Given the success of Volume I of this Research Topic, and the rapidly evolving subject area, we are pleased to announce the launch of Volume II: Fc-Mediated Antibody Functions and Fc-Receptor Polymorphism.

Antibodies (Ab) mediate protective functions against infectious agents by: (i) binding to pathogens and preventing their entry into target cells, referred to as neutralizing function, as well as (ii) facilitating the recruitment of Fc-receptor bearing cells that can eliminate pathogens or infected cells by mediating phagocytosis or cytotoxic activity, referred to as Fc-mediated functions. Antibodies can, therefore, be defined as neutralizing (nAb) and capable of mediating both functions, and non-neutralizing (non-nAb) restricted to Fc-mediated functions. Non-nAb have been previously reported to play a significant role in protection from a wide range of viral infections including Smallpox, Sindbis, Yellow Fever, Ebola, and Influenza; as well as against non-viral infections such as Tuberculosis and Malaria. Interestingly, some non-nAb responses shown to protect against lethal alphavirus encephalitis are directed against epitopes present on the surface of infected cells, but not on virions. These findings suggest that this class of Abs may be distinct from those mediating neutralizing activities and could have a more variable epitope specificity. Although protection is the expected favorable outcome related to Fc-mediated Ab responses, both vaccine- and infection-induced Ab responses mediating antibody-dependent enhancement (ADE) of infection or clinical disease severity have been reported. Previous observations of ADE for Flaviviruses and more recently Coronaviruses, raise the need for a broader discussion on how to best tune Ab functions toward favorable protective outcomes while minimizing unintended enhancement of disease.

Fc-mediated Ab functions can be elicited as a component of vaccine strategies but can be further exploited in the development of monoclonal antibody (mAb) and mAb-based passive prophylaxis and/or immunotherapeutic regimens. The interactions between Ab and complement or Fc receptor-bearing effector cells are influenced by multiple factors including host genetics such as Fc receptor polymorphisms; antibody isotypes, subclasses, and glycoforms; and the phenotypic and molecular characteristics of effector cells. Some studies to investigate Fc-mediated function can be performed in small animal models, but others, such as the modeling of HIV-1 infection, require the utilization of non-human primates. Importantly, multiple knowledge gaps persist related to the extent which Fc-mediated functions are conserved in humans and animal models. This is due to the genotypic and phenotypic differences that exist among the species for both Ab Fc regions and Fc receptors.

In this Research Topic, we aim to gather a series of articles that address Fc-mediated Ab functions and the factors that influence them in both humans and in different mammalian species with a focus on how to use the animal models for vaccine and passive immunization pre-clinical trials. A particular focus will also be placed on the similarities and differences of species-related FcR phenotypes, that impact functional immunity, in order to fully translate pre-clinical observations into clinical studies. Therefore, we seek articles that cover, but are not limited to, the following topics:

1. Protective and/or pathogenic roles of Fc-mediated Ab functions against infectious pathogens

2. Mechanisms of antibody-dependent enhancement of infection and disease

3. Host genetic factors regulating and impacting Fc-mediated Ab functions

4. Molecular mechanisms involved in Fc-Fc-receptor interactions

5. Optimizing Fc-FcR interactions

6. Animal models to investigate and predict outcome of Fc-mediated Ab responses

7. Effector cells responsible for Fc-mediated Ab functions

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Frontiers in Immunology

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