Fc-Dependent IgG-Mediated Suppression of the Antibody Response: Fact or Artefact? (original) (raw)
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Scandinavian Journal of Immunology, 1989
Nine monoclonal IgG-anti-TNP antibodies were investigated for their ability to modulate anticarrier responses in mice immunized with sheep red blood cells 2.4.6-tHnitrophenyl (SRBC-TNP) or keyhole limpet haemocyanin TNP (KLH-TNP). The antibodies enhanced the anticarrier response when KLH TNP was used as antigen but suppressed it when SRBC TNP was used. The enhancing and suppressive efTects were not exerted by entirely the same sets of antibodies. The suppression was correlated to efficient antigen binding, but not complement activation, haemagglutination. or isolype of the monoclonal antibodies. In contrast, enhancement was correlated to isotypc and complement activation but not to antigen binding capacity. Both the enhancing and the suppressive effects seem to require Fc-mediated functions of the IgG molecules since they modulate the anti-carrier response although they recognize hapten determinants. Thus, one and the same monoclonal hapten-specific igG-antibody can enhance the anti-KLH response up to 38-fold whereas it suppresses the anti-SRBC response by more that 10-fold.
IgG‐mediated suppression of antibody responses: Hiding or snatching epitopes?
2020
Antibodies forming a complex with antigen in vivo can dramatically change the antibody response to this antigen. In some situations, the response will be a 100‐fold stronger than in animals immunized with antigen alone, and in other situations, the response will be completely suppressed. IgG is known to suppress the antibody response, for example to erythrocytes, and this is used clinically in Rhesus prophylaxis. The mechanism behind IgG‐mediated immune suppression is still not understood. Here, we will review studies performed in experimental animal models and discuss the various hypotheses put forward to explain the profound suppressive effect of IgG. We conclude that an exclusive role for negative regulation of B cells through FcγRIIB, increased clearance of erythrocytes from the circulation or complement‐mediated lysis is unlikely. Epitope masking, where IgG hides the epitope from B cells, or trogocytosis, where IgG removes the epitope from the erythrocyte, is compatible with ma...
Scandinavian Journal of Immunology, 1988
The determinant specificity of the IgG-mediated suppression of the humoral immune response in mice was studied. One hour before or 2.5, 6, 12. or 24 h after the injection of sheep erythrocytes (SRBC) or SRBC-TNP. CBA/Ca mice received SRBC-specific monoclonal IgG antibodies. The antibodies did not cross-react with TNP or goat erythrocytes. Ihe latter an antigen which shows 30% cross-reactivity with SRBC. Five days later the determinant-specific plaque-forming cell response against SRBC and the non-determinant-specifk response against goat erythrocytes and TNP were deiermined. Regardless of whether the antibodies were injected before or after the antigen, they suppressed not only the response to the antigenic determinant they bound to, but also the response to other epitopes on the same antigen. This shows that Fe parts of the IgG molecules play a crucial part in suppression of the in vivo antibody response even when, as in a natural situation, the antigen is presented to the immune system before the antibody.
Transfusion Clinique et Biologique, 2002
Sixty four IgG Rh monoclonal antibodies (Mabs) submitted to the Fourth International Workshop on Monoclonal Antibodies Against Human Red Blood Cells and Related Antigens were characterised and tested in quantitative functional assays at five laboratories. The biological assays measured the ability of anti-D to mediate phagocytosis or extracellular lysis of RBC by IgG Fc receptor (FcγR)-bearing effector cells. Interactions of RBC pre-sensitised with anti-D (EA-IgG) with monocytes in chemiluminescence (CL) assays were found proportional to the amount of IgG anti-D on the RBC. Using antibodies to inhibit FcγRI, FcγRII or FcγRIII, the only receptor utilised in the monocyte CL and ADCC assays for interactions with EA-IgG1 was found to be FcγRI. In these assays, enhanced interactions were promoted by EA-IgG3 and additional Fcγ receptors may have contributed. IgG2 anti-D was not reactive in these assays and EA-IgG4 promoted weak reactions through FcγRI. A macrophage ADCC assay showed that haemolysis of EA-IgG3 was greater than that of EA-IgG1, mediated mainly through FcγRIII. In ADCC assays using lymphocytes (NK cells) as effector cells and papainised RBC target cells, only a minority of IgG1 anti-D Mabs were shown to be able to mediate haemolysis in the presence of monomeric IgG (AB serum or IVIg). These interactions were mediated solely through FcγRIII. Haemolysis via FcγRIII may depend on the presence of certain sugars on the oligosaccharide moiety of IgG. Most Mabs (IgG1, IgG2, IgG3 and IgG4) elicited intermediate, low or no haemolysis in these assays. Blocking studies indicated that low activity IgG1 and IgG4 anti-D utilised only FcγRI. Other IgG1 and IgG3 Mabs appeared to promote haemolysis through FcγRI and FcγRIII while IgG2 was inhibited by Mabs to both FcγRII and FcγRIII, suggesting a variety of FcγR are utilised for anti-D of low haemolytic activity. Excellent agreement between the results of the lymphocyte ADCC assays and antibody quantitation was observed between the participating laboratories.
