Passively transferred IgG enhances humoral immunity to a red blood cell alloantigen in mice

Abstract

Antibodies are typically thought of as the endpoint of humoral immunity that occur as the result of an adaptive immune response. However, affinity-matured antibodies can be present at the initiation of a new immune response, most commonly because of passive administration as a medical therapy. The current paradigm is that immunoglobulin M (IgM), IgA, and IgE enhance subsequent humoral immunity. In contrast, IgG has a “dual effect” in which it enhances responses to soluble antigens but suppresses responses to antigens on red blood cells (RBCs) (eg, immunoprophylaxis with anti-RhD). Here, we report a system in which passive antibody to an RBC antigen promotes a robust cellular immune response leading to endogenous CD4+ T-cell activation, germinal center formation, antibody secretion, and immunological memory. The mechanism requires ligation of Fcγ receptors on a specific subset of dendritic cells that results in CD4+ T-cell activation and expansion. Moreover, antibodies cross-enhance responses to a third-party antigen, but only if it is expressed on the same RBC as the antigen recognized by the antibody. Importantly, these observations were IgG subtype specific. Thus, these findings demonstrate that antibodies to RBC alloantigens can enhance humoral immunity in an IgG subtype-specific fashion and provide mechanistic elucidation of the enhancing effects.

IgG Subclass Determines Suppression Versus Enhancement of Humoral Alloimmunity to Kell RBC Antigens in Mice

“…Why IgG2a and IgG2b enhanced in the current (and recent) reports ( 11 ) but suppressed in the report by Yu et al ( 29 ) is unclear. However, it is worth noting that each of the antibodies used by Yu et al ( 29 ) had different antigen binding domains, different affinities, and bound to different epitopes; as such, it is not possible to isolate IgG subclass as an independent variable.…”

“…The observed ability of IgG2a and IgG2c to enhance alloimmunity to RBC alloantigens in mice is not particular to the K1 system or the PUMA1 antibody; we recently reported a similar effect using a different RBC alloantigen (HOD RBCs) and a distinct panel of switch variants from a monoclonal antibody recognizing a Duffy epitope on the HOD RBCs (PUMA6) (11). In this case, IgG2a, and IgG2c (but not IgG2b) enhanced IgM and IgG responses to HOD.…”

“…It is also important to note that the current studies did not include a control IgG of each subclass but against a third party antigen not in the system so as to rule out non-specific effects. However, the same antibody used in these studies (PUMA1) had no effect in the IgG2c form when used in the presence of a non-K1 RBC alloantigen in a separate study (11). Future studies will be required to address if and how affinity, epitope target, and other possible factors may also regulate suppressing vs. enhancing effects separate from IgG subclass.…”

“…PUMA1 and PUMA 6 and their switch variants were isolated, expressed, and purified to homogeneity as previously described ( 10 , 11 ). B6 mice were passively immunized by tail vein injection with 0.25μg of PUMA1 IgG1, IgG2a, IgG2b, IgG2c, or IgG3 in a total volume of 250 μL of PBS, 2 h before the transfusion.…”

Antibodies to Low-Copy Number RBC Alloantigen Convert a Tolerogenic Stimulus to an Immunogenic Stimulus in Mice

“…Recently, we have reported that pre-treatment of mice with an IgG2c specific for an RBC antigen can substantially enhance the humoral immune response upon transfusion of RBCs expressing that antigen (16,17). Herein, we tested antigen copy number as an independent variable with regards to how IgG2c affects immune response.…”