Editorial: JAK inhibition in autoimmune and inflammatory diseases

publishedVersionNon peer reviewe

Editorial: JAK inhibition in autoimmune and inflammatory diseases

publishedVersionNon peer reviewe

The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS

Mutational analysis and NMR studies of the death domain of the tumor necrosis factor receptor-1

Tumor necrosis factor receptor-1 (TNFR-1) death domain (DD) is the intracellular functional domain responsible for the receptor signaling activities. To understand the transduction mechanism of TNFR-1 signaling we performed structural and functional analysis of the TNFR-DD. The secondary structure of the TNFR-DD shows that it consists of six anti-parallel a-helices. The determination of the topological fold and an extensive mutagenesis analysis revealed that there are two opposite faces that are involved in self-association and interaction with the TRADD death domain. Interestingly, the same critical residues in TNFR-DD are involved in both interactions. There is a good correlation between the binding activities of the mutant proteins and their cytotoxic activities. These results provide important insight into the molecular interactions mediating TNFR-DD self-association and subsequent recruitment of TRADD in the signaling activity of TNFR-1

Jak3 deficiency blocks innate lymphoid cell development

Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive (AR) severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of the immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1tm1Ven/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3 generating a SCID phenotype, with an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC progenitor (ILCP) and the pre-NK cell progenitor (pre-NKP). We further demonstrate that the pan-JAK inhibitor tofacitinib and specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis (RA) and is under clinical trial for several other immune-mediated conditions. Our data suggests that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy