Systemic and organ-specific Autoimmune Diseases Research Group (AIM)
The research in the AIM group is focused on the pathogenesis of both organ-specific and systemic autoimmune diseases with an emphasis on the role of cells of the myeloid compartment. The next ten years the research will aim at identification of novel biomarkers for these diseases and translation of this knowledge into clinical practice. These biomarkers will be used for establishment of early diagnosis in the pre-symptomatic phase of the disease, monitoring disease progression and prognosis, as novel targets for therapeutic intervention and ultimate prevention of disease development. The identified biomarkers will in combination with novel imaging techniques using specific tracers open a new field of non-invasive medical monitoring with the aim to improve patient care and come to personalized medicine.
The current studies focus on:
1. Abnormalities of monocytes in the circulation in systemic autoimmune diseases
2. Abnormalities of myeloid cells in the target organs in autoimmune diseases
3. The role of Interferon type I activation in systemic autoimmune diseases
This theme comprises the fundamental aspects of the first steps in the development of an autoimmune disease as well as translational research aiming at the identification of monocyte abnormalities to improve the diagnosis, classification and treatment of autoimmune diseases. The research is performed in mouse models, that spontaneously develop several autoimmune diseases, and is translated into human studies using patient samples. The aim of the research is early detection of the autoimmune diseases. This will allow early intervention, prevention of irreversible damage and ultimately prevention of disease development.
Autoimmune diseases have a multifactorial cause involving disturbances in the immune system and in the target organ(s) to which the autoimmune reaction(s) is (are) directed. Dendritic cells (DC) are potent antigen presenting cells capable to activate naïve T cells. Under steady state conditions DC and tissue macrophages pick up auto-antigens in peripheral tissues, for instance in the skin, submandibular glands or in the pancreas and subsequently transport these to the draining lymph nodes to activate T cells. Under steady state conditions the auto-antigen loaded DC and macrophages are in a tolerogenic mode, interacting with T cells in such a way that the induction of autoimmune responses is prevented by a preferential generation of tolerogenic regulator T cells. Under conditions of “danger” (e.g. bacterial or viral infection) DC and macrophages leave their steady tolerogenic state, become aggressive cells and are able to initiate effector T cell responses resulting in the induction of specific immunity and the ultimate elimination of pathogens.
DC accumulation in organ-specific autoimmune diseases
Studies in animal models for autoimmunity have revealed that the first immune cells excessively accumulating in a target organ are DC, which are apparently not tolerogenic. In the NonObese Diabetic (NOD) mouse model for diabetes and Sjögren’s syndrome we demonstrated the accumulation of DC in the pre-diabetic pancreas and the salivary glands prior to the appearance of lymphocyte infiltrates. DC and macrophages are thought to originate from pro-monocytes in the bone marrow and to migrate as monocytes through the blood to the peripheral tissues. In addition to the blood monocyte as a precursor for tissue macrophages and DC, evidence is accumulating that in many tissues monocyte-like precursors for macrophages and DC are locally present.We have identified precursor cells for DC in the pre-diabetic pancreas in the NOD mouse model. We have indications that these precursor cells are already abnormal in this stage (show a high proliferation rate) and contribute to the abnormal accumulation of non-tolerogenic DC in the pre-diabetic pancreas. The accumulating DC themselves are also intrinsically abnormal: The population has been developed from the precursors in such a way that the progeny is poorly tolerogenic and more inflammatory.In summary, our studies on DC subsets and their local precursors reveal a specific pattern of accumulation and several abnormalities in the proportion and/or phenotype of the DC subsets which we assume contribute to the development of diabetes. The molecular reflections of these early abnormalities might in the future be used for early detection of disease development.
