Section 01 — The Core Principle
01Not who has autism — who has immune-driven autism
Autism spectrum disorder is not a single biological entity. It is a constellation of neurodevelopmental presentations that share a common behavioural phenotype but can have meaningfully different underlying mechanisms. The cascade framework identifies at least six biological branches — immune/inflammatory, metabolic/mitochondrial, gut-driven, genetic/syndromic, regression, and environmental exposure — that converge on similar downstream presentations through different upstream pathways.
IMIG addresses one node in the cascade: the upstream cytokine environment that drives IDO1 activation and initiates the inflammatory cascade. Children whose autism is primarily driven by that mechanism are the candidates. Children whose autism is driven predominantly by other mechanisms — mitochondrial dysfunction, genetic variants, or structural differences — are not direct IMIG candidates, even if they carry an ASD diagnosis.
The question is not "does this child have autism?" The question is "is there active, measurable immune dysregulation driving this child's neurodevelopmental trajectory?" If the answer is yes, IMIG addresses the mechanism directly. If the answer is unclear or no, it does not.
This distinction is not a limitation of IMIG — it is its scientific strength. Biomarker-stratified patient selection is what makes the proposed pilot study fundable, ethical, and likely to produce a meaningful clinical signal. It is also what separates this from the historical pattern of ASD intervention trials that enrolled unselected populations and diluted real effects into statistical noise.
Section 02 — Primary Markers
02Primary markers — active immune cascade loading
These are the markers with the strongest direct evidence linking immune dysregulation to IVIG/IMIG response in the published literature. Elevation in any two or more of the following, in a child with ASD, constitutes a strong IMIG candidacy signal. These are standard clinical laboratory tests available through most paediatric immunology or integrative medicine services.
IFN-γ (Interferon-gamma)
Serum cytokine panel · Standard lab
The primary upstream driver of IDO1 upregulation. Elevated IFN-γ is the most direct signal that the cascade trigger is active. IFN-γ elevation with ASD phenotype is a near-definitive indicator that the immune-inflammatory pathway is the primary mechanism in this child.
Primary signal
TNF-α (Tumour Necrosis Factor-alpha)
Serum cytokine panel · Standard lab
Co-driver of neuroinflammation alongside IFN-γ. Multiple IVIG studies showed TNF-α reduction accompanying clinical improvement. Elevated TNF-α in ASD is associated with the strongest behavioural responses to immunoglobulin therapy in the published literature.
Primary signal
IL-6 (Interleukin-6)
Serum cytokine panel · Standard lab
Sustained IL-6 elevation drives chronic microglial activation and contributes to the neuroinflammatory environment that loads the cascade. Elevated IL-6 in ASD children correlates with severity of social communication deficits and is a consistent finding in regression-phenotype subgroups.
Primary signal
Kynurenine / Tryptophan Ratio (KTR)
Plasma amino acid panel · Specialist lab
A direct biochemical measure of IDO1 activity and kynurenine pathway flux. An elevated KTR confirms the cascade is actively loaded at the IDO1 node — it is not just an upstream marker but evidence that the downstream pathway is engaged. IMIG's mechanism predicts KTR normalisation with sustained treatment.
Cascade confirmation
Section 03 — Strong Supporting Markers
03Strong supporting markers — immune system dysregulation
These markers do not directly measure cytokine activity but indicate underlying immune system dysfunction that predisposes to the inflammatory cascade. In combination with elevated cytokines, they substantially strengthen the candidacy signal. In isolation — without cytokine elevation — they suggest immune vulnerability but do not alone confirm active cascade loading.
IgG Subclass Deficiency
Serum immunoglobulin panel · Standard lab
Deficiency in IgG1, IgG2, IgG3, or IgG4 subclasses indicates impaired humoral immune regulation. Present in a significant subset of ASD children with recurrent infections and inflammatory phenotype. Multiple IVIG studies enrolled children specifically for this finding. Low IgG subclasses with ASD is one of the clearest indications for immunoglobulin therapy in the clinical literature.
Strong supporting
Total IgG below age-adjusted reference range
Serum immunoglobulins · Standard lab
Low total IgG (hypogammaglobulinaemia or low-normal) indicates reduced antibody-mediated immune regulation. Children with low total IgG and ASD are the population in whom IVIG has the most established clinical indication and the strongest historical response data from the published literature.
Strong supporting
Anti-brain Autoantibodies
Specialised neuroimmunology panel
Antibodies targeting neuronal or glial proteins — including anti-NMDA receptor, anti-MOG, anti-basal ganglia, or anti-neuronal antibodies. Present in a subset with regression phenotype. The strongest predictor of IVIG response in the literature. The PANS population — which showed the strongest IMIG response in Fourie & Armstrong 2024 — is defined by anti-basal ganglia autoantibodies.
