Multiple sclerosis (MS) is a chronic inflammatory autoimmune neurological disease characterized by the recurrent appearance of demyelinating lesions and progressive disability. Currently, there are multiple disease-modifying treatments, however, there is a significant need to develop new therapeutic targets, especially for the progressive forms of the disease. This review article provides an overview of the most recent studies aimed at understanding the inflammatory processes that are activated in response to the accumulation of kynurenine pathway (KP) metabolites, which exacerbate an imbalance between immune system cells (e.g., Th1, Th2, and T reg) and promote the release of pro-inflammatory interleukins that modulate different mechanisms: membrane-receptors function; nuclear factors expression; and cellular signals. Together, these alterations trigger cell death mechanisms in brain cells and promote neuron loss and axon demyelination. This hypothesis could represent a remarkable approach for disease-modifying therapies for MS. Here, we also provide a perspective on the repositioning of some already approved drugs involved in other signaling pathways, which could represent new therapeutic strategies for MS treatment.
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http://dx.doi.org/10.3390/ph17080983 | DOI Listing |
JAMA Netw Open
December 2024
Department of Cell Biology, The Province and Ministry Cosponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Tianjin Institute of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Importance: Patients with juvenile idiopathic arthritis (JIA) may develop adult rheumatic diseases later in life, and prolonged or recurrent disease activity is often associated with substantial disability; therefore, it is important to identify patients with JIA at high risk of developing adult rheumatic diseases and provide specialized attention and preventive care to them.
Objective: To elucidate the full extent of the genetic association of JIA with adult rheumatic diseases, to improve treatment strategies and patient outcomes for patients at high risk of developing long-term rheumatic diseases.
Design, Setting, And Participants: In this genetic association study of 4 disease genome-wide association study (GWAS) cohorts from 2013 to 2024 (JIA, rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], and systemic sclerosis [SSc]), patients in the JIA cohort were recruited from the US, Australia, and Norway (with a UK cohort included in the meta-analyzed cohort), while patients in the other 3 cohorts were recruited from US and Western European countries.
JAMA Netw Open
December 2024
Department of Epidemiology and Health Care Atlas, Central Research Institute of Ambulatory Health Care, Berlin, Germany.
Importance: A growing body of literature suggests the presence of a prodromal period with nonspecific signs and symptoms before onset of multiple sclerosis (MS).
Objective: To systematically assess diseases and symptoms diagnosed in the 5 years before a first MS- or central nervous system (CNS) demyelinating disease-related diagnostic code in pediatric patients compared with controls without MS and controls with another immune-mediated disorder, juvenile idiopathic arthritis (JIA).
Design, Setting, And Participants: This population-based, matched case-control study included children and adolescents (aged <18 years) in Germany with statutory health insurance from January 2010 to December 2020.
Elife
December 2024
Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States.
Inhibition of Bruton's tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders, and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib, and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib.
View Article and Find Full Text PDFTomography
December 2024
Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Using a pediatric-focused lens, this review article briefly summarizes the presentation of several demyelinating and neuroinflammatory diseases using conventional magnetic resonance imaging (MRI) sequences, such as T1-weighted with and without an exogenous gadolinium-based contrast agent, T2-weighted, and fluid-attenuated inversion recovery (FLAIR). These conventional sequences exploit the intrinsic properties of tissue to provide a distinct signal contrast that is useful for evaluating disease features and monitoring treatment responses in patients by characterizing lesion involvement in the central nervous system and tracking temporal features with blood-brain barrier disruption. Illustrative examples are presented for pediatric-onset multiple sclerosis and neuroinflammatory diseases.
View Article and Find Full Text PDFToxins (Basel)
December 2024
Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences-Campus Bellvitge, University of Barcelona, 08907 Barcelona, Spain.
Epsilon toxin (ETX) from is a pore-forming toxin (PFT) that crosses the blood-brain barrier and binds to myelin structures. In in vitro assays, ETX causes oligodendrocyte impairment, subsequently leading to demyelination. In fact, ETX has been associated with triggering multiple sclerosis.
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