Κλινική Ρευματολογίας, Κλινικής Ανοσολογίας και Αλλεργιολογίας
Ιατρικής Σχολής, Πανεπιστημίου Κρήτης



Objectives (research directions)

 

Overview of the Laboratory

 

The Laboratory of Rheumatology, Autoimmunity and Inflammation together with the Affiliated Clinical Research Unit at the University Hospital, represent an interdisciplinary group of physician scientists, bio-scientists, clinicians and nurses that invesatigates   medical inflammation in the context of autoinflammatory-autoimmune rheumatic diseases (rheumatoid arthritis [RA]), systemic lupus erythematosus [SLE], familial Mediterranean fever).


The laboratory explores mechanisms of tissue injury and repair with the ultimate goal of developing novel therapies. We use animal models of SLE, RA, and other autoimmune diseases, as well as tissues obtained from humans (blood, bone marrow, skin, synovium and kidney), investigating innate and adaptive immune responses under the premise that they share common effector pathways for tissue injury. Importantly, we explore the relative contribution of these pathways in human diseases by studying well characterized patient cohorts seeking to identify molecular biomarkers for diagnosis and monitoring. We seek to understand how novel therapies work and explore molecular or genetic biomarkers that predict response or toxicity to therapy.


We are interested in understanding how these mechanisms intersect in the context of "immune tolerance" and the "homeostatic regulation" of the inflammatory response that protects the organism from inflammation-induced injury. We also seek to understand how variations in genome and gene expression observed in these diseases may contribute to aberrant function of immune cells. Because these diseases are associated with an increased risk for infection due to inherent immune defects and the effect of immunosuppressive and biologic drugs, we are interested in defining host-defenses against specific pathogens such as fungi..To gain further insight in the dynamics of host-fungal interplay, we have developed mini-host models of fungal disease in Drosophila, an ideal model organism to perform high- throughput genetic screens.

 

Inflammation and Inflammatory Diseases

 

Inflammation– a type of a non-specific immune response – is the biologic process by which the body responds to infection, irritation or other injury or environmental exposures. When inflammation involves primarily the musculoskeletal system, this may result to pathogenesis of diseases collectively called inflammatory rheumatic diseases”. Some of the most well-known inflammatory rheumatic diseases include:

  •         Chronic inflammatory arthritides (RA and spondyloarthropathies)
  •         Collagen vascular diseases (SLE, systemic sclerosis, myositis)
  •         Systemic vasculitides (Adamantiades-Behcet's disease, ANCA-associated vasculitides).
  •         Other autoinflammatory diseases such as the familial Mediterranean fever (FMF).

Inflammatory rheumatic diseases are not uncommon affecting approximately 1-2% of the population. People of both sexes and across all ages may be affected. In general, women tend to be affected more commonly than men; in fact, some autoimmune rheumatic diseases such as SLE, have a very strong predilection for women of the reproductive age. If not managed appropriately, inflammation may lead to irreversible injury (damage) of the joints (bone and cartilage), kidneys, heart and lung, blood, skin or other organs, resulting in significant morbidity and disability.

Inflammatory rheumatic diseases are characterized by acute and chronic inflammation. Inflammation is provoked either by an immune response directed against self-constituents (auto-immunity) or by yet unidentified non-self, non-pathogen targets (auto-inflammation). Research has thus far revealed the important role of cells (B and T lymphocytes, monocytes and monocyte-derived cells, neutrophils), co-stimulatory or inhibitory molecules such as CTLA-4, PD-1, and BTLA, as well as cytokines such as tumor necrosis factor (TNF), interferon-gamma (IFN-γ) and interleukins in mediating tissue injury. De-regulation of cytokine production or cytokine networks have also been implicated in their pathogenesis.

 

Research Interests

 

  • We are developing the idea that effector mechanisms in autoimmune inflammation involve components of both the adaptive and the innate immune responses. We are also exploring whether autoimmune and auto-inflammatory diseases may be using common effector pathways. Such pathways include: a) extracellular and intracellular immune receptors such as toll like receptors (TLRs) and other danger signal receptors (e.g. NOD-like receptors) that transduce signals via the adaptor molecules, b) immune receptors that participate in the formation of the inflammasome, c) cytokines (such as IFNs, IL-10 and IL-21), d) innate immunity pathways such as autophagy and NETosis.
  • We are interested in the regulation of genes involved in T- and B-cell function and how epigenetic factors (micro-RNAs) may contribute to pathogenesis of autoimmune disorders.
  • At the translational level, we use novel biologic therapies targeting specific components of the immune response to characterize their importance in the disease and in selected aspects. Based on preliminary clinical and laboratory information, we are promoting the notion that quantitative and qualitative characteristics of the response of tissues to the inflammatory attack (kidneys, joints) may contribute to the disease phenotype.
  • In collaborative studies with the Laboratory of Experimental Hematology, we investigate the biology of bone marrow stem cells and their ability to repair injury caused by inflammation.

For the above-mentioned interest we are in close collaboration with research institutes in:

  • The Biomedical Research Foundation of the Academy of Athens (BRFAA)
    • Dimitrios T. Boumpas, MD, FACP, FACR University Faculty, Affiliated Investigator. Center: Clinical, Experimental Surgery, & Translational Research
    • Panayotis Verginis, PhD, Investigator - Lecturer. Center: Clinical, Experimental Surgery, & Translational Research.
  • The Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis
    • Konstantinos Ritis, MD, Professor of Hematology
    • Konstantinos Kambas, PhD, researcher.

