Tertiary lymphoid structures in pulmonary granulomas of cattle experimentally infected with aerosolized Mycobacterium bovis.

Abstract

Mycobacterium bovis is the primary cause of tuberculosis in animals, most notably cattle. In cattle and other susceptible hosts, the hallmark lesion of tuberculosis is the granuloma. Granulomas represent the host-pathogen interface where disease outcome is determined; therefore, it is critical to understand host-pathogen interactions at the granuloma level. Granulomas are highly structured lesions with distinct cellular compartments for T cells, macrophages, multinucleated giant cells, and B cells. A recognized but poorly understood morphologic feature of many granulomas is the presence of structures resembling follicular or germinal center-like arrangements of B cells known as tertiary lymphoid organs, or tertiary lymphoid structures. Pulmonary granulomas from cattle experimentally infected with M. bovis were collected at 15-, 30-, 90-, 180- and 270-days post-infection and examined for the presence of tertiary lymphoid-like structures. Follicle-like structures associated with granulomas were first seen 90 days after infection and persisted in later time points. Compartmentalization of T cells and B cells similar to follicles in germinal centers of lymph nodes was demonstrated using in situ hybridization. Additionally, the presence and arrangement of myeloid cells, endothelial cells, T follicular helper cells, and chemokines critical to tertiary lymphoid structure formation was shown to be similar to lymph node follicles and that described for tertiary lymphoid structures in other species. This represents the first demonstration by in situ hybridization of the similarities of follicle-like structures associated with pulmonary bovine tuberculous granulomas to tertiary lymphoid structures in other species and follicles within secondary lymphoid organs such as lymph nodes.