Molekulare und zelluläre Charakterisierung der Multi-Komponenten-Plasmazell-Nische
Final Report Abstract
In this project we investigated different plasma cell subsets and the factors that enable them to survive for extended times even up to live-time as the huge majority (>90%) of plasma cells that are formed during an infection or vaccination dies after a few days. However, some remain and provide long-term immunoprotection due to continuous production of protective antibodies. The dark side of this humoral memory is that also pathogenic plasma cells that produce autoreactive antibodies can become longlived and thus form a stable pathogenic memory. These autoreactive memory plasma cells are extremely hard to eliminate because they are protected by their microenvironment – the so called survival niche – and lead to the reestablishment of the autoimmune disease even after successful immunosuppressive therapy. Therefore, a major goal for the therapy of autoimmune diseases like systemic lupus erythematosus (SLE) is the complete elimination of the pathogenic memory e.g. pathogenic memory plasma cells, which may bear the potential to finally cure autoimmune diseases. At the same time, this treatment shall be specific to mainly eliminate pathogenic while sparing protective plasma cells to maintain immunoprotection. To approach this goal, we investigated protective and pathogenic plasma cells with special focus on differences between their respective survival niches. We established a specific staining of dsDNA reactive plasma cells that allowed for the first time the comparative analysis of pathogenic (dsDNA) and protective (Ova) plasma cells via fluorescence microscopy. Moreover, by this method we were able to identify several plasma cell sub-populations according to produced immunoglobulin class, longevity, CD28 expression. We compared the hematopoietic cell components and the produced survival factors within the alternative niches and found that the hematopoietic niche components strongly fluctuate under immunotherapeutic treatment (e.g. proteasome inhibitor, chemokine blocker) and only plasma cells in the proximity of hematopoietic niche components survived. Interestingly, the cell numbers of both hematopoietic cell types - megakaryocytes and eosinophils - that were identified by us and others to be the main hematopoietic contributors to plasma cell survival in the bone marrow, responded differently to the diverse treatments. Thus, they were compensating each other and stabilizing the memory plasma cell compartment. Moreover, megakaryocyte and eosinophil numbers increased during proteasome inhibitor treatment, meaning an increase of plasma cell survival niches that is counteracting the initial therapeutic approach. We also investigated the specific contribution of megakaryocytes to plasma cell related diseases like multiple myeloma and SLE and were able to demonstrate that megakaryocytes support survival of myeloma cells in cell culture and in mice thus representing a potential indirect target to eliminate malignant myeloma cells. In mice that develop an SLE like disease we identified a correlation between plasma cells and megakaryocytes, with ten times higher numbers of both cell types in the spleen compared to healthy mice. The megakaryocytes in these mice responded much stronger to proliferative signals than in healthy mice. Moreover, immunization of SLE mice with protein antigen and adjuvant resulted in an increase of megakaryocyte numbers and an unspecific generation of selfreactive dsDNA plasma cells. Altogether indicating a supportive contribution of megakaryocytes on the pathogenesis in SLE.
Publications
- Bone marrow of NZB/W mice is the major site for plasma cells resistant to dexamethasone and cyclophosphamide: Implications for the treatment of autoimmunity. J Autoimmun. 2012 Sep;39(3):180-8
Mumtaz IM, Hoyer BF, Panne D, Moser K, Winter O, Cheng QY, Yoshida T, Burmester GR, Radbruch A, Manz RA, Hiepe F
(See online at https://doi.org/10.1016/j.jaut.2012.05.010) - Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy J Immunol. 2012 Dec 1;189(11):5105-11
Winter O, Dame C, Jundt F, Hiepe F
(See online at https://doi.org/10.4049/jimmunol.1202317) - Blockade of CXCR4 by AMD3100 reduces homing and survival of plasma cells in lupus mice NZB/W. Zeitschrift für Rheumatologie 2013 Sep 1 (Vol. 72, pp. 34-34)
Cheng Q, Khodadadi L, Taddeo A, Winter O, Hoyer B, Radbruch A, Hiepe F
- Eosinophils and megakaryocytes support the early growth of murine MOPC315 myeloma cells in their bone marrow niches. PLoS One. 2014 Oct 1;9(10):e109018
Wong D, Winter O, Hartig C, Siebels S, Szyska M, Tiburzy B, Meng L, Kulkarni U, Fähnrich A, Bommert K, Bargou R, Berek C, Chu VT, Bogen B, Jundt F, Manz RA
(See online at https://doi.org/10.1371/journal.pone.0109018) - A8. 26 Bortezomib ameliorates the disease progression due to ovalbumin immunisation in NZB/W F1 lupus prone mice. Annals of the Rheumatic Diseases. 2015 Mar 1;74(Suppl 1):A92
Khodadadi L, Cheng Q, Winter O, Taddeo A, Radbruch A, Hoyer BF, Hiepe F
(See online at https://dx.doi.org/10.1136/annrheumdis-2015-207259.211) - Analyzing pathogenic (double-stranded DNA specific) plasma cells via immunofluorescence microscopy. Arthritis Res Ther. 2015 Oct 21;17:293
Winter O, Musiol S, Schablowsky M, Cheng QY, Khodadadi L, Hiepe F
(See online at https://doi.org/10.1186/s13075-015-0811-2)