Systemic autoimmune diseases and the Interferon type I signature
Apart from local precursors (see before for the pancreas and salivary glands) also blood monocytes can act as precursors for DC and macrophages. Investigations of peripheral blood monocytes in systemic autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematodes (SLE), systemic sclerosis and Sjögren’s syndrome (pSS), revealed a variety of different phenotypic and functional abnormalities in the monocytes, offering an opportunity to study these cells in systemic autoimmune diseases for abnormalities that contribute to the failure of the immune system to preserve a tolerogenic steady state. We recently identified an Interferon (IFN) type I signature in monocytes of patients with pSS. The detection of this IFN type I signature in monocytes of pSS patients and the demonstration of IFN type I activity in the serum of patients points to a systemic activation of this pathway. Also in subgroups of patients with other systemic autoimmune diseases like SLE, rheumatoid arthritis and systemic sclerosis the IFN signature has been found. The present concept on IFN type I activation in rheumatic diseases is that plasmacytoid DCs (pDC) secrete IFN type I in response to activation by e.g. immune complexes containing nucleic acids released from damaged cells. Subsequently, this IFN type I activity results in an up regulation of a large number of IFN type I inducible genes, the so-called IFN type I signature. Whether the first initiating event is a viral infection, another environmental trigger or abnormal apoptosis remains to be established. In pSS the monocytic IFN type I signature identifies a subgroup of patients with a higher clinical disease activity together with higher BAFF mRNA expression. Especially the effect of IFN type I on monocytes seems to be important for the pathogenesis of rheumatic diseases since IFN type I induces monocytes to differentiate into DC and to express B cell–activating factor (BAFF). BAFF in turn contributes to the survival and hyperactivity of auto-reactive B cells, which is a hallmark in systemic autoimmune diseases (Figure 1).
Fig.1 Disease model for IFN type I activity in primary Sjögren’s Syndrome. A viral infection induces plasmacytoid DC (pDC) to produce type I IFN. IFN type I induces the expression of IFN inducible genes (the IFN signature) in monocytes. One of the genes induced in these cells is BAFF, which promotes B cell survival and antibody production. Increased production of autoantibodies results in immune complexes that can activate the pDC to produce IFN type I.
Expression of IFN-I van be induced by three different receptor families: Toll-like receptors (TLRs), RIG-like receptors (RLRs) and DNA-sensing receptors (DSRs). Recent work of the Versnel group indicated a possible contribution by RLRs like MDA5 and RIG-I as well as DSRs to the systemic IFN activation. TANK-binding kinase (TBK1), is an important signaling hub downstream of these RLRs and DSRs. TBK1 inhibition was found to reduce expression of ISGs by pSS blood cells in vitro indication TBK1 as a potential treatment target.
Identification of monocyte gene expression signatures in larger cohorts will provide insight into the pathogenesis of rheumatic diseases and provide tools for better classification of patients. As the identified monocyte signatures are based on functional pathways affected in these diseases blocking of the aberrantly expressed molecules will provide new options for specific treatment. Furthermore upon specific treatment the monocyte signatures might be useful for monitoring the efficacy of the treatment.
Fig 2. Schematic overview of the IFN type I inducing signaling pathways and the downstream induction of ISGs.
Our current research lines are:
- Role of IFN activation in pathogenesis of Sjögren’s Syndrome and other systemic autoimmune diseases
- Fatigue or tolerance induction in Sjögren’s syndrome: detrimental or beneficial role for IDO and the tryptophan catabolic pathway? Supported by a grant from ReumaNederland.
- Interferon Type I, II and III activity patterns in childhood onset SLE.
For clinicians the IFN signature is upon request available at the Laboratory of Medical Immunology (Dr. W.A. Dik; firstname.lastname@example.org). Recently the IFN signature has been shown to be useful to contribute to establishment of the diagnosis of monogenic interferonopathies and monitor treatments interfering with the IFN pathway like JAK/STAT inhibitors.
Our research is in close collaboration with the Clinical Immunology group, Pediatric Rheumatology, national and international collaborators (Utrecht, Ireland, England, France, Sweden, Italy and the USA).
- Marjan A. Versnel, Group leader
- Corine G. van Helden-Meeuwsen, Research Assistant
- Erika Huijser, PhD student
- Jawad Wahadat, PhD student
- Sander van Tilburg, MSc student
- Several students for internships for their Master or Bachelor degree
(Check for all publications: https://www.ncbi.nlm.nih.gov/pubmed/?term=versnel+ma)
Bodewes ILA, Gottenberg JE, van Helden-Meeuwsen C.G., Mariette X, Versnel M.A. Hydroxychloroquine treatment downregulates systemic interferon activation in primary Sjögren’s Syndrome in the JOQUER randomized clinical trial. Rheumatology, In press.
