High Levels of Serum IFN-Alpha Mark a Subgroup of SLE Patients with Distinct Immunophenotypic Features and Hyperresponsiveness to Toll-like Receptor Stimulation

Uma Thanarajasingam¹, Mark A. Jensen², Jessica M. Dorschner³ and Timothy B. Niewold³, ¹Division of Rheumatology, Mayo Clinic, Rochester, MN, ²Divsion of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN, ³Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Dendritic cells, interferons, regulatory cells and toll-like receptors, SLE

Session Information

Date: Sunday, November 8, 2015

Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

IFN-alpha is a pathogenic factor in SLE. High serum interferon activity (IFN-high) marks a subgroup of SLE patients strongly associated with increased disease severity and autoantibody formation. Genetic variations associated with risk for SLE are enriched within this subgroup, however differences in the cellular immune system between IFN-high and IFN-low patients remain largely unknown. In this study, we sought to better characterize the IFN-high and IFN-low subgroups in human SLE by studying relevant immune cell subsets, and stimulated cytokine responses post whole blood stimulation by Toll-like receptor (TLR) agonists.

Methods:

SLE patients (n= 25) meeting ACR criteria for SLE and healthy controls (n=10) were recruited. Serum IFN-activity scores were calculated using the WISH assay, and used to bin patients as IFN-high and IFN-low. Demographic and serologic data were analyzed. Immune cell subsets including plasmacytoid dendritic cells (pDCs) and CD19⁺CD24^hiCD38^hi regulatory B cells (Bregs) were quantitated by flow cytometry of whole blood. Microspheres allowed for the quantitation of absolute numbers of CD24 and CD38 receptors on Bregs. Whole blood was dispensed into tubes coated with the TLR agonists LPS, CpG and R848 (Tru-Culture.) The stimulated IFN-alpha production was measured by WISH. Flow and Tru-Culture stimulation were performed within 6 hours of less of phlebotomy.

Results:

Of the 25 patients studied, 9 were IFN-high and 16 were IFN-low. Compared to IFN-low, IFN-high patients were younger (39.0 versus 46.5 years) and had more autoantibodies such as anti-Sm and anti-dsDNA, similar to previous studies. Medication usage was not significantly different between groups. The frequency of circulating pDCs was significantly lower in IFN-high SLE patients as compared to controls (p=0.0159). The frequency of Bregs and their surface expression of CD38 was also lower in IFN-high compared IFN low and controls. With respect to TLR signaling, both IFN-high and IFN-low SLE patients responded more robustly to R848 stimulation than controls. Interestingly, IFN-high patients responded more dramatically to LPS than IFN-low SLE patients (p<0.05), and controls (p=0.05).

Conclusion:

We have observed clinical and novel biologic differences between IFN-high and low SLE subgroups. The fact that pDC counts were only reduced in the high IFN patients would suggest trafficking out of the circulation and into inflamed tissue prior to IFN production. We find decreased Breg numbers and decreased CD38 expression in the IFN-high patients, which could indicate decreased regulatory potential from this cell type in high IFN SLE. Finally, our study demonstrates that IFN-high patients are significantly more responsive to TLR4 stimulation– a novel finding that may shed light on differential responses to SLE therapies. Further studies of Breg function in SLE and the stimulated inflammatory cytokine response are ongoing.

Disclosure: U. Thanarajasingam, None; M. A. Jensen, None; J. M. Dorschner, None; T. B. Niewold, None.

To cite this abstract in AMA style:

Thanarajasingam U, Jensen MA, Dorschner JM, Niewold TB. High Levels of Serum IFN-Alpha Mark a Subgroup of SLE Patients with Distinct Immunophenotypic Features and Hyperresponsiveness to Toll-like Receptor Stimulation [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/high-levels-of-serum-ifn-alpha-mark-a-subgroup-of-sle-patients-with-distinct-immunophenotypic-features-and-hyperresponsiveness-to-toll-like-receptor-stimulation/. Accessed .

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