Autoantibody

 Autoantibody is a very misleading term for certain antibodies, because it covers very different situations. This probably is largely due to Ehrlich's initial proposals, formulated at the beginning of the twentieth century, of the horror autotoxicus dogma, leading later to the discrimination between self and nonself (1). If one sticks to this view, one must consider that autoantibodies escape from the dogma and produce a pathological situation, as is the case for autoimmune diseases. Two main observations have led us to revisit this view: one is the existence of idiotypes and anti-idiotypes, and the other is the presence of the so-called natural autoantibodies.

It was proposed by Jerne (2) that immunoglobulins are organized as a large idiotypic network in which Ig molecules regulate each other by their interactions. Another, more pragmatic approach would be to consider that the millions of different Ig molecules present at any given time in one individual provide a sufficient number of different specificities to recognize any potential epitope, including those expressed by the immunoglobulins themselves, and more generally by any self-epitope, unless subject to strict negative selection during differentiation, leading to an absolute tolerance state, which would be in agreement with Ehrlich's concept. Is this the case? During B-cell differentiation, before leaving bone marrow as immature B lymphocytes, newly formed cells are screened against the local environment, and self-aggressive cells are eliminated, providing the major basis for B-cell tolerance. But this is not an all-or-none phenomenon. It is believed to be relatively flexible, based on the average affinity of IgM molecules expressed at the surface of immature B cells. This view leaves open the possibility that immature B cells circulating in the periphery have retained some autoreactive potential against a possible self antigen.

 The next question is, Are there natural immunoglobulins endowed with properties of recognition of self molecules? The answer is undoubtedly yes and is supported by many observations, especially those from the groups of Avrameas and Coutinho (3). Natural antibodies in whole serum were first described as having the essential characteristic of being polyreactive, a conclusion that was not a priori surprising because of their polyclonality. When analysis at the monoclonal level was made possible with the hybridoma technology, it was realized that most natural antibodies had a wide recognition spectrum, as observed from their patterns of binding to many different molecules used for systematic screening. Most natural antibodies were IgM, and complementary DNA sequencing of their V_H and V_L regions revealed that they contained very few mutations, indicating that they reflected transcription of germline genes. Affinity measurements revealed moderate but significant association constants. Natural monoclonal autoantibodies thus seem best defined as primarily germline-encoded and polyreactive. Polyreactivity contains in itself the possibility of having both anti-self and anti-nonself specificities. Presumably due to their relatively modest affinities, low concentration, and, of course, the fact that they passed the screen for potentially aggressive anti-self specificities, these antibodies qualify as harmless and may be regarded as the pool of basic circulating immunoglobulins of wide spectrum, endowed with a high connectivity, and constituting the primary germline idiotypic network. By contrast, aggressive autoantibodies found in the serum of patients suffering autoimmune diseases generally contain mutated sequences and are often of isotypes other than IgM.

One may thus consider active immunization as bringing a transient perturbation of the background of the natural equilibrium, leading to the emergence of clones that acquire a greater affinity and an increased specificity through the occurrence of somatic hypermutations.

References

1. P. Ehrlich (1900) The Croonian lecture: On immunity. Proc. Roy. Soc. Lond. (Biol.) 66, 424. 

2. N. K. Jerne (1974) Towards a network theory of the immune system. Ann. Immunol. 125C, 373–389.

3. A. Coutinho, M. D. Kazatchkine, and S. Avrameas (1995) Natural autoantibodies. Curr. Opin. Immunol. 7, 812–818.