TY - JOUR
T1 - Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity
AU - Groß, Miriam
AU - Speckmann, Carsten
AU - May, Annette
AU - Gajardo-Carrasco, Tania
AU - Wustrau, Katharina
AU - Maier, Sarah Lena
AU - Panning, Marcus
AU - Huzly, Daniela
AU - Agaimy, Abbas
AU - Bryceson, Yenan T.
AU - Choo, Sharon
AU - Chow, C. W.
AU - Dückers, Gregor
AU - Fasth, Anders
AU - Fraitag, Sylvie
AU - Gräwe, Katja
AU - Haxelmans, Sabine
AU - Holzinger, Dirk
AU - Hudowenz, Ole
AU - Hübschen, Judith M.
AU - Khurana, Claudia
AU - Kienle, Korbinian
AU - Klifa, Roman
AU - Korn, Klaus
AU - Kutzner, Heinz
AU - Lämmermann, Tim
AU - Ledig, Svea
AU - Lipsker, Dan
AU - Meeths, Marie
AU - Naumann-Bartsch, Nora
AU - Rascon, Jelena
AU - Schänzer, Anne
AU - Seidl, Maximilian
AU - Tesi, Bianca
AU - Vauloup-Fellous, Christelle
AU - Vollmer-Kary, Beate
AU - Warnatz, Klaus
AU - Wehr, Claudia
AU - Neven, Bénédicte
AU - Vargas, Pablo
AU - Sepulveda, Fernando E.
AU - Lehmberg, Kai
AU - Schmitt-Graeff, Annette
AU - Ehl, Stephan
N1 - Funding Information:
M.G., A.M., K.G., B.V.K., A.S.G., and S.E. were supported by the Deutsche Forschungsgemeinschaft ( SFB1160 , TP A1 and Z1). This work was further supported by the Deutsche Kinderkrebsstiftung ( DKS 2016.04 and DKS 2018.11 ). T.G.C. was supported by the French State funding from the Agence Nationale de la Recherche under “Investissements d’avenir” program ( ANR-10-IAHU-01 ) and the “ Fondation Bettencourt Schueller .” J.M.H. was financially supported by the Grand Duchy of Luxembourg through the Ministries of Health and of Higher Education and Research.
Funding Information:
Disclosure of potential conflict of interest: A. Fasth received personal fees outside the submitted work from Lipum as member of the advisory board. S. Ehl received a research grant from UCB outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.
Publisher Copyright:
© 2021 American Academy of Allergy, Asthma & Immunology
PY - 2022/1/22
Y1 - 2022/1/22
N2 - 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.
AB - 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.
KW - Cytotoxicity
KW - Griscelli syndrome type 2
KW - granuloma
KW - hemophagocytic lymphohistiocytosis
KW - live vaccine
KW - primary immunodeficiency
KW - rubella virus
UR - http://www.scopus.com/inward/record.url?scp=85108564181&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/34033843
U2 - 10.1016/j.jaci.2021.05.007
DO - 10.1016/j.jaci.2021.05.007
M3 - Article
C2 - 34033843
AN - SCOPUS:85108564181
SN - 0091-6749
VL - 149
SP - 388-399.e4
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -