Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency

Abstract

Granulomas may develop as a response to a local antigenic trigger, leading to the activation of macrophages and T-lymphocytes. Primary immunodeficiency (PID) is associated with the development of extensive cutaneous granulomas, whose aetiology remains unknown. We performed high-throughput sequencing of the transcriptome of cutaneous granuloma lesions on two consecutive index cases, and RT-PCR in a third consecutive patient. The RA27/3 vaccine strain of rubella virus-the core component of a universally used paediatric vaccine-was present in the cutaneous granuloma of these three consecutive PID patients. Controls included the healthy skin of two patients, non-granulomatous cutaneous lesions of patients with immunodeficiency, and skin biopsy samples of healthy individuals, and were negative. Expression of viral antigens was confirmed by immunofluorescence. Persistence of the rubella vaccine virus was also demonstrated in granuloma lesions sampled 4-5 years earlier. The persistence of the rubella virus vaccine strain in all three consecutive cutaneous granuloma patients with PID strongly suggests a causal relationship between rubella virus and granuloma in this setting.

Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies

“…Similar to the previous report, 3 AT was the most common single diagnosis among RV-positive patients. We have also identified additional PIDs (cartilage hair hypoplasia and CID) in which RV was found in granulomas.…”

“…1,2 Rubella virus (RV) vaccine strain RA27/3 has been recently detected in disseminated cutaneous granulomas of 2 patients with ataxia telangiectasia (AT) and a patient with Simpson-Golabi-Behmel syndrome (who had combined immunodeficiency [CID]). 3 However, a more detailed study of a larger series of granuloma cases in patients with different PIDs was required to confirm and extend this observation.…”

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT)

“…Not surprisingly, in our group of patients with another DNA repair defect, five NBS patients developed granulomas. The RA27/3 vaccine strain of rubella virus has been found in some of PID granulomas before (21–23). We detected the rubella virus in homogenized granuloma tissue samples from three out of five of our patients.…”

Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency

“…First of all, although the association between skin granulomas and RV infection has been clearly demonstrated in individuals with some primary immune deficiencies (Bodemer et al, 2014;Perelygina et al, 2016), the causal role of RV infection in the formation of granulomas has not yet been proven. However, the absence of RV RNA in the unaffected skin ((Bodemer et al, 2014); our unpublished observations) and detection of RV in granulomas in the internal organs of some PID patients ( (Neven et al, 2017); our unpublished observations) suggest the causality. Of course, with lesions that develop years or even decades after vaccination, causality determinations will likely require prospective studies with long-term follow up.…”

“…Chronic recurrent rubella-associated arthritis can develop after immunization of adults (Fraser et al, 1983;Tingle et al, 1985). Granulomas in persons with primary immune deficiencies (PID) and Fuchs's uveitis are newly suggested diseases associated with decades-long persistent RV infections (Abernathy et al, 2015;Bodemer et al, 2014;Doan et al, 2016;Perelygina et al, 2016). Currently, there are no antiviral drugs to treat rubella infections and identification of treatments for chronic rubella diseases will be beneficial.…”