Multiple sclerosis: molecular pathogenesis and therapeutic intervention

Abstract

Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, axonal loss, and neuroinflammation, culminating in progressive neurological disability. Despite significant advances in understanding its immunopathogenesis, current immunotherapies remain limited in their ability to halt disease progression, making multiple sclerosis incurable and highlighting the critical need for novel therapeutic strategies. Antigen-specific immunotherapy represents a groundbreaking approach that aims to restore immune tolerance to myelin-derived antigens while preserving the protective functions of the immune system. Unlike broad immunosuppressive strategies, antigen-specific immunotherapy offers the potential for highly targeted modulation of pathogenic immune responses, reducing off-target effects and enhancing safety profiles. Over the last two decades, preclinical studies and clinical trials have explored diverse antigen-specific immunotherapy modalities, ranging from peptide-based vaccines to nanoparticle platforms, each aimed at achieving durable tolerance in multiple sclerosis. This review provides a comprehensive overview of multiple sclerosis, covering its etiology, clinical features, pathogenesis, pathology, and current therapeutic approaches. Thus, it delves into the current state of antigen-specific immunotherapy research, critically examining its successes and limitations while addressing the translational challenges that must be overcome to realize its therapeutic potential. By integrating insights from immunology, biotechnology, and translational medicine, we propose directions for advancing antigen-specific approaches in the quest for transformative multiple sclerosis therapies.

Fig. 1

The interplay of genetic, environmental, and epigenetic factors in multiple sclerosis risk. Multiple sclerosis (MS) risk is influenced by the interaction of genetic susceptibility, environmental exposure, and epigenetic modifications. This Venn diagram illustrates how these three factors overlap, with MS emerging at their intersection. Genetics (pink) contributes to inherited susceptibility, with variations in immune-related genes playing a key role. Environmental factors (blue), such as infections, vitamin D levels, and smoking, can affect disease risk. Epigenetics (green) represents the dynamic regulatory mechanisms that mediate the effects of the environment on gene expression, shaping immune responses and disease progression. The surrounding bubbles represent the contributions of individual factors and their interplay, emphasizing the multifactorial nature of MS pathogenesis. Created in https://BioRender.com

Fig. 2

Immunopathogenesis of multiple sclerosis. Although the antigen responsible for the initiation of the autoimmune reaction in multiple sclerosis (MS) has not yet been described, it is hypothesized that antigens derived from the central nervous system (CNS) would reach the periphery and be presented to autoreactive CD4⁺ T cells in the lymph nodes. Alternatively, other self-antigens, pathogenic or gut microbial peptides sharing high homology with myelin antigens, have been postulated as candidates for autoimmune MS. The pool of autoreactive CD4⁺ T cells, which are enriched in brain-homing clones, circulate inside the CNS upon activation. Peripheral tolerance mechanisms involving the suppressor functionality of regulatory T (Treg) cells, including reduced suppressor function of Treg cells, loss of FoxP3 or resistance of effector T cells to Treg-mediated suppressive mechanisms, have also been shown to be dysregulated in MS patients. Once inside the CNS, autoreactive CD4⁺ T cells are reactivated by local antigen-presenting cells and differentiate into encephalitogenic T helper (Th)1/Th17 effector cells, initiating a series of immunological events that lead to demyelination and neuronal damage. Myeloid cells are the most abundant immune cell type found in MS lesions and are involved in multiple aspects of MS pathogenesis, including the differentiation of CD4⁺ T cells and the recruitment of other immune cells at the lesion site. CD8⁺ T cells are also recruited into the CNS and are clonally expanded, although the heterogeneity of clones is much greater than that of CD4⁺ T-cell clones. The formation of tertiary lymphoid structures similar to germinal centers in the meninges results in the activation of T and B cells, along with the sustained secretion of antibodies. APC, antigen-presenting cell; BCR, B-cell receptor; CNS, central nervous system; IFN- γ, interferon gamma; MHC-II, class II major histocompatibility complex; IgG, immunoglobulin isotype G; TCR, T-cell receptor; Th, T helper cell. Created in https://BioRender.com

