Background Tertiary lymphoid organs (TLOs) are organized clusters of immune cells that preferentially form in autoimmune diseases such as Sjogren's syndrome (SS). TLOs are believed to contribute to disease progression and lymphoma development in SS. Within TLOs, the ectopic expression of lymphoid chemokines has been shown to correlate with size/degree of organization of the lymphoid aggregates and with the production of autoantibodies (1,2). Recent observational studies in SS have proposed a relationship between IL22 expression, B cell infiltration and humoral autoimmunity (3,4,5), however they failed to provide a molecular mechanism for this relationship.
Objectives To investigate the functional role of IL22 in ectopic B cell recruitment and humoral autoimmunity during TLO formation.
Methods Inducible mouse model of TLO formation and autoantibody production by retrograde cannulation of the salivary glands with a replication deficient adenovirus (6) was used to assess the role of IL22 in vivo. Salivary glands of C57BL/6 mice (wildtype;WT) and knockout mice (IL22-/-) were cannulated and sacrificed at different time points post cannulation (p.c.) and analysed by immunofluorescence, flow cytometry and RT-PCR.
Results Virus cannulation of WT mice salivary glands leads to TLOs formation and autoantibody production. Increased expression of IL22 was found to occur within hours of salivary gland cannulation with different cell populations involved in its production. Surprisingly, Il22-/- mice and WT mice treated therapeutically with anti-IL22 antibody were characterized by profound defects in TLO maturation. Absence or blocking of IL22 impairs CXCL13 and CXCL12 production, resulting in reduced B cell accumulation within the TLOs and abolition of autoantibody production. IL22 exerts a differential effect depending on the target stromal cell in which IL22Rα is expressed. On igp38+ IL22Rα+ stromal cells, IL22 