Background/Purpose:

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects multiple organs, whose pathology is mainly caused by the augmented interferon (IFN) signaling pathway. The aim of this study was to analyze the particular contribution of CD4+ T cells and monocytes with respect to cell type-specific IFN signatures detectable in patients with SLE by global gene expression profiling. The major focus was set on the comparison of disease-active and -inactive patients either by standard drug treatment or by autologous stem cell transplantation (ASCT) that is assumed to completely reset the autoreactive immunologic memory.

Methods:

Affymetrix Human Genome U133 Plus 2.0 Array were made from purified peripheral CD4+ T cells from 6 active SLE (SLEDAI>6), 2 inactive SLE (SLEDAI<2) by standard drug treatment and 3 inactive SLE who underwent ASCT as well as 3 healthy donors (ND). In addition, using the same donors, arrays were made from purified peripheral monocytes from 1 active SLE, 1 inactive SLE, 3 ASCT-treated SLE and 3 ND. ASCT-treated patients in this study have achieved long-term remission with SLEDAI 0~2, whose blood were taken at the time point of 6~11 years after ASCT. A reference list of 2220 IFN pathway-related genes was obtained from a recent publication on PBMCs and used to estimate IFN imprints in SLE patients.

Results:

In CD4+ T cells, inactive SLE showed a marginal IFN-imprint characterized by 233 only weakly expressed probe sets compared to active SLE characterized by 573 probe sets. Unexpectedly, 562 differentially expressed probe sets were also identified in ASCT-treated patients who are under long-term remission. However, considering the absolute magnitude of expression of IFN-regulated transcripts, the imprint in ASCT-treated patients was much weaker than in active SLE. For example, significantly up-regulated expression levels of IFI27 / IFIT1 / IFI44L was greater in active SLE (fold change; FC 41.4 / 15.8 / 11.3, respectively) than in ASCT-treated patients (FC 11.8 / 5.8 / 4.8), and no significant regulation was observed in inactive SLE . It was obvious that monocytes showed a more complex IFN response characterized by 918 differentially expressed probe sets in active SLE. Marginal IFN-imprint characterized by 652 and 592 probe sets were observed in monocytes respectively from inactive SLE and ASCT-treated patients. Different fromCD4+ T cells, monocytes from ASCT-treated patients showed no apparent IFN signatures. For example, significantly up-regulated expression of IFI27 / IFIT1 / IFI44L were observed in active SLE (FC 125.1 / 9.8 / 8.4), but not in ASCT-treated patients and inactive SLE.

Conclusion:

We could show for the first time detailed cell type-specific IFN signatures for CD4+ T cells and monocytes isolated from active and inactive SLE patients. Most interestingly, the intriguing question comes up, why only CD4+ T cells, but not monocytes of ASCT-treated patients, are characterized by an apparent IFN imprint although patients are under long-term remission. Our results indicate for a cell type-specific pro-inflammatory cytokine memory in CD4+ T helper lymphocytes even after ASCT-therapy in patients with SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cell-type-specific-type-i-interferon-signatures-in-autologous-stem-cell-transplanted-lupus-patients-different-molecular-behavior-between-cd4-t-cells-and-monocytes/