Huijser E, van Helden-Meeuwsen CG, Groot N, Bodewes ILA, Wahadat MJ, Schreurs MWJ, van Daele PLA, Dalm VASH, van Laar JAM, van Hagen PM, Waris M, Kamphuis S, Versnel MA. MxA is a clinically applicable biomarker for IFN type I activation in systemic lupus erythematosus and systemic sclerosis. Rheumatology, March 15, 2019 Epub.
Bodewes ILA, van der Spek PJ, Leon LG, Wijkhuijs AJM, van Helden-Meeuwsen CG, Tas L, Schreurs MWJ, van Daele PLA, Katsikis PD, Versnel MA. Fatigue in Sjögren’s Syndrome: A search for biomarkers and treatment targets. Front Immunol. 2019 Feb 26;10:312.
Bodewes ILA, Björk A, Versnel MA*, Wahren-Herlenius M*. Innate immunity and interferons in the pathogenesis of Sjögren’s syndrome. Rheumatology, Feb 15, 2019 Epub. * shared last.
Meesilpavikkai K, Dik WA, Schrijver B, van Helden-Meeuwsen CG, Bijlsma EK, Ruivenkamp CAL, Oele MJ, Versnel MA, van Hagen PM, Dalm VASH. Efficacy of baricitinib in the treatment of chilblains associated with the type I interferonopathy Aicardi-Goutières syndrome. Arthritis Rheumatol 2019, 71(5):829-831.
Bodewes ILA, Huijser E, van Helden-Meeuwsen CG, Tas L, Huizinga HG, van Daele PLA, Dalm VAS, van Hagen PM, Versnel MA. TBK1 a key regulator and future treatment target for IFN positive Sjögren’s syndrome, systemic lupus erythematosus and systemic sclerosis.
J Autoimmunity. 2018 Apr 16 epub.
Wahadat MJ, Bodewes ILA, van Helden-Meeuwsen CG, van Dijk-Hummelman A, Steenwijk EC , Kamphuis S, Versnel MA.Type I IFN signature in childhood-onset Systemic Lupus Erythematosus: a conspiracy of DNA- and RNA-sensing receptors?
Arthritis Res Ther. 2018 Jan 10, 20 (1):4.
Bodewes ILA, Al-Ali S, van Helden-Meeuwsen CG, Maria NI, Tarn J, Lendrem DW, Schreurs MWJ, Steenwijk EC, van Daele PLA, Both T, Bowman SJ, Griffiths B.
The UK Primary Sjögren’s Syndrome registry, Ng W-F, Versnel MA.
Systemic interferon type I and type II signatures in primary Sjögren’s syndrome reveal differences in biological disease activity.
Rheumatology 2018, 57(5):921-930.
van den Hoogen LL, Fritsch-Stork RD, Versnel MA, Derksen RH, van Roon JA, Radstake TR.
Monocyte type I interferon signature in antiphospholipid syndrome is related to pro-inflammatory monocyte subsets, hydroxychloroquine and statin use.
Annals Rheum Dis 2016 75(12).
Maria NI, Steenwijk EC, IJpma AS, van Helden-Meeuwsen CG, Vogelsang P, Beumer W, Brkic Z, van Daele PL, van Hagen PM, van der Spek PJ, Drexhage HA, Versnel MA.
Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren’s syndrome.
Annals Rheum Dis 2017 76(4):721-730. Epub Sep 26. doi: 10.1136/annrheumdis-2016-209589.
Drexhage HA, Dik WA, Leenen PJ, Versnel MA.
The immune pathogenesis of Type 1 diabetes: not only thinking Outside the cell but also outside the Islet and out of the box.
Diabetes. 2016 Aug;65(8):2130-3. doi: 10.2337/dbi16-0030.
Maria NI, van Helden-Meeuwsen CG, Brkic Z, Paulissen SM, Steenwijk EC, Dalm VA, van Daele PL, van Hagen PM, Kroese FG, van Roon JA, Harkin A, Dik WA, Drexhage HA, Lubberts E, Versnel MA.
Association of increased Tregs with elevated Indoleamine-2,3-dioxygenase activity and an imbalanced Kynurenine pathway in IFNpositive primary Sjögren’s syndrome.
Arthritis Rheumatol. 2016 Feb 11. doi: 10.1002/art.39629. Epub ahead of print.
Brkic* Z, van Bon* L, Cossu M, van Helden-Meeuwsen CG, Vonk MC, Knaapen H, van den Berg W, Dalm VA, Van Daele PL, Severino A, Maria NI, Guillen S, Dik WA, Beretta L, Versnel MA** and Radstake T**.
