A Single Nucleotide ADA Genetic Variant Is Associated to Central Inflammation and Clinical Presentation in MS: Implications for Cladribine Treatment.

Mario Stampanoni Bassi,Girolama Alessandra Marfia,Giuseppe Matarese,Stefano Gambardella,Andrea Paolillo,Fabio Buttari,Marco Salvetti,Andrea Visconti,Diego Centonze,Ilaria Simonelli,Luana Gilio,Annamaria Finardi,Francesca De Vito,Rosangela Ferese,Marianna Storto,Antonio Uccelli,Roberto Furlan

doi:10.3390/genes11101152

Abstract

In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various proinflammatory cytokines, promoting neuroinflammation and negatively affecting the course of the disease. The immune response homeostasis is crucially regulated by the activity of the enzyme adenosine deaminase (ADA), as evidenced in patients with genetic ADA deficiency and in those treated with cladribine tablets. We investigated in a group of patients with MS the associations of a single nucleotide polymorphism (SNP) of ADA gene with disease characteristics and cerebrospinal fluid (CSF) inflammation. The SNP rs244072 of the ADA gene was determined in 561 patients with MS. Disease characteristics were assessed at the time of diagnosis; furthermore, in 258 patients, proinflammatory and anti-inflammatory molecules were measured in the CSF. We found a significant association between rs244072 and both clinical characteristics and central inflammation. In C-carriers, significantly enhanced disability and increased CSF levels of TNF, IL-5 and RANTES was observed. In addition, lower CSF levels of the anti-inflammatory cytokine IL-10 were found. Finally, the presence of the C allele was associated with a tendency of increased lymphocyte count. In MS patients, ADA SNP rs244072 is associated with CSF inflammation and disability. The selective targeting of the ADA pathway through cladribine tablet therapy could be effective in MS by acting on a pathogenically relevant biological mechanism.

Highlights

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by demyelination and the neurodegeneration of the central nervous system (CNS)
The genetic screening of a population of 561 patients with multiple sclerosis (MS) showed no significant departure from Hardy–Weinberg equilibrium in the study population
These results indicate that the different genetic variants of adenosine deaminase (ADA) single nucleotide polymorphism (SNP) rs244072 could participate in determining the CNS inflammation in MS patients

Summary

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by demyelination and the neurodegeneration of the central nervous system (CNS). T cells enter CNS and interact with local immune cells, initiating the inflammatory cascade that amplifies the immune response and leads to both excitotoxic synaptopathy and consequent brain damage [3,4]. Both CD4+ and CD8+ autoreactive T lymphocytes have been identified in demyelinating lesions [1] and have been related to the severity of axonal damage and inflammation [3]. B lymphocytes contribute to MS development and progression, acting as antibody-producing and antigen-presenting cells, as well as releasing soluble mediators involved in tissue damage and in the regulation of the immune response [2]. Proinflammatory cytokines released by lymphocytes and microglial cells alter the blood brain barrier, increasing immune cell extravasation [6], and contributing to demyelinating damage [7]

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Conclusion