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Characterisation of the immunomodulatory effect of stromal cells in health and disease

Projectomschrijving

Reumatoïde artritis (ontstekingsreuma) is een ontstekingsziekte, waarbij door een ongewenste afweerreactie tegen lichaamseigen eiwitten de ziekte in stand wordt gehouden. In de vroegste fase van ontstekingsreuma is het afweersysteem in de lymfeklieren, waar afweerreacties starten, al geactiveerd. Wij hebben gevonden dat in muizen de steuncellen van de lymfeklieren essentieel zijn voor de onderdrukking van afweerreacties tegen lichaamseigen eiwitten. In dit project onderzoeken wij of steuncellen van patiënten met ontstekingsreuma, en van personen met een verhoogd risico op reuma, afwijkend zijn wanneer we deze vergelijken met gezonde individuen. Tevens bestuderen wij het mechanisme waarmee deze steuncellen de afweerreactie onderdrukken. Door meer inzicht in dit proces te krijgen hopen we met het onderzoek uiteindelijk nieuwe medicaties te kunnen ontwikkelen die verdere ziekte-ontwikkeling kunnen voorkomen.

Producten

Titel: Characterization of Human Lymph Node Stromal Cells During the Earliest Phases of Rheumatoid Arthritis.
Auteur: Karouzakis E*, Hähnlein J*, Grasso C, Semmelink JF, Tak PP, Gerlag DM, Gay S, Ospelt C, van Baarsen LGM.
Magazine: Frontiers in Immunology
Titel: Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses.
Auteur: Nadafi R, Gago de Graça C, Keuning ED, Koning JJ, de Kivit S, Konijn T, Henri S, Borst J, Reijmers RM, van Baarsen LGM, Mebius RE
Magazine: Cell Reports

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Samenvatting van de aanvraag

Rheumatoid arthritis (RA) is a prototypic inflammatory autoimmune disease targeting synovial joints, with a prevalence of ~2% in the Netherlands and a higher incidence in females. Given the destructive nature of the disease, early diagnosis and start of treatment is extremely important. The production of autoantibodies can be detected already years before onset of RA, enabling the identification of seropositive individuals at risk of developing RA. In the AMC these individuals are studied to investigate the earliest phases of systemic autoimmunity wherein self-tolerance is lost but where chronic inflammation is not yet present. Of importance, not all autoantibody positive individuals will develop disease. To identify the immunoregulatory mechanisms involved in disease development, Dr. van Baarsen initiated molecular studies on this exceptional cohort of patients, by investigating unique synovial and lymph node biopsies obtained from RA-risk and early RA patients. Production of antibodies is characteristically initiated in secondary lymphoid organs. The group of Dr. van Baarsen recently found higher frequencies of proinflammatory T- and B-cells in lymph node biopsies of RA-risk and early-stage RA patients when compared to healthy controls. Thus, the state-of-the-art indicates that lymph nodes are potential initiation sites for RA development. Notably, lymph node stromal cells (LN-SC) are critical for efficient T-B-cell interactions, as stromal cells regulate their migration and survival. Furthermore, LN-SC are instrumental for deletion of autoreactive CD8+ T-cells, thereby preventing autoimmune responses. The group of Prof. Mebius has a strong expertise in LN-SC biology and recently found that LN-SC can present self-antigens to CD4+ T-cells resulting in the maintenance of regulatory T-cells (Treg) having the capacity to prevent autoimmune responses. Additional preliminary in vivo studies show that these self-antigen presenting LN-SC also control B-cells specific for these self-antigens. Of interest, first human LN-SC studies performed within the group of Dr. van Baarsen revealed epigenetic and gene expression changes in LN-SC of RA-risk and RA patients compared with healthy controls. Altogether, these data strongly implicate a key role for LN-SC in directing autoimmune responses in RA. We propose that lack of immunoregulatory functioning LN-SC of (pre-clinical) RA patients contribute to the early activation of autoreactive T- and B-cells within lymph nodes at the initiation phase of the disease. We aim to determine which molecules are involved in LN-SC-mediated control of autoreactive lymphocytes during health and disease using a mice-to-man approach. The combination of the unique expertise’s of both labs, in which the Mebius lab has the methods to analyze antigen presentation by LN-SC in an antigen-specific manner in mice and the van Baarsen lab has the ability to collect, culture and analyze LN-SC from healthy individuals, RA-risk individuals and RA patients, cannot be matched by other research groups. By combining state-of-the-art technologies, (transgenic) mouse models and unique patient materials, we will reveal which molecular pathways and modes of antigen presentation in LN-SC are instrumental in T-cell mediated B-cell activation and whether these processes are aberrant already during the earliest phases of RA. The proposed intertwined mouse and human studies will reveal the molecular definition by which LN-SC control autoreactive T- and B-cells, facilitating the identification of molecular drug targets that can interfere with T- and B-cell activation to block further progression into disease. This from-mice-to-man research program will provide a rationale for repurposing existing (or experimental) drugs as well as leads for novel drugs for RA-risk individuals with as ultimate opportunity disease prevention. The obtained knowledge on how LN-SC control T cell tolerance against self-antigens and thereby prevent autoantibody production will be of interest not only for RA, but also for other B-cell driven chronic diseases such as Sjögren’s syndrome, multiple sclerosis, systemic sclerosis, and chronic graft-versus-host disease. Results obtained within this project may thus provide insight in early intervention targets for these diseases as well. Only through the combination of the worldwide unique research lines of the Mebius and van Baarsen groups, a quick translation of pioneering scientific evidence into a clinical setting can be made.

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Kenmerken

Projectnummer:
91217014
Looptijd: 100%
Looptijd: 100 %
2018
2023
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
prof. dr. R.E. Mebius
Verantwoordelijke organisatie:
Amsterdam UMC Locatie VUmc