Immunological Targets in Generalized Myasthenia Gravis Treatment: Where Are We Going Now?

Abstract

Background: Generalized myasthenia gravis (gMG) is a heterogeneous autoimmune disorder marked by antibody-mediated disruption of neuromuscular transmission. Despite advancements in immunosuppressive therapies and biologics, a subset of patients remains refractory, necessitating more targeted and personalized treatment strategies.

Objective: This review aims to synthesize current knowledge of the immunopathological mechanisms across gMG subtypes and to explore emerging therapeutic targets tailored to these diverse disease phenotypes.

Methods: A narrative review was conducted, integrating recent findings from clinical trials, immunogenetic studies, and preclinical research to describe subtype-specific immune mechanisms and corresponding therapeutic innovations.

Results: gMG subtypes-characterized by autoantibody profiles (AChR, MuSK, LRP4, or seronegative), thymic histopathology, and age of onset-demonstrate distinct immunological pathways. Early-onset MG is associated with thymic hyperplasia and Th17-driven inflammation; thymoma-associated MG involves central tolerance breakdown; late-onset MG shows immune senescence and altered T-cell regulation. MuSK- and LRP4-positive MG exhibit unique cytokine and antibody signatures. Novel therapeutic strategies include B cell- and T cell-targeted therapies (e.g., anti-CD19, anti-CD38, JAK inhibitors), cytokine inhibitors (IL-6, IL-17, IL-23), FcRn antagonists, complement inhibitors, and gene- or cell-based therapies such as CAR-T and CAAR-T cells.

Conclusion: The evolving landscape of gMG treatment reflects a shift toward immunopathology-based precision medicine. Better characterization of subtype-specific molecular signatures and immune dysfunctions is essential to guide clinical decision-making and improve outcomes for treatment-refractory patients.

Keywords: autoantibodies; biological therapies; generalized myasthenia gravis; immunopathology.

Figure 1

B and T cell immunologically targeted therapies. This figure illustrates the key targets and corresponding therapies aimed at B and T cells. The figure is intentionally schematic to facilitate understanding and highlight the main therapeutic strategies. Experimental drugs with evidence from preclinical models are shown with green arrows; agents already used in other diseases with targets potentially relevant for MG are highlighted in pink; drugs evaluated in RCTs are highlighted in blue; and those reported in case reports or case series are highlighted in orange. The white line crossing the drug name indicates agents that did not show favorable responses or cases where the trial was terminated due to other reasons. The larger green star on B cells compared to T cells for cladribine is intentional, as this drug has a predominant effect on B cells. Abbreviations: BAFF, B-cell Activating Factor; BAFFR, BAFF Receptor; BCR, B-cell Receptor; CXCL13, C-X-C Motif Chemokine Ligand 13; CXCR5, C-X-C Motif Chemokine Receptor 5; IL-2, Interleukin-2; IL-6, Interleukin-6; IL-6R, Interleukin-6 Receptor; IL-10, Interleukin-10; IL-17, Interleukin-17; IL-21, Interleukin-21; IL-22, Interleukin-22; IL-23, Interleukin-23; JAK, Janus Kinase; TCR, T-cell Receptor; TGF-β, Transforming Growth Factor Beta; TNF-α, Tumor Necrosis Factor Alpha; TNFR, Tumor Necrosis Factor Receptor.

Figure 2

Complement cascade-targeted therapies. This figure shows the key targets and corresponding therapies in the complement cascade. The figure is intentionally schematic to facilitate understanding and highlight the main therapeutic strategies. Agents already used in other diseases with targets potentially relevant for MG are highlighted in pink; drugs evaluated in RCTs are highlighted in blue. The white line crossing the drug name indicates agents that did not show favorable responses.