Fig. 3

Neuropathogenesis of multiple sclerosis. Multiple sclerosis (MS) is caused by demyelination, which begins with microglial activation, macrophage infiltration, and accumulation of CD8⁺ tissue-resident memory T cells, which drive inflammatory changes in astrocytes and microglia. Chronic microglial activation leads to the release of proinflammatory cytokines and reactive oxygen and nitrogen species, which contribute to demyelination, tissue damage and neurodegeneration. Similarly, chronically reactive astrocytes release cytokines and chemokines that recruit additional immune cells, deposit inhibitory chondroitin sulfate proteoglycans that impair remyelination, and contribute to glial scar formation, which further hinders repair. Humoral immunity also plays a role in demyelination through antibody deposition and complement activation. IgG and IgM antibodies trigger the classical complement pathway, leading to opsonization, formation of the membrane attack complex (MAC), and direct damage to oligodendrocytes and neurons. In addition, the C3 component impairs remyelination. The failure of oligodendrocyte progenitor cells to mature into fully functional oligodendrocytes further exacerbates remyelination deficits. Over time, chronically demyelinated neurons experience axonal injury and metabolic stress, causing calcium accumulation within axons, activation of proteases, and consequently axonal degeneration. Additionally, chronic inflammation exacerbates neurodegeneration by exposing neurons to cytotoxic molecules such as nitric oxide and glutamate excitotoxicity. Together, these mechanisms drive progressive tissue damage and disease progression in MS. Created in https://BioRender.com

Fig. 4

Disease-modifying therapies (DMTs) approved for multiple sclerosis. The figure represents the different DMTs according to their clinical efficacy (horizontal axis) and safety concerns (vertical axis). The colors indicate the route of administration: subcutaneous or intramuscular (yellow), oral (orange), or intravenous (red). The dashed borders denote DMTs approved for both relapsing-remitting multiple sclerosis (RRMS) and either secondary progressive MS (SPMS) or primary progressive MS (PPMS). FDA Food and Drug Administration. Created in https://BioRender.com

Fig. 5

Schematic diagram depicting ongoing antigen-specific immunotherapies for multiple sclerosis. a Peptide and protein-based approaches include the use of whole antigens, unaltered myelin peptide ligands, altered peptide ligands (APLs), and soluble myelin peptide–MHC complexes. b The DNA vaccination approach relies on a bacterial plasmid carrying a gene encoding a specific antigen peptide. Peptide-loaded carrier approaches can be divided into biological and synthetic methods. c Biological carrier approaches induce tolerance by using cells or extracellular vesicles (EVs) as carriers, such as autologous peripheral blood mononuclear cells (PBMCs) or erythrocytes loaded with multiple sclerosis (MS) autoantigen peptides. d Synthetic carrier approaches, on the other hand, use drug delivery nanosystems to transport antigenic molecules to target tissues, including pegylated gold (PEG) nanoparticles (NPs), mannosylated NPs, polylactide-coglycolide (PLGA) NPs, and phosphatidylserine (PS) NPs, as well as peptide‒MHC complex-loaded NPs and peptides conjugated to antibodies. e Cellular immunotherapy approaches involve immunization with autologous attenuated autoreactive T cells, the use of autologous tolerogenic dendritic cells (tolDCs), and engineered Treg cells expressing myelin-specific chimeric antigen receptors (CARs). These therapies aim to induce an anti-inflammatory microenvironment; promote the secretion of cytokines such as IL-10, TGF-β, and IL-35; induce T-cell anergy; and generate Treg cells, IL-10⁺ regulatory CD4⁺ T-cell type 1 (Tr1) cells, and B regulatory (Breg) cells, ultimately suppressing autoreactive attack and restoring immune tolerance at the central nervous system (CNS) level. Abbreviations: BBB, blood–brain barrier; tolAPC, tolerogenic antigen-presenting cell; Ag, auntoantigen; Immunomod; immunomodulator. Created in https://BioRender.com