IL-6, IL-10 may be biomarkers of Huntington’s progression: Review
Patients have higher blood levels of both molecules than do healthy people
People with Huntington’s disease have significantly higher levels of the proinflammatory molecule interleukin-6 (IL-6) and the anti-inflammatory molecule IL-10 in their blood relative to healthy people, according to a review study.
The IL-6 difference was true for both pre-manifest patients — those carrying Huntington’s-causing mutations, but not yet having overt motor symptoms — and for those already showing motor symptoms. No significant differences in levels were found between the two groups.
IL-6 and IL-10 can possibly be considered biomarkers of Huntington’s progression, the researchers wrote in “Circulating levels of inflammatory biomarkers in Huntington’s disease: A systematic review and meta-analysis,” which was published in the Journal of Neuroimmunology.
Huntington’s is caused by excessive repeats of a sequence of three DNA building blocks — CAG — in the HTT gene, which provides instructions for producing the huntingtin protein. A higher than normal number of CAG repeats results in abnormally long huntingtin proteins being produced that form clumps, leading to inflammation and damage in affected brain areas. This results in a range of symptoms that include motor, psychiatric, and cognitive problems.
Huntington’s inflammatory response
Neuroinflammation — an inflammatory response in the central nervous system (CNS), which is made up of the brain and spinal cord — is marked by the activation of the CNS’ resident immune cells, called microglia, and the production of toxic and pro-inflammatory molecules. This can cause nerve cell dysfunction and damage.
“Significantly activated microglia have been found in manifest [Huntington’s disease] patients compared to premanifest carriers, indicating that inflammation may contribute to disease progression and/or neurodegeneration,” the researchers wrote.
CNS tissues from deceased patients have high levels of several proinflammatory molecules and models of the disease show inflammation outside the CNS. This suggests certain proinflammatory molecules in the blood might serve as prognostic biomarkers and/or therapeutic targets.
“An unmet need in the management of [Huntington’s] is the lack of biomarkers to assess disease progression and response to therapy,” wrote researchers in Iran who reviewed studies published up to March 2023 that reported blood levels of inflammation-related markers in Huntington’s patients and healthy people, who served as controls.
The study protocol was registered in PROSPERO — International Prospective Register of Systematic Reviews — with the ID CRD42022296078. Of the 25 reports assessed for eligibility, 13 studies were included in the systematic review analysis and 10 had enough quantitative data to be included in the meta-analysis. The 10 studies were published between 1998 and 2021; about half were conducted in Europe and two in the U.S.
Blood levels of IL-6, IL-10
The meta-analysis included 860 people, 548 with Huntington’s and 312 healthy controls. Data on nine inflammation markers — IL-1beta, IL-2, IL-6, IL-8, IL-10, TNF-alfa, IFN-gamma, complement component 3, and C-reactive protein (CRP) — were also included.
Blood levels of IL-6, a proinflammatory molecule, were significantly higher in people with Huntington’s disease than healthy controls. These findings were based on pooled data from seven studies with 310 Huntington’s patients and 194 healthy controls.
Similar results were seen when comparing 84 pre-manifest patients versus 86 healthy controls and 226 manifest patients versus 138 healthy controls. No significant differences in blood IL-6 levels were detected between pre-manifest and manifest patients, suggesting it may be an early marker of Huntington’s.
Pooled results from two studies of 156 patients and 99 healthy people showed patients also had significantly higher blood levels of IL-10, an anti-inflammatory molecule. A subgroup analysis couldn’t be performed due to the low number of available studies.
Because previous data from Huntington’s animal models suggest reduced IL-10 levels in the CNS, there is a “need for conduction of studies on larger populations to reach a consensus on this matter,” the researchers wrote.
Moreover, blood levels of CRP, a marker of inflammation in the body, were analyzed in four studies of 264 patients and 118 controls. Although CRP levels were generally higher in patients, the difference reached only borderline statistical significance, meaning it may be due to chance. A subgroup analysis showed patients with and without overt symptoms had similar blood CRP levels relative to healthy controls. There were no other significant differences in inflammation markers between Huntington’s patients and healthy people.
“To the best of our knowledge, this is the first meta-analysis conducted on the alterations in [blood] levels of inflammatory biomarkers in HD patients in comparison with healthy controls, as well as comparing premanifest and manifest patients,” wrote the researchers, who noted the results “showed that IL-6 and IL-10 levels were significantly higher in HD patients in comparison with controls.” Higher levels in pre-manifest patients early in the course of the disease suggests both may serve as biomarkers of disease progression, they said.