Article
Normalization of type I interferon (IFN) signature after resetting the immune system with immunoablation and in systemic lupus erythematosus (SLE)
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Published: | August 29, 2016 |
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Background: Our previous research provided the evidence that an autoreactive immune system can be “reset” into a healthy, tolerant state by immunoablative treatment to eradicate pathogenic effector cells, followed by transplantation of hematopoietic progenitor. Recently, gene expression profiling in peripheral blood revealed an up-regulation of type I interferon (IFN) related genes in systemic lupus erythematosus and their first-degree relatives. Here, we aimed to analyze the IFN signature in SLE patients after receiving HSCT to evaluate whether IFN signature is normalized after “immune reset” or is permanently present, resembling a heritable trait.
Methods: Since 1998, ten patients with treatment-refractory SLE received a CD34+-selected autologous stem cell transplantation after immunoablation with antithymocyte-globulin and cyclophosphamide. Two patients died from transplant-related infections; from the remaining eight patients, five are in long-term remission (SELENA-SLEDAI ≤3) for up to 17 years after HSCT, while three patients suffered a relapse of SLE. IFN2a was investigated in serum with DELFIA assay (Miltenyi Biotec) and Siglec-1 expression on CD14+ monocytes (as IFN surrogate) analyzed using flow cytometry. In addition, gene expression profile was analyzed with Microarray (Affymetrix) from purified CD14+ monocytes (FACSAria cell sorter) and compared to active SLE and healthy donors.
Results: Serum IFNa levels significantly decreased from a median 43.1pg/ml at baseline to 3.01 pg/ml at 2 years after HSCT (p<0.001) and Siglec-1 expression on monocytes, which is increased in active SLE, completely normalized in responding patients after HSCT and was only elevated in patients during viral infections. Based on gene expression profiling, the number of IFN signature probe-sets with a cut-off of fold change ≥2 or ≤2 was decreased down to 24% (77/320) in patients after HSCT compared to active SLE and completely clustered with healthy controls suggesting a normalization of type I IFN signature.
Conclusion: Resetting the immune system with HSCT is associated with a complete normalization of the IFN signature in SLE suggesting that up-regulation of IFN-related genes is not a predisposition but rather the consequence of chronic autoimmunity in SLE. Apparently, immunoablation resets the innate immune system into a self-tolerant state where even up-regulation of IFN during viral infections is not associated with reactivation of SLE.