The Interferon type I signature is present in Systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis.
In press, Ann Rheum Dis. 2016 Aug;75(8):1567-73. doi: 10.1136/annrheumdis-2015-207392. Epub 2015 Sep 14.*,** authors contributed equally.
Maria NI, Vogelsang P, Versnel MA.
The clinical relevance of animal models in Sjögren’s syndrome: the IFN signature from Mouse to Man.
Arthritis Research and Therapy 2015, 17 (3):172.
Beumer, W, Welzen-Coppens JCM, van Helden-Meeuwsen C.G., Gibney SM, Drexhage HA,
The gene expression profile of CD11c+CD8α- dendritic cells in the pre-diabetic pancreas of the NOD mouse.
Plos one 2014; Aug 9 (8) 1-11.
Brkic, Corneth OB, van Helden-Meeuwsen CG, Dolhain RJ, Maria NI, Paulissen SM, Davelaar N, van Hamburg JP, van Daele PL, Dalm VA, van Hagen PM, Hazes JM, Versnel MA, Lubberts E.
T helper 17 cell cytokines and interferon type I: partners in crime in systemic lupus erythematosus?
Arthritis Res Ther. 2014 Mar 6;16(2):R62.
Brkic Z, Versnel MA.
Type I IFN signature in primary Sjögren’s syndrome.
Expert Rev Clin Immunol. 2014 Apr;10(4):457-67. Epub 2014 Jan22.
Maria N, Brkic Z,Waris M, Helden-Meeuwsen CG, Heezen K, van de Merwe J, van Daele P, Dalm VASH, Drexhage HA, Versnel MA.
MxA as a clinically applicable biomarker for identifying systemic Interferon type I in primary Sjögren’s Syndrome.
Ann Rheum Dis. 2014 Apr; 1052-9 Epub 2013 Jul 6.
Welzen-Coppens JMC, van Helden-Meeuwsen CG, Leenen PJM, Drexhage HA, Versnel MA.
The kinetics of plasmacytoid dendritic cell accumulation in the pancreas of the NOD mouse during the early phases of insulitis.
PLOS one 2013, 8 (1) Epub 2013, Jan 25.
Welzen-Coppens JM, van Helden-Meeuwsen CG, Leenen PJ, Drexhage HA, Versnel MA.
Reduced numbers of dendritic cells with a tolerogenic phenotype in the prediabetic pancreas of NOD mice.
J Leukoc Biol. 2012 Dec;92(6):1207-13. doi: 10.1189/jlb.0312168. Epub 2012 Sep 25.
Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC, Steiner J, Connor TJ, Harkin A, Versnel MA, Drexhage HA.
The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes.
J Leukoc Biol. 2012 Nov;92(5):959-75. Epub 2012 Aug 8. Review.
Brkic Z, Maria NI, van Helden-Meeuwsen CG, Wildenberg ME, van de Merwe JP, Beumer W, Drexhage HA, Versnel MA.
Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren’s syndrome and association with disease activity and BAFF gene expression.
Ann Rheum Dis. 2013 72 (5):728-35.2012 Epub Jun 26.
Beumer W, Drexhage RC, De Wit H, Versnel MA, Drexhage HA, Cohen D.
Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome.
Psychoneuroendocrinology 2012 Dec;37(12):1901-11. Epub 2012 Apr 27.
Bikker A, Kruize AA, Wenting M, Versnel MA, Bijlsma JW, Lafeber FP, van Roon JA.
Increased interleukin (IL)-7Rα expression in salivary glands of patients with primary Sjogren’s syndrome is restricted to T cells and correlates with IL-7 expression, lymphocyte numbers and activity.
Ann Rheum Dis. 2012 Jun;71(6):1027-33. Epub 2012 Feb 6.
Drexhage RC, Weigelt K, van Beveren N, Cohen D, Versnel MA, Nolen WA, Drexhage HA.
Immune and neuroimmune alterations in mood disorders and schizophrenia.
Int Rev Neurobiol. 2011;101:169-201. Review .
Welzen-Coppens JM, van Helden-Meeuwsen CG, Drexhage HA, Versnel MA.
Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes.
Eur J Immunol. 2012 Jan;42(1):186-94. Epub 2011 Nov 28.