- Intestinal posttranslationally modified proteins and their potential to induce rheumatoid arthritis (RA).
We are investigating how modified intestinal proteins are involved in the early onset of modified protein antibodies (AMPA) responsible for synovial inflammation in arthritis. Modified proteins may act as novel antigens and provide the basis for early autoantibody production that later cross-reacts with local tissue antigens in joints, promoting disease onset and severity. Therefore, we aim to elucidate the role of AMPA in synovial inflammation in RA. It is expected that our findings can be directly applied to novel treatment strategies for emerging RA.
- Influence of dysbiosis on the intestinal barrier.
Dysbiosis of the gut microbiome and a defect of the gut barrier represent a risk factor that can lead to the development of autoimmune diseases such as RA. Mice with collagen-induced arthritis show alteration of the gut microbiome and increased gut barrier permeability even before the onset of disease symptoms. Therefore, we hypothesize that alterations in gut bacterial composition and the resulting metabolites cause changes in the gut barrier. This project addresses the question of which early changes in the gut are involved in the development of arthritis.
- Alcohol modulates immune responses.
It has long been known that moderate to high alcohol consumption reduces the severity of autoimmune diseases, but at the same time reduces the efficacy of vaccination. Unfortunately, specific cellular or molecular mechanisms by which alcohol modulates the immune system are poorly understood. Recently, we have uncovered cellular mechanisms by which acetate, the metabolite of alcohol, reduces T helper cell responses. Currently, we are investigating molecular mechanisms in T cells that are directly responsible for reduced T cell function as a consequence of increased alcohol exposure.
- Influence of short-chain fatty acids on autoimmunity.
Short-chain fatty acids (SCFA) are metabolites of our intestinal bacteria that are formed during the conversion of dietary fiber. Preventive treatment with SCFA has a protective effect on the development of inflammatory diseases, such as RA, but the influence of SCFA on already established inflammatory processes is largely unknown. We investigate the influence of SCFA propionate on the resolution of RA. Here, we analyze the effect of propionate supplementation on gut flora and its secreted metabolites and how these may attenuate ongoing inflammatory processes. Our goal is to gain a better understanding of the relationship between gut flora and inflammation, as well as to establish new, nutritional therapies for inflammatory diseases such as rheumatoid arthritis.
- BTN in T Cell Activation.
T cells, together with B lymphocytes, form the adaptive arm of the immune defense. Many autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis or systemic lupus erythrematosus, are characterized by unwanted T cell responses against the body's own characteristics. In healthy humans, the activation of such T cells is prevented by various tolerance mechanisms. We investigate the influence of butyrophilins (BTNs), a group of co-stimulatory molecules, on T cell activation, both during maturation in the thymus and on peripheral T cells. Using genetic "knockout" models, we aim to characterize how BTNs contribute to prevent this tolerance break and test potential therapeutic approaches with co-inhibitory BTNs.
- Relationship between intestinal inflammation and bone loss - What is the role of the hormone erythropoietin?
Severe bone loss in patients with rheumatoid arthritis is often accompanied by intestinal inflammation. In contrast, patients with inflammatory bowel disease have an increased risk of osteoporosis and osteopenia. Against this background, we are investigating the relationship between intestinal inflammation and the development of arthritis. We will also specifically investigate the effects of erythropoietin (EPO), a hormone secreted mainly in the kidney that stimulates red blood cell production. EPO also has effects on other cells, including the intestinal endothelium - blood vessel-lining cells - and osteoclasts (bone-degrading) and osteoblasts (bone-building progenitor cells). Thus, EPO could be a key link between bone loss and intestinal inflammation.
- Role of lymph node scaffold cells in the regulation of the immune response.
Previously viewed primarily as scaffold cells to facilitate the confluence of B, T, and dendritic cells (DC), lymph node stromal cells (LNSCs) have recently attracted more attention due to their demonstrated ability to actively regulate immune cell function. Here, we are interested in investigating the role of a specific LNSC subset, fibroblastic reticular cells (FRCs), specifically in popliteal lymph nodes (pLNs) during the initiation of RA.