IgE-mediated enhancement of antibody responses: the beneficial function of IgE?
Allergy, 2002
Antigen in complex with antibodies elicits profoundly different antibody responses than does antigen alone (1). Small amounts of passively administered, as well as actively produced, antibodies can cause complete suppression or more than a 1000-fold enhancement of antibody responses to the antigens to which they bind. An important feature of feedback regulation is that it is antigen-but not epitope-specific. This means that when an animal is immunized with e.g. immunoglobulin (Ig)G anti-TNP (trinitrophenyl) and TNP-BSA (bovine serum albumin) and an unrelated antigen such as ovalbumin (OVA), responses to both TNP and BSA, but not to OVA, will be regulated. Although the antibody feedback regulation was described already over 100 years ago (2), the molecular mechanisms behind the phenomenon remain elusive. An immune complex is composed of antigen, antibody, and, when the antibody is of a complement-activating class, complement factors and can bind to B-cell receptors (BCR) as well as to Fc-and complement-receptors. Ligation and coligation of these receptors can affect cell activation, both negatively and positively. Cocrosslinking of BCR and FccRIIB (CD32) leads to inhibition of B-cell activation through an ITIM (immuno-receptor tyrosine-based inhibitory motif) in the cytoplasmic tail of FccRIIB (3). When an ITIM is brought in close contact with other receptors containing ITAMs (immuno-receptor tyrosine-based activation motifs), such as the BCR, T-cell receptor (TCR), FccRI (CD64), FccRIIA (CD32), FccRIII (CD16) and FceRI, it inhibits cell activation through the latter. Other explanations for antibody-mediated suppression may be that immune complexes are eliminated via Fcor complement-receptor-mediated phagocytosis before
The Journal of Immunology, 1999
Immunization with IgG/Ag or IgE/Ag complexes leads to a higher production of specific Abs than immunization with Ag alone. The enhancing effect of IgE is exclusively dependent upon the low-affinity receptor for IgE, Fc⑀RII, whereas the mechanism behind IgG-mediated enhancement is unknown. We have investigated whether receptors for the Fc part of IgG are required for responses to IgG/Ag. Mice lacking the ␥ subunit of Fc receptors (FcRs) (FcR␥ ؊/؊), Fc␥RII (Fc␥RII ؊/؊), or Fc␥RIII (Fc␥RIII ؊/؊) were immunized with BSA-2,4,6-trinitrophenyl (TNP) alone or BSA-TNP complexed to monoclonal TNP-specific IgG1, IgG2a, or IgG2b. As expected, all subclasses enhanced the Ab-response to BSA in wild-type mice. Enhancement was in the same order of magnitude in Fc␥RIII ؊/؊ mice (<177-fold of controls administered Ag alone), whereas it was abrogated in FcR␥ ؊/؊ mice and augmented in Fc␥RII ؊/؊ mice (<5147-fold of controls). The response to IgE/Ag complexes in FcR␥ ؊/؊ and Fc␥RII ؊/؊ mice was similar to that seen for wild-type mice, demonstrating that non-Fc␥R-dependent responses were normal. Our observations suggest that IgG/Ag complexes enhance Ab responses via Fc␥Rs. Moreover, they reveal a strong negative regulation of Ab responses to IgG/Ag exerted by Fc␥RII.
