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

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

doi:10.1016/j.jaci.2021.05.007

Cited by 17 publications

(26 citation statements)

References 55 publications

(69 reference statements)

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“…Both CVID patients in our cohort had low CD3 + T cells and a phenotype supportive of abnormal T-cell function suggesting it was the T-cell defect rather than the humoral deficiency that contributed to RuV susceptibility. The genetic etiologies of the three HLH patients reported here, and 12 patients recently reported by Gross et al, which include the RAB27A, UNC13D , and PRF1 genes, impacted CD8 + T-cell cytotoxicity ( 25 ). In addition, we report several previously undocumented conditions responsible for increased susceptibility to RuV -associated granulomas.…”

Section: Discussionmentioning

confidence: 53%

“…Only one pattern of RuV-associated inflammation in IEI patients, M-type, has been previously described ( 16 , 17 , 25 ). The reasons why we were able to identify additional patterns in this study are the inclusion of individuals with diverse IEI types and the relatively large size of the patient cohort.…”

Section: Discussionmentioning

confidence: 99%

“…Cutaneous granulomas are the most frequent manifestation diagnosed, but other organs including the liver, spleen, and lungs can also be affected ( 4 , 22 , 23 ). RuV antigen is localized in M2 macrophages at the center of the granulomas in previously described cases ( 16 , 17 , 24 , 25 ), but a detailed description of the spatial organization of RuV associated granulomas and its cellular constituents is lacking.…”

Section: Introductionmentioning

confidence: 95%

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Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

et al. 2021

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Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

et al. 2021

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“…Cartilage hair hypoplasia patients have granulomas among their clinical manifestations as well ( 41 , 54 – 56 ). Rubella virus-associated granulomas have also been described in 21 IEI patients having cytotoxicity defects with significant frequency in MUNC13–4 and RAB27A (Griscelli syndrome type 2) deficiency ( 57 ). Of note, GLILD has also been described in Griscelli Syndrome type 2 ( 58 ).…”

Section: Introductionmentioning

confidence: 99%

“…This finding highlights the importance for thorough antigen screening in tissue biopsy particularly since treatment of granulomas in IEI has classically focused on use of immunosuppression. The RuV antigen and/or RNA has been identified in at least 66 IEI cases -predominantly cases of AT and CID, and defects of cytotoxicity, but much rarer in primary antibody deficiencies ( 10 , 57 ). Of note, varicella zoster vaccine, mumps and RuV vaccine strain were all identified in granulomas of a patient with late onset hypomorphic RAG2 deficiency ( 100 ).…”

Section: Introductionmentioning

confidence: 99%

Granulomatous inflammation in inborn errors of immunity

Sacco

Gazzin²,

Notarangelo³

et al. 2023

Front. Pediatr.

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Granulomas have been defined as inflammatory infiltrates formed by recruitment of macrophages and T cells. The three-dimensional spherical structure typically consists of a central core of tissue resident macrophages which may merge into multinucleated giant cells surrounded by T cells at the periphery. Granulomas may be triggered by infectious and non-infectious antigens. Cutaneous and visceral granulomas are common in inborn errors of immunity (IEI), particularly among patients with chronic granulomatous disease (CGD), combined immunodeficiency (CID), and common variable immunodeficiency (CVID). The estimated prevalence of granulomas in IEI ranges from 1%–4%. Infectious agents causing granulomas such Mycobacteria and Coccidioides presenting atypically may be ‘sentinel’ presentations for possible underlying immunodeficiency. Deep sequencing of granulomas in IEI has revealed non-classical antigens such as wild-type and RA27/3 vaccine-strain Rubella virus. Granulomas in IEI are associated with significant morbidity and mortality. The heterogeneity of granuloma presentation in IEI presents challenges for mechanistic approaches to treatment. In this review, we discuss the main infectious triggers for granulomas in IEI and the major forms of IEI presenting with ‘idiopathic’ non-infectious granulomas. We also discuss models to study granulomatous inflammation and the impact of deep-sequencing technology while searching for infectious triggers of granulomatous inflammation. We summarize the overarching goals of management and highlight the therapeutic options reported for specific granuloma presentations in IEI.

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Rubella Virus–Associated Granulomas in Immunocompetent Adults—Possible Implications

Notarangelo

2022

JAMA Dermatol

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Granulomas are inflammatory infiltrates consisting primarily of macrophages, histiocytes, and lymphocytes that contain and limit insulting agents. They often develop in response to chronic infection, but may also be a manifestation of type IV delayed-type hypersensitivity reaction in response to noninfectious agents, including drugs and foreign bodies. Whenever microbial or noninfectious causes of granulomas cannot be identified, granulomas are defined as idiopathic.Granulomatous lesions involving the skin or other organs are particularly common among patients with inborn errors of immunity (IEI), for which their overall prevalence is estimated to be 1% to 4%. This prevalence is highest among patients with combined immune deficiency (CID), common variable immune deficiency (CVID), and chronic granulomatous disease. 1 Furthermore, while granulomas involving sinopulmonary, gastrointestinal, and other visceral locations are more common in patients with CVID and chronic granulomatous disease, the skin represents the primary site of granulomatous manifestations in patients with CID. 1 In this issue of JAMA Dermatology, Wanat et al 2 report the presence of rubella virus (RuV) in idiopathic skin granulomas from 4 clinically immunocompetent adults. In 3 of these cases, vaccine-derived RuVs were detected, whereas wild-type RuV was present in the fourth patient. 2 Rubella is typically a mild disease, but when contracted during pregnancy, it may cause miscarriage or serious birth defects, collectively termed congenital rubella syndrome (CRS). Before development of the RuV vaccine, during a major rubella epidemic in Europe and the US from 1962 to 1964, CRS left more than 11 000 infants with deafness, more than 3500 with blindness, and nearly 2000 with intellectual disability. 3 In rare cases, persistent RuV infection in adults is associated with an increased risk of Fuchs uveitis, encephalitis, and arthritis. Vaccination with the RA27/3 strain, which is used in most countries as live-attenuated vaccine against rubella in combination with measles and mumps-attenuated viruses and more recently with varicella virus vaccine, is effective and safe and has substantially contributed to global elimination of rubella and prevention of CRS. 3

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

Cited by 17 publications

References 55 publications

Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

Granulomatous inflammation in inborn errors of immunity

Rubella Virus–Associated Granulomas in Immunocompetent Adults—Possible Implications

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