, timing of antibody arrival relative to viral load and host variations in inflammatory response. It can further be inferred that single antibody specificity (as defined by clonal lineage and paratope) may be protective, harmful or impotent depending upon Ig isotype and its consequences. (e) CTAb, often polyfunctional, are those that bind viral antigen on virus-infected (and sometimes uninfected but virus-sensitized) cells, potentially marking cells for damage or destruction by FcR-bearing cells before peak viral production by the antigen-bearing cells. Antibody-mediated protection in vivo is very often dependent upon Fc–FcR interactions regardless of whether antibodies are also categorized as neutralizing. Opsonization facilitated by antibodies against virion surfaces may play a role in vivo, but the larger body of virological evidence points toward CTAb mediating protection in concert with FcR-bearing cells of various types.
Mentions: In reporting findings with monoclonal antibodies (MAbs) some 34 years ago (Schmaljohn et al.1982), the term ‘non-neutralizing’ seemed helpful to emphasize that NAbs are not solely responsible for antibody-mediated protection against viruses, and that other Abs (lacking in demonstrable neutralizing activity) are also important for many viruses. Today, the distinction between neutralizing and non-neutralizing Abs serves mostly to create a false dichotomy in which devout adherents of a notional in vitro phenomenon called ‘neutralization’ endeavor to dismiss CTAbs. The time has surely arrived to retire the term ‘non-neutralizing antibodies’ as a negative descriptor, which for the sake of precise language must be regularly distinguished as either protective or non-protective. There is common ground in the data. NAbs are important, and so are CTAbs, and foremost in this regard, many NAbs are CTAbs (Schmaljohn 2013). If the term CTAb describes an expansive set of antibodies that generally includes NAbs (Fig 1), does it matter if research efforts (and funding) revolve almost exclusively around NAbs? Yes, insofar as NAbs are potentially polyfunctional in vivo, either preventing viral entry into cells or alternatively acting at a later step in viral replication, perhaps in concert with Fc receptor-bearing cells or complement. For the latter mechanisms, the Fc portion of the Ab molecule may be decisive in the quality of antiviral effect observed in vivo, partially or wholly independent of the neutralization activity observed in vitro (Hessell et al.2007; Boesch, Brown and Ackerman 2015; Chung et al.2015). Even more obviously—and where unhelpful battle lines are sometimes drawn—there exist antibodies that protect wholly as CTAbs despite lacking neutralization activity and sometimes lacking even the capacity to bind virion surfaces (Schmaljohn 2013).

Bottom Line: To be clear, many NAbs are also CTAbs, and in the case of Ebola the great majority of NAbs are likely CTAbs.Isotype, glycosylation, and other features of CTAbs are likely crucial in their capacity to mediate protection.Overall, results and analysis invite an increasingly complex view of antibody-mediated immunity to enveloped viruses.

View Article: PubMed Central - PubMed

Affiliation: Microbiology & Immunology, University of Maryland School of Medicine, USA aschmaljohn@som.umaryland.edu.

No MeSH data available.


Related in: MedlinePlus