Mevalonate kinase deficiency (MKD) is a metabolic disorder caused by a block in the mevalonate pathway, leading to impaired synthesis of cholesterol and isoprenoids. Clinically, MKD presents with recurrent inflammatory attacks. A characteristic feature is elevated serum IgD, although the underlying mechanism remains unclear. This study assessed whether geranylgeraniol (GG) supplementation, which provides downstream isoprenoids missing due to the metabolic block, can modulate inflammatory and metabolic profiles in MKD. We also examined the plasma cell compartment, focusing on IgD-producing cells. Earlier reports described IgD-producing bone marrow plasma cells with strong cytoplasmic IgD. We extend these observations using new cellular, cytometric, and single-cell RNA sequencing data.
Six MKD patients (4 females, 2 males; age 12–51) were followed over 2 years. Treatments included on-demand anakinra (n = 4), continuous anakinra (n = 1), and nonsteroidal anti-inflammatory drugs (NSAIDs)/corticosteroid therapy (n = 1). Immunological assays, proteomics (SomaLogic SomaScan 7k), and metabolomics (gas chromatography–time-of-flight mass spectrometry [GC-TOF MS]) were performed before and after 3 months of GG supplementation (150 mg GGOH). Single-cell RNA sequencing in one patient not receiving IL-1 blockade revealed a subset of unusual IgD+ cells with plasma cell features.
GG supplementation was well-tolerated without significant adverse effects. Proteomic and metabolomic analyses indicated downregulation of innate immune pathways and metabolic adjustments consistent with an anti-inflammatory response, including partial normalization of protein and metabolite profiles. Serum IgD concentrations remained unchanged. A distinct population of plasma-like cells with high IGHD transcript levels was identified in the patient, not on IL-1 blockade, but was absent in healthy controls. These cells expressed XBP1, CD27, and CD38 yet showed aberrant expression of transcription factors involved in class-switch recombination and plasma cell differentiation. Unlike conventional plasma cells with broad IGHV/IGLV induction, this subset selectively upregulated IGHV4, IGHV6, and IGHD. Differential expression analysis highlighted a transcriptional signature linked to cell cycle regulation.
We describe a transcriptionally unique IgD+ plasma-like population in MKD that may contribute to persistently elevated serum IgD, observed so far in one patient not receiving IL-1 blockade. GG supplementation modulates inflammatory and metabolic pathways but does not influence IgD. Further research is needed to define the origin and persistence of these atypical cells.
