👤 Jorge I Velez

Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology. Show less

Compound heterozygotes occur when different variants at the same locus on both maternal and paternal chromosomes produce a recessive trait. Here we present the tool VarCount for the quantification of variants at the individual level. We used VarCount to characterize compound heterozygous coding variants in patients with epileptic encephalopathy and in the 1000 Genomes Project participants. The Epi4k data contains variants identified by whole exome sequencing in patients with either Lennox-Gastaut Syndrome (LGS) or infantile spasms (IS), as well as their parents. We queried the Epi4k dataset (264 trios) and the phased 1000 Genomes Project data (2504 participants) for recessive variants. To assess enrichment, transcript counts were compared between the Epi4k and 1000 Genomes Project participants using minor allele frequency (MAF) cutoffs of 0.5 and 1.0%, and including all ancestries or only probands of European ancestry. In the Epi4k participants, we found enrichment for rare, compound heterozygous variants in six genes, including three involved in neuronal growth and development - PRTG (p = 0.00086, 1% MAF, combined ancestries), TNC (p = 0.022, 1% MAF, combined ancestries) and MACF1 (p = 0.0245, 0.5% MAF, EU ancestry). Due to the total number of transcripts considered in these analyses, the enrichment detected was not significant after correction for multiple testing and higher powered or prospective studies are necessary to validate the candidacy of these genes. However, PRTG, TNC and MACF1 are potential novel recessive epilepsy genes and our results highlight that compound heterozygous variants should be considered in sporadic epilepsy. Show less

Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. The DNA of eight patients affected by MAS [all of whom presenting with Sjögren's syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic-deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity. Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti-inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very well known autoimmunity genes. Novel and rare exonic mutations that may account for autoimmunity were identified. Among those, the LRP1/STAT6 novel mutation has the strongest case for being categorised as potentially causative of MAS given the presence of intriguing patterns of functional interaction with other major genes shaping autoimmunity. Show less

Lymphoma is a common disease of the head and neck. Mucosal-associated lymphoid tissue (MALT) lymphoma constitutes a rare type of extranodal lymphoma. The Waldeyer's ring is one of the most common sites of occurrence, but MALT lymphoma may also arise in salivary glands, lung, stomach, or lacrimal glands. In the oral cavity, it may be confused with swellings from dental infection or sinus inflammation. Often, the patient will seek a dentist because of mobile teeth or because a denture no longer fits. We report a case of a female patient with salivary gland dysfunction and pain of several years' duration, who, after numerous tests and hospitalizations, was diagnosed with Sjögren's syndrome. She later developed mucosal-associated lymphoid tissue lymphoma. We discuss the diagnosis, treatment, and prognosis of this entity. MALT lymphoma is rare in salivary glands. In primary-Sjögren's syndrome, predisposition of the patient for development of malignant non-Hodgkin's lymphoma (4% to 10%) is well established. In this case, long-standing sialadenitis and Sjögren's syndrome seem to be the etiological factors. In cases of chronic infection of salivary glands and the presence of autoimmune syndromes, MALT lymphoma should be considered in the differential diagnosis. Consults should be called to ophthalmology, rheumatology, and head and neck oncologists for proper workup, staging, and treatment. Show less