tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2021 Feb 23;118(8):e2018102118.
doi: 10.1073/pnas.2018102118.
Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes
Alec W Freyn[SUP] 1 2 [/SUP], Julianna Han[SUP] 3 [/SUP], Jenna J Guthmiller[SUP] 4 [/SUP], Mark J Bailey[SUP] 1 2 [/SUP], Karlynn Neu[SUP] 4 [/SUP], Hannah L Turner[SUP] 3 [/SUP], Victoria C Rosado[SUP] 1 [/SUP], Veronika Chromikova[SUP] 1 [/SUP], Min Huang[SUP] 4 5 [/SUP], Shirin Strohmeier[SUP] 1 6 [/SUP], Sean T H Liu[SUP] 1 [/SUP], Viviana Simon[SUP] 1 [/SUP], Florian Krammer[SUP] 1 [/SUP], Andrew B Ward[SUP] 3 [/SUP], Peter Palese[SUP] 7 8 [/SUP], Patrick C Wilson[SUP] 4 5 [/SUP], Raffael Nachbagauer[SUP] 7 [/SUP]
Affiliations
Abstract
In this study, we utilized a panel of human immunoglobulin (Ig) IgA monoclonal antibodies isolated from the plasmablasts of eight donors after 2014/2015 influenza virus vaccination (Fluarix) to study the binding and functional specificities of this isotype. In this cohort, isolated IgA monoclonal antibodies were primarily elicited against the hemagglutinin protein of the H1N1 component of the vaccine. To compare effector functionalities, an H1-specific subset of antibodies targeting distinct epitopes were expressed as monomeric, dimeric, or secretory IgA, as well as in an IgG1 backbone. When expressed with an IgG Fc domain, all antibodies elicited Fc-effector activity in a primary polymorphonuclear cell-based assay which differs from previous observations that found only stalk-specific antibodies activate the low-affinity FcγRIIIa. However, when expressed with IgA Fc domains, only antibodies targeting the stalk domain showed Fc-effector activity in line with these previous findings. To identify the cause of this discrepancy, we then confirmed that IgG signaling through the high-affinity FcγI receptor was not restricted to stalk epitopes. Since no corresponding high-affinity Fcα receptor exists, the IgA repertoire may therefore be limited to stalk-specific epitopes in the context of Fc receptor signaling.
Keywords: Fc receptor; IgA; influenza.
. 2021 Feb 23;118(8):e2018102118.
doi: 10.1073/pnas.2018102118.
Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes
Alec W Freyn[SUP] 1 2 [/SUP], Julianna Han[SUP] 3 [/SUP], Jenna J Guthmiller[SUP] 4 [/SUP], Mark J Bailey[SUP] 1 2 [/SUP], Karlynn Neu[SUP] 4 [/SUP], Hannah L Turner[SUP] 3 [/SUP], Victoria C Rosado[SUP] 1 [/SUP], Veronika Chromikova[SUP] 1 [/SUP], Min Huang[SUP] 4 5 [/SUP], Shirin Strohmeier[SUP] 1 6 [/SUP], Sean T H Liu[SUP] 1 [/SUP], Viviana Simon[SUP] 1 [/SUP], Florian Krammer[SUP] 1 [/SUP], Andrew B Ward[SUP] 3 [/SUP], Peter Palese[SUP] 7 8 [/SUP], Patrick C Wilson[SUP] 4 5 [/SUP], Raffael Nachbagauer[SUP] 7 [/SUP]
Affiliations
- PMID: 33593910
- DOI: 10.1073/pnas.2018102118
Abstract
In this study, we utilized a panel of human immunoglobulin (Ig) IgA monoclonal antibodies isolated from the plasmablasts of eight donors after 2014/2015 influenza virus vaccination (Fluarix) to study the binding and functional specificities of this isotype. In this cohort, isolated IgA monoclonal antibodies were primarily elicited against the hemagglutinin protein of the H1N1 component of the vaccine. To compare effector functionalities, an H1-specific subset of antibodies targeting distinct epitopes were expressed as monomeric, dimeric, or secretory IgA, as well as in an IgG1 backbone. When expressed with an IgG Fc domain, all antibodies elicited Fc-effector activity in a primary polymorphonuclear cell-based assay which differs from previous observations that found only stalk-specific antibodies activate the low-affinity FcγRIIIa. However, when expressed with IgA Fc domains, only antibodies targeting the stalk domain showed Fc-effector activity in line with these previous findings. To identify the cause of this discrepancy, we then confirmed that IgG signaling through the high-affinity FcγI receptor was not restricted to stalk epitopes. Since no corresponding high-affinity Fcα receptor exists, the IgA repertoire may therefore be limited to stalk-specific epitopes in the context of Fc receptor signaling.
Keywords: Fc receptor; IgA; influenza.