Altered ER Stress-Induced Autophagic Reactions Are Associated With Increased Apoptosis of T Lymphocytes in Systemic Lupus Erythematosus

Won Seok Lee¹, Myung-Soon Sung¹, Eun-Gyeong Lee¹, Chang-Hoon Lee², Myeung Su Lee³, Yun-Hong Cheon⁴, Sang-il Lee⁴, Yun Kyoung Hong⁵ and Wan-Hee Yoo⁶, ¹Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Jeonju, South Korea, ²Department of Internal Medicine, School of medicine, Wonkwang university, Iksan, Chonbuk, South Korea, ³Department of Internal Medicine, School of Medicine, Wonkwang University, Iksan, Chonbuk, South Korea, ⁴Division of Rheumatology, Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, South Korea, ⁵Rheumatology, Department of internal medicine, Presbyterian medical center, Jeonju, South Korea, ⁶Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Jeonju, South Korea

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: ER Stress, SLE and T cells

Session Information

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis: Mechanisms and Biomarkers

Session Type: Abstract Submissions (ACR)

Background/Purpose:

The autophagic responses to ER stress are involved in the regulation of the maintenance of lymphocyte homeostasis and has been implicated in the pathogenesis of autoimmunity. However, there were no studies about the roles of autophagic responses and its relations with apoptosis of T lymphocytes in systemic lupus erythematosus (SLE). Thus, we investigated to study about the pathogenetic roles of ER stress-mediated pathways, autophagic and apoptotic reactions in the T lymphocyte survival and death in SLE.

Methods:

We investigated the spontaneous and induced autophagic and apoptotic behavior of T lymphocytes from patients with SLE compared with that of T lymphocytes from healthy donors by measuring the autophagy marker microtubule-associated protein 1 light chain 3 (LC3) II and autophagosome by scanning electron microscope. The molecular mechanism of the altered autophagic and apoptotic responses and their relations were investigated in T lymphocyte transfected with siRNA for beclin 1, CHOP and T lymphocyte with overexpression of GRP78 by transfection. The apoptosis, autophagy and ER stress signaling molecules were examined by immunoblotting.

Results:

There were increased apoptosis and decreased autophagic responses to Thapsigargin (TG) in T lymphocytes from healthy controls compared with these cells from patients with SLE. The activation of ER stress signaling molecules, including PERK, p-eIF2a, IRE1 and ATF6 to TG were decreased in lupus T cells. The expression of anti-apoptotic molecules, Bcl-2, Bcl-XL were decrease and proapoptotic molecules, Bax, caspase-6 were increased in lupus T cells. Our results also revealed that CHOP expression was increased and GRP78 was decreased in lupus T cells. GRP78 overexpression and CHOP siRNA knockdown in T cells from healthy donors were associated with altered apoptotic cell death.

Conclusion:

The autophagic and apoptotic responses to TG-induced, ER stress are altered and contribute to the abnormal T cell homeostasis with increased apoptotic T cell death. We hypothesize that aberrant autophagic and apoptotic reactions of T lymphocytes to ER stress are involved in the pathogenesis of SLE and might be an important target of treatment.

Disclosure:

W. S. Lee,
None;

M. S. Sung,
None;

E. G. Lee,
None;

C. H. Lee,
None;

M. S. Lee,
None;

Y. H. Cheon,
None;

S. I. Lee,
None;

Y. K. Hong,
None;

W. H. Yoo,
None.

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