A1: Define the impact of shift work on autoimmunity and autoimmune diseases

Background. In our modern 24/7 society about 10 % of German employees work in night or rotating shifts. Resulting circadian disruption, mistimed sleep and emerging sleep disturbances can lead to low-grade systemic inflammation, loss of counter-regulatory anti-inflammatory control mechanisms, as well as impaired innate and adaptive immune defense against pathogens (Physiol Rev 99:1325; Proc Natl Acad Sci USA 113:E1402). Shift work is therefore a potential risk factor for diabetes, cardiovascular diseases, and cancer. Shift work is also associated with an increase in the prevalence of autoantibodies against thyreoperoxidase (Int J Immunopathol Pharmacol 19:31) and might promote autoimmune diseases like SLE (J Rheumatol 31:1928). First experiments confirm enhancing effects of sleep deprivation (Am J Physiol 291:R1527) or circadian disruption (Comp Med. 67:116) on disease progression in lupus-prone mice. The exact cellular and molecular mechanisms, however, remained elusive. We aim to fill this gap by analyzing inflammation and autoimmunity in shift workers and in mouse models.

Objectives. (i) Deep immunophenotyping of circadian disruption in humans and mice. (ii) Assess prevalence of defined autoantibodies in shift workers and in mouse models of circadian disruption. (iii) Circadian disruption in experimental models of autoimmune diseases.

Work program. To address the objectives (i) and (ii), a cohort of shift workers with day-time workers as controls (recruited from UKSH), and mice in which shift work is mimicked or mutant mice which lack clock genes will be deeply immunophenotyped (FACS analyses for immune cell repertoire, bead-based assay for chemo- and cytokines, whole-transcriptome analysis). This will be paralleled by determination of sleep parameters and autoantibodies. To functionally investigate the role of circadian disruption on the early development of autoimmune disease and to delineate potential mechanisms, the light-dark schedule will be manipulated in mice that develop spontaneous autoimmune disease (NZM2410 and BXD2).