AUTHOR=Perelygina Ludmila , Faisthalab Raeesa , Abernathy Emily , Chen Min-hsin , Hao LiJuan , Bercovitch Lionel , Bayer Diana K. , Noroski Lenora M. , Lam Michael T. , Cicalese Maria Pia , Al-Herz Waleed , Nanda Arti , Hajjar Joud , Vanden Driessche Koen , Schroven Shari , Leysen Julie , Rosenbach Misha , Peters Philipp , Raedler Johannes , Albert Michael H. , Abraham Roshini S. , Rangarjan Hemalatha G. , Buchbinder David , Kobrynski Lisa , Pham-Huy Anne , Dhossche Julie , Cunningham Rundles Charlotte , Meyer Anna K. , Theos Amy , Atkinson T. Prescott , Musiek Amy , Adeli Mehdi , Derichs Ute , Walz Christoph , Krüger Renate , von Bernuth Horst , Klein Christoph , Icenogle Joseph , Hauck Fabian , Sullivan Kathleen E. TITLE=Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.796065 DOI=10.3389/fimmu.2021.796065 ISSN=1664-3224 ABSTRACT=

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.