|Mario Zaiss||Research group leader|
|Yuichi Maeda||Postdoctoral researcher|
|Kerstin Dürholz||Postdoctoral researcher|
|Jumpei Temmoku||Postdoctoral researcher|
|Heike Danzer||Biological technical assistant|
|Ilann Sarfati||Scientific doctoral student|
|Eva Schmid||Scientific doctoral student|
CRC 1181 "Microbiota-derived metabolite induced mechanisms during resolution of inflammation." (2019-2023)
Individual application "Influence of the short-chain fatty acid propionate as a metabolite of the human intestinal microbiome in the context of arthritic diseases." (since 2020)
GRK 2740 "Immunomicrotope: Microenvironmental, Metabolic and Microbial Signals Regulating Immune Cell-Pathogen Interactions" (2022-2027)
Bundesministerium für Bildung und Forschung (BMBF)
Interdisciplinary research networks musculoskeletal diseases
"MASCARA - Molecular Assessment of Signatures ChAracterizing the Remission of Arthritis.” (2020-2022)
Else Kröner-Fresenius-Stiftung (EKFS)
"The impact of intestinal metabolites on bone homeostasis." (2016)
IZKF, Universitätsklinikum Erlangen
A92 - "FRCs and immune tolerance induction" (2020-2023)
ELAN-Program, Friedrich-Alexander University Erlangen-Nürnberg
P061 - "Modified proteins in the gut break tolerance and induce autoimmune arthritis" (2020-2021)
- Martinsson K, Dürholz K, Schett G, Zaiss MM, Kastbom A. (2022) Higher serum levels of short-chain fatty acids are associated with non-progression to arthritis in individuals at increased risk of RA. Ann Rheum Dis. 81(3):445-447.
- Frech M, Schuster G, Andes FT, Schett G, Zaiss MM, Sarter K. (2021) RANKL-Induced Btn2a2 - A T Cell Immunomodulatory Molecule - During Osteoclast Differentiation Fine-Tunes Bone Resorption. Front Endocrinol (Lausanne). 12:685060.
- Zaiss MM, Joyce Wu HJ, Mauro D, Schett G, Ciccia F. (2021) The gut-joint axis in rheumatoid arthritis. Nat Rev Rheumatol. 17(4):224-237.
- Omata Y, Frech M, Lucas S, Primbs T, Knipfer L, Wirtz S, Kadono Y, Saito T, Tanaka S, Sarter K, Schett G, Zaiss MM. (2020) Type 2 innate lymphoid cells inhibit the differentiation of osteoclasts and protect from ovariectomy-induced bone loss. Bone. 136:115335.
- Tajik N, Frech M, Schulz O, Schälter F, Lucas S, Azizov V, Dürholz K, Steffen F, Omata Y, Rings A, Bertog M, Rizzo A, Iljazovic A, Basic M, Kleyer A, Culemann S, Krönke G, Luo Y, Überla K, Gaipl US, Frey B, Strowig T, Sarter K, Bischoff SC, Wirtz S, Cañete JD, Ciccia F, Schett G, Zaiss MM. (2020) Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.Nat Commun. 11(1):1995.
- Azizov V, Dietel K, Steffen F, Dürholz K, Meidenbauer J, Lucas S, Frech M, Omata Y, Tajik N, Knipfer L, Kolenbrander A, Seubert S, Lapuente D, Sokolova MV, Hofmann J, Tenbusch M, Ramming A, Steffen U, Nimmerjahn F, Linker R, Wirtz S, Herrmann M, Temchura V, Sarter K, Schett G, Zaiss MM. (2020) Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis. Nat Commun. 11(1):1998.
- Häger J, Bang H, Hagen M, Frech M, Träger P, Sokolova MV, Steffen U, Tascilar K, Sarter K, Schett G, Rech J, Zaiss MM. (2019) The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study. Nutrients. 11(10):2392.
- Omata Y, Frech M, Primbs T, Lucas S, Andreev D, Scholtysek C, Sarter K, Kindermann M, Yeremenko N, Baeten DL, Andreas N, Kamradt T, Bozec A, Ramming A, Krönke G, Wirtz S, Schett G, Zaiss MM. (2018) Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice. Cell Rep. 24(1):169-180.
- Lucas S, Omata Y, Hofmann J, Böttcher M, Iljazovic A, Sarter K, Albrecht O, Schulz O, Krishnacoumar B, Krönke G, Herrmann M, Mougiakakos D, Strowig T, Schett G, Zaiss MM. (2018) Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun. 9(1):55.
- Zaiss MM, Rapin A, Lebon L, Dubey LK, Mosconi I, Sarter K, Piersigilli A, Menin L, Walker AW, Rougemont J, Paerewijck O, Geldhof P, McCoy KD, Macpherson AJ, Croese J, Giacomin PR, Loukas A, Junt T, Marsland BJ, Harris NL. (2015) The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation. Immunity. 43(5):998-1010.