Risk HLA Variants Affect the T-Cell Repertoire in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The major histocompatibility complex (MHC) locus has a predominant role in the genetic predisposition to multiple sclerosis (MS), with 32 associations found to be involved. We aimed to investigate the impact of MHC MS-risk alleles on T-cell repertoire in patients with MS. METHODS: We studied 161 untreated patients with relapsing-remitting MS for whom Class I and II human leukocyte antigen (HLA) alleles were inferred from whole-genome genotyping data, and T-cell receptor (TCR) CDR3 sequences were obtained through next-generation sequencing. T-cell repertoire features including diversity, public clones, and architecture were evaluated. RESULTS: We identified 5 MS-risk loci associated with TCR diversity: HLA-DRB1*15:01 (7.65 × 10-3), rs9271366 (1.96 × 10-3), rs766848979 A (1.89 × 10-2), rs9277626 (2.95 × 10-2), and rs11751659 (1.92 × 10-2), with evidence of expanded clonotypes in carriers of risk alleles. Moreover, HLA-DRB1*15:01 (4.99 × 10-3), rs9271366 (6.54 × 10-3), rs1049079 C (4.37 × 10-2), AA DQΒ1 position -5 L (1.05 × 10-3), and AA DQΒ1 position 221 Q (9.39 × 10-4) showed an association with the CDR3 aminoacidic sequence architecture, suggesting an impact on the antigen recognition breadth as well. Evaluating the sharing of clones across MS-risk allele carrier individuals revealed the presence of highly shared clonotypes predicted to target viral antigens, including Epstein-Barr virus. DISCUSSION: Our study supports the association between MHC-risk alleles and macrofeatures of the T-cell repertoire in the context of MS. Further studies are needed to understand the underlying molecular mechanisms.

Subacute sensory neuronopathy associated with Merkel cell carcinoma with unknown primary: a case report with literature review.

Paraneoplastic neurologic syndromes (PNSs) are a wide spectrum of neurologic diseases characterized by different clinical features, associated with a neoplasia, and triggered by an immune-mediated process. In most cases, it is possible to detect specific neuronal antibodies and the Hu protein is one of the most frequently recognized intracellular antigens in patients with PNSs. Small-cell lung cancer is the most common cancer associated with PNSs, followed by urological, gynecological and hematological malignancies. Otherwise, extra-pulmonary small-cell carcinomas, including Merkel cell carcinoma (MCC), have been rarely described as related to PNSs. In this article we report, for the first time in the published literature, a case of anti-Hu antibody-related subacute sensory neuronopathy in association with MCC.

Transcranial extradural subtemporal repair for sphenoid sinus lateral recess meningoencephalocele: technical note.

Cranial meningoencephalocele is a rare condition consisting of the herniation of meninges, CSF, and brain tissue through a cranial or skull base defect. Sphenoid sinus lateral recess meningoencephalocele is of particular interest due to the complex anatomy surrounding the bone defect and their demanding surgical management. In this technical note, we reported a step-by-step description of a rare case of sphenoid sinus lateral recess meningoencephalocele causing headache due to recurrent cerebrospinal fluid leak treated with a subtemporal craniotomy with extradural middle cranial fossa drilling and meningoencephalocele removal with multilayer reconstruction. The transcranial route is a safe and effective treatment for sphenoid sinus lateral recess meningoencephalocele repair. The subtemporal extradural approach allows for an optimal exposure of the relevant anatomy minimizing risks and improving the possibility to perform an effective multilayer skull base reconstruction.

Relevance of solute carrier family 5 transporter defects to inherited and acquired human disease.

The solute carrier (SLC) group of membrane transport proteins is crucial for cells via their control of import and export of vital molecules across the cellular membrane. Defects in these transporters with narrow substrate specificities cause monogenic disorders, giving us essential clues of their precise roles in cellular functioning. The SLC5 family in particular has been linked to various human diseases, of mild and severe phenotype as well as high and low prevalence. In this review, we describe the effects on health of SLC5 dysfunction and dysregulation by summarizing findings in patients with transporter gene defects. Patients display a plethora of pathologies which include glucose/galactose malabsorption, familiar renal glycosuria, thyroid dyshormonogenesis, and distal hereditary motor neuronopathies. In addition, the therapeutic potential of intervening in transporter activities for treating common diseases such as diabetes and cancer is explored.