Abstract

The presence of Ig deposits and tertiary lymphoid tissues (tLTs) connected to remodeled vessels in PAH lungs suggests lymphoid neogenesis as a critical step in maintaining immunity against local autoantigens. We searched for an immune signature in the lung and peripheral blood of PAH patients. T cell repertoire of 26 patients with iPAH, hPAH or PVOD (11 transplanted) and 24 controls were analyzed in peripheral purified CD4+ T cells and after laser-microdissection of perivascular tLTs. Genomic detection of T cell receptor (TCR) rearrangements by multiplex PCR on the TCR loci was used for exhaustive analysis of the combinatorial diversity of immune repertoires. Using advanced pattern recognition algorithms and statistics we identified 6 rearrangements that best discriminate patients and controls using peripheral blood samples, with an accuracy of 82%. One of these rearrangements was the most contributive to the signature (p<0.0035, Chi-square test), and 3 rearrangements were associated to the presence of circulating autoantibodies. Whereas repertoire diversity was preserved in the periphery, it was highly restricted and expanded in tLTs. This was also confirmed in a retrospective validation set of 10 cases from our tissue bank. Further analysis in the overall lung cases (n=21), revealed a set of 6 rearrangements that showed expansion in about 70% of lung cases, whatever the PH subtype, suggesting a local immune response with a public repertoire usage. Other highly expanded rearrangements in less cases or individual cases may represent a more private repertoire. These immune signatures provide additional clues for local autoimmunity in PAH, that could be further exploited for future biomarkers of PH condition