Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity - 05/01/22

Doi : 10.1016/j.jaci.2021.05.007

Miriam Groß, MSc ^a,^b, Carsten Speckmann, MD ^a,^c, Annette May, MD ^d, Tania Gajardo-Carrasco, MSc ^e,^f, Katharina Wustrau, MD ^g, Sarah Lena Maier, MD ^g, Marcus Panning, MD ^h, Daniela Huzly, MD ^h, Abbas Agaimy, MD ⁱ, Yenan T. Bryceson, PhD ^j,^k, Sharon Choo, MD ^l, C.W. Chow, MD ^m, Gregor Dückers, MD ⁿ, Anders Fasth, MD, PhD ^o, Sylvie Fraitag, MD ^p, Katja Gräwe, MTA ^a, Sabine Haxelmans, TA ^q, Dirk Holzinger, MD ^r, Ole Hudowenz, MD ^s, Judith M. Hübschen, PhD ^t, Claudia Khurana, MD ^u, Korbinian Kienle, PhD ^v, Roman Klifa, MD ^w, Klaus Korn, MD ^x, Heinz Kutzner, MD ^y, Tim Lämmermann, PhD ^v, Svea Ledig, MD ^g, Dan Lipsker, MD ^z, Marie Meeths, MD, PhD ^aa,^ab,^ac, Nora Naumann-Bartsch, MD ^ad, Jelena Rascon, MD, PhD ^ae,^af, Anne Schänzer, MD ^ag, Maximilian Seidl, MD ^d,^ah, Bianca Tesi, MD, PhD ^ab,^ai, Christelle Vauloup-Fellous, PhD ^aj, Beate Vollmer-Kary, TA ^d, Klaus Warnatz, MD ^ak,^al, Claudia Wehr, MD ^al,^am, Bénédicte Neven, MD, PhD ^f,^an,^ao, Pablo Vargas, PhD ^ap, Fernando E. Sepulveda, PhD ^e,^f,^aq, Kai Lehmberg, MD ^g, Annette Schmitt-Graeff, MD ^al, Stephan Ehl, MD ^a,^⁎
^a Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany
^b Faculty of Biology, University of Freiburg, Freiburg, Germany
^c Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany
^d Institute for Surgical Pathology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany
^e Molecular Basis of Altered Immune Homeostasis Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM), Unite Mixte de Recherche (UMR) 1163, Paris, France
^f Imagine Institute, Université de Paris, Paris, France
^g Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
^h Institute of Virology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany
ⁱ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
^j Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
^k Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway
^l Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, Australia
^m Department of Anatomical Pathology, The Royal Children's Hospital, Melbourne, Australia
ⁿ Helios Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Krefeld, Germany
^o Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden
^p Department of Pathology, Necker-Enfants Malades Hospital, Paris, France
^q Life Imaging Center, University of Freiburg, Freiburg, Germany
^r Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
^s Department of Rheumatology, Immunology, Osteology, and Physical Medicine, Campus Kerckhoff of Justus-Liebig-University Gießen, Bad Nauheim, Germany
^t World Health Organization European Regional Reference Laboratory for Measles and Rubella, Luxembourg Institute of Health, Department of Infection and Immunity, Esch-sur-Alzette, Luxembourg
^u Department of Pediatric Hematology and Oncology, Children’s Center Bethel, University Hospital Ostwestfalen-Lippe (OWL)/University Bielefeld, Bielefeld, Germany
^v Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
^w Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris (AH-PH), Paris, France
^x Institute of Virology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
^y Dermatopathology, Friedrichshafen, Germany
^z Faculté de Médecine, Université de Strasbourg and Clinique Dermatologique, Hôpitaux Universitaires, Strasbourg, France
^aa Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
^ab Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
^ac Theme of Children's Health, Karolinska University Hospital, Stockholm, Sweden
^ad Division of Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany
^ae Center for Pediatric Oncology and Hematology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
^af Faculty of Medicine, Vilnius University, Vilnius, Lithuania
^ag Institute of Neuropathology, Justus Liebig University Gießen, Gießen, Germany
^ah Institute of Pathology, Heinrich Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany
^ai Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
^aj AP–HP, Hôpital Paul-Brousse, Department of Virology, World Health Organization Rubella National Reference Laboratory, Groupe de Recherche sur les Infections pendant la Grossesse, University Paris Saclay, INSERM U1193, Villejuif, France
^ak Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany
^al Center for Chronic Immunodeficiency, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany
^am Department of Medicine I, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany
^an Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France
^ao Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Imagine Institute, Université de Paris, Paris, France
^ap Institut Curie, Centre National de la Recherche Scientifique (CNRS) UMR 144 and Institut Pierre-Gilles de Gennes, and INSERM U932 Immunité et Cancer, Institut Curie, Paris Sciences et Lettres Research University, Paris, France
^aq Centre National de la Recherche Scientifique (CNRS), Paris, France

^∗Corresponding author: Stephan Ehl, MD, Institute for Immunodeficiency, University Medical Center Freiburg, Breisacher Strasse 115, 79104 Freiburg, Germany.Institute for ImmunodeficiencyUniversity Medical Center FreiburgBreisacher Strasse 115Freiburg79104Germany

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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Key words : Cytotoxicity, rubella virus, live vaccine, granuloma, primary immunodeficiency, hemophagocytic lymphohistiocytosis, Griscelli syndrome type 2

Abbreviations used : 3D, AT, CHS, fHLH, GS2, HLH, HSCT, IEI, MMR, NK, P1, RV

Plan

Flow cytometry–based assays

T-cell migration assays

Results

A patient with GS2 and rubella granulomas

Skin and visceral granulomas are common in patients with genetic defects in cytotoxicity

Clinical and immunohistochemical variability of granulomas

Clinical course of granulomas and response to treatment

Risk of rubella granuloma varies with genetic diagnosis

No evidence for impaired T-cell migration in patients with genetic defects of lymphocyte cytotoxicity

Discussion

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.

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.

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Vol 149 - N° 1

P. 388 - janvier 2022 Retour au numéro

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Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity - 05/01/22

Abstract

Background

Objective

Methods

Results

Conclusions

Plan

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