The pathological Huntingtin CAG triplet expansion differentially affects the diagnosis of systemic and organ-specific...

In Huntington's disease (HD), signs of inflammatory activation are found in the brain, cerebrospinal fluid, and blood. HD monocytes are reported to be hyperreactive in vitro. Thus, HD mutation might affect the immune system.

To explore the frequency of autoimmune diseases (AIDs) in HD mutation carriers (people with the HD mutation, PwHD) compared to control participants (CPs) as markers of immune dysfunction related to CAG triplet expansion in the Huntingtin (HTT) gene.

Analysis of the Enroll-HD periodic dataset #5 (European sites) was conducted. Definite AIDs, coded using the abbreviated ICD-10 in the dataset for comorbidities, were identified. AIDs were grouped by organ specificity into arthropathy-dominant AIDs of musculoskeletal and connective tissues (arthropathic), as well as endocrine, dermatological, and gastrointestinal AIDs.

Although AID frequency was not different in PwHD (709/10,594; 6.7%) compared to CPs (176/2,477; 7.1%, p = 0.451), the AID subgroup distribution differed (p = 0.033) with endocrine AIDs being less frequent in PwHD [odds ratio (OR): 0.80; 95% confidence interval (95% CI) 0.68-0.95], while dermatological AIDs tended to be more common [OR (95% CI): 1.13 (0.94-1.38)]. These observations were explained by a reduced frequency of Hashimoto thyroiditis in PwHD [OR (95% CI): 0.69 (0.56-0.86)], while carriership of the HD mutation was associated with an increased risk of psoriasis [OR (95% CI): 1.27 (1.03-1.60)]. Among PwHD, those with an AID had lower CAG repeats [median (interquartile range): 42 (41-44)] than those without [43 (41-45), p < 0.0001]. When adjusted for sex and age, each extra pathological CAG repeat reduced the AID risk [OR (95% CI): 0.69 (0.61-0.78), p < 0.001]. The CAG dependency of the AID frequency among PwHD was mostly explained by arthropathic AID. In a well-defined early-manifest PwHD core group, each additional CAG repeat reduced the likelihood of an AID_arthro when adjusted for functional impairment, sex, and age at enrollment with an odds ratio of 0.57 (95% CI: 0.44-0.74, p < 0.0001).

Both the presence and the exact size of the pathological CAG triplet expansion in the HTT gene differentially affect the frequency of certain AIDs. Our results support the idea that HD mutations affect immune function, but in a complex, disease-specific pattern.