Immune T-cells may damage tissue, cause relapse in PR3-associated AAV
Specific inflammatory T-cells found in kidneys of patient group with active disease
Immune T-cells positive for the GPR56 receptor protein — a marker for cell-killing immune cells — may contribute to local tissue damage in ANCA-associated vasculitis (AAV) patients whose disease is associated with antibodies against the proteinase 3 (PR3) protein, a study showed.
Notably, these cells were more likely to launch an inflammatory attack against the PR3 protein, and they showed a specific receptor repertoire that was shared by several patients with early relapse activity.
The finding “encourages us to explore the possibility of T cell screening … which could identify individuals at high risk for disease relapse,” Ravi Kumar, PhD, the study’s first author and a postdoctoral researcher at the Karolinska Institutet in Sweden, said in an institute press release.
The study, “Identification of proteinase 3 autoreactive CD4+T cells and their T-cell receptor repertoires in anti-neutrophil cytoplasmic antibodies associated vasculitis,” was published in Kidney International.
Anti-PR3 antibodies mostly linked to GPA, AAV type with higher relapse risk
AAV is caused by inflammation in small blood vessels that damages organs, especially the vessel-rich kidneys. This inflammation is thought to be driven mainly by self-targeting antibodies, called anti-neutrophil cytoplasmic autoantibodies (ANCAs).
Antibodies are proteins produced by immune B-cells that are able to stick to a particular molecular target with extreme specificity. When an antibody binds to its target, it triggers the immune system to attack that target.
ANCAs typically target one of two proteins — proteinase 3 or myeloperoxidase — in neutrophils, a type of immune cell, promoting their aberrant activation. Notably, anti-PR3 antibodies are mostly found in people with granulomatosis with polyangiitis (GPA), a type of AAV typically linked to a higher risk of relapse.
While the role of ANCAs in AAV is well characterized, less is understood about how other parts of the immune system, such as T-cells, are involved in the disease.
T-cells are immune cells equipped with a specialized protein receptor, known as a T-cell receptor or TCR. Similar to antibodies, a given TCR can bind to a specific molecular target with high specificity, and in binding to its target, the TCR triggers the T-cell to go on the offensive.
A team led by researchers at Karolinska Institutet analyzed the role of T-cells producing GPR56, a cytotoxicity marker, in 72 people with PR3-associated GPA. Cytotoxicity refers to the ability of certain chemicals or mediator cells, such as T-cells, to kill living cells.
Initial work found that T-cells positive for this receptor protein also produced high levels of other cytotoxicity-associated proteins like perforin.
Blood levels of T-cells producing GPR56 and other cytotoxicity markers tended to be lower in patients with active disease and higher in those in remission.
This finding was “most likely impacted by several factors, including the different immunosuppressive treatment regimens and/or migration of T cells to sites of inflammation during active disease,” the researchers wrote.
The latter hypothesis was supported by kidney biopsy findings from seven patients with active disease, as well as follow-up biopsies from four of the patients once they were in therapy-induced remission. Results showed that GPR56-positive T-cells were only found in the kidneys of patients during active disease.
During active disease, GPR56-positive inflammatory T-cells likely migrate to the kidneys to cause organ damage, so fewer of the cells are detectable in the blood. This suggests these cells contribute to “local tissue destruction, which may reveal previously unrecognized disease mechanisms,” Kumar said.
GPR56-positive T-cells more likely to attack PR3 protein than viral protein
Additional experiments demonstrated that GPR56-positive T-cells from GPA patients were more likely to launch an inflammatory attack against PR3 protein than against a viral protein.
In 17 out of 23 patients, only GPR56-positive T-cells — and no other T-cell populations — had an inflammatory response to PR3. By contrast, in most patients, T-cells both with and without GPR56 positivity responded to a viral protein.
A subsequent analysis of the TCR repertoire of T-cells that responded to PR3 showed that “AAV patients share [self-targeting] TCR sequences, whereas the TCRs differ when comparing PR3- and [virus]-responsive TCRs,” the team wrote.
Notably, three of four patients with these shared TCRs had early relapse activity, suggesting that “screening for T cells has a potential for diagnostic value in predicting relapse,” the researchers wrote, stressing that further research is necessary to validate and expand the findings.
“We suggest that the continuous investigation of functional aspects of [self-targeting] T cells, in … blood, affected kidneys and possibly in urine can have direct impact on clinical challenges in the management of GPA including prediction of response to therapy and risk of relapse,” the team added.
As a next step, the team plans to “find clinical utility of assays to detect these self-reactive T cells and their role in disease [development] using both patient samples, and human [TCR-based animal models],” Kumar said.
“In the longer perspective, future therapies can be aimed at specific depletion of such T cells or re-educating the immune system by designing [PR3-based] vaccines,” Kumar added.
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