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

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 - Copyright © 2021 American Academy of Allergy, Asthma & Immunology. All rights reserved.

PY - 2022/1

Y1 - 2022/1

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 - Child

KW - Child, Preschool

KW - Female

KW - Granuloma/etiology

KW - Humans

KW - Infant

KW - Phenotype

KW - Rubella/genetics

KW - Rubella Vaccine/adverse effects

KW - Skin/immunology

KW - T-Lymphocytes/immunology

U2 - 10.1016/j.jaci.2021.05.007

DO - 10.1016/j.jaci.2021.05.007

M3 - SCORING: Journal article

C2 - 34033843

VL - 149

SP - 388-399.e4

JO - J ALLERGY CLIN IMMUN

JF - J ALLERGY CLIN IMMUN

SN - 0091-6749

IS - 1

ER -