Huntington Disease is NOT an Autoimmune Disease
Huntington disease (HD) is definitively an autosomal dominant genetic neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene on chromosome 4p16.3—it has no autoimmune etiology whatsoever. 1
Disease Classification and Mechanism
HD is classified as a hereditary neurodegenerative disease, not an autoimmune condition. The pathophysiology involves:
- Genetic mutation: An abnormal expansion of CAG repeats (≥40 repeats for full penetrance) in exon 1 of the HTT gene 1
- Protein misfolding: The expanded CAG repeat translates into an elongated polyglutamine tract in the huntingtin protein, causing toxic protein aggregation 1
- Neuronal death: Selective loss of neurons occurs primarily in the caudate nucleus and putamen through a toxic gain-of-function mechanism, not immune-mediated destruction 1
Key Distinguishing Features from Autoimmune Disease
Inheritance pattern: HD follows autosomal dominant transmission with 100% penetrance when CAG repeats are ≥40, meaning every person inheriting the mutation will develop disease if they live long enough 1
No immune system involvement: The disease mechanism involves:
- Direct neurotoxicity from mutant huntingtin protein 1
- Progressive neurodegeneration over 15-20 years 1
- No antibody formation, no inflammatory markers, and no response to immunosuppression 2, 3
Genetic testing is diagnostic: A simple DNA test measuring CAG repeat length confirms diagnosis with 100% specificity for alleles ≥40 repeats 1
Clinical Implications
The non-autoimmune nature of HD means:
- Immunosuppressive therapies have no role in HD management 4
- Current treatment is purely symptomatic: Dopamine-depleting agents (deutetrabenazine, valbenazine) for chorea, antipsychotics for behavioral symptoms 4, 5
- Future therapies target the genetic defect: Gene silencing with antisense oligonucleotides, RNA interference, and gene editing approaches are in clinical trials 1, 4
Common pitfall: Do not confuse the neuroinflammation that occurs secondary to neuronal death in HD with primary autoimmune pathology—the inflammation is a consequence, not a cause 6, 7