Redoxproteomics zur Aufklärung der Rolle des oxidativen Stresses in der Pathophysiologie der Autoimmunthrombozytopenie Purpura (AITP)
Final Report Abstract
Immune thrombocytopenia (ITP) is a simple model for all autoimmune diseases. In this study, we investigated factors associated with oxidative stress in the pathophysiology of ITP. Increased systemic oxidative stress status was primarily found in female patients (Ref 1). However, a reduced antioxidant capacity and increased levels of oxidative stress in platelets from patients with ITP was found in both male and females with a small trend of increased prevalence in females. Antibody-based microarray screening of over 800 cytokines not only revealed cytokine dysregulation in ITP, but identified that most differentially expressed cytokines are regulated by redox-sensitive transcription factors (Ref 3). As BAFF and APRIL are two main cytokines involved in autoimmune dysregulation, we focused on the regulation of These cytokines. BAFF allows autoreactive immune cells to evade apoptosis and is strongly redox-sensitive. Treatment with the antioxidant dexamethasone is thus potent in significantly reducing BAFF levels in patients to below the mean value observed in healthy controls (Ref 5). A new proteomic approach - called MS-AMIDA - was developed. Using this method, we identified that most antigens are of intracellular origin, pointing towards improper clearance of intracellular structures in ITP (Ref 3 and Ref 6). This finding was confirmed by luminex-based profiling of over 4,000 antigens (Ref 6). Using lipidomics, lysophosphatidyl-choline 22:0 (LPC 22:0) was found to be a profound marker for ITP (Ref 6). LPC 22.0 is involved in many autoimmune dysregulation steps, such as autoantibody development and activation/regulation of various immune cells. Comprehensively, data suggested autophagy dysregulation in ITP, leading to an improper clearance of immune complexes, thus leading to or enhancing autoimmune dysregulation and autoantibody formation. In the framework of this grant, many exciting new insights into the pathophysiology of ITP were revealed that are also potentially relevant for other autoimmune diseases. Future studies are required for in-depth exploration of the pathomechanisms in ITP.
Publications
- Reduced antioxidant capacities in platelets from patients with autoimmune thrombocytopenia purpura (ITP). Platelets, Vol. 23. 2012, Issue 3, pp. 184-194.
Kamhieh-Milz J, Bal G, Sterzer V, Kamhieh-Milz S, Arbach O, Salama A
(See online at https://dx.doi.org/10.3109/09537104.2011.610909) - Oxidative stress is predominant in female but not in male patients with autoimmune thrombocytopenia. Oxidative Medicine and Cellular Longevity, Vol. 2014 (2014), Article ID 720347, 9 pages.
Kamhieh-Milz J, Salama A
(See online at https://doi.org/10.1155/2014/720347) - Identification of novel biomarkers in chronic immune thrombocytopenia (ITP) by microarray-based serum protein profiling.
British Journal of Haematology, Vol. 172. 2016, Issue 4, pp. 602–615.
Bal G, Futschik ME., Hartl D., Kamhieh-Milz J., Sterzer V., Hoheisel JD., Alhamdani M.S.S. and Salama A
(See online at https://doi.org/10.1111/bjh.13861) - Identification of novel autoantigens via mass spectroscopy-based antibody-mediated identification of autoantigens (MS-AMIDA) using immune thrombocytopenic purpura (ITP) as a model disease. Journal of Proteomics, Vol. 157. 2017, pp. 59–70.
Kamhieh-Milz J, Sterzer V, Celik H, Khorramshahi O, Fadl Hassan Moftah R, Salama A.
(See online at https://doi.org/10.1016/j.jprot.2017.01.012)
