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

Miriam Groß, Carsten Speckmann, Annette May, Tania Gajardo-Carrasco, Katharina Wustrau, Sarah Lena Maier, Marcus Panning, Daniela Huzly, Abbas Agaimy, Yenan T. Bryceson, Sharon Choo, C. W. Chow, Gregor Dückers, Anders Fasth, Sylvie Fraitag, Katja Gräwe, Sabine Haxelmans, Dirk Holzinger, Ole Hudowenz, Judith M. HübschenClaudia Khurana, Korbinian Kienle, Roman Klifa, Klaus Korn, Heinz Kutzner, Tim Lämmermann, Svea Ledig, Dan Lipsker, Marie Meeths, Nora Naumann-Bartsch, Jelena Rascon, Anne Schänzer, Maximilian Seidl, Bianca Tesi, Christelle Vauloup-Fellous, Beate Vollmer-Kary, Klaus Warnatz, Claudia Wehr, Bénédicte Neven, Pablo Vargas, Fernando E. Sepulveda, Kai Lehmberg, Annette Schmitt-Graeff, Stephan Ehl*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)388-399.e4
JournalJournal of Allergy and Clinical Immunology
Issue number1
Early online date24 May 2021
Publication statusPublished - 22 Jan 2022


  • Cytotoxicity
  • Griscelli syndrome type 2
  • granuloma
  • hemophagocytic lymphohistiocytosis
  • live vaccine
  • primary immunodeficiency
  • rubella virus


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