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

Ludmila Perelygina 1, Raeesa Faisthalab 1, Emily Abernathy 1, Min-Hsin Chen 1, LiJuan Hao 1, Lionel Bercovitch 2, Diana K Bayer 3, Lenora M Noroski 4, Michael T Lam 4, Maria Pia Cicalese 5, Waleed Al-Herz 6 7, Arti Nanda 8, Joud Hajjar 4, Koen Vanden Driessche 9, Shari Schroven 9, Julie Leysen 10, Misha Rosenbach 11, Philipp Peters 12, Johannes Raedler 12, Michael H Albert 12, Roshini S Abraham 13, Hemalatha G Rangarjan 14, David Buchbinder 15 16, Lisa Kobrynski 17, Anne Pham-Huy 18, Julie Dhossche 19, Charlotte Cunningham Rundles 20, Anna K Meyer 21, Amy Theos 22, T Prescott Atkinson 23, Amy Musiek 24, Mehdi Adeli 25, Ute Derichs 26, Christoph Walz 27, Renate Krüger 28, Horst von Bernuth 28 29 30 31, Christoph Klein 12, Joseph Icenogle 1, Fabian Hauck 12, Kathleen E Sullivan 32

Affiliations

20 December 2021

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doi: 10.3389/fimmu.2021.796065

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.

Keywords: granuloma treatments; granulomatous inflammation; inborn errors of immunity; macrophages; neutrophils; primary immunodeficiency; skin lesion; vaccine-derived rubella viruses.

Conflict of interest statement

MA is employed by Sidra Medicine and Hamad Medical Corporation, Qatar. HB is employed by Labor Berlin GmbH, Germany. JH received grants from Immune Deficiency Foundation, the US immunodeficiency network, Chao-physician Scientist award, the Texas Medical Center Digestive Diseases Center and the Jeffrey Modell Foundation. JH received honorarium, consultation fees from Horizon, Pharming, Baxalta, CSL Behring, the National guard, and Al-Faisal University Hospital. TPA received consultation fees from Horizon, Pharming, CSL Behring. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
 

Figures

Figure 1 Characteristics of the patient cohort. Underlying immunodeficiencies (A). Genetic causes (B). Frequency of chronic infections (C). Organs involved in inflammation (D). Granuloma location at onset (E). Age of the patients at the granuloma onset by the IEI type (F).

Figure 1 Characteristics of the patient cohort. Underlying immunodeficiencies (A). Genetic causes (B). Frequency of chronic infections (C). Organs involved in inflammation (D). Granuloma location at onset (E). Age of the patients at the granuloma onset by the IEI type (F).

Figure 2 A structure of M-type RuV-associated cutaneous granuloma and its cellular elements. Histological double immunofluorescent staining of sequential tissue sections (P18) for RVC (red) and one of the cell type markers (green) shows the presence of RVC predominantly in CD206+ M2 macrophages (A) and infrequently in CD163+ M2 macrophages (B), CD14+ monocytes (C) and in sporadic MPO+ neutrophils (D). Layers of many RVC- CD3+ T cells surround RVC+/CD206+ granuloma centers (E). Scale bar: 200 µm. Schematic of M-type RuV-associated granuloma pattern (F).

Figure 2 A structure of M-type RuV-associated cutaneous granuloma and its cellular elements. Histological double immunofluorescent staining of sequential tissue sections (P18) for RVC (red) and one of the cell type markers (green) shows the presence of RVC predominantly in CD206+ M2 macrophages (A) and infrequently in CD163+ M2 macrophages (B), CD14+ monocytes (C) and in sporadic MPO+ neutrophils (D). Layers of many RVC- CD3+ T cells surround RVC+/CD206+ granuloma centers (E). Scale bar: 200 µm. Schematic of M-type RuV-associated granuloma pattern (F).

Figure 3 A progression of cutaneous granuloma from M-type to M(n)-type. Histological double staining of sequential tissue slides (P18) for either RVC (red) and one of the cell type markers (green). Non-necrotizing M-type granuloma contains RVC+CD206+ M2 macrophages in the center with infrequent, mainly RVC- neutrophils and abundant surrounding RVC-CD3+ T cells (A). Necrotizing M(n)-type granulomas with MPO+ and CD3 + staining of the necrotic centers surrounded by RVC+CD206+ macrophages (B, C). Notice a rim CD3+ T cells located between acellular necrotic center and RVC+CD206+ macrophages (C). Scale bar: 100 µM. Schematic of M(n)-type RuV-associated granuloma pattern (D).

Figure 3 A progression of cutaneous granuloma from M-type to M(n)-type. Histological double staining of sequential tissue slides (P18) for either RVC (red) and one of the cell type markers (green). Non-necrotizing M-type granuloma contains RVC+CD206+ M2 macrophages in the center with infrequent, mainly RVC- neutrophils and abundant surrounding RVC-CD3+ T cells (A). Necrotizing M(n)-type granulomas with MPO+ and CD3 + staining of the necrotic centers surrounded by RVC+CD206+ macrophages (B, C). Notice a rim CD3+ T cells located between acellular necrotic center and RVC+CD206+ macrophages (C). Scale bar: 100 µM. Schematic of M(n)-type RuV-associated granuloma pattern (D).

Figure 4 A structure of N-type RuV-associated cutaneous granuloma and its cellular elements. Histological double immunofluorescent staining of sequential tissue sections of skin biopsy (P21) for RVC (red) and one of the cell type markers (green) shows predominant RVC staining of MPO+ neutrophils (A), infrequent RVC staining of CD206+ M2 macrophages (B), CD163+ M2 macrophages (C), and CD14+ monocytes (D). Numerous RVC-CD3+ T cells surround the RVC+ neutrophil core (E). Scale bars: 200 µm and 20 µm (inlet). Schematic of N-type RuV-associated granuloma pattern (F).

Figure 4 A structure of N-type RuV-associated cutaneous granuloma and its cellular elements. Histological double immunofluorescent staining of sequential tissue sections of skin biopsy (P21) for RVC (red) and one of the cell type markers (green) shows predominant RVC staining of MPO+ neutrophils (A), infrequent RVC staining of CD206+ M2 macrophages (B), CD163+ M2 macrophages (C), and CD14+ monocytes (D). Numerous RVC-CD3+ T cells surround the RVC+ neutrophil core (E). Scale bars: 200 µm and 20 µm (inlet). Schematic of N-type RuV-associated granuloma pattern (F).

Figure 5 Biopsy of a newly developed cutaneous lesion (P1). Double histological immunofluorescent staining shows small clusters of RVC+CD206+ M2 macrophages under the epidermis. Scale bars: 100 µm (top panel) and 20 µm (bottom panel).

Figure 5 Biopsy of a newly developed cutaneous lesion (P1). Double histological immunofluorescent staining shows small clusters of RVC+CD206+ M2 macrophages under the epidermis. Scale bars: 100 µm (top panel) and 20 µm (bottom panel).

Figure 6 A structure of DNI-type RuV-associated granuloma and its cellular elements. Histological double immunofluorescent staining for RVC and either MPO (A), CD206 (B, D), or CD3 (C) showing RVC+MPO+ neutrophils, RVC+CD206+ macrophages with globular RVC likely in a phagosome (yellow arrow) and abundant RVC-CD3+ T cells in the inflamed GI tissue of P16 (A–C). RVC+ neutrophil phagocytized by CD206+ macrophage (D). Scale bars: 100 µm (A-C), 20 µm (inlets), and 2 µm (D). Schematic of DNI-type RuV- associated granuloma pattern (E).

Figure 6 A structure of DNI-type RuV-associated granuloma and its cellular elements. Histological double immunofluorescent staining for RVC and either MPO (A), CD206 (B, D), or CD3 (C) showing RVC+MPO+ neutrophils, RVC+CD206+ macrophages with globular RVC likely in a phagosome (yellow arrow) and abundant RVC-CD3+ T cells in the inflamed GI tissue of P16 (A–C). RVC+ neutrophil phagocytized by CD206+ macrophage (D). Scale bars: 100 µm (A-C), 20 µm (inlets), and 2 µm (D). Schematic of DNI-type RuV- associated granuloma pattern (E).

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