Abstract 2067: High Mobility Group Box Chromosomal Protein 1 (HMGB-1) a New Inducer of MHC Class I Expression in Muscle Fibers
Authors
Ingrid E. Lundberg, Cecilia Grundtman, Joseph Bruton, Ulf Andersson, Helena Erlandsson Harris, Håkan Westerblad.
Background
High mobility group box chromosomal protein 1 (HMGB-1) is a DNA-binding protein. Extracellular HMGB-1 functions as a potent pro-inflammatory cytokine. In untreated myositis patients with inflammatory infiltrates HMGB1 was detected with extracellular and extranuclear expression in muscle tissue. This study aimed to investigate whether HMGB-1 could have a role as inducer of major histocompatibility complex (MHC) class I expression in muscle fibers in patients with myositis.
Methods
Muscle biopsies from 31 patients with polymyositis, dermatomyositis, or inclusion body myositis were included in the study. Depending on duration of myositis, and on presence or absence of inflammatory cellular infiltrates in muscle tissue the patients were divided into three subgroups, (1) clinically active disease without inflammatory cells (n=14), (2) chronic inactive disease without inflammatory cells (n=9), and (3) active inflammatory disease with cellular infiltrates (n=8). Biopsies were analyzed for HMGB-1 and MHC class I expression ia immunohistochemistry. Double staining was performed to co-localize expression of the molecules. Conventional microscopic evaluation and digital image analysis were performed. Muscle fibers from
toe muscles of C57BL/6 mice were stimulated in vitro with HMGB-1 and investigated for MHC class I expression.
Results
HMGB-1 was expressed with extranuclear staining in endothelial cells, sarcoplasm, and inflammatory cells in all patients in all three subgroups. MHC class I was expressed in the sarcolemma in 27 patients and in the sarcoplasm in 23. Patients with inflammatory active disease group (1) and (3) had significantly more fibers with HMGB-1 and MHC class I expression in the sarcoplasm compared to treated patients in group (2). MHC class I expression in the sarcoplasm was co-localized with HMGB-1 expression. In early cases without detectable inflammatory infiltrates there were substantially more fibers with sarcoplasmic HMGB-1 expression than with MHC class I staining, whereas in chronic phase the number of fibers with HMGB-1 or MHC class I in the sarcoplasm did not differ. In vitro HMGB-1 stimulated muscle fibers displayed upregulation of MHC class I in the sarcolemma after 12 hours and in sarcoplasm after 24, 36, and 72 hours of stimulation respectively..
Conclusion
HMGB-1 can by itself induce MHC class I expression muscle fibers after in vitro stimulation. This observation together with co-localization of HMGB-1 and MHC class I in muscle fibers from myositis patients observed even without adjacent inflammatory cell infiltrates suggets that sarcoplasmic HMGB-1 may be an inducer of MHC class I expression in muscle fibers in vivo, especially in early disease.
Editorial Comment
MHC Class I is induced in DM/PM but how that induction
occurs is not understood. This group's experiments provide a plausible theory: n that sarcoplasmic HMGB-1 is an inducer of MHC class I expression in muscle fibers in vivo, particularly in early disease.
