Translational Immunology research: a support for clinical immunological research

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A major project that involves the TIS is the definition of molecular biomarkers for autoimmune and autoinflammatory diseases. We are also collaborating with Drs. Peter Grayson and Marcela Ferrada on the characterization of the novel VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. We measured cytokine levels in the serum of patients and assessed their deregulated immune functions in response to extracellular stimuli. The work was published in New England Journal of Medicin and a second article in Arthritis and Rheumatology describing how somatic mutations in UBA1 define a subset of patients with Relapsing polychondritis (RP). Moreover, Dr. Grayson 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 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. We are currently assessing the signaling downstream of the IL-6R in patients carrying the polymorphism and patients with wild type alleles In collaboration with Dr. Mariana Kaplan who is conducting an observational study to characterize the effects of COVID-19 on systemic inflammation, autoimmunity and vasculopathy, including the response to potential antiviral treatments or vaccines, in adult and pediatric patients with a prior diagnosis of systemic autoimmunity. Primary endpoints of the study are mechanistic measures of the clinical and the immunological response (gene expression changes, immune cell subset proportions, serum cytokine levels) in patients with inflammatory or autoimmune pathologies treated with immune modulators, including vaccines or antiviral therapeutics. To support this clinical study, the TIS has designed and optimized a deep immunophenotyping 38-color panel that will be utilized to assess changes in immune cell composition/distribution during the course of the study. 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. 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. Ombrellos research by performing deep immunophenotyping of PBMC to classify subjects in that cohort. In a collaborative study with Dr. Dan Kastner and Ivona Aksentijevich (NHGRI) focusing on the spectrum of autoinflammatory diseases that include defects in deubiquitination. One of the projects aims at characterizing the first patient with SHARPIN deficiency. SHARPIN is a component of the linear ubiquitin assembly complex (LUBAC) that includes HOIP, HOIL1 and is essential for proper immune response. Patients with HOIP and HOIL1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen deposits in the heart, skeletal muscle and liver. In mice, loss of SHARPIN leads to severe dermatitis associated with excessive cell death in keratinocytes. In the patient, the deficiency results in fever, arthritis, colitis, chronic otitis media and hepatic glycogenosis but unexpectedly, no dermatologic manifestations. The TIS measured cytokine production upon stimulation with LPS or IL-1beta in PBMCs from a SHARPIN-deficient patient in comparison to a HOIP-deficient patient. A paper describing these results is currently under review. In collaboration with Professor Francesca Romana Spinelli from Universit Sapienza (Rome, Italy) who visited the TIS as a guest researcher during the summer 2023 and who has access to a sizable cohort of rheumatoid arthritis patients treated with JAK inhibitors. She will provide frozen PBMC obtained from patients before treatment and at subsequent time points during the therapy. The availability of a larger number of samples will help us achieve more robust conclusions regarding the effects of these drugs on ILC biology. In collaboration with Dr. Giuseppe Sciume at Sapienza University in Rome, Italy, we have shown that the transcription factor STAT4 played an unexpectedly divergent role in regulating effector differentiation of ILC1 and NK cells during intestinal inflammation in mice. A manuscript describing these results has recently been accepted for publication in Proceedings of National Academy of Sciences U.S.A. 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 alternation of this signaling cascade with JAK inhibitors is an attractive alternative strategy to study 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 the studies are still currently ongoing.