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Autophagy as target to reduce sterile inflammation: a potential treatment for auto-immune diseases.

Keywords:
immunology Autophagy animal models

Researchers:
prof. F.G.M. Kroese
prof. A. Vissink
prof. H. Bootsma

Nature of the research:
cell culture, animal models, patient material (i.e., tissue/blood/saliva/tears), molecular immunology, pharmacology

Fields of study:
immunology reumatology molecular biology

Background / introduction
Autoimmunity results from a pathogenic immunogical self-reaction, mediated mainly by the adaptive immune system. Systemic Lupus Erythematosus (SLE) and Sjögren’s syndrome (SjS) are chronic (auto-)inflammatory syndromes, both with unknown pathogenesis. SLE can, amongst others, affect skin, joints, kidneys, lungs, nervous system and serous membranes. Hallmark of disease is the production of antinuclear antibodies. Thereby, SLE typically leads to fatigue, fever and weight loss; depending on the organs involved it might give rise to arthritis, skin lesions (i.e., facial butterfly rash), Raynaud, renal disease, vasculitis, lung disease (i.e., interstitial lung disease, but also pleurisy, pneumonitis, alveolar hemorrhage). SjS is an autoimmune inflammatory disorder that particularly affects lacrimal and salivary glands. Frequent presenting symptoms are sicca complaints (i.e., dry mouth/eyes), often in conjunction with malaise and fatigue. In addition, amongst others purpura, polyneuropathy and arthritis can be present. The estimated prevalence of SjS in the general population is between 0.5-1.0%, which makes SjS, after rheumatoid arthritis (RA), the most common systemic autoimmune disease. SjS can present as primary SjS in patients without other auto-immune diseases (pSjS), but can also present as secondary SjS (sSjS) in patients with another auto-immune disease (e.g. RA SLE). In addition to its association with SLE, SjS is associated with organ-specific autoimmune diseases; in particular, autoimmune thyroid disease, primary biliary cirrhosis and autoimmune gastritis [Kassan and Moutsopoulos 2004]. Further, patients have an 18.8 fold increased risk of developing lymphomas [Zinfzaras et al 2005]. These symptoms may restrict patients in their activity and social participation, leading to a reduced quality of life [Meijer et al 2009]. To date, treatment is only supportive, as no curative treatment is available yet. The development of such novel potential curative treatments is hampered by the limited knowledge about the pathogenesis of the syndromes.

Although the precise mechanisms that lead to the development of auto-immunity remain to be unraveled, (sterile) inflammation is suggested to be the major determinant of tissue destruction in SjS. Although the function of the immune system has been clearly characterized in response to pathogens such as bacteria and viruses (i.e., septic inflammation), the precise mechanisms leading to sterile inflammation, as can be induced by auto-immunity, but also secondary to ischemia/reperfusion, remain to be unraveled. We speculate that autophagy might be involved in the pathogenesis of chronic (auto-)inflammatory disorders such as RA, SLE and SjS. Autophagy (autophagocytosis) is a process by which unnecessary and dysfunctional cellular component are cleared through the action of lysosomes and allows recycling of the components. The autophagic function of the cell is influenced by, amongst others, metabolism (i.e.,starvation), age, inflammation and infections. Clearance of dysfunctional cellular components by autophagy limits the release of intracellular macromolecules/peptides upon cell death. The release of cellular macromolecules (i.e., potential auto-antigens), might play a key role in the induction and/or maintenance of the auto-inflammatory response in SLE and SjS; e.g.,mitochondrial DNAcan activate toll like receptors (TLRs) expressed on B cells and thereby, initiate an autoimmune response [Oka et al 2012]. The hypothesis that ongoing release of cellular debris plays a role in the pathogenesis of SLE and SjSis supported by the finding that auto-antibodies in SLE and SjS are mainly directed against intracellular auto-antigens. Unraveling the mechanisms that lead to the induction of the inflammatory response in SLE and SjS, might lead to the development of novel pharmacological targets to treat auto-immunity.

The research group: research in SLE en SjS has evolved to an important multidisciplinary research line within
the Department of Rheumatology and Clinical Immunology and the Department of Oral and Maxillofacial Surgery of the UMCG. We have currently many PhD and postdoc projects and an open, close and very productive collaboration with the Departments of Ophthalmology, Haematology and Pathology, whichis rather unique in the world. The focus of theresearch is on clinical and translational aspects and has resulted in more than35 publications in leading journals over the last 5 years. Within the UMCG, the researchline is embedded in TRIGR (TRanslational Immunology Groningen) with its central theme of HealthyImmune Ageing and Autoimmunity, which is part of research institute GUIDE. National there arecollaborations with Erasmus MC Rotterdam and UMC Utrecht. Internationally, a number of NIH grants in Sjögren’s syndrome has been obtained together with dr. D. Wong (UCLA), dr. N. Rhodus (Minesota) en dr. K.Moser (Oklahoma). Furthermore, we are part of the EULAR task force on disease indices in Sjögren’s syndrome. Recently, substantial funding was obtained from the Dutch Rheumatology foundation (Reumafonds).
Research question / problem definition
The pathogenesis of SLE and SjSare largely unknown (as is for other autoimmune diseases), although both syndromes share considerable overlap. The limited knowledge about the pathogenesis of the syndrome, hampers the development of a potential curative treatment. Yet, although various symptomatic (i.e.,biologicals), supportive and palliative treatment options are available, there is still no established curative or causal treatment for SLE and SjS.

