The Autoreactive Repertoire Is An Important Component Of The Normal Bcell Repertoire

In 1956, Witebsky and Rose [9] induced for the first time, an experimental autoimmune disease mediated by autoantibodies: autoimmune thyroiditis. They succeeded in inducing the disease by injecting thyroglob-ulin in the presence of Freund's adjuvant. Since they were able to produce autoantibodies, the precursor B cells producing these should exist. More recently, considerable data have accumulated raising doubts concerning the clonal deletion theory as an unique explanation for tolerance since: (1) autoimmune diseases can be induced by injecting organ extracts [9]; (2) numerous autoantibodies have been demonstrated under normal conditions [10-12]; and (3) autoantibodies have been induced from normal B lymphocytes upon mitogenic stimulation [13, 14],

In the early eighties, our group [15], and several other groups [16, 17], demonstrated the presence of polyreactive auto-Abs naturally occurring in the serum of all normal subjects, and that myeloma proteins frequently correspond to expansion of these polyreactive auto-Abs [18, 19]. We could also demonstrate a high frequency of precursor B cells displaying natural autoantibody (NAA) activity [20, 21]. These data were further confirmed and expanded to wider developments by multiple functional and structural studies (reviewed in [22, 23]).

Thus, we have evolved from Ehrlich and Morgen-roth's [3,4] "horror autotoxicus" notion, to Burnet and Fenner's [7] forbidden clones hypothesis, to now reach the view that autoimmunity is a normal physiological phenomenon. But, how can we reconcile the experiments from Metchnikoff [1] with those from Ehrlich and Morgenroth [3, 4] and Landsteiner [5], since all these results could never be challenged. Experiments with transgenic mice allows for the integration of all this experimental evidence. Nemazee and Burki [24] created transgenic mice by transfecting both an Ig transgene with antibody activity against class I antigens of the major histocompatibility complex (MHC), and the respective MHC antigen recognized by the antibody transgene. This is a very critical situation, since the transgene is recognizing a determinant of polymorphism, that is a real self-antigen. In that case, according to Burnet and Fenner's prediction, the transgene is deleted. However, if transgenic mice are created expressing Ig transgenes with autoantibody activity, which is not directed against critical self-polymorphic determinants as is the case for anti-DNA and antilysozyme antibodies, the transgene is not deleted—it is simply down-regulated or anergized [25, 26]. These experiments throw light on the apparent discrepancy between Ehrlich and Morgenroth [3, 4], Landsteiner [5] and Metchnikoff [1]. Indeed, the observation that a subject expressing the A or B group will never produce autoantibodies against these determinants is widely accepted, and we know of no cases of autoimmune hemolytic anemias displaying autoantibodies with this specificity. However, the production of autoantibodies against public antigens like the I group, is a common phenomenom. Hemolytic anemia autoantibodies are all directed against these public antigens. So, the B-cell repertoire that is going to be directed against critical self-determinants will probably be subjected to a very stringent negative selection, i.e., deletion, whereas the repertoire that is directed against determinants shared by all individuals without belonging to the species (public self-antigens) is probably not deleted and is an important component of the normal immune repertoire. These NAA are characterized by their widespread- but low affinity-binding pattern.

These results indicate that, in normal serum, a substantial proportion of circulating Igs are indeed NAA, and the precursors of this autoreactive repertoire account for a substantial part of the normal B cells. As these autoantibodies express recurrent idiotopes and V genes frequently in germinal configuration and predominate early in life, they are the expression of the germinal repertoire [27-30]. They are autoantibodies because they bind autoantigens. However, they are not self-specific, because they have never been reported to exist against the very critical self-antigens such as the A and B red blood-cell groups. On the contrary, these autoantibodies bind public epitopes shared by all individuals belonging to a given species, and even antigens that are well conserved during evolution. However, this is also the characteristic of pathogenic autoantibodies observed in autoimmune diseases. For example, anti-red blood cell autoantibodies recognize public antigens; anti-DNA from systemic lupus ery-

thematous (SLE) patients recognize human, rat and murine DNA; anti-AChR autoantibodies recognize human and even fish receptors, etc. [22],

One of the major characteristics of NAA is their broad specificity that allows them to bind self- and nonself-antigens such as microbial molecules. Interestingly, this repertoire has been found in species phylogenetically distant from mammals such as fish and batracians [31], where this specificity can be associated with the immune defences against infections [32], We know that these animals are unable to make somatic mutations and produce highly specific, high-affinity antibodies. Hence, their repertoire is much less diverse [32]. When the possibility of high diversification is absent, the only possible strategy is to produce these polyreactive, low-affinity antibodies. The reason why they are conserved during evolution is probably to serve as a first barrier of defence. Even with a memory response to a foreign antigen it takes 5-6 days to obtain high-affinity antibodies. This polyreactive NAA repertoire might be the system that is coping with aggression during this time. The possibility exists that these polyreactive NAA could constitute a template on which Ag-driven selection and somatic mutation could operate to derive highly specific immune antibodies [20, 22], However, this hypothesis requires an experimental verification.

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