       

Structure of the groups, group leaders and specific research interests

 

The laboratory consists of the following sections-research interests (leaders):

  1. Rheumatoid Arthritis (RA) (P. I. Sidiropoulos, MD, Associate Professor).Effect of novel biologic therapies in specific disease-associated biologic processes such as anemia of chronic inflammation and atherosclerosis. Function of mesenchymal stem. Innate immunity pathways in RA pathogenesis (Inflammasome-associated inflammatory pathways, Neutrophil exracellular traps – NETs).
  2. Systemic Autoimmunity-Systemic lupus Erythematosus. (G Bertsias MD, PhD, Lecturer).Role of peripheral T cell tolerance in the pathogenesis of SLE. The role of the innate immunity and bone marrow micro-environment in promoting lymphocyte hyperactivity in SLE
  3. Gene expression and regulation in autoimmunity/autoinflammation (G Bertsias MD, PhD, Lecturer). The role of genetic variation and epigenetics in gene expression in human and animal models of autoimmunity.
  4. The Clinical Research Unit (P Sidiropoulos, G Bertsias, N. Avgoustidis, A. Repa, M. Tzanakakis, A. Fanouriakis, E. Kampouraki)

 

Funding for the Lab

 

During the last 5 years funding for research activities was based on:

1. European research grants

  • Funding Source:INTEGRATED PROJECT UNDER THE EUROPEAN COMMUNITY FRAMEWORK 6 PROGRAMME. Title: Curing autoimmune disease. A translational approach to autoimmune disease in the post-genomic era using inflammatory arthritis and myositis as prototypes and learning examples”

2. National research grants

  • Funding Source: General Secretariat for Research and Technology (GR) – “Cooperation Grant”. Title: Targeted strategies for new therapies of cardiovascular and inflammatory diseases based on protective actions of High Density Lipoproteins (HDL)
  • Funding Source: General Secretariat for Research and Technology (GR) – “Cooperation Grant”. Title: Investigation of Novel Inflammatory Pathways in Chronic Autoinflammatory and Autoimmune Diseases Like Familial Mediterranean Fever (And Other Periodic Fever Syndromes), Uric Acid Arthritis, Crohn's Disease, Rheumatoid Arthritis and Still's Disease»
  • Funding Source: General Secretariat for Research and Technology (GR) – “Cooperation Grant”. Title: Investigation of Novel Inflammatory Pathways in Chronic Autoinflammatory and Autoimmune Diseases Like Familial Mediterranean Fever (And Other Periodic Fever Syndromes), Uric Acid Arthritis, Crohn's Disease, Rheumatoid Arthritis and Still's Disease»
  • Funding Source:Hellenic Society of Rheumatology (ERE). Title: Pathogenesis and treatment of rheumatic diseases. Annual, competitive research grants.
  • Funding Source: Research grants, investigator initiated studies & donations of pharma industry, through the “Special Account of Research, University of Crete”. Title: “Investigation of pathogenesis, natural history and treatment of autoimmune, inflammatory systemic diseases”.

 

Publications (Selected)

 

1. Nakou M, Knowlton N, Frank MB, Bertsias G, Osban J, Sandel CE, Papadaki H, Raptopoulou A, Sidiropoulos P, Kritikos I, Tassiulas I, Centola M, Boumpas DT. Gene expression in systemic lupus erythematosus: bone marrow analysis differentiates active from inactive disease and reveals apoptosis and granulopoiesis signatures. Arthritis Rheum. 2008;58: 3541-9.

2. Bertsias GK, Nakou M, Choulaki C, Raptopoulou A, Papadimitraki E, Goulielmos G, Kritikos H, Sidiropoulos P, Tzardi M, Kardassis D, Mamalaki C, Boumpas DT. Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus. Arthritis Rheum. 2009;60: 207-18.

3. Papadimitraki ED, Tzarsi M, Bertsias G, Sotsiou E, Boumpas DT. Glomerular expression of toll-like receptor-9 in lupus nephritis but not in normal kidneys: implications for the amplification of the inflammatory response. Lupus. 2009;Aug;18(9):831-5.

4. Bertsias GK, Nakou M, Choulaki C, Raptopoulou A, Papadimitraki E, Goulielmos G, Kritikos H, Sidiropoulos P, Tzardi M, Kardassis D, Mamalaki C, Boumpas DT. Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus Arthritis Rheum. 2009;60: 207-18.

5. Nakou M, Bertsias G, Stagakis I, Centola M, Tassiulas I, Hatziapostolou M, Kritikos I, Goulielmos G, Boumpas DT, Iliopoulos D. Gene network analysis of bone marrow mononuclear cells reveals activation of multiple kinase pathways in human systemic lupus erythematosus. PLoS One. 2010;5.

6. Stagakis E, Bertsias G, Verginis P, Nakou M, Hatziapostolou M, Kritikos H, Iliopoulos D, Boumpas DT. Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann Rheum Dis. 2011; 70: 1496- 506.

7. Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, Sidiropoulos P, Boumpas DT. Interleukin-21 is increased in active systemic lupus erythematosus patients and contributes to generation of plasma B cells.Clin Exp Rheumatol. 2013;Mar-Apr;31(2):172-9

8. Stagakis I, Bertsias G, Karvounaris S, Kavousanaki M, Virla D, Raptopoulou A, Kardassis D, Boumpas DT, Sidiropoulos PI. Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Res Ther. 2012 Jun 12;14(3):R141

9. Repa A, Bertsias GK, Petraki E, Choulaki C, Vassou D, Kambas K, Boumpas DT, Goulielmos G, Sidiropoulos P. Dysregulated production of interleukin-1β upon activation of the NLRP3 inflammasome in patients with familial Mediterranean fever. Hum Immunol. 2015 Jul;76(7):488-95