Antibody-mediated immune suppression by antigen modulation is antigen-specific

Abstract

Alloantibodies developing after exposure to red blood cell (RBC) alloantigens can complicate pregnancy and transfusion therapy. The only method currently available to actively inhibit RBC alloantibody formation is administration of antigen-specific antibodies, a phenomenon termed antibody-mediated immune suppression (AMIS). A well-known example of AMIS is RhD immune globulin prophylaxis to prevent anti-D formation in RhD− individuals. However, whether AMIS is specific or impacts alloimmunization to other antigens on the same RBC remains unclear. To evaluate the specificity of AMIS, we passively immunized antigen-negative recipients with anti-KEL or anti-hen egg lysozyme (HEL) antibodies, followed by transfusion of murine RBC expressing both the HEL-ovalbumin-Duffy (HOD) and human KEL antigens (HOD × KEL RBC). Significant immunoglobulin G deposition on transfused HOD × KEL RBC occurred in all passively immunized recipients. Complement deposition and antigen modulation of the KEL antigen occurred on transfused RBC only in anti-KEL–treated recipients, whereas HEL antigen levels decreased only in the presence of anti-HEL antibodies. Western blot analysis confirmed the specificity of antigen loss, which was not attributable to RBC endocytosis and appears distinct for the 2 antigens. Specifically, removal of KEL was attenuated by clodronate treatment, whereas loss of HEL was unaffected by clodronate in vivo but sensitive to protease treatment in vitro. Antigen-specific modulation correlated with antigen-specific AMIS, with anti-KEL treated recipients forming antibodies to the HOD antigen and anti-HEL–treated recipients developing antibodies to the KEL antigen. Together, these results demonstrate that passively administered antibodies can selectively inhibit the immune response to a specific antigen.

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

“…The ability of some IgG subclasses (i.e., IgG2a, IgG2b, and IgG2c) to enhance alloimmunity to an RBC antigen contradicts the current "dual effect" model, in which IgG against soluble antigens enhances immunity whereas IgG against an RBC alloantigen suppresses (17). The dual effect model has been based upon numerous reports in which IgG can enhance responses to soluble antigens, combined with separate reports in multiple animal models that IgG against RBC antigens is suppressive (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and the well-known suppressive effects of anti-RhD in humans. In particular support of the dual effect model, Enriquez-Rincon and Klaus reported that the same monoclonal antibodies (against a hapten) enhance humoral immunity to a haptenated soluble protein but suppress responses to haptenated RBCs (30).…”

IgG‐mediated suppression of antibody responses: Hiding or snatching epitopes?

“…SRBC or SRBC conjugated to haptens such as trinitrophenyl (TNP) or 4‐hydroxy‐3‐nitrophenylacetyl (NP) has frequently been used 7,9,36‐42 . More recently, murine transgenic erythrocytes expressing the entire human KEL glycoprotein (KEL‐RBC), 43,44 hen egg lysozyme in sequence with ovalbumin (OVA) and the complete human Duffy b transmembrane protein (HOD‐RBC), 45‐49 or both HOD and KEL antigens 50 were used as antigen.…”

“…More recently, splenic germinal centre B cells as well as IgG‐producing long‐lived plasma cells in the bone‐marrow were shown to be suppressed 40 . Also primary serum IgM and IgG responses to xenogeneic 39‐41,54 as well as to allogeneic 43‐50 erythrocytes are suppressed by IgG.…”

“…Epitope specificity would indicate that, for example, epitope masking explains suppression while non‐epitope specificity would indicate an Fc‐dependent mechanism such as lysis, clearance or FcγRIIB‐mediated inhibition of B‐cell activation. However, both epitope‐specific 39‐41,50,53,77 and non‐epitope‐specific suppression 36‐39,41,42,46,48,76 have been demonstrated and it has therefore been difficult to draw mechanistic conclusions from this type of experiments.…”

IgG Suppresses Antibody Responses to Sheep Red Blood Cells in Double Knock-Out Mice Lacking Complement Factor C3 and Activating Fcγ-Receptors

“…We find it unlikely that this mechanism can explain the complete suppression of antibody responses to all epitopes on SRBC. This would require that trogocytosis destroys all erythrocytes and in experimental systems using transferred allogeneic erythrocytes these remain intact in the circulation for hours or days during conditions where trogocytosis has removed specific epitopes ( 20 , 37 ).…”