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Stanford Team Uses Immune Repertoire Sequencing to ID Signature in Rare Autoimmune Disease

NEW YORK (GenomeWeb) – A Stanford University research team has used immune repertoire sequencing to identify disease-related signatures in the immune systems of patients with systemic sclerosis with pulmonary hypertension (SSc-PAH), a rare chronic autoimmune disease that affects the connective tissue and is often lethal.

The researchers published the results this week in Science Immunology and wrote in the study that the work would help to better understand the immune repertoire of systemic sclerosis patients and in particular the impact of treatment on the B cell repertoire.

In the study, the researchers analyzed 11 patients who were taking part in a clinical trial evaluating the use of rituximab to treat SSc-PAH, evaluating multiple longitudinal samples from each patient. Because the clinical trial was double-blinded, the researchers were also blinded to whether a given patient was receiving rituximab or not.

In total, the team analyzed the B cell repertoire of 85 samples from patients, all women, who received either a placebo or rituximab at the beginning of the trial and two weeks later, as well as from 15 controls.

Although the researchers did not know whether it was the patients in study arm A or study arm B who received treatment, sequencing uncovered clear differences in the immune repertoire of the two arms and also between the patients and healthy controls.

The researchers targeted the immunoglobulin heavy chain region of the patients' B cells and compared the sequences of patients with healthy controls. Overall, they found that SSc-PAH patients had lower B cell receptor diversity but higher immunoglobulin D diversity. In addition, they found that patients had elevated proportions of both naïve and antigen-specific B cell receptors, suggesting a "sustained immune response against self antigens," according to the paper.

Looking deeper, they also found that the average expression of specific B cell receptors was higher in the disease group. In addition, certain genes were underutilized in the disease cohort, notably IGHV2-5.

Looking at the two study arms, the researchers could clearly see differences that appeared to indicate which group received rituximab and which received the placebo. Rituximab is a B cell depleting therapy and the individuals of one group had signs of reduced levels of B cells and B cell receptor diversity. In addition, in samples analyzed post treatment, the researchers identified a reduction in the abnormalities associated with SSc-PAH — for instance, the usage of the IGHV2-5 gene was restored in the treatment group.

The authors added that the results are preliminary, involved a small number of patients, and did not include an analysis of clinical outcomes. Nonetheless, the findings help shed light on the "basic science of the immune repertoire of SSc patients and the immune repertoire response" to rituximab, they wrote, which could potentially be used to further understand the therapeutic response mechanism and eventually enable researchers to predict which patients will respond.