Immune imbalance between T helper 1, T helper 17 and regulatory T cells fuels amyotrophic lateral sclerosis pathogenesis: disease trajectory, diagnosis and therapeutic implications

Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease, causing motor neuron loss and with limited treatment options. Although traditionally considered non-immune in origin, accumulating evidence implicates the adaptive immune system, particularly CD4+ T cell subsets, as key modulators of disease progression. Among these, T helper (Th)1 and Th17 cells are elevated in ALS blood, cerebrospinal fluid and central nervous system tissues, and drive pro-inflammatory cascades. By contrast, regulatory T cells (Tregs) suppress pathogenic inflammation and maintain immune homeostasis; however, in ALS, both Treg number and suppressive function decline, with remaining Tregs showing reduced FOXP3 (the master transcription factor governing Treg function) expression and impaired regulatory capacity. Integrating human and preclinical evidence, we describe how ALS-associated proteins can act as autoantigens that trigger adaptive immune responses, and how Th1/Th17 amplification and Treg insufficiency couple to microglial activation, blood–brain barrier disruption, and motor neuron degeneration, to impact disease trajectory. Convergent signalling pathways and their intersection with metabolic stress provide a mechanistic link between the adaptive immune response and neurodegeneration. We outline biomarker frameworks, spanning immune cell phenotypes, cytokine signatures and transcriptional readouts that define alterations in Th1, Th17 and Treg responses in ALS. Finally, we address the emerging immunomodulatory therapeutic approaches, including the targeted blockade of specific cytokines and signalling pathways, augmentation of Treg number and function, and attenuation of Th1/Th17 activity, while preserving protective Tregs using selective small-molecule approaches. Collectively, the evidence we provide establishes adaptive T cell imbalance as a central, targetable driver of ALS neuroinflammation and provides a rationale for biomarker-guided therapeutics designed to rebalance adaptive immunity and slow disease progression.