| 1. |
|
|
| 2. |
- Carlström, Karl E., et al.
(författare)
-
Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
- 2019
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10:1, s. 1-13
-
Tidskriftsartikel (refereegranskat)abstract
- Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.
|
|
| 3. |
- Liang, Frank, et al.
(författare)
-
Recurrent Herpes Zoster Ophthalmicus in a Patient With a Novel Toll-Like Receptor 3 Variant Linked to Compromised Activation Capacity in Fibroblasts
- 2020
-
Ingår i: JOURNAL OF INFECTIOUS DISEASES. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 221:8, s. 1295-1303
-
Tidskriftsartikel (refereegranskat)abstract
- Background. Herpes zoster ophthalmicus occurs primarily in elderly or immunocompromised individuals after reactivation of varicella zoster virus (VZV). Recurrences of zoster ophthalmicus are uncommon because the reactivation efficiently boosts anti-VZV immunity. A 28-year-old female presented to our clinic with a history of multiple recurrences of zoster ophthalmicus. Methods. Whole-exome sequencing (WES), analyses of VZV T-cell immunity, and pathogen recognition receptor function in primary antigen-presenting cells (APCs) and fibroblasts were performed. Results. Normal VZV-specific T-cell immunity and antibody response were detected. Whole-exome sequencing identified a heterozygous nonsynonymous variant (c.2324C > T) in the Toll-like receptor 3 (TLR3) gene resulting in formation of a premature stop-codon. This alteration could potentially undermine TLR3 signaling in a dominant-negative fashion. Therefore, we investigated TLR3 signaling responses in APCs and fibroblasts from the patient. The APCs responded efficiently to stimulation with TLR3 ligands, whereas the responses from the fibroblasts were compromised. Conclusions. We report a novel TLR3 variant associated with recurrent zoster ophthalmicus. Toll-like receptor 3 responses that were unaffected in APCs but diminished in fibroblasts are in line with previous reports linking TLR3 deficiency with herpes simplex virus encephalitis. Mechanisms involving compromised viral sensing in infected cells may thus be central to the described immunodeficiency.
|
|
