Investigations into the aetiopathogenesis of orofacial granulomatosis using multiple omics technologies reveals a potential role for B cells

The aim of this study was to utilise multiple ‘omics’ technologies to determine the aetiopathogenesis of orofacial granulomatosis (OFG) and its relationship to Crohn’s Disease (CD) Thirty-two participants with OFG, with and without CD, and forty-three healthy controls were recruited. Expression of genes in buccal mucosal tissue of participants was compared using RNA-seq. Genetic variants associated with OFG were determined by whole exome sequencing (WES). The salivary inflammatory proteome was determined using Olink® PEA technology and ELISAs. The oral microbiome of participants was determined using 16S rRNA sequencing. RNA-seq demonstrated upregulation of genes involved in B-cell regulatory pathways in OFG. WES identified deleterious variants in the SRGAP2 and AK2 genes are associated with OFG. Salivary inflammatory proteome analysis revealed increased expression of proteins involved in adaptive immune responses and calprotectin. Microbiome analysis revealed a reduced microbial diversity and decreased compositional similarity in OFG. In OFG, the presence of concurrent CD had no impact on any findings.The immunopathogenesis of OFG (irrespective of concurrent CD) was characterised by the upregulated expression of genes and proteins involved B cell responses. In addition, mutations in genes which play a role in B cell function, such as AK2, may predispose participants to OFG. There is evidence of dysbiosis of the oral microbiome in participants with OFG. Although the exact aetiological cause of OFG remains elusive, the evidence suggests that OFG is a B cell driven disease and biological therapies such as Rituximab may be repurposed to manage the condition.