In general, auto-immunity might arise either by a change in the immune system thereby allowing self-reactivity (i.e., post-infectious cross reactivity), or a alteration in the tissue allowing leading to 'molecular mimicry' and thereby precluding the immune system to distinguish self/non-self. According to Witebsky's postulates, a disease can be characterized as auto-immune if there is: direct evidence from transfer of pathogenic antibody or pathogenic T cells, indirect evidence based on reproduction of the autoimmune disease in experimental animals, circumstantial evidence from clinical clues and genetic architecture clustering with other autoimmune diseases.

In this line of research we aim to:
1) set up a mouse model of SLE and pSjS to study the pathogenesis of the syndromes;
2) test whether SLE and pSjS comply to Witebsky's postulates and thereby, can be considered as auto-immune disease or should be considered as chronic (not auto-immune) inflammatory response (i.e., post-infectious);
3) unravel the pathogenesis of SLE and pSjS by characterizing the molecular footprint of the sterile inflammatory response and determine the role of autophagy;
4) develop potential curative immunotherapeutics that limit the auto-inflammatory response by targeting the molecular signaling pathways revealed previously, e.g., by reducing autophagy or the induction of suppressor T cells;
5) regenerate destructed tissues, such as lacrimal/salivary gland using stem cells, after cessation of the auto-inflammatory response

In order to test these hypotheses, we combine fundamental translation studies with clinical research. Using transgenic mice that are prone for auto-immunity, we study the role of autophagy and toll-like receptors in the pathogenesis of disease. Therefore, cell culture techniques and mouse models are combined; e.g., by transfusing in vitro modified cells or pharmacological inhibition of autophagy in an epithelial cell line in vitro. Molecular analysis such as (q)PCR, Western Blot, ELISA and immunohistochemistry are commonly used techniques.
Workplan
In this research line, we are searching for master students medicine, pharmacy and medical/molecular biology and topmaster students medical pharmaceutical drug innovation (MPDI). We offer the opportunity for research internships ('wetenschappelijke stage' or masterstage) and highly encourage motivated students to enroll into the (D)MD/PhD-programme. The precise workplan will be made together with the student and will depend on personal interests and our research aims. Depending on the work that will be planned (i.e., animal work, transfections, molecular analysis), the prerequisite courses will be arranged as well. In addition, our (inter)national research network allows to perform part of the research abroad (i.e., as part of the MD/PhD-programme). Of course, publications that will arise from the performed work will be (co-)authored by the student.
References
Biomarkers: new biomarker for Sjögren's syndrome--time to treat patients. Kroese FGM, Bootsma H. Nat Rev Rheumatol. 2013 Oct;9(10):570-2.

Current and future challenges in primary Sjögren's syndrome. Vissink A, Bootsma H, Spijkervet FK, Hu S, Wong DT, Kallenberg CG. Curr Pharm Biotechnol. 2012 Aug;13(10):2026-45.

Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model. Horvath S, Nazmul-Hossain AN, Pollard RP, Kroese FG, Vissink A, Kallenberg CG, Spijkervet FK, Bootsma H, Michie SA, Gorr SU, Peck AB, Cai C, Zhou H, Wong DT. Arthritis Res Ther. 2012 Nov 1;14(6):R238.

Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K. Nature. 2012 May 10;485(7397):251-5.

Autophagy in immunity and inflammation. Levine B, Mizushima N, Virgin HW. Nature. 2011 Jan 20;469(7330):323-35.

Effectiveness of rituximab treatment in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled trial. Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N, Brouwer E, Kallenberg CG, Bootsma H. Arthritis Rheum. 2010 Apr;62(4):960-8.

Sjögren syndrome: advances in the pathogenesis from animal models. Chiorini JA, Cihakova D, Ouellette CE, Caturegli P. J Autoimmun. 2009 Nov-Dec;33(3-4):190-6.

Treatment of primary Sjogren syndrome with rituximab: extended follow-up, safety and efficacy of retreatment. Meijer JM, Pijpe J, Vissink A, Kallenberg CG, Bootsma H. Ann Rheum Dis. 2009 Feb;68(2):284-5.

The risk of lymphoma development in autoimmune diseases: a meta-analysis. Zintzaras E, Voulgarelis M, Moutsopoulos HM. Arch Intern Med. 2005 Nov 14;165(20):2337-44.

Clinical manifestations and early diagnosis of Sjögren syndrome. Kassan SS, Moutsopoulos HM. Arch Intern Med. 2004 Jun 28;164(12):1275-84.
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