Induction of immune tolerance in NMOSD and MOGAD

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are autoimmune diseases characterized by immune-mediated damage to the central nervous system. Current treatments primarily focus on chronic immunosuppression. Immune tolerance induction offers a novel approach to restoring immune balance while minimizing systemic side effects. Central and peripheral immune tolerance mechanisms regulate autoreactive lymphocytes, ensuring immune homeostasis. Dysregulation of these pathways underpins NMOSD and MOGAD pathogenesis. Antigen-specific therapies targeting aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) autoantigens include peptide-based vaccines and nanoparticle delivery systems, promoting T cell anergy and regulatory T cell (Treg) expansion. Cell-based therapies utilizing ex vivo-expanded Tregs or regulatory B cells (Bregs) have shown promise in preclinical models but face challenges in clinical translation due to scalability and safety concerns. Gene-editing technologies such as CRISPR/Cas9 present opportunities to modulate immune pathways and restore tolerance, although delivery and off-target effects remain obstacles. Additionally, strategies addressing double-seronegative NMOSD, which lacks detectable autoantibodies, emphasize broad immune modulation rather than antigen specificity. While significant progress has been achieved, the transition to clinical application requires overcoming hurdles such as optimizing antigen delivery, ensuring long-term efficacy, and identifying reliable biomarkers. Advances in personalized medicine hold promise for achieving sustained remission, reducing dependency on immunosuppression, and improving patient outcomes in NMOSD and MOGAD. This review explores advancements in tolerance strategies, highlighting their potential in NMOSD and MOGAD.

Keywords: MOGAD; NMOSD; autoimmunity; immune tolerance.

Figure 1.

Mechanisms of immunotolerance. Immune tolerance to Self-Ag is primarily established during development, occurring in the thymus for T cells and in the bone marrow for B cells. This process eliminates self-reactive T cells through apoptosis in response to excessive reactivity to self-antigens presented by major histocompatibility complex molecules. Subsequently, positive selection ensures the survival of functionally competent T cells released into the periphery. A similar selection process occurs in the bone marrow to limit B cell autoreactivity. Central tolerance is maintained through receptor editing and apoptosis, significantly reducing the potential for autoimmunity. Receptor editing involves ongoing immunoglobulin light chain gene recombination, leading to secondary rearrangements that modify antigen receptor specificity by replacing one light chain with another. Despite these central tolerance mechanisms, some self-reactive mature T and B cells evade deletion and enter the peripheral lymphoid compartment. Multiple peripheral tolerance mechanisms further regulate immune homeostasis and prevent self-reactive immune cells from mediating tissue damage. These mechanisms include Treg and Breg cells, activation-induced cell death, and the absence of co-stimulatory signals that induce anergy. For clarity, some steps involved in tolerance induction are not depicted in the accompanying schematic. Breg, regulatory B; DC, dendritic cells; IL, interleukin; nTreg, natural regulatory T cells; Self-Ag, self-antigens; TLR, Toll-like receptor; Treg, regulatory T.

Figure 2.

Pathophysiological mechanisms and induction of immune tolerance in NMOSD and MOGAD. (1) Peptide-based tolerance induction: Peptide vaccines containing self-antigen epitopes promote immune tolerance by interacting with APCs, thereby modulating T-cell differentiation and regulating the secretion of inflammatory cytokines. (2) Role of tolerogenic DCs: Tolerogenic DCs are crucial for maintaining central and peripheral immune tolerance. They achieve this through mechanisms such as T cell clonal deletion, induction of T cell anergy, and the generation and activation of Treg cells. (3) Breg cell exert immunoregulatory functions through multiple pathways, including the secretion of immunomodulatory cytokines, the release of cytotoxic granzyme B, which induces T cell apoptosis, and the upregulation of FasL, PD-1, and PD-L1. These molecules suppress CD4+ and CD8+ T cell activity and promote the differentiation of Tr1 cells. (4) Targeted elimination of autoreactive B cells: CAR T cells targeting B cell markers such as CD19 facilitate the broad depletion of autoreactive B cells. Alternatively, CAR-modified Treg cells can suppress autoreactive responses without complete B cell depletion. (5) Gene editing technologies, such as CRISPR-Cas9, offer a strategy to restore antigen-specific immune tolerance by engineering DCs into a tolerogenic phenotype, expanding autoantigen-specific Treg and Breg populations and optimizing CAR-T cell function. (6) Synthetic nanoparticles—including polymeric, lipid-based, metallic, and peptide-polymer formulations—can be engineered to co-deliver antigens, antibodies, nucleic acids (DNA/RNA), and immunomodulatory agents in tailored combinations to modulate immune responses. Source: Modified from Carnero Contentti and Correale. Ag, antigen; APCs, antigen-presenting cells; AQP4, Aquoporin4; Breg, regulatory B; CAR, chimeric antigen receptor; CAS9, CRISPR associated protein 9; CRISPR, clustered regulatory interspaced short palindromic repeats; DCs, dendritic cells; FasL, FS-7-associated surface antigen ligand (also known as the cell surface death receptor); PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; Tr1, type 1 regulatory T; Treg, regulatory T.