Some proteins are much more highly conserved than others. For example, his-tones are among the most highly conserved proteins, and their amino acid sequence varies little between species. As the amino acid sequence of proteins becomes closer and closer to self, they tend to become less and less immunogenic, and gaps in the repertoire become more and more apparent. The limiting of the repertoire owing to tolerance in the case of antigens that are very similar to self reveals another level of control, the histocompatibility-linked immune response genes (Ir genes; Benacerraf and McDevitt, 1972). For example, when mice are immunized with the B subunit of lactate dehydrogenase from pig hearts, some strains respond well while others respond very poorly. The genes that control responsiveness map to the class II region of the mouse MHC (Melchers et al., 1973). It is now clear that Ir genes often reflect the ability of individual peptides to bind to MHC molecules and thus initiate immune responses (Rammensee et al., 1993; Engelhard, 1994a, b).
The genetic factors that govern immune responsiveness are particularly well seen when inbred mice are immunized with proteins from different mouse strains where there are slight allelic differences in the sequence of that protein. Allelic differences between proteins of different individuals within a species are known as allotypes. In many cases, allotypic differences were first detected serologically by cross-immunization between strains of mice. In some cases, the structural difference has been shown to be a single amino acid substitution. The immune response to allotypic differences in proteins epitomizes the exquisite ability of the immune system to detect minor differences in protein structure.
For example, the T cell membrane glycoprotein Thy-1 has two allelic forms (Thy-1.1 and Thy-1.2) which differ by a single amino acid (Williams and Gagnon, 1982; Williams, 1989; Reif and Schlesinger, 1989). Immunization of Thy-1.1 mice with T cells from Thy-1.2 mice results in the production of antibodies that recognize the Thy-1.2 allele but not the Thy-1.1 allele, because the recipient lymphocytes are tolerant to the self allele. Although nonspecific T cell help is available for potential anti-Thy-1.1 B cells by virtue of T cell stimulation with the nonself Thy-1.2 antigen, the fact that anti-Thy- 1.1B cells do not respond may be taken as evidence that B cells with this antiself specificity are either non-responsive or deleted.
Interestingly, the very small difference between the self and nonself forms of Thy-1 is also reflected in MHC-linked immune response genes that control the ability to respond to the foreign Thy-1 allele. These genes are almost certainly identical to the Aa and Ap loci of the H-2 complex (Klein and Zaleski, 1989).
Allelic forms of mouse p2 microglobulin differ in a single amino acid, and yet this difference can be detected by the immune system, as confirmed by the production of monoclonal antibodies (Michaelson et al., 1980; Goding and Walker, 1980; Chorney etal, 1982).
There are also several allelic forms of mouse IgM, which reflect genetic differences in the constant region of the p. chain gene (Warner et al., 1977; Black et al., 1978; Schreier et al., 1986; Schuppel et al., 1987). The difference between two IgM alleles is a single conservative amino acid substitution at codon 222 (lysine versus arginine) out of more than 400 amino acids for the whole constant region (Schreier et al., 1986). This minor difference is sufficient to elicit easily detectable allele-specific antibodies.
Membrane IgD also has multiple allelic forms in the mouse (Goding et al., 1976; Goding, 1977, 1980). One site of variation is on the Fc portion, while another is on the Fd portion, presumably in the CH1 domain (Kessler et al., 1979; Goding, 1980). Anti-allotype antibodies can be very useful as structural probes, as these antibodies have very high specificity. Antibodies to IgD allotypes provided some of the first highly specific antibodies to IgD and were generated without the need to purify the IgD molecule. This approach of alloimmunization was a key tool in the early analysis of lymphocyte membrane proteins and the classification of lymphocyte subsets, but has now been superseded by the use of monoclonal antibodies. Immunoglobulin allotypes will be discussed in more detail in Chapter 6.
When the amino acid sequences of proteins are very similar to self, the immune response is often very weak or undetectable. In such cases, the use of immunological adjuvants such as Freund's complete adjuvant (see Section 4.10) may make the difference between a detectable and a nondetectable response.
In the case of cell-surface antigens, it has often been observed that immunization with cells from mice that differ only in the protein of interest will not elicit antibodies, but if the donor and recipient also differ for other genes, strong antibodies may be found (Goding et al., 1977; Lake and Douglas, 1978; Zaleski and Gorzynski, 1980; Lake et al., 1989; Klein and Zaleski, 1989). The presence of multiple genetic differences appears to have a strong adjuvant effect. Cross-immunization of immunoglobulin congenic C57BL/6 mice with immunoglobulin heavy chain congenic partner strain C57BL/6.Ige (which differs from C57BL/6 only in the immunoglobulin heavy chain locus) will not generate detectable antibodies to IgD (Goding et al, 1977). However, immunization of C57BL/6 mice with CBA mice, in which there are multiple genetic differences, results in very strong antibodies to IgD.
These effects are not very well understood. Both MHC and non-MHC genes have been implicated. The additional determinants required for a vigorous response have been variously called 'helper' or 'carrier' determinants, but because they are probably not directly analogous to the classical meaning of these terms, Klein and Zaleski have proposed the term acolyte determinants.
The requirement for acolyte determinants could be important when mice are immunized with mouse cells that have been transfected with human genes, because it is sometimes found that the antibody response to the human gene product is poor unless the transfected cells are derived from a different strain of mouse than the recipient.
A particularly interesting example where the body encounters antigens that are very close to self occurs in cancer, where the neoplastic process results from somatic mutations, translocations and deletions, many of which could be expected to produce 'modified self' proteins that could be detected by the immune system (see also Section 2.6). In a few cases, an immune response can be detected by the presence of cytotoxic T cells or the presence of antitumour antibodies (reviewed by Houghton, 1994; Boon et al., 1994), but the response is usually weak and ineffectual, as demonstrated by the continued growth of the tumour. The same types of considerations regarding weak alloantigens such as Thy-1 presumably apply to tumour antigens. In addition, it would be expected that in most cases, the tumour cells would lack specialized lymphocyte-activating molecules such as the CD28 ligands B7 and CTLA-4. Accordingly, the tumour cells would not be able to provide the necessary second signal, without which antigenic stimulation may lead to specific anergy or nonresponsiveness (Nossal, 1994).
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