Autoimmune responses may play role in ocular sarcoidosis: Study
Such responses, against healthy proteins in eye, may drive inflammation
Autoimmune responses against healthy proteins in the retina, which is the back of the eye, could play a role in driving a type of eye inflammation called uveitis in people with ocular sarcoidosis, per a new study.
According to the researchers, self-reactive antibodies against the retina were found more often in sarcoidosis patients with uveitis than in those without it. Additional experiments by the team, from Erasmus MC University Medical Center Rotterdam in the Netherlands, identified possible targets of these antibodies, namely the piccolo presynaptic cytomatrix protein, or PCLO, and other immune processes that might be involved.
Overall, the findings suggest “a link to autoimmune processes” in the development of sarcoidosis-related uveitis, or sarcoid uveitis, the researchers wrote.
The study, “Anti-retinal immune response in sarcoid uveitis: A potential role for PCLO as an antigenic target,” was published in the Journal of Autoimmunity.
Researchers analyzed blood samples from over 90 patients
Sarcoidosis is characterized by granulomas, or small clusters of inflammatory immune cells, that can accumulate in various tissues throughout the body.
As many as 50% of sarcoidosis patients have granulomas in the eyes and are therefore classified as having ocular sarcoidosis. A common manifestation of ocular sarcoidosis is uveitis, or inflammation of the uvea, which is the middle layer of the eye responsible for blood supply to the retina.
Exactly how sarcoidosis arises isn’t known, but some evidence suggests that autoimmune responses, in which the immune system mistakenly attacks healthy parts of the body, may be involved.
Genetic variants linked to immune function and autoimmunity have been associated with an increased risk of sarcoidosis-related uveitis. Moreover, some small studies have anecdotally reported the presence of anti-retinal antibodies, or ARAs, in people with sarcoidosis, regardless of uveitis.
ARAs are a type of self-reactive antibody that attacks the retina, the light-sensitive tissue at the back of the eye that sends signals to the brain to enable vision.
To learn more about a possible autoimmune component to sarcoidosis-related uveitis, the researchers analyzed blood samples from 91 sarcoidosis patients — 46 with uveitis and 45 without it — and 60 healthy people from a previous study.
The results showed that ARAs were definitively detected in the blood of more than half of the sarcoidosis patients with uveitis (52%). This was a significantly higher frequency relative to patients without uveitis, where it was detected in 22% of the individuals, and among healthy controls, where it was found in 17%.
Further experiments in patients with uveitis identified three retinal proteins as possible targets of these self-reactive antibodies: activin A receptor type 2b, known as ACVR2B; Golgin A4, called GOLGA4; and PCLO.
ACVR2B and GOLGA4 are found in a wide range of tissues, while PCLO is more specifically found in just a few, including those of the retina. PCLO is involved in transporting proteins, and its loss in animal models leads to retinal problems. As such, the researchers further explored its possible role in sarcoidosis-associated uveitis.
The team found that sarcoidosis patients testing positive for ARAs had significantly higher levels of self-reactive antibodies against PCLO than those without ARAs. However, there was no difference in anti-PCLO antibody levels based on whether sarcoidosis patients had uveitis or not.
Self-reactive antibodies seen in more ocular sarcoidosis patients with uveitis
Analyses of immune cells from three patients with uveitis showed the presence, in all three, of immune T-cells specifically primed to react against PCLO.
It remains unclear whether self-reactive ARAs, or specifically anti-PCLO antibodies, occur in ocular sarcoidosis as a consequence of retinal damage or if they are initiators of the damaging inflammation that marks the disease.
Importantly, none of the patients without uveitis but testing positive for anti-PCLO antibodies developed the condition over a 3.5-year follow-up, the study found. That suggests, according to the team, that these antibodies on their own are not enough to drive uveitis. However, “their role … remains unknown,” the researchers wrote.
Further analyses revealed distinct immune T-cell and B-cell populations between ARA-positive and ARA-negative patients. These populations differed in the genetic sequences that inform which specific proteins they will recognize, and the ones to which they will respond.
The scientists hypothesized that some of these immune cells may have been primed to respond to environmental triggers, such as infectious agents, but become abnormally reactive to healthy retinal protein, driving eye inflammation in sarcoidosis.
Our study provides important insights into the pathogenesis [disease development] of sarcoidosis … and indicates that an anti-retinal autoimmune response plays a role in at least [some] … patients.
Further research into the specific targets of these immune cell populations “may link past infections to SU [sarcoid uveitis] development, offering critical insights into disease mechanisms,” the researchers noted.
“Our study provides important insights into the pathogenesis [disease development] of sarcoidosis/SU and indicates that an anti-retinal autoimmune response plays a role in at least [some] … patients,” the researchers wrote.
Among the study’s limitations, the team noted that the analyses were done in blood samples instead of eye tissue or fluid, which may be enriched in PCLO-reactive immune cells.
“Investigating PCLO-reactive [T-cells] in [eye fluid] of patients with SU and their correlation with anti-PCLO [self-reactive antibody] levels is of interest in a future study,” the researchers wrote.
Future long-term studies could also help better identify the most relevant immune components involved in sarcoidosis or sarcoid uveitis, the team noted.
About the Author
