Alteration of an Autoantigen by Chlorination, a Process Occurring During Inflammation, Can Overcome Adaptive Immune Tolerance

Autoimmune diseases are characterized by chronic inflammation in target organs and immunoreactivity towards one or multiple autoantigens. Several potential mechanisms of tolerance breaking have been postulated, one being inflammation‐associated events. We have investigated whether chlorination of an autoantigen can lead to disruption of self‐tolerance. Chlorination of antigens might occur during inflammation via the granulocyte‐specific, myeloperoxidase‐catalysed conversion of hydrogen peroxide to hypochlorous acid (HOCl). HOCl, being a strong oxidant, reacts with proteins both within cellular phagosomes and in the immediate extracellular environment. By immunizing Lew.1AV1 rats with chlorinated or unmodified rat serum albumin (RSA), we could detect tolerance‐breaking effects of chlorination. RSA is a systemic autoantigen in rat not inducing antibody production upon immunization in its unmodified form. Rats immunized with chlorinated RSA (RSA‐Cl) developed high titres of immunoglobulin G (IgG) specific for RSA‐Cl which cross‐reacted with native RSA. T cells reactive with both RSA‐Cl and RSA were detected by [3H]‐thymidine incorporation. We hence speculated that immunological tolerance established for unmodified proteins, during certain circumstances such as inflammation, might be broken by induced protein chlorination. T cells specific for the chlorinated protein can confer help to B cells recognizing both the chlorinated and the native form of the protein, leading to the formation of high‐affinity autoreactive antibodies and possibly autoimmune disease.