Strongest predictor
Specific Polysaccharide Antibody Deficiency (SPAD)
Post-vaccination antibody titres · Standard lab
Impaired antibody response to polysaccharide antigens (measured by pre/post pneumococcal vaccination titres). Associated with recurrent sinopulmonary infections and immune dysfunction. SPAD with ASD indicates a specific deficit in innate immune regulation that immunoglobulin supplementation directly addresses.
Strong supporting
Section 04 — Clinical Picture
04The clinical picture that accompanies the laboratory findings
Laboratory markers do not exist in isolation. The strongest IMIG candidates typically present with a clinical history that is consistent with immune-driven neurodevelopmental change. The following clinical features, in combination with elevated biomarkers, substantially strengthen the candidacy assessment.
Clinical features associated with immune-driven ASD and IMIG candidacy
Any combination of these features alongside elevated biomarkers strengthens the signal
- Regression phenotype — loss of previously acquired language, social skills, or motor function, particularly if onset followed a febrile illness, infection, or vaccination period. The regression phenotype is Branch E in the cascade framework and is strongly associated with autoantibody-mediated neuroinflammation.
- Acute or subacute onset of symptom worsening — behavioural deterioration that is episodic rather than static, often correlated with illness, infection, or immune challenge. This pattern suggests an active inflammatory driver rather than fixed developmental difference.
- Recurrent infections — frequent ear infections, sinusitis, upper respiratory infections, or gastrointestinal infections suggesting impaired immune regulation and consistent with IgG subclass deficiency or SPAD.
- GI inflammatory symptoms — chronic constipation, diarrhoea, bloating, or food reactivity patterns consistent with gut-immune dysregulation contributing to the upstream cytokine load. Gut-immune activation is Branch A in the cascade and can be a primary driver of cytokine elevation.
- Family history of autoimmune conditions — maternal or first-degree relative autoimmune disease is associated with elevated risk of anti-brain autoantibodies and immune-dysregulated ASD subtype in multiple epidemiological studies.
- Positive response to anti-inflammatory interventions — prior improvement with corticosteroids, NSAIDs, or dietary anti-inflammatory protocols suggests the inflammatory pathway is clinically active and targetable.
- Younger age at assessment with recent biomarker elevation — the timing hypothesis from Fourie & Armstrong predicts that children with more recent inflammatory loading will respond more strongly. A child with elevated cytokines identified at age 4–6 is a stronger candidate than one with a decade of established neuroinflammatory loading.
Section 05 — Who Is Not a Candidate
05Who is not a candidate — and why this matters
Being precise about who is not a candidate is as important as identifying who is. It protects children from unnecessary intervention, focuses the trial on the population most likely to benefit, and prevents the dilution of the treatment signal that has historically made ASD intervention trials difficult to interpret.
Not a primary IMIG candidate
ASD without measurable immune dysregulation
Children with ASD whose laboratory workup shows normal cytokines, normal immunoglobulin levels, no autoantibodies, and normal kynurenine/tryptophan ratio do not have the measurable upstream immune activation that IMIG addresses. Their autism may be driven by genetic factors, mitochondrial dysfunction, structural differences, or other mechanisms outside the immune-inflammatory branch of the cascade. IMIG is not indicated, and the pilot study would not enrol them. This does not mean their autism is less real or less impactful — it means the mechanism is different, and a different intervention framework applies.
Children with purely genetic or syndromic ASD (identified chromosomal variants, fragile X, Rett syndrome, tuberous sclerosis) are similarly outside the immune-inflammatory subgroup that IMIG targets, unless they carry concurrent immune dysregulation markers.
06From candidate identification to clinical action
This page is intended as a scientific reference for clinicians and researchers evaluating the IMIG pilot study framework. It is not a clinical decision tool. Patient-level decisions about whether to pursue IMIG require a qualified paediatrician or paediatric immunologist who can interpret the full clinical picture in context.
Biology of Autism Suite — Testing Reference
For the broader cascade testing framework — covering all six biological branches, not just the immune-inflammatory pathway — see the
Testing Strategy and
Test Reference documents in the Biology of Autism suite at DecodingAutismNow.com. The suite's testing protocol is designed for clinicians and informed parents working through the full cascade framework. The candidate markers on this page represent the immune-specific subset of that broader protocol, presented here for the specific purpose of IMIG candidate identification.
Clinicians with potential candidates
Dr. Fourie is the appropriate clinical contact for paediatricians or child psychiatrists with patients who present the biomarker and clinical profile described on this page. Direct clinical enquiries — including questions about the IMIG protocol and current patient programme — to Dr. Fourie directly.
Contact Dr. Fourie
Researchers and trial partners
The candidate identification framework on this page will inform the inclusion and exclusion criteria for the Proposed IMIG for Autism Controlled Pilot Study. For the full trial design rationale — including patient selection criteria, endpoints, and infrastructure — see the Trial page.
See the Trial Design