Rheumatology and Clinical Immunology Clinic
School Of Medicine, University Of Crete

Objectives (research directions)


1.1 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 investigates medical inflammation in the context of autoinflammatory-autoimmune rheumatic diseases (rheumatoid arthritis [RA]), systemic lupus erythematosus [SLE], familial Mediterranean fever). It has been officially approved as a research laboratory of the Medical School, University of Crete (FEK 1207, 26 April 2016).

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.


1.2 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:

a) Chronic inflammatory arthritides [Rheumatoid arthritis (RA) and spondyloarthropathies (SpA)]
b) Collagen vascular diseases (SLE, systemic sclerosis, myositis)
c) Systemic vasculitides (Adamantiades-Behcet's disease, ANCA-associated vasculitides).
d) 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.


1.3 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, IL-33 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.
  • We focus on the role of immune cells (dendritic cells, Tregs cells, plasmacytoid DCs (pDCs), myeloid derived suppressor cells MDSCs) in controlling immune tolerance in the context of human immune mediated diseases.
  • 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.


1.4 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, Assistant Professor). 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, Assistant Professor). 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, A Repa, N Avgoustidis)


1.5 Common Funding for the Lab

Title: The role of innate immunity in SLE nephritis pathogenesis

Funding Source: Secretariat for Research and Technology (GR) – “Pythagoras I” ”, co-funded, 3rd framework

Contract Number: ELKE PK KA 1935

Status : Principal investigator – D.Boumpas

Budget: 100.000 €

Duration: 01/03/2004-31/12/2007


Title: Invastigating the haetiopathology, clinical progress, prognosis and response to therapy in SLE: prospective and comparative study using DNA arrays in Bone Marrow and Peripheral Blood.

Funding Source: General Secretariat for Research and Technology (GR) – “Pythagoras II””, co-funded , 3rd framework

Contract Number: ELKE PK KA 2086

Status: Principal investigator – P. Sidiropoulos

Budget: 50.000€

Duration: 1/1/2005-31/12/2007


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” (AUTOCURE)


Contract Number: LSHB CT2006018661

Status: partner– D.Boumpas

Budget (for the team): 212,900 €

Duration: 01/09/2007-28/02/2011


Title: Pathogenesis of autoimmune rheumatic diseases

Funding Source: Hellenic Society of Rheumatology (ERE)

Contract Number:

Status: Principal investigator– D.Boumpas

Budget (for the team): 100,000 €

Duration: 2007-12


Title: Pathogenesis of autoimmune rheumatic diseases

Funding Source: ABBOTT

Contract Number:

Status: Principal investigator– D.Boumpas

Budget: 260.500 €

Duration: 2008-2013


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

Contract Number: 09ΣΥΝ-12-897 -‐AP260

Status: partner– D.Boumpas/P.Sidiropoulos

Budget (for the team): 110.000€

Duration: 18/02/11 – 17/02/14


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

Contract Number: 09-SYN-12-898-AP1371

Status: coordiantor– D.Boumpas

Budget (for the team): 350,000 €

Duration: 21/06/11 – 20/06/14


Title: Untraveling the Mode of Action of Antigen-Specific Regulatory T Cells: Implication of Cell-Based Therapy of Autoimmune Diseases – P. Verginis

Funding Source: ESPA Postdoctoral Fellowships

Contract Number: LS6-16963/6-12-10

Status: Principal investigator – D.Boumpas/P.Verginis

Budget: 150.000,00 €

Duration: 18/01/12 – 17/01/15


Title: Interdisciplinary network for Alzheimer Disease study

Funding Source: General Secretariat for Research and Technology (GR) – “Thalis Grant

Status: partner– D.Boumpas

Contract Number: ΟΠΣ 377299

Budget (for the team): 50.000 €

Duration: 01/04/2012– 31/03/2015


Title: Dissection of the Pathogenesis of Autoimmune Diseases for Targeted Therapeutics Using Systemic Lupus Erythematosus as Prototype

Funding Source: General Secretariat for Research and Technology (GR) ΕSPA - EXCELLENCE

Contract Number: AutoimmuneSearch / 2344

Status: Principal investigator– D.Boumpas

Budget: 332.100,00€

Duration: 01/08/12 – 30/09/15


Title:    Prediction of response to abatacept in Rheumatoid Arthritis (RA) patients based on a detailed immunological profile of cytokine networks

Funding Source: Bristo Meyers Sqibbs (BMS)

Contract Number: IM 101-558

Status: Principal investigator– PI Sidiropoulos

Budget: 101.329 €

Duration: 09/08/15 – 31/12/17


Title: Prediction of response to abatacept in Rheumatoid Arthritis (RA) patients based on a detailed immunological profile of cytokine networks
Funding Source:
Bristol Meyers Sqibbs (BMS)
Contract Number:
IM 101-558
Status :
Principal investigator– PI Sidiropoulos
101.329 €
09/08/15 – 31/12/17


Title: NGS in Peripheral Blood and HSCs in SLE: Mechanisms of Disease, Novel Therapeutic Targets and Biomarkers for Disease Activity and Response to Therapy
Funding Source: Foundation for Rheumatology Research (FOREUM)
Contract Number: KA4586
Status: Co-Principal investigator – G Bertsias
Budget: 60.000 €
Duration: 12/2015 – 12/2018


Title: The role of interleukin-33 in modulation of plasmacytoid dendritic cell function and generation of pathogenic immune responses in systemic lupus erythematosus
Funding Source: UoC Research Account (ELKE)
Contract Number: KA4718
Status: Principal investigator– G Bertsias
Budget: 10.000 €
Duration: 05/2017 – 05/2019


