Centromere Defects Linked to SSc Autoimmunity
Chromosomal changes correlated with inflammation markers, fibrosis, immune pathway activation
A new study has found that defects in centromeres — specific regions of chromosomes — are evident in skin cells from people with systemic sclerosis (SSc).
People with diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) forms of the disease showed specific alterations relative to healthy people, but chromosomal changes were correlated with markers of inflammation, fibrosis (scarring), and activation of certain immune pathways in all patients.
In lcSSc patients, chromosome defects were linked to anti-centromere antibodies (ACAs), a type of self-reactive antibody in some patients with the autoimmune disease.
“These findings provide the framework for a model in which centromere abnormalities and [chromosome instability] are central to the molecular processes that drive autoimmunity in SSc,” the researchers wrote.
The study, “Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis,” was published in Nature Communications.
Chromosomes, which reside in the nucleus of cells and contain genetic information, are each comprised of two identical halves held together by a centromere.
Containing repeated sequences of a type of DNA called alpha satellite DNA, centromeres are critical for helping chromosomes split apart when cells divide and replicate, ensuring each new cell contains the same DNA as its parent cell. Defects in these functions can cause chromosomes to become unstable or abnormal, resulting in significant cellular impairment.
ACA antibodies, found in about 43% of lcSSc patients and less commonly in dcSS, recognize and attack a number of centromere proteins. Still, “despite the presence of ACAs in SSc, the role that centromere sequences and proteins play in the pathogenesis [disease development] of SSc remains unexplored,” said the researchers, who examined the DNA of centromeres in fibroblasts from skin lesions of SSc patients as well as forearm skin samples from healthy adults. Fibroblasts are a type of connective tissue cell implicated in the buildup of scar tissue that marks SSc.
Analyzing differences in dcSSc and lcSSc patients
They analyzed samples from 11 dcSSc patients (9 women) and nine lcSSc patients (three women).
Results showed dcSSc patients tended to have significant deletions of DNA in certain regions of centromeres that weren’t observed in healthy cells or cells from lcSSc patients, regardless of whether they were using immunosuppressive treatments.
Most dcSSc patients (10 of 11) also exhibited aneuploidy, or an abnormal number of chromosomes, in some fibroblasts.
All patients showed other types of chromosomal abnormalities relative to healthy people, including in the formation of micronuclei. Micronuclei, formed outside of a cell’s nucleus, contain chromosomes (or their fragments) that failed to be properly incorporated into the nucleus during cell division.
A higher number of micronuclei was correlated with thicker skin, assessed with the modified Rodnan Skin Score, but “it remains to be determined whether the number of micronuclei found is related to overall disease severity,” the researchers wrote.
In most lcSSc samples, centromere proteins that normally reside in the nucleus, including one called CENPA, were instead found outside the nucleus in the cytoplasm. This mis-localization was only observed in lcSSc patients who tested positive for ACA antibodies. CENPA is one of the centromere proteins that ACAs target.
The membrane surrounding the nucleus in these patients’ fibroblasts may be leaky, allowing proteins that normally reside there to diffuse out. This leakage might drive immune responses leading to ACA production, the researchers hypothesized.
Fibroblasts from all SSc patients showed the activation of several fibrotic genes, indicative of fibrotic and inflammatory factors being produced, as well as signs of oxidative stress, a type of cellular damage that occurs when toxic free radicals outweigh the body’s antioxidant defenses.
Data also indicated the cGAS-STING pathway was activated in SSc cells. A surveillance pathway involved in immune responses, cGAS-STING was likely activated in response to the abnormal presence of proteins outside the nucleus, according to the researchers.
This suggests “a link between centromere alterations, chromosome instability, SSc autoimmunity, and fibrosis,” the researchers wrote, noting inhibiting the cGAS-STING pathway could offer therapeutic potential for SSc. Such therapies, “presently being developed to treat autoimmune diseases and cancer, may prove to be a viable treatment option for patients with SSc.”
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