The Significance of Natural Autoantibodies

Since Burnet first introduced his “forbidden clones” theory, the discrimination between self and non-self and the physiologic mechanisms of avoiding autoimmunity remained an enigma. The realization in the past two decades that autoantibodies reacting with various self antigens are common in normals has led to intensive research on the origin and physiologic role of these “natural autoantibodies”. After reviewing the extensive literature on the appearance of natural autoantibodies in normal animals and humans, and the studies proving unequivocally that natural autoantibodies are coded by gern line genes, we will discuss the current hypotheses explaining their appearance and physiologic role. Despite the fact that numerous hypotheses explaining the origin of natural autoantibodies have been postulated only the two important ones will be discussed. The first, proposed by Cunningham, holds that clonal deletion as viewed by Burnet operates in early life; however, later in life all autoreactive B cells not eliminated, during ontogeny are prevented from expanding and secreting anti-self antibodies by a compensatory suppressor mechanism. Therefore, natural autoantibodies are postulated to be autoantibodies which are produced only in minute quantities allowed by the suppressor mechanism. The second hypothesis views autoantibody formation as a result of cross reaction between foreign and self determinants. It is suggested that the part of the B cell population which gives rise to autoantibodies carries a polyspecific receptor; fixation of a foreign antigen to this receptor induces the B cell to undergo a series of divisions and mutations, which under the selective pressure of the antigen leads to production of a highly specific antibody. Thus natural autoantibodies may constitute the antibodies secreted by these B cells prior to encountering foreign antigens. The biologic role of natural autoantibodies is also elusive. The common denominator to all the theories dealing with that puzzling question is the view that natural autoantibodies have a positive role in normal immune reactions, perhaps even an essential role without which normal immune function would be disrupted. Grabar suggested that natural autoantibodies are part of a physiologic mechsnism for cleansing the organism of self and non-self products in which classical antibodies serve to clear the body of foreign invading agents, while natural autoantibodies rid the organism of its own catabolic products. Cohen and Cooke suggested that natural autoantibodies, by binding to self antigens, act as a filter preventing powerful immune response against self triggered by self mimicking determinants on foreign invading microorganisms. Others have suggested a role for natural autoantibodies in the idiotypic network. We propose a different function for natural autoantibodies, namely enhancing host immune reactions to foreign infectious agents, in a similar manner in which HLA antigens participate in the activation of B and T cells, The question of the origin and biologic role of natural autoantibodies is not a purely academic one, and understanding these mechanisms will certainly clarify the pathogenesis of autoimmune diseases and autoimmunity in general.