Increase in intracellular protein modification associated with altered lymphocyte functions in autoimmunity

Abstract

Lymphocytes that react with ubiquitous self-antigens are typically eliminated within the thymus and bone marrow to prevent autoimmune response. However, not all self-antigens exist during thymic selection, which results in the escape of autoreactive T and B cells to the peripheral circulation. Posttranslational modification of protein usually generates neo-epitopes from self-proteins, causing a break in immune tolerance. One such modification, termed isoaspartyl (isoAsp), is the spontaneous non-enzymatic modification of aspartate or asparagine residues occurring at physiologic pH and temperature. The widely distributed protein L-isoaspartate-O-methyl-transferase (PIMT) enzyme is the repair system for abnormal isoaspartyl residues in vivo. Our laboratory has previously reported that PIMT deficient mice exhibit T cell hyperproliferation and lupus-like autoimmunity. Recently, we found that in contrast to control B10.BR mice, the isoAsp content in MRL autoimmune mice increased and accumulated with age in erythrocytes, brain, kidney, and in T lymphocytes. The lupus-CD4+ T cells exhibit hyperproliferative response to antigen stimulation and increase in isoaspartyl content both in vitro and in vivo as T cells are activated. These studies demonstrate a role for the accumulation of intracellular isoaspartyl proteins associated with T cell proliferative defects in autoimmune. (These studies were supported by NIH grant AI-48120 to MJM.)