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

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.

Overview of Neuro-Ophthalmic Findings in Leukodystrophies.

Background: Leukodystrophies are a group of rare genetic diseases that primarily affect the white matter of the central nervous system. The broad spectrum of metabolic and pathological causes leads to manifestations at any age, most often in childhood and adolescence, and a variety of symptoms. Leukodystrophies are usually progressive, resulting in severe disabilities and premature death. Progressive visual impairment is a common symptom. Currently, no overview of the manifold neuro-ophthalmologic manifestations and visual impact of leukodystrophies exists. Methods: Data from 217 patients in the Hamburg leukodystrophy cohort were analyzed retrospectively for neuro-ophthalmologic manifestations, age of disease onset, and magnetic resonance imaging, visual evoked potential, and optical coherence tomography findings and were compared with data from the literature. Results: In total, 68% of the patients suffered from neuro-ophthalmologic symptoms, such as optic atrophy, visual neglect, strabismus, and nystagmus. Depending on the type of leukodystrophy, neuro-ophthalmologic symptoms occurred early or late during the course of the disease. Magnetic resonance imaging scans revealed pathologic alterations in the visual tract that were temporally correlated with symptoms. Conclusions: The first optical coherence tomography findings in Krabbe disease and metachromatic leukodystrophy allow retinal assessments. Comprehensive literature research supports the results of this first overview of neuro-ophthalmologic findings in leukodystrophies.