Julia R Hirsiger1, Giorgio Tamborrini2, Dorothee Harder3, Glenn R Bantug4, Gideon Hoenger5, Mike Recher6, Christian Marx7, Quan-Zhen Li8, Ivan Martin9, Christoph Hess4, Arnaud Scherberich9, Thomas Daikeler10, Christoph T Berger11. 1. Translational Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. 2. Ultrasound Center for Rheumatology (UZR), Basel, Switzerland; Rheumatology Clinic, University Hospital Basel, Basel, Switzerland. 3. Department of Radiology, University Hospital Basel, Basel, Switzerland. 4. Immunobiology Lab, Department Biomedicine, University of Basel, Basel, Switzerland. 5. HLA-Diagnostics and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland. 6. Immunodeficiency Lab, Department Biomedicine, University of Basel, Basel, Switzerland. 7. Rheumatology Zürcher Oberland (RZO), Uster, Switzerland. 8. Department of Immunology & Internal Medicine, IIMT Microarray Core Facility, University of Texas Southwestern Medical Center, USA. 9. Laboratory of Tissue Engineering, Departments of Surgery and Biomedicine, University Hospital of Basel, University of Basel, Basel, Switzerland. 10. Rheumatology Clinic, University Hospital Basel, Basel, Switzerland. 11. Translational Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland; Interdisciplinary Center for Immunology, Departments of Dermatology, Internal Medicine, and Rheumatology, University Hospital Basel, Basel, Switzerland. Electronic address: christoph.berger@usb.ch.
Abstract
BACKGROUND: Viral infections may trigger autoimmunity in genetically predisposed individuals. Immunizations mimic viral infections immunologically, but only in rare instances vaccinations coincide with the onset of autoimmunity. Inadvertent vaccine injection into periarticular shoulder tissue can cause inflammatory tissue damage ('shoulder injury related to vaccine administration, SIRVA). Thus, this accident provides a model to study if vaccine-induced pathogen-specific immunity accompanied by a robust inflammatory insult may trigger autoimmunity in specific genetic backgrounds. METHODS: We studied 16 otherwise healthy adults with suspected SIRVA occurring following a single work-related influenza immunization campaign in 2017. We performed ultrasound, immunophenotypic analyses, HLA typing, and influenza- and self-reactivity functional immunoassays. Vaccine-related bone toxicity and T cell/osteoclast interactions were assessed in vitro. FINDINGS: Twelve of the 16 subjects had evidence of inflammatory tissue damage on imaging, including bone erosions in six. Tissue damage was associated with a robust peripheral blood T and B cell activation signature and extracellular matrix-reactive autoantibodies. All subjects with erosions were HLA-DRB1*04 positive and showed extracellular matrix-reactive HLA-DRB1*04 restricted T cell responses targeting heparan sulfate proteoglycan (HSPG). Antigen-specific T cells potently activated osteoclasts via RANK/RANK-L, and the osteoclast activation marker Trap5b was high in sera of patients with an erosive shoulder injury. In vitro, the vaccine component alpha-tocopheryl succinate recapitulated bone toxicity and stimulated osteoclasts. Auto-reactivity was transient, with no evidence of progression to rheumatoid arthritis or overt autoimmune disease. CONCLUSION: Vaccine misapplication, potentially a genetic predisposition, and vaccine components contribute to SIRVA. The association with autoimmunity risk allele HLA-DRB1*04 needs to be further investigated. Despite transient autoimmunity, SIRVA was not associated with progression to autoimmune disease during two years of follow-up.
BACKGROUND: Viral infections may trigger autoimmunity in genetically predisposed individuals. Immunizations mimic viral infections immunologically, but only in rare instances vaccinations coincide with the onset of autoimmunity. Inadvertent vaccine injection into periarticular shoulder tissue can cause inflammatory tissue damage ('shoulder injury related to vaccine administration, SIRVA). Thus, this accident provides a model to study if vaccine-induced pathogen-specific immunity accompanied by a robust inflammatory insult may trigger autoimmunity in specific genetic backgrounds. METHODS: We studied 16 otherwise healthy adults with suspected SIRVA occurring following a single work-related influenza immunization campaign in 2017. We performed ultrasound, immunophenotypic analyses, HLA typing, and influenza- and self-reactivity functional immunoassays. Vaccine-related bone toxicity and T cell/osteoclast interactions were assessed in vitro. FINDINGS: Twelve of the 16 subjects had evidence of inflammatory tissue damage on imaging, including bone erosions in six. Tissue damage was associated with a robust peripheral blood T and B cell activation signature and extracellular matrix-reactive autoantibodies. All subjects with erosions were HLA-DRB1*04 positive and showed extracellular matrix-reactive HLA-DRB1*04 restricted T cell responses targeting heparan sulfate proteoglycan (HSPG). Antigen-specific T cells potently activated osteoclasts via RANK/RANK-L, and the osteoclast activation marker Trap5b was high in sera of patients with an erosive shoulder injury. In vitro, the vaccine component alpha-tocopheryl succinate recapitulated bone toxicity and stimulated osteoclasts. Auto-reactivity was transient, with no evidence of progression to rheumatoid arthritis or overt autoimmune disease. CONCLUSION: Vaccine misapplication, potentially a genetic predisposition, and vaccine components contribute to SIRVA. The association with autoimmunity risk allele HLA-DRB1*04 needs to be further investigated. Despite transient autoimmunity, SIRVA was not associated with progression to autoimmune disease during two years of follow-up.