Section G – Regulation of the immune response
G4 R EGULATION BY ANTIGEN
microbe pattern recognition by receptors of the innate immune system or antigen-specific receptors on lymphocytes (Topics B3, E1, F2). The nature of the antigen is also important in that particulate antigens produce stronger immune responses than soluble forms of the same antigen. This may in part be due to the ability of soluble antigens to produce a tolerogenic response rather than an immune response. Aggregated antigens are also more likely to be taken up and processed by antigen-presenting cells.
The successful generation of an antigen-driven cell-mediated and/or antibody response, leads in most cases to removal of the invading microbes. Microbial debris and dead virus-infected cells are cleared by the phagocytic system, thus removing the antigenic source and therefore the stimulus. In particular, as a result of elimination of antigen by antibody, restimulation of antigen-specific T and B cells stops, preventing more specific antibodies from being made at a time when antigen is being effectively cleared from the system. The ability of preformed antibodies to inhibit specific unwanted host responses to antigens has been shown clinically by passive immunization. Injection of antibodies to RhD into RhD− mothers before or immediately after birth of an RhD+ infant removes RhD+ erythrocytes that may have passed into the maternal circulation.
This prevents the development of hemolytic disease of the newborn from occur- ring as a result of future pregnancies (Topic K3). This results from the simple removal of antigen (RhD+ erythrocytes), such that the mother never develops a memory response to RhD antigen.
Similarily, unresponsiveness of the newborn to certain antigens may be related to the passive immunity acquired from the mother (Topic C5). Due to transfer of maternal IgG across the placenta during fetal life, the infant at birth has all of the IgG-antibody-mediated humoral immunity of the mother.
Furthermore, maternal IgA obtained by the infant from colostrum and milk during nursing coats the infant’s gastrointestinal tract and supplies passive mucosal immunity (Topics C5, D8 and E4). Thus, until these passively supplied antibodies are degraded or used up, they may bind antigen and remove it, thereby interfering with development of active immunity.
Of note, some microbes persist and continuously stimulate specific T and B cells. For example, Epstein–Barr virus, which causes glandular fever, persists for life at low levels in the pharyngeal tissues and B cells, continually restimulating immunity to the virus.
Antibodies of the IgM class appear to be important in enhancing humoral immunity. In particular, antigen–IgM–complement complexes that bind to the B cell antigen receptor stimulate the cell more efficiently than antigen alone (Fig.
1). This is probably the result of simultaneous interaction of the C3b component of complement with the CD21 molecule of the antigen receptor complex, which then transduces a positive signal to the B cell.
The interaction of IgG–antigen complexes with antigen-specific B cells through the simultaneous binding of both the B cell antigen receptor and the FcγRII molecule of the B cell receptor complex can deliver a negative signal to the B cell (Fig. 1). Thus, IgG, which is produced later in the antibody response, could interact with antigen (if present) forming a complex that, on binding to antigen- specific B cells, may provide feedback inhibition mediated via FcγRII, decreas- ing the amount of antigen-specific antibody being produced.
Negative
feedback by IgG Positive effects of antibodies Removal of antigen
G4 – Regulation by antigen and antibody 153
The hypervariable region, the idiotype, of the immunoglobulin molecule (Topic D4) is immunogenic, and thus antibody and T cell responses can be produced to this region. It has been suggested that these immune responses to idiotypes have an immunoregulatory role. That is, antibodies or T cells directed to the idiotype of an antigen-induced antibody may, by interacting directly with the B or T cell, regulate its further proliferation and differentiation. Anti-idiotypic antibodies or T cells may thus form networks of connectivity and act as inducers and regulators of their own responses. In the absence of antigen, B cells or T cells with idiotypic and anti-idiotypic antigen receptors may directly anergize other B and T cells through direct contact of the antigen receptors.
Furthermore, two different sets of antibodies can be produced against the idio- type of an antibody molecule. One set of antibodies may express anti-idiotype binding sites that resemble the antigenic determinant on the original antigen.
Thus, for example, an antibody directed against an antigenic determinant on a microbe may stimulate an immune reaction that results in anti-idiotypic antibod- ies with variable regions that resemble the antigenic determinant on the microbe.
Anti-idiotypes so produced can potentially act as surrogate antigens. For example, antibodies to hepatitis B antibodies have been used as vaccines for hepatitis B. Anti-idiotype antibodies behaving as surrogate antigens may permit the immune system to boost its own response during infection. In this way, during an immune response to a microbe, anti-idiotypic antibodies that mimic microbial antigens may amplify the immune response against the microbes.
It is also possible that anti-idiotypic antibodies which mimic self molecules may cause enhanced autoimmune responses. For example, antibodies made against a hormone may induce anti-idiotypic antibodies that mimic the hormone and thus bind to and stimulate the hormone receptor (Topic L3).
The idiotype network
154 Section G – Regulation of the immune response
BCR
BCR IgM
IgG
CD21
FcR (CD32) C
Positive (enhancement)
Positive B
Negative (suppression)
Negative
B
Fig. 1. Regulation of B cell activity by antibody. IgM bound to antigen recognized by the BCR fixes complement which then interacts with CD21 giving a positive signal to the B cell.
However, IgG bound to antigen attached to the BCR binds to FcgR (CD32) and delivers a negative signal to the B cell.
Section G – Regulation of the immune response