Title: A prediction score for individuals at risk for SLE by integrating clinical, serologic and transcriptomic data
Funding Source: Foundation for Rheumatology Research (FOREUM)
Contract Number: KA10002
Status: Principal investigator – G Bertsias
Budget: 110.000 € (total grant: 400.000 €)
Duration: 01/2018 – 12/2020



Publications, Laboratory of Rheumatology, Autoimmunity and Inflammation, University of Crete Medical School (2012-2020) 


  1. Panousis NI, Bertsias GK, Ongen H, Gergianaki I, Tektonidou MG, Trachana M, Romano-Palumbo L, Bielser D, Howald C, Pamfil C, Fanouriakis A, Kosmara D, Repa A, Sidiropoulos P, Dermitzakis ET, Boumpas DT. Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity. Ann Rheum Dis. 2019 Aug;78(8):1079-1089. doi: 10.1136/annrheumdis-2018-214379. Epub 2019 Jun 5. PMID: 31167757.
  2. Frangou E, Chrysanthopoulou A, Mitsios A, Kambas K, Arelaki S, Angelidou I, Arampatzioglou A, Gakiopoulou H, Bertsias GK, Verginis P, Ritis K, Boumpas DT. REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A). Ann Rheum Dis. 2019 Feb;78(2):238-248.
  3. Gkirtzimanaki K, Kabrani E, Nikoleri D, Polyzos A, Blanas A, Sidiropoulos P, Makrigiannakis A, Bertsias G, Boumpas DT, Verginis P. IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion. Cell Rep. 2018 Oct 23;25(4):921-933.e5. doi: 10.1016/j.celrep. 2018.09.001. PMID: 30355498.
  4. Latsoudis H, Mashreghi MF, Grün JR, Chang HD, Stuhlmüller B, Repa A, Gergiannaki I, Kabouraki E, Vlachos GS, Häupl T, Radbruch A, Sidiropoulos P, Doukoumetzidis K, Kardassis D, Niewold TB, Boumpas DT, Goulielmos GN. Differential Expression of miR-4520a Associated With Pyrin Mutations in Familial Mediterranean Fever (FMF). J Cell Physiol. 2017 Jun;232(6):1326-1336. doi: 10.1002/jcp.25602. Epub 2016 Dec 20. PMID: 27636101.
  5. Myrthianou E, Zervou MI, Budu-Aggrey A, Eliopoulos E, Kardassis D, Boumpas DT, Kougkas N, Barton A, Sidiropoulos P, Goulielmos GN. Investigation of the genetic overlap between rheumatoid arthritis and psoriatic arthritis in a Greek population. Scand J Rheumatol. 2017 May;46(3):180-186. doi: 10.1080/03009742.2016.1199734. Epub 2016 Jul 20. PMID: 27440135.
  6. Papadaki G, Kambas K, Choulaki C, Vlachou K, Drakos E, Bertsias G, Ritis K, Boumpas DT, Thompson PR, Verginis P, Sidiropoulos P. Neutrophil extracellular traps exacerbate Th1-mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation. Eur J Immunol. 2016 Nov;46(11):2542-2554. doi: 10.1002/eji.201646542. Epub 2016 Oct 5. PMID: 27585946.
  7. Vlachou K, Mintzas K, Glymenaki M, Ioannou M, Papadaki G, Bertsias GK, Sidiropoulos P, Boumpas DT, Verginis P. Elimination of Granulocytic Myeloid-Derived Suppressor Cells in Lupus-Prone Mice Linked to Reactive Oxygen Species-Dependent Extracellular Trap Formation. Arthritis Rheumatol. 2016 Feb;68(2):449-61. doi: 10.1002/art.39441. PMID: 26414650.
  8. Choulaki C, Papadaki G, Repa A, Kampouraki E, Kambas K, Ritis K, Bertsias G, Boumpas DT, Sidiropoulos P. Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis. Arthritis Res Ther. 2015 Sep 19;17:257. doi: 10.1186/s13075-015-0775-2.PMID: 26385789.
  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. doi:10.1016/j.humimm.2015.06.007. Epub 2015 Jun PMID: 26074413.
  10. Zervou MI, Myrthianou E, Flouri I, Plant D, Chlouverakis G, Castro-Giner F, Rapsomaniki P, Barton A, Boumpas DT, Sidiropoulos P, Goulielmos GN. Lack of association of variants previously associated with anti-TNF medication response in rheumatoid arthritis patients: results from a homogeneous Greek population. PLoS One. 2013 Sep 10;8(9).
  11. Cobb JE, Plant D, Flynn E, Tadjeddine M, Dieudé P, Cornélis F, Ärlestig L, Dahlqvist SR, Goulielmos G, Boumpas DT, Sidiropoulos P, Krintel SB, Ørnbjerg LM, Hetland ML, Klareskog L, Haeupl T, Filer A, Buckley CD, Raza K, Witte T, Schmidt RE, FitzGerald O, Veale D, Eyre S, Worthington J. Identification of the tyrosine-protein phosphatase non-receptor type 2 as a rheumatoid arthritis susceptibility locus in europeans. PLoS One. 2013 Jun 20;8(6):e66456. doi: 10.1371/journal.pone.0066456.
  12. Vazgiourakis VM, Zervou MI, Eliopoulos E, Sharma S, Sidiropoulos P, Franek BS, Myrthianou E, Melissourgaki M, Niewold TB, Boumpas DT, Goulielmos GN. Implication of VEGFR2 in systemic lupus erythematosus: a combined genetic and structural biological approach. Clin Exp Rheumatol. 2013 Jan-Feb;31(1):97-102.
  13. 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
  14. 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