Natural Human Antibodies to Synthetic Peptide Autoantigens: Correlations with Age and Autoimmune Disease

Abstract

Clinically healthy humans as well as patients suffering from various autoimmune diseases produce natural antibodies against a variety of self-components. Such antibodies have been proposed to carry out a physiologic role in maintaining the integrity of self, as well as potentially destructive roles in the generation of autoimmune diseases. Because human autoantigens, particularly membrane proteins, are usually present in extremely small amounts, it is generally impossible to obtain enough to carry out a detailed characterization of the antibodies or the antigenic determinants recognized. To circumvent this difficulty, we developed synthetic autoantigens predicted from the gene sequence of two functionally critical membrane proteins; the band 3 anion transport protein which is found on all cells, and the T-cell receptor (β chain) which is the antigen-specific receptor on thymus-derived lymphocytes. We have investigated the natural human IgM and IgG antibody responses to peptides selected on the basis of predicted molecular surface exposure and previously known antigenicity, and correlate levels of binding with changes in age and by comparison with autoimmune diseases. We report that the IgM response to synthetic autoantigens tends to be higher than that of IgG molecules, but significant IgG binding occurs to some peptides. This situation is particularly noticeable in comparison of rheumatoid arthritis patients with normal individuals. Distinct peptide portions of individual molecules are recognized differently by the autochthonous immune system as manifested by age dependence of the response and differential levels of IgM and IgG activity. The synthetic autoantigens that tend to generate the highest amounts of natural antibody are those that are either exposed on the surface of the cell (band 3 peptides) or are exposed in the predicted 3-dimensional folding of the molecule (T-cell receptor β peptides). Rheumatoid arthritis patients tend to give higher IgM reactivities to both band 3 and Tcr β peptides than do normals, with this effect being less pronounced in the distinct autoimmune disease systemic lupus erythematosus. Studies of normal humans ranging in age from 20 to 90 years suggest two major patterns for the IgM natural antibody response to synthetic peptides giving high response. The first is that the level of IgM reactivity is high early in life and remains high throughout. The second pattern is one in which the reaction is high in younger individuals, but diminishes substantially in the latter decades of life. Although there is substantial variation in the IgG autoantibody responses, which most probably are strongly dependent upon T-cell help, the overall pattern is for these to be low early in life, and to increase with increasing age. We speculate that the antibody activities detected in the normal individuals carry out a physiologic regulatory role, as opposed to a destructive autoimmune dysfunction, because these molecules can be present in high levels throughout life.

Autoantibodies to the alpha/beta T-cell receptors in human immunodeficiency virus infection: dysregulation and mimicry.

“…There is a constitutive autoimmunity in healthy individuals to immunoregulatory segments of TCR (3 chain (13,14). The levels of autoantibodies with characteristic specificity for these V(3-CDR1, V(-FR3, and CP determinants are substantially increased after HIV infection.…”

“…We have shown that normal humans (13) and individuals suffering from autoimmune diseases (14,15) can have elevated levels of autoantibodies directed against peptide determinants forming putative immunoregulatory sites on the V domains making up complementarity-determining region (CDR) 1, framework region (FR) 3, and a region of the constant (C) domain. Studies with mice show that these types of autoantibodies are generated after experimentally induced infection with retrovirus (16).…”

“…Antibodies to CDR1 and FR3 of TCRs are probably regulatory and are present in low amounts in serum from healthy individuals. In marked contrast, serum from patients with autoimmune disease such as rheumatoid arthritis (14,15) contain high levels of autoantibodies directed against peptides 3 (CDR1), 8 (FR3), and 17 (C(3 "loop"). 3.…”

Human monoclonal natural autoantibodies against the T‐cell receptor inhibit interleukin‐2 production in murine T cells

“…14-16 A prevalence of anti-TCR antibodies, however, has been reported in conditions such as ageing, 17,18 pregnancy, 19 allograft transplantation, 20,21 retroviral infections, 22,23 and autoimmune diseases. 14,15,17,18 It has been proposed that NAAbs against the TCR may serve in immunoregulation of T cells.…”

Retrovirally Induced Mouse Anti‐TCR Monoclonals can Synergize the In Vitro Proliferative T Cell Response to Bacterial Superantigens

“…The detection of autoantibodies directed against peptide defined epitopes of the T-cell receptor (TCR) b chain in normal sera and various physiological and disease states has been established in our laboratory using synthetic overlapping peptides and subsequent synthetic peptide epitope homologue analysis [1][2][3][4]. Initially, 22 nested synthetic 16-mer peptides were synthesized with five residue overlaps in order to mimic the covalent structure of the TCR b chain for epitope mapping studies of the Bence-Jones protein Mcg (l light chain: see [5]) and the YT35 TCR b gene product (TCR Vb8.1 human: see Refs 1,4 and 6).…”