The idiotypic network in the regulation of autoimmunity: Theoretical and experimental studies

Abstract

The regulation of autoimmunity is a key issue in fundamental immunology. Despite outstanding achievements on this front, we currently have more questions than answers. The idea of an immune network as a regulatory mechanism is quite attractive, since it enables us to explain the selectivity (specificity), and moreover the clonality, of the regulation. Nevertheless it remains unclear how this mysterious network of immune cells is organized, how it operates, and how it exerts control over autoimmunity. This article presents an attempt to understand how the immune network functions and how it controls autoreactivity. We present a mathematical model of the immune network that is based on principles of immune network organization and function that we arrived at from a survey of the available literature. To test the principles on which the mathematical model is based, we studied the model and compared the different responses to antigen that it generated with the results obtained from experimental studies of immune response. The modeled kinetics of idiotype and anti-idiotype in response to the administration of antigen are in good agreement with the experimental kinetics of idiotypic and anti-idiotypic antibodies. To obtain evidence of the existence of idiotypic mechanisms for regulating autoimmunity, we studied a mathematical model containing autoclones and compared the model results with data from experimental studies in a model of autoimmune hemolytic anemia in mice. Because the results from the theoretical and the experimental studies coincide, there is justification to conclude that autoreactive lymphocytes are normal components of the immune network within which they are regulated. We discuss a possible molecular/cellular mechanism for negative control of autoreactive cells as affected by anti-idiotypic antibodies.

Introduction

The regulation of autoimmunity is a key issue in fundamental immunology. No one today will deny that autoreactive lymphocytes are normal representatives of lymphocyte clones, that they have access to the corresponding autoantigens, and that they exhibit activity under normal conditions (von Boehmer and Waldmann, 2010). Furthermore, Carneiro has suggested that autoreactive lymphocytes be viewed as growth points for the entire lymphocyte network during early ontogenesis, with these lymphocytes ultimately determining the repertoire of the body׳s lymphocyte receptors for antigen recognition (Leon et al., 1998). The question then arises: how is autoreactive lymphocyte activity regulated such that autoimmune responses remain nonaggressive under normal conditions? Ever since the clonal selection theory was published, researchers have held to the idea that mechanisms exist for the negative regulation of autoreactive lymphocytes. The idea of these mechanisms evolved along two lines. One of them was focused on the search for a special population of cells that provide negative control of autoreactivity. The idea of such cells has gone from “veto” cells to T-suppressor and regulatory T cells. Despite outstanding achievements on this front, we currently have more questions than answers.

The other approach is based on the idea that there is an idiotypic network which itself, as a system, serves as the negative control mechanism (Jerne, 1974). The idea of an immune network as a regulatory mechanism is quite attractive, since it enables us to explain the selectivity (specificity), and moreover the clonality, of the regulation. Clonality of regulation in an immune network is explained by the fact that for a lymphocyte to be recognized as a regulatory target, an idiotype of an antigen-recognition receptor is used that is unique to each lymphocyte.

Outstanding contributions to the development of this idea in the wake of Jerne were made by such scholars as Behn (Behn, 2007), Carneiro (Carneiro, 1997), Cohen (Cohen and Atlan, 1989), Coutinho (Coutinho, 2003a, Coutinho, 2003b), De Boer (De Boer and Hogeweg, 1989), Hoffmann (Hoffmann, 1975), Perelson (Perelson, 1989), Rodkey (Rodkey, 1980), Root-Bernstein (Root-Bernstein and Couturier, 2006), Shoenfeld (Shoenfeld, 2004), Schulz (Schulz et al., 2013), Sulzer (Sulzer et al., 1994) The history of how knowledge of the immune network has developed is presented in outstanding survey articles (Behn, 2007, Paul, 1984, Rodkey, 1980). Despite significant achievements, it remains unclear how this mysterious network of immune cells is organized, how it operates, and how it exerts control over autoimmunity. Study of the idiotype-anti-idiotypic network is a complex task that requires mathematical modeling. Theoretical ideas have played a profound role in the development of the idiotypic network theory. Mathematical models can help in the precise translation of speculative ideas into quantitative predictions. They can also help establish general principles and frameworks for thinking (Perelson, 1989).

This article presents an attempt to understand how the immune network functions and how it controls autoreactivity. We present a mathematical model of the immune network that is based on principles of immune network organization and function that we arrived at from a survey of the available literature. To test the principles on which the mathematical model is based, we studied the model and compared the different responses to antigen that it generated with the results obtained from experimental studies of immune response. To obtain evidence of the existence of idiotypic mechanisms for regulating autoimmunity, we studied a mathematical model containing autoclones and compared the model results with data from experimental studies in a model of autoimmune hemolytic anemia in mice. We discuss a possible molecular/cellular mechanism for negative control of autoreactive cells as affected by anti-idiotypic antibodies.