The mutation PTPN6Ala455Thrcausing pulmonary emphysema affects B cell populations and causes spontaneous pulmonary tertiary lymphoid tissue formation

Abstract

Abstract Rationale: A new mutation causing severe pulmonary emphysema was recently discovered in a French-Canadian family. The mutation is located in the PTPN6 gene (PTPN6 Ala455Thr) leading to a reduction in the activity of SHP-1, a phosphatase that regulates pathways associated to B cells. We aimed to characterize B cell abnormalities associated with aging in both humans and mice carrying this mutation. Methods: Circulating B cell populations in humans carrying the PTPN6Ala455Thrmutation were analyzed by flow cytometry and immunoglobulin levels were measured in serum. In mice carrying the same mutation (Ptpn6Ala457Thr) aged up to 12 months, B cell populations were analyzed by flow cytometry and lung tissue histology performed. Mice were immunized with the T cell-independent antigen and NP-specific antibodies were measured in plasma. Results: Human carriers of the PTPN6Ala455Thrmutation had reduced IgG1 and IgG4, and increased IgG3 levels as well as a lower ratio of naive B cells/ isotype switched memory B cells compared to controls. Aging Ptpn6Ala457Thrmice developed spontaneous pulmonary tertiary lymphoid tissues and exhibited higher proportion of B-1 cells, age-associated B cells and germinal center B cells along with lower B-2 cells in the lung and spleen. Ptpn6Ala457Thrmice had lower levels of NP-specific IgG1 antibodies compared to the wild-type group. Conclusion: SHP-1 appears to affect aging of B cells as the PTPN6Ala455Thrmutation leads to changes in B cell populations associated with age, tertiary lymphoid tissue formation and an alteration of immunoglobulin levels. The link between B cell abnormalities, aging and emphysema requires further investigation. Funding:CIHR, FRQS CIHR, FRQS