Complement activation is not required for IgG-mediated suppression of the antibody response
European Journal of Immunology, 1988
Complement activation is not required for IgG-mediated suppression of the antibody response* Feedback suppression of the antibody response by IgG is known to be dependent on intact Fc regions. However, it is not clear which of the Fc-mediated effector functions is required. In the present report we have studied whether ability or inability of the IgG antibodies to activate the complement system was of consequence for their immunosuppressive effect. First, a monoclonal IgG1-anti-2,4,6-trinitrophenyl (TNP) antibody, unable to activate complement via the classical or alternate pathway, was shown to be able to inhibit more than 90% of the in vivo sheep erythrocyte-specific antibody response in mice when TNP coupled to sheep erythrocytes was used as antigen. Second, we investigated the immunosuppressive ability of a non-complement-activating mutant IgG2,-anti-TNP monoclonal antibody. The mutant differs from the wild type by a single amino acid substitution in the CH2 domain leading to inability to fix complement factor Clq. However, the mutant has the same affinity for antigen and the same Fc receptor-binding capacity as the wild type antibody. It is demonstratd that the mutant was as efficient as the wild type antibody in inhibiting an in vitro antibody response to TNP-coupled sheep erythrocytes. These findings confirm the non-determinant specificity and Fc dependence of IgGmediated suppression, and show that the Fc-mediated effector mechanism is independent of complement activation. The results instead suggest binding to Fc receptors as a necessary step in feedback immunosuppression and favor inactivation of B cells by cross-linking of Fc and antigen receptors on their surface rather than elimination of antigen by complement-dependent phagocytosis as the effector mechanism.
Cellular Immunology, 1985
The direct splenic anti-sheep erythrocyte (anti-SRBC) responses as well as the serum IgG,, IgGzn, IgG2t,, and IgGs anti-SRBC responses of CBA/Cal mice were monitored 4-35 days after immunization with: (1) a suboptimal dose of SRBC, (2) a suboptimal dose of SRBC plus monoclonal IgM anti-SRBC, or (3) a high dose of SRBC. The direct plaque-forming cell (PFC) responses of mice in treatment group 2 were significantly higher than those in group 1 but similar to the responses in group 3. The serum anti-SRBC antibody responses of all IgG sub&sses were significantly enhanced by IgM anti-SRBC and were generally even higher than the responses obtained with high doses of SRBC. The relative proportions of each serum IgG subclass were similar in all three groups. These data suggest that the enhancement of suboptimal anti-SRBC antibody responses by IgM anti-SRBC extends through IgM and all of the IgG subclasses and, further, that the isotype profile in antibody-enhanced responses is similar to that obtained with high doses of SRBC. o 1985 Academic PBS, IX.
The Journal of Immunology
Six different monoclonal IgG antibodies with specificities for sheep erythrocytes (SRBC) were tested for immunosuppressive ability. Four of them, one IgG3, two IgG2a, and one IgG1, could yield suppression of more than 90% of the anti-SRBC response. The remaining two antibodies, which were both IgG2a, were found to have no significant effect. The degree of suppression correlated well with the amount of antibodies used that could bind to SRBC, as measured by an ELISA assay. High avidity for SRBC was also a factor making the monoclonal antibody more efficient as an immunosuppressor. The response against antigenic determinants on the SRBC other than those for which the monoclonals were specific, was suppressed to an equal degree. This was established by immunizing mice with SRBC using monoclonal anti-SRBC antibodies that did or did not bind to goat RBC (GRBC). The PFC responses against both SRBC and GRBC were then measured. The anti-SRBC and GRBC responses were suppressed in parallel re...
Scientific reports, 2018
Specific IgG antibodies, passively administered together with erythrocytes, suppress antibody responses against the erythrocytes. Although used to prevent alloimmunization in Rhesus (Rh)D-negative women carrying RhD-positive fetuses, the mechanism behind is not understood. In mice, IgG suppresses efficiently in the absence of Fcγ-receptors and complement, suggesting an Fc-independent mechanism. In line with this, suppression is frequently restricted to the epitopes to which IgG binds. However, suppression of responses against epitopes not recognized by IgG has also been observed thus arguing against Fc-independence. Here, we explored the possibility that non-epitope specific suppression can be explained by steric hindrance when the suppressive IgG binds to an epitope present at high density. Mice were transfused with IgG anti-4-hydroxy-3-nitrophenylacetyl (NP) together with NP-conjugated sheep red blood cells (SRBC) with high, intermediate, or low NP-density. Antibody titers and the...