1386 Immunoglobulin Diversity and Idiotypes

Two of the intriguing questions in immunology, which in many instances may be related, are the mechanisms by which the vast array of immunoglobulin diversity is generated and the structure of antigenic determinants associated with these molecules. It is now clear that several processes contribute to immunoglobulin diversity. First, there are an apparently large number of both light (L) ~ and heavy (H) chain germline genes (1-4). Second, both L (5-8) and H (9-18) polypeptide chains are encoded in multiple genetic elements, and various combinations of these segments produce a large amount of structural diversity. Third, the joining of these various gene segments may not be precise (6-8, 1113, 17-21), resulting in diversity at the points of recombination. Fourth, L and H chains may randomly pair, although the actual extent of such chain 'shuffling' is undetermined. Fifth, somatic point mutations occur that impose additional diversity on the system (22-29). Sixth, gene interaction (such as gene conversion) among related members of immunoglobulin variable (V) region families may alter primary sequences (30-32). It is thus of interest to analyze the primary structure of groups of related antibodies in terms of the genetic mechanisms that have contributed to the generation of individual molecules. Comparison of related antibodies further presents the opportunity to assess the structural basis of antigenic determinants associated with these molecules and analyze the role of the various genetic processes in the generation of these markers. Since the original discovery in humans (33) and rabbits (34) of individual antigenic specificities (subsequently termed idiotypes) associated with homogeneous immunoglobulins, the structure and potential biologic role of these markers have been of great interest in the field of immunology. Numerous idiotypic systems have been generated and studied in great detail in a variety of species. Most of these studies have dealt with serological characterization of the antibodies involved and very little is known about the molecular basis of idiotypy. Interest in the potential role of idiotypes as biological regulators has been stimulated by the proposal of Jerne (35) suggesting that these determinants constitute a network that may serve to regulate the immune response. In view of the potential value of idiotypes as models for protein antigens, as well as their possible role in immune regulation, it is important to understand the molecular basis of these determinants. One of the systems being used in this laboratory to assess this