Translational Immunology research: a support for clinical immunological research

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications & trials

Abstract

A major project that involves the TIS is the definition of molecular biomarkers for autoimmune and autoinflammatory diseases. We have collaborated with Dr. Peter Grayson who has recently identified a group of patients with giant cell arteritis who respond less favorably to tocilizumab, an interleukin 6 (IL6) receptor (IL6R) antagonist. Individuals with the Asp358Ala genetic variant of IL-6R are less likely to achieve complete clinical response when treated with tocilizumab. This is a relatively common polymorphism associated with an increase in IL6 and in soluble IL-6R (sIL-6R) serum levels resulting in reduced IL-6-induced C-reactive protein (CRP) production. Notably, T cells from individuals with the minor CC genotype (wild type) compared to the AA genotype show impaired classic IL-6 signaling due to enhanced disintegrin and metalloproteinase (ADAM)-mediated shedding of the membrane-bound IL-6R. This has been associated with protection from development of autoimmune pathologies like rheumatoid arthritis and type 1 diabetes (T1D). It was suggested that increased sIL-6R may lead to decreased IL-6 classic- or increased IL-6 trans-signaling. A manuscript describing these results was recently published in Annals of Rheumatic Diseases. The group led by Dr. Michael Ombrello, a Tenure-Track IRP investigator, discovered that a class II human leukocyte antigen (HLA) region haplotype that encodes the HLA-DRB1*11 allele is the strongest genetic risk factor for systemic JIA (sJIA). They further identified a strong association between HLA-DRB1*15 alleles and a new, life-threatening form of lung disease. Dr. Ombrello has assembled an sJIA cohort that includes many severely affected patients. sJIA patients display T cell skewing towards T helper 17 (Th17) and away from regulatory T cell phenotypes. Therefore, the TIS is currently supporting Dr. Ombrello’s research by performing deep immunophenotyping of PBMC to classify subjects in that cohort. In collaborative work with Drs. Dan Kastner and Ivona Aksentijevich (NHGRI) focusing on the spectrum of autoinflammatory diseases, the TIS supported a project aimed at characterizing the decreased activity of mevalonate kinase (MK) which is associated with inherited human autoinflammatory disorders. To do this, we analyzed ellular populations in blood and IFN-g signature in muscle biopsies and in blood of patients carrying a rare pathogenic variant in the HMGCS1 gene (c.265C>T, p. Arg89Trp), encoding for HMG-CoA synthase and compared these to healthy donors of such patients. Moreover, we developed a flow cytometry assay to assess STAT phosphorylation in myeloid and lymphoid cell populations of patients carrying biallelic pathogenic variants in the MEFV gene that encodes the myeloid-restricted inflammasome sensor pyrin. NHGRI clinicians and collaborators have identified 45 compound heterozygotes for Ile692del and Val726Ala who present with a more severe clinical phenotype that is refractory to colchicine therapy. The clinical presentation of these patients also overlaps with features of other autoinflammatory diseases Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) and Pyogenic Arthritis, Pyoderma gangrenosum and acne (PAPA), and has been designated as having compound heterozygosity for the Ile692del and Val726A pathogenic MEFV variants and Elevated IL-18 (CHIVE syndrome). In collaboration with Dr. Giuseppe Sciumé at Sapienza University in Rome, Italy, we are assessing the role of the transcription factor STAT4 in regulating effector differentiation of ILC1 and NK cells during intestinal inflammation in mice. The TIS has also been investigating novel approaches for the treatment of autoimmune diseases. In collaboration with the O'Shea and Kaplan groups we are currently evaluating the effects of tofacitinib and second-generation JAK-selective inhibitors on T cells and innate lymphoid cells. Since a major limitation of JAK/STAT gene knockout studies in mice is the complete loss of Innate Lymphoid Cell (ILC) populations (including natural killer cells), pharmacological alteration of this signaling cascade with JAK inhibitors is an attractive alternative strategy for studying the role of cytokine signaling in ILC biology. We have been investigating the effects of pan and JAK-selective inhibitors on the development and functions of invariant natural killer T cells and these studies are still currently ongoing.