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A8.24 autophagy may contribute to glucocorticoid resistance in myositis patients by maitaining muscle T cells homeostasis
  1. Mei Zong,
  2. John Jörholt,
  3. Julia Winter,
  4. Eva Lindroos,
  5. Helena E Harris,
  6. Ingrid E Lundberg
  1. Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden

Abstract

Background and Objectives Infiltrating T cells is a typical histopathologic feature in muscles of patients with myositis and they play important roles in the disease development. In contrast to macrophages which usually can be reduced extensively after glucocorticoid (GC) treatment, T cells often persist, and the reasons are still unclear. Autophagy helps cells to survive under variable cellular stresses. In this context the effects of endogenous, cytosolic high mobility group box 1 (HMGB1) protein is of interest as HMGB1 can induce autophagy by binding Beclin1 (an upstream protein initiating autophagy) and thereby contribute to cell survival. In this study, we will investigate whether autophagy initiated by HMGB1-Beclin1 binding can contribute to T cell survival in the muscles of patients with myositis, and whether these homeostatic T cells are related to GC treatment resistance.

Materials and Methods Muscle biopsies were obtained from poly- and dermato- myositis patients with no or limited clinical response to GC and from patients with good response to GC. Biopsies were investigated by immunohistochemistry for macrophages (CD163, CD68), T cells (CD3), HMGB1 and Beclin1. Computer image analysis was performed for each marker. Co-localization of HMGB1, Beclin1 and T cells was done by consecutive section staining and was confirmed by double fluorescence staining.

Results Both HMGB1 and Beclin1 expression was detected in muscle tissue of patients with myositis; furthermore, the expression co-localised to the infiltrating T cells as demonstrated by consecutive section staining and double fluorescence staining. Moreover, the expression of autophagy marker Beclin1 correlated with both HMGB1 and T cells (p<0.05). In nine patients who are good responders to GC, the number of T cells in the muscles was decreased after treatment, and simultaneously the HMGB1 and Beclin1 expression was decreased. Analyses are ongoing on the non-responders. According to our hypothesis in these patients T cells will not be reduced as much as good responders after treatment and HMGB1 and Beclin1 expression will maintain at high levels too.

Conclusions Markers of autophagy are present in the invading T cells in muscle tissue of myositis patients. Autophagy initiated by HMGB1-Beclin1 binding may contribute to T cell survival in the muscles of patients with myositis. And this homeostasis in T cells could be a factor that contributes to the GC resistance.

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