Abstract:
Evidence increasingly implicates immune–brain interactions in autism spectrum disorder (ASD). This review
synthesizes human and translational findings on neuroinflammation and its relevance to ASD heterogeneity
and treatment prospects. Narrative review of post-mortem, cerebrospinal fluid (CSF), blood, neuroimaging,
and animal literature examining glial activation, cytokine profiles, blood–brain barrier (BBB) integrity, and
peripheral–central immune crosstalk in ASD. Post-mortem studies frequently report microglial and astroglial
activation, altered complement signaling, and cytokine dysregulation in cortical and cerebellar regions. CSF
and peripheral assays often demonstrate elevated pro-inflammatory mediators (e.g., IL-6, TNF-α), though
effect sizes vary and subgroups exist. Positron emission tomography using TSPO ligands shows mixed results,
reflecting methodological limits (ligand affinity polymorphisms, age/sex effects) and biological heterogeneity.
Genomic and transcriptomic data suggest immune-related pathways in subsets of individuals with ASD, while
maternal immune activation models recapitulate ASD-like behaviors and microglial priming, underscoring
developmental timing. Emerging work links gut dysbiosis and epithelial permeability to peripheral immune
activation and possible BBB effects, but causality remains unresolved. Clinically, immune signatures correlate
with symptom severity in some cohorts; however, anti-inflammatory or microglia-modulating interventions
(e.g., minocycline, ibudilast, omega-3s) yield inconsistent, small-sample benefits and lack robust biomarkers to
guide selection. Overall, convergent evidence supports context-dependent neuroinflammation in ASD—not
universal, but salient in biologically defined subtypes. Priorities include longitudinal, multimodal studies
(peripheral + CSF + imaging), stratification by age/sex/comorbidity, and development of validated
inflammatory endophenotypes to enable targeted trials.
