Autoantibodies to intracellular antigens form a large family of immunoglobulins directed to a variety of ubiquitously expressed intracellular molecules, including numerous enzymes, some ribonucleoproteins and double-stranded DNA. These anti-self antibodies have been found to be selectively expressed in sera of patients with several systemic (non-organ-specific) autoimmune diseases, such as systemic sclerosis (SSc), SLE, mixed connective tissue disease, Sjögren's syndrome and idiopathic myopathies. Despite their important diagnostic and prognostic value and their utility in assessing disease activity, little is known about the molecular mechanisms involved in their generation and role in autoimmune diseases nor is it known why particular autoantibodies are preferentially expressed in certain diseases. Here, we review the different lines of research which are presently being conducted to understand how these autoantibodies are generated (e.g. through apoptotic body formation, molecular mimicry and other mechanisms) and how they encounter antigen in order to cause an autoimmune disease. The recently reported mechanism of intracellular immunity mediated by Ro52 (or tripartite motif containing 21, TRIM21) in a cellular model of adenovirus infection is opening new perspectives for studying the effects of autoantibodies once they get inside cells.
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