Shang, Pei

MOGAD is a rare autoimmune encephalomyelitis that shares similar clinical manifestations with other central nervous system demyelinating diseases. However, they must be distinguished due to their distinct pathogenesis and treatment methods. Currently, the clinical diagnosis of MOGAD primarily relies on patients’ clinical manifestations and imaging features, with biomarker application being relatively limited. Meanwhile, research on MOGAD biomarkers has advanced rapidly, with findings mainly focusing on imaging features, antibody titers, nerve cell markers, cytokines, and inflammatory cell ratios. These biomarkers can distinguish among various autoimmune with similar clinical manifestations and exhibit certain specificity. If these biomarker findings are applied to the clinical diagnosis of MOGAD, they could enhance diagnostic accuracy and support earlier and more accurate diagnosis, while providing a scientific basis for evaluating disease progression and prognosis. We discuss the biomarkers and emerging biomarkers of MOGAD, emphasizing the specific changes and aspects that may be applicable to clinical diagnosis and treatment.

Deep brain stimulation (DBS), a cornerstone neurosurgical intervention for advanced Parkinson’s disease, exerts modulatory effects on aberrant basal ganglia circuitry through continuous high-frequency electrical stimulation. This approach yields sustained amelioration of motor symptoms while concurrently reducing the requisite dosage of dopaminergic pharmacotherapy. Nonetheless, DBS still has its limitations: its efficacy on non-motor symptoms remains limited, electrode implantation leads to biological reactions, and it cannot alter the trajectory of disease progression. Embryonic stem cells and induced pluripotent stem cells can be directed to differentiate into functionally mature nigrostriatal dopaminergic neurons, demonstrating the potential for neuronal replacement and neuroprotective effects in preclinical models and early-phase clinical trials. Mesenchymal stem cells and their derived exosomes mitigate neuroinflammation and impede α-synuclein aggregation through neurotrophic support and immunomodulatory mechanisms. This article reviews two core domains that have achieved breakthroughs in the treatment of Parkinson’s disease—DBS and stem cells—and covers their current status and future prospects. First, this review elucidates the therapeutic mechanisms of DBS, including neurotransmitter release regulation and neuroinflammation suppression, while evaluating its long-term efficacy (e.g., the sustainability of motor improvement and advancements in directional stimulation technology) and safety challenges (e.g., cognitive impairment, mood disturbances, and glial scar formation induced by electrode implantation). Second, it provides an in-depth analysis of the differentiation mechanisms of stem cells from different sources (embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, etc.), preclinical efficacy validation, and early-phase clinical trial outcomes (e.g., the long-term safety and motor function enhancement observed in the transplantation of induced pluripotent stem cell-derived nigrostriatal dopaminergic progenitor cells). Third, the article addresses the standardization of stem cell therapy protocols, strategies for managing immune rejection, and current international regulatory and ethical frameworks. The core challenges of current Parkinson’s disease treatment paradigms are as follows: DBS shows limited efficacy in improving axial symptoms (e.g., freezing of gait), whereas stem cell transplantation faces issues such as low long-term graft survival and insufficient functional integration. Looking ahead, multidisciplinary integration is essential to promote the synergistic application of DBS and stem cell therapy, develop personalized treatment protocols under the guidance of precision medicine, and translate novel neural interface materials and genetic engineering technologies into clinical practice. Ultimately, such integrated strategies hold the promise of advancing Parkinson’s disease therapy from mere symptom control to true disease modification.

ABSTRACT Background High-titer glutamic acid decarboxylase 65 (GAD65) antibodies are found in patients with GAD65 antibody-associated neurological disorders, including stiff-person syndrome (SPS), GAD65 cerebellar ataxia (CA), and GAD65 epilepsy. Given the intracellular localization of the antigenic target, a direct pathogenic role for GAD65 autoantibodies is unlikely. Instead, the autoantibody may be a biomarker for the existence of pathogenic anti-GAD65 autoreactive CD8 + T cells. Methods PBMC-derived dendritic cells (DCs) from 20 GAD65 antibody-positive patients with neurological manifestations (SPS, n=10; CA, n=7; epilepsy, n=3) and 15 healthy controls were pulsed with full-length GAD65 protein, full-length GAD67 protein, overlapping 15-mer peptide pools spanning GAD65 and GAD67, individual GAD65 15-mer peptides, or GAD65 9-mer peptides selected from predicted class I binding hotspots. T cell activation was quantified by flow cytometry-based activation-induced marker (AIM) assays using CD69 upregulation. Class I and class II HLA haplotypes were determined by high resolution typing. NetMHCpan v4.2c was used to generate residue-level peptide:HLA binding density maps across GAD65, and candidate 9-mers were validated for HLA binding by peptide:MHC monomer affinity testing. GAD65-peptide-HLA-restricted CD8 + T cells were identified by co-staining with two separately assembled tetramers carrying the same peptide:HLA complex on different fluorophores (APC and BV421), with double-positive events scored as antigen-specific. HLA-restricted cytotoxicity was measured by coculture of patient CD8 + T cells with GAD65-expressing HEK-293T cells reconstituted with defined HLA class I alleles using AAV-delivered Cre-dependent HLA-2A-eGFP cassettes. Results CD8 + T cells from GAD65 antibody-positive patients showed increased activation in response to DCs pulsed with full-length GAD65 relative to healthy controls (P=0.0157, Welch’s t-test), whereas responses to GAD67 did not differ significantly between groups. CD4 + T cells responded to both GAD65 (P=0.0004) and GAD67 (P=0.0051). Peptide pool screening of GAD65 identified discrete CD8 + and CD4 + immunogenic regions, with refinement using individual 15-mers localizing CD8 + activity to multiple subdomains within GAD65 (205-300) , GAD65 (316-435) , and GAD65 (447-520) . HLA class I haplotyping in 16 non-Hispanic White GAD65 + patients revealed enrichment of HLA-B*08:01 (3.0-fold) and HLA-B*40:01 (4.1-fold) relative to USA NMDP European Caucasian reference frequencies (both BH q < 0.05), with suggestive enrichment of HLA-C*03:04 (2.9-fold; q = 0.09). Additionally, 44% of patients carried the HLA-A*01:01, HLA-B*08:01, and HLA-C*07:01 8.1 ancestral haplotype, approximately four-fold higher than the expected population frequency. Dual-fluorophore tetramer staining identified CD8 + T cells in GAD65 + subjects that bound a subset of HLA-A*11:01- and HLA-B*08:01-restricted GAD65 9-mers, with the clearest disease-skewed signals localized to GAD65 (213-221) , GAD65 (257-265) , and GAD65 (529-537) . In an HLA-reconstituted target-cell killing assay, CD8 + T cells from an HLA-B*08:01-positive GAD65 + patient mediated antigen- and HLA-restricted depletion of GAD65-expressing HEK-293T cells, with HLA-restricted target loss also observed in single-donor experiments across additional HLA-A, -B, and -C contexts. Conclusions Patients with GAD65 antibody-associated neurological disorders harbor circulating CD8 + T cells that recognize discrete HLA class I-restricted GAD65 peptides and that are capable of cytotoxicity against GAD65-expressing HLA-matched target cells. We characterize the immunogenetic and cellular features of class I-restricted CD8 + T cell responses in GAD65 autoimmunity, including overrepresentation of the 8.1 ancestral haplotype, complementing the historical focus on antibodies and CD4 + T cell help, and we provide a panel of validated GAD65 peptide:HLA tetramers for prospective isolation, clonotypic analysis, and longitudinal monitoring of candidate pathogenic CD8 + T cell populations across the GAD65 antibody-associated neurological disease spectrum.

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory and degenerative disease of the central nervous system (CNS). Typically occurring in young and middle-aged individuals, untreated MS can have high rates of disability and recurrence, thereby imposing a significant burden on the patient, their family, and society. Many factors are implicated in the etiology of MS, with the relationship between Epstein-Barr Virus (EBV) infection and the development of MS being the subject of extensive research recently. When the human body experiences a decline in immune function, it may trigger reactivation of EBV, and this reactivation is also believed to increase the risk of onset or relapse of MS. Currently, the phenomenon of cross-reactivity resulting from molecular mimicry following EBV infection (including reactivation status) is theorized as a contributing etiology. EBV-mediated abnormalities in T cells and B cells also play a key role in the development of MS. However, the underlying mechanisms have not been thoroughly understood. Meanwhile, the limited availability of effective treatment options for MS, in particular MS progression, underscores the urgent need for novel therapeutic strategies. Here, we discuss the pathophysiological mechanisms underlying MS, specifically emphasizing the relationship between EBV infection and the disease pathology. Furthermore, we introduced relevant pharmacological targets in order to propose a broader range of therapeutic alternatives for individuals diagnosed with MS.