IMMUNOLOGY - Roit A. - Mir 2000

Chapter 13. Regulation of the Immune Response

REGULATORY EFFECTS OF ANTIBODIES

It has been established that Antibodies regulate the Immune Response via a feedback mechanism. Passively administered IgM antibodies, given alongside an antigen, specifically enhance the Immune Response to that antigen, whereas IgG antibodies suppress it. This phenomenon was initially discovered using a passive immunization model with polyclonal antibodies and was subsequently confirmed in experiments employing Monoclonal Antibodies (Fig. 13.4).

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Fig. 13.4. Mice were administered monoclonal IgM or IgG antibodies against sheep erythrocytes, or culture medium alone (control). After 2 h, animals in all 3 groups were immunized with SRBC, and antibody production was assessed over the subsequent 8 days by measuring the number of plaque-forming Cells (PFC). IgM antibodies enhanced the immune response, whereas IgG suppressed it.

The capacity of passively administered antibodies to either enhance or suppress the immune response is taken into account during vaccination and utilized in clinical practice.

✵ Immunization with certain Vaccines (such as those against measles and mumps) is typically administered to children over one year of age. This is because maternal IgG antibodies persist in the child's Blood in significant amounts for at least 6 months after birth, and the presence of such passively acquired antibodies during vaccination can substantially reduce its efficacy.

✵ In cases of rhesus (Rh) incompatibility, administering anti-RhD antibodies to an Rh-negative mother prevents primary sensitization by fetal Rh⁺ erythrocytes, likely by eliminating the foreign antigen (fetal erythrocytes) from the maternal Circulation (see Ch. 24).

The mechanisms underlying antibody-mediated modulation of the immune response are not yet fully understood. It is hypothesized that the increased production of plaque-forming cells induced by IgM antibodies may be driven by two factors.

✵ IgM-containing immune complexes are taken up via Fc receptors or C3 receptors On the surface of APCs and are processed more efficiently than free antigen.

✵ IgM-containing immune complexes stimulate The production of anti-idiotypic antibodies against IgM, which in turn enhance the immune response. (The Role of anti-idiotypic antibodies in immunoregulation is discussed below.)

IgG antibodies can suppress the Synthesis of specific IgG

IgG-mediated suppression can occur via several pathways.

Blocking action of antibodies. Passively administered antibodies bind antigen, competing with B cells (Fig. 13.5). In this scenario, The Effect of IgG antibodies heavily depends on their concentration, as well as The ratio of their affinity for the antigen relative to the affinity of B-Cell receptors. Only B cells bearing high-affinity receptors successfully compete with antibodies for the antigen, and this competitive mechanism is independent of the antibody Fc fragment.

Fig. 13.5. Blocking effect of antibodies: present in high doses, soluble Ig blocks the interaction between the antigenic determinant (epitope) and membrane-bound immunoglobulin on The surface of B cells. Consequently, B cells lose their ability to recognize the antigen (Ag). Receptor blockade also prevents B-cell priming. This effect is elicited exclusively by antibodies that bind to the exact same epitope recognized by the B-cell receptor. Receptor cross-linking: present in low doses, soluble antibodies do not prevent antigen binding to either B-cell Fc receptors or their antigenic receptors. The FcγRIIb receptor interacts with Tyrosine phosphatase (SHP-1), which inhibits cellular activation triggered by antigen receptor-associated tyrosine Kinases. As a result, B-cell priming occurs, but antibody synthesis is suppressed. Antibodies directed against various epitopes of the antigen may act via this mechanism.

Receptor cross-linking. IgG antibodies also exert a regulatory effect mediated by the Fc fragment of their molecule. Experimental evidence demonstrates that immunoglobulin can inhibit B-Cell Differentiation by cross-linking the antigenic receptor with the Fc receptor (FcγRII) on the surface of the same cell (Fig. 13.5). In this case, the antibodies may recognize distinct epitopes.

At doses insufficient to completely suppress antibody production, IgG increases their average affinity because only B cells bearing high-affinity receptors can successfully compete with the passively administered antibodies for the antigen. Feedback regulation by antibodies is thought to play a crucial role in the affinity maturation process of antibodies (Fig. 13.6).

Fig. 13.6. Effect of passively administered antibodies on the affinity and concentration of secreted antibodies. On day one, antibodies ("passive" antibodies) were administered to one of two rabbits. On day two, both animals were immunized with an antigen, and the concentration and affinity of the resulting antigen-specific antibodies were monitored over several days. "Passive" antibodies decreased the concentration while increasing the affinity of the produced antibodies.

Immune complexes can enhance or suppress immune responses

One mechanism of the modulating influence of antibodies (IgM or IgG) on the immune response is Fc-dependent and associated with The formation of antigen-antibody immune complexes. Immune complexes can either inhibit or enhance the immune response (Fig. 13.7). By activating Complement, immune complexes can localize through interactions with CR2 on follicular dendritic cells. This promotes the immune response by providing a continuous source of antigen. The CR2 receptor is also expressed on B cells, and co-ligation of CR2 with membrane IgM (mIgM) is known to activate B cells; thus, the interaction of immune complexes with CR2—a component of the B-cell co-receptor complex—and mIg can lead to an enhancement of the specific immune response.

In patients with malignant tumors, immunoreactivity is frequently suppressed; this is hypothesized to be linked to the presence in the blood of immune complexes composed of antibodies and tumor cell Antigens.

Fig. 13.7. Immune complexes can either suppress or enhance the immune response. Suppression: when an immune complex cross-links the B cell's Fc receptor with its antigen receptor, the B cell receives a signal that inhibits the initial phase of antibody production. Passively administered IgG antibodies can exert this effect.

Enhancement: antibodies facilitate antigen presentation to B cells by being localized on antigen-presenting cells (APCs) via binding through Fc receptors or, as shown in the figure, through complement receptors (CR2) on follicular dendritic cells (FDCs).