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Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity

Miriam Gross 1 Carsten Speckmann 2 Annette May 2 Tania Gajardo-Carrasco 3 Katharina Wustrau 4 Sarah Lena Maier 4 Marcus Panning 2 Daniela Huzly 2 Abbas Agaimy 5 Yenan Bryceson 6 Sharon Choo 7 C.W. Chow 7 Gregor Dückers 8 Anders Fasth 9 Sylvie Fraitag 10 Katja Gräwe 2 Sabine Haxelmans 1 Dirk Holzinger 11 Ole Hudowenz 12 Judith Hübschen 13 Claudia Khurana 14 Korbinian Kienle 15 Roman Klifa 10 Klaus Korn 16 Heinz Kutzner Tim Lämmermann 15 Svea Ledig 4 Dan Lipsker 17, 18 Marie Meeths 19 Nora Naumann-Bartsch 16 Jelena Rascon 20 Anne Schänzer 12 Maximilian Seidl 21 Bianca Tesi 19 Christelle Vauloup-Fellous 22 Beate Vollmer-Kary 2 Klaus Warnatz 2 Claudia Wehr 2 Bénédicte Neven 3 Pablo Vargas 23, 24, 25 Fernando Sepulveda 3 Kai Lehmberg 4 Annette Schmitt-Graeff 2 Stephan Ehl 2 
Abstract : Background: Rubella virus–induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive. Objective: This study sought to understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas. Methods: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, this study combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. The investigators performed rubella virus immunohistochemistry and PCR and T-cell migration assays. Results: This study identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before 2 years of age and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3-dimensional migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps, or varicella live-attenuated vaccine or severe infections with other viruses. Conclusions: This study identified lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps, or varicella vaccines. Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity.
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Submitted on : Wednesday, November 17, 2021 - 11:00:12 AM
Last modification on : Monday, August 8, 2022 - 1:30:05 PM
Long-term archiving on: : Friday, February 18, 2022 - 6:59:21 PM


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Miriam Gross, Carsten Speckmann, Annette May, Tania Gajardo-Carrasco, Katharina Wustrau, et al.. Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity. Journal of Allergy and Clinical Immunology, Elsevier, In press, ⟨10.1016/j.jaci.2021.05.007⟩. ⟨hal-03432275⟩



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