The Chicken or Egg dilemma: are antibodies to aberrantly modified conformational peptide epitopes in autoimmunity reminiscent of early infections?

Autoimmune diseases affecting an increasing number of individuals throughout the world, represent a large and diverse group of disorders categorized by tissue injury or pathology. Thus, characterisation of reliable biomarkers is necessary not only for an early diagnosis but also for monitoring disease activity. Growing evidences indicate that aberrant post-translational (PTMs) modifications (i.e., acetylation, lipidation, citrullination, phosphorylation, glycosylation, glycation, etc.) may play a fundamental role in triggering specific antibody response to aberrantly modified native antigens in immune compromised diseases. We have been developing since years, structure-based designed N-glucosylated peptides, characterized by β-turn structures, as Synthetic Antigenic Probes (SAPs) accurately measuring in sera of statistically significant patient populations of neuroinflammatory diseases, i.e. Multiple Sclerosis and Rett Syndrome, high affinity antibodies as biomarkers of disease activity. This “chemical reverse approach” allowed to identify a cross-reactive hyperglucosylated bacterial adhesin protein, i.e., non-typeable Haemophilus influenzae that is leading to discover a possible early infection [1]. Therefore, a series of peptide scaffolds modified with different aberrant PTMs, were designed, developed, and selected to recognise specific antibodies in coeliac disease [2], primary biliary cirrhosis [3], T1 diabetes [4], rheumatoid arthritis [5]. On the other hand we and others demonstrated that glycoreplica peptides could mimic the carbohydrate epitope of human natural killer cell-1, HNK-1, that is considered the antigenic determinant of myelin-associated glycoprotein and the target of clinically relevant autoantibodies in autoimmune neurological disorders such as IgM monoclonal gammopathy and demyelinating polyneuropathy [6,7]. Therefore, the collection of these SAPs have been proposed to develop multiple diagnostic/prognostic immunoassays with a theranostic value. Last but not least, the SAPs can be fundamental tools to characterise cross-reactions with bacterial and/or viral infection-mediating enzyme activity involved in aberrant modifications of native antigens and triggering antibodies, as early causative agents of immune-dysregulation.