Toward an immunological classification of autism spectrum disorder: A PRISMA-ScR-compliant scoping review.

Abstract

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition increasingly linked to disturbances in immune signaling and neuroimmune cross-talk. This PRISMA-ScR-guided scoping review synthesizes contemporary evidence to propose a structured immunological classification of ASD comprising six immune-related subtypes: immune overactivation, immune deficiency, autoimmunity-linked ASD, gut-immune axis dysregulation, post-infectious or immune-triggered onset patterns, and maternal immune activation. Each subtype is defined by characteristic neuroimmune features - including cytokine imbalances, aberrant microglial activation, altered microbiome-immune communication, and prenatal immune priming - reflecting distinct biological pathways through which immune dysfunction may influence neurodevelopment. Based on 42 mapped sources identified through a search strategy that primarily emphasized literature published between 2020 and 2025, while incorporating selected foundational earlier studies through citation chaining when necessary for conceptual and mechanistic context, and spanning human clinical and epidemiological studies, animal models, and integrative neuroimmune reviews, this synthesis identifies candidate biomarkers and immune signatures relevant to each subtype, including systemic and CNS-localized inflammation, autoantibodies, disrupted gut-immune-brain pathways, and maternal cytokine profiles. The framework also clarifies ongoing debates by distinguishing immune-mediated vulnerability and timing-dependent unmasking of susceptibility from assumptions of direct causation regarding environmental or infectious exposures. Conceptualizing ASD along immune-related subtypes provides a foundation for precision-based diagnostic and therapeutic approaches, highlighting opportunities for targeted immunomodulation, microbiome-informed interventions, and biomarker-driven stratification, thereby advancing translational efforts at the interface of immunology, neuroscience, and developmental psychopathology.