IMMUNOLOGY - Roit A. - Mir 2000

Chapter 14. Immunological Tolerance

B-CELL TOLERANCE TO SELF-ANTIGENS

The production of high-affinity IgG depends on T Cells (see Chapter 11). For this reason, and bearing in mind that the threshold of T-Cell sensitivity to tolerance induction is lower than that of B cells, the simplest assumption is that the unresponsiveness of B lymphocytes to self-Antigens is determined by the absence of T-cell help (Fig. 14.9).

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Fig. 14.9.

1. If helper T cells are absent (either because they are entirely missing from the T-cell repertoire or due to deletion during the induction of self-tolerance in the Thymus), the corresponding autoreactive B cells will be unable to produce autoantibodies.

2. The production of autoantibodies can occur if autoreactive B cells interact with helper T cells specific for other cross-reacting antigens that contain both "self" and "foreign" determinants.

Under certain conditions, B-cell tolerance must be induced by the direct action of antigen

Cells of certain microbes contain cross-reacting antigens that comprise foreign epitopes stimulating T cells, as well as other epitopes similar to the body's own epitopes capable of stimulating B cells. Such antigens can provoke a strong humoral response against autoantigens (Fig. 14.9). Furthermore, unlike TCRs, immunoglobulin receptors of mature, antigen-stimulated B cells can change As a result of hypermutation and ultimately acquire reactivity against self-antigens. Thus, B-cell tolerance can arise both during their development and following antigen stimulation in secondary lymphoid Tissues.

Autoreactive B cells can be deleted or rendered anergic depending on B-cell receptor affinity and The Nature of the antigen

The induction of self-tolerance can lead to either cell deletion or anergy. This depends on the affinity of the B-cell antigen receptors and the Nature of the respective antigen, in particular whether it is an integral cell membrane protein or a soluble, circulating, predominantly monomeric protein. The Fate of autoreactive B cells has been traced in experiments on Transgenic Animals (Figs. 14.10 and 14.11).

Fig. 14.10. Non-H-2^b haplotype mice were transferred with a foreign H-2^b Gene encoding an MHC class I membrane protein. The gene contained a Liver-specific metallothionein promoter. In this way, MET-K^b Transgenic Mice were obtained. Other mice, also of the non-H-2^b haplotype, were transferred with a gene encoding Antibodies against the H-2K^b product (transgenic mice with anti-K^b Ig). Both types of mice were crossed to yield double-transgenic F1 progeny whose livers expressed H-2K^b, while the B cells leaving the Bone Marrow were specific for H-2K^b. However, such autoreactive B cells were partially deleted in the Spleen and completely deleted in the Lymph Nodes, as a result of which autoantibody formation never occurred. An idiotype identical to anti-K^b Ig was not detected in the transgenic parental strains of mice.

Fig. 14.11. Mice of one of two strains were transferred with the hen egg Lysozyme (HEL) gene linked to a tissue-specific promoter. The HEL product (mainly its soluble form) induced T- and B-cell tolerance. Transgenic mice of the second strain (producing anti-HEL Ig) possessed rearranged heavy and light chain genes of high-affinity anti-HEL antibodies bearing the IgH^a allotypic marker, which distinguishes them from endogenously produced IMMUNOGLOBULINS (IgH^b). The majority of B cells in these transgenic mice carried IgM and IgD of the "a" allotype. Double-transgenic F1 hybrids were highly tolerant to HEL and produced neither antibodies nor plaque-forming cells. HEL-binding (autoreactive) B cells were not deleted; however, they failed to express surface IgM receptors while retaining IgD receptor expression and exhibited a state of anergy.

B cells reacting against membrane-bound autoantigens are ultimately deleted

Contact of autoreactive B cells with membrane-bound autoantigens capable of binding B-cell Ig receptors with high affinity yields the following result. In the bone marrow, the number of immature autoreactive B lymphocytes does not decrease, despite the suppression of IgM receptor expression following binding to membrane-bound self-antigens. Thus, immature B cells are less sensitive to the deleting action of autoantigens than T cells at Cytology/cytology/16.html">Early stages of differentiation. Nevertheless, these B cells have a short lifespan and are, so to speak, doomed to death (presumably via apoptosis) usually even before entering peripheral lymphoid tissues.

B cells binding soluble autoantigens become anergic

In peripheral lymphoid tissues, where autoreactive B lymphocytes may be present in large numbers, they are not deleted upon exposure to soluble (mainly monomeric) antigens, but instead transition into a state of anergy. Such an effect occurs only under the condition that the antigen concentration exceeds a certain critical level. Anergy is associated with a decrease in the expression of IgM, but not IgD, receptors. The anergic effect is accompanied by the cessation of B-cell maturation in the mantle of splenic follicles and a sharp drop in the number of B cells displaying high-level surface IgM expression in the marginal zone. Thus, unlike B cells undergoing clonal deletion, anergic B lymphocytes migrate to peripheral Lymphoid Organs but are unable to interact there with corresponding helper T cells, which is indirectly due to the lack of IgM expression. In addition, the half-life of anergic B cells is only a few days, whereas in normal peripheral B lymphocytes it is several weeks. The Development of anergy is probably not mediated by suppressor T cells or anti-idiotypic B cells, as studies on transgenic animals have revealed no influence of such factors.

B-cell anergy is a reversible state. Thus, anergic B cells can respond to antigen-independent, CD40-mediated signals received from helper T cells; in this case, a physiological concentration of antigen can be generated On the surface of anergic B lymphocytes via IgD receptors for presentation to helper T lymphocytes (see Chapter II). At the same time, anergy impairs The ability to upregulate B7 molecule expression on The Cell surface following antigen receptor ligation. The insufficient costimulatory activity of these cells can be restored under METABOLISM/18.html">The Influence of cytokines (e.g., IL-4) or various polyclonal activators (such as lipopolysaccharide). Furthermore, chronic T-cell activation caused by infectious agents can lead to the activation of neighboring B cells mediated by CD40 molecules and cytokines.

Secondary immunoglobulin gene rearrangement

In the majority of B cells, once productive immunoglobulin gene rearrangement is complete, no further rearrangement occurs. However, in mice carrying artificially rearranged transgenes, potentially autoreactive B cells escape deletion or anergy by undergoing secondary immunoglobulin gene rearrangement. Such A change in receptor Specificity (also referred to as receptor editing) may serve as one of the mechanisms for B-cell survival during ongoing somatic mutation.