Activation of Non-Canonical NF-Kappa B Signalling in Dendritic Cells Induces Extrathymic Autoimmune Regulator (AIRE) Expression

Leonie Huitema¹, Boy Helder¹, Ae-Ri Noort², Chrissta Maracle¹, Louis Boon³, Cristina Lebre⁴, Frans G.M. Kroese⁵ and Sander W. Tas⁶, ¹Amsterdam Rheumatology & immunology Center | Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, ²Department of Clinical Immunology & Rheumatology and Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, ³Bioceros, Utrecht, Netherlands, ⁴Div. of Clinical Immunology & Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, Netherlands, ⁵Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, Netherlands, ⁶Division of Clinical Immunology and Rheumatology, Academic Medical Center / University of Amsterdam, Amsterdam, Netherlands

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Dendritic cells, Immune regulation, rheumatic disease and tolerance, Sjogren's syndrome

Session Information

Date: Sunday, November 8, 2015

Title: Innate Immunity and Rheumatic Disease Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Immune regulation is necessary for limiting excessive immune responses and for preventing autoimmune diseases. Nuclear factor (NF)-κB signalling plays an important role in the regulation of immune responses. We have previously demonstrated that the activation of the non-canonical NF-κB pathway in dendritic cells (DC) via CD40 stimulation is important for the induction of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). Non-canonical NF-κB signalling is also important for the expression of Autoimmune Regulator (AIRE) in the thymus, which is essential for establishment of central tolerance. We have recently found extrathymic AIRE-expressing cells (eTACs) in glandular tissue from Sjögren’s syndrome patients and in rheumatoid arthritis inflamed synovial tissue. eTACs are mainly antigen presenting cells, including DC, that can induce peripheral tolerance. However, stimuli that induce extrathymic AIRE expression in DC are unknown. Therefore, we studied whether activation of non-canonical NF-κB signalling induces AIRE expression in DC.

Methods: Monocyte-derived DC were generated by culturing healthy donor monocytes for 6 days with GM-CSF and IL-4. Maturation was induced by addition of LPS or CD40 stimulating antibodies and/or RANKL for 48 hours. AIRE and IDO expression was quantified by qPCR and cleavage of p100 into p52 (indicative of active non-canonical NF-κB signalling) was analyzed by western blot. Presence of AIRE and IDO protein was also analyzed by western blot and immunofluorescence staining. Additionally, Aire and Ido gene expression was analyzed in anti-CD40 stimulated murine bone marrow-derived (BM)DC generated from wild type and Nik^-/- mice.

Results: Both anti-CD40 and RANKL stimulation of DC induced cleavage of p100 into p52, accompanied by upregulation of IDO and AIRE expression. Anti-CD40 stimulation also induced Ido and Aire expression in murine wildtype BMDC, but not in BMDC from Nik-/- mice.

Conclusion: Non-canonical NF-κB signaling is involved in AIRE and IDO expression in DC. This may reflect an imunoregulatory program in these cells. Eventually, this knowledge may be exploited to develop new treatment modalities for patients with autoimmune diseases, including DC-based therapies to modulate immune responses.

Disclosure: L. Huitema, None; B. Helder, None; A. R. Noort, None; C. Maracle, None; L. Boon, None; C. Lebre, None; F. G. M. Kroese, None; S. W. Tas, None.

To cite this abstract in AMA style:

Huitema L, Helder B, Noort AR, Maracle C, Boon L, Lebre C, Kroese FGM, Tas SW. Activation of Non-Canonical NF-Kappa B Signalling in Dendritic Cells Induces Extrathymic Autoimmune Regulator (AIRE) Expression [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/activation-of-non-canonical-nf-kappa-b-signalling-in-dendritic-cells-induces-extrathymic-autoimmune-regulator-aire-expression/. Accessed .

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