Progression of Lung Fibrosis in Scleroderma May Be Predicted by Antibody-Specific T-cells

Immune T-cells induced by the autoantigen topoisomerase-I were linked to lung fibrosis and found to predict disease progression in scleroderma patients. The finding may open new avenues of research into treatments that selectively target the various tissue-specific disease manifestations of scleroderma — a substantial improvement to the nonselective immunosuppression used today.

In scleroderma, autoantibodies targeting specific structures are linked to various clinical representations of the disease. One such antibody against the enzyme topoisomerase-I, crucial for the winding and unwinding of DNA molecules during gene expression and cell divisions, is present in 20 percent to 45 percent of scleroderma patients and linked to diffuse skin disease and lung fibrosis. Patients with anti-topoisomerase-I antibodies also have more severe disease.

Despite these clear links, earlier studies demonstrated that blood levels of these antibodies cannot be used to predict disease activity and prognosis, suggesting that some other factor may explain the link between disease and topoisomerase-1.

Researchers at Johns Hopkins University School of Medicine, in a collaborative effort with those at the University of California, San Francisco, found this factor might be T-cells wrongfully reacting to topoisomerase-1.

An autoantigen is really a normal protein, just like the topoisomerase-1 enzyme, that the immune system starts attacking. T-cells, initially identifying the protein as a threat,  initiate a chain of events leading to the production of autoantibodies against this structure.

In the study, “Frequency of circulating topoisomerase-I-specific CD4 T cells predicts presence and progression of interstitial lung disease in scleroderma,“ published in the journal Arthritis Research & Therapy, the researchers measured T-cells specifically reacting to topoisomerase-I antigens in 27 scleroderma patients and 4 healthy individuals, and compared T-cell activities to clinical symptom findings.

T-cells reactive to the enzyme were present in all patients who had such antibodies, but were absent in the healthy controls. These cells were mainly of the inflammatory Th17 type.

The amount of circulating topo-I-specific T-cells was also higher in patients with lung fibrosis, and the proportion of these T-cells could predict fibrosis progression defined by the loss of lung volume. In contrast, the researchers could see no obvious relationship between the levels of the antibodies and the frequency of specific T-cells against the topoisomerase enzyme, indicating complex immune processes are at work in the activation of T-cells and the antibody production that follows.

In conclusion, measuring topo-I-specific responses might be a way to assess the efficacy of treatments, but such an application of the findings needs to be evaluated in future studies.