Aggregates of lymphocytes and stromal cells known as tertiary lymphoid structures (TLSs) form in peripheral tissues and contribute to autoantibody production and pathology in autoimmune diseases such as primary Sjögren syndrome (pSS). Insight into the mechanism by which TLSs form in pSS is raising hope that this process could one day be targeted therapeutically.

Credit: Stuart Miles/Alamy Stock Photo

“We believed that this process was driven, within the TLS, by the presence of ‘immunofibroblasts’, a population of non-haematopoietic stromal cells that are capable of supporting both B and T lymphocyte survival, migration, activation and proliferation and that have similar functional properties to the stromal fibroblasts described in secondary lymphoid organs,” explains co-corresponding author Francesca Barone.

On the basis of this belief, Barone and colleagues examined TLSs from patients with pSS, which contained podoplanin-positive fibroblasts that expressed molecules related to either lymphocyte survival within TLSs or to TLS organization. In vitro, these ‘immunofibroblasts’ proliferated and upregulated cell adhesion molecules in response to IL-22 and IL-13, respectively.

Using a viral infection model of pSS in various types of knockout mice, the researchers unravelled the precise mechanisms by which these immunofibroblasts participate in TLS formation. Activation and proliferation of immunofibroblasts preceded the infiltration of lymphocytes into tissues, was indispensable for TLS formation and was controlled by both IL-13 and IL-22. “Interestingly these cytokines are very different from the signalling programme that drives the formation of secondary lymphoid organs,” notes Barone.

proliferation of immunofibroblasts preceded the infiltration of lymphocytes into tissues

“Blocking these cytokines, or eliminating the immunofibroblasts in vivo, was sufficient to disrupt TLSs,” states co-corresponding author Mark Coles. “This is particularly important because drugs targeting these two different cytokines have already been developed for other inflammatory conditions, thus can be repurposed for TLS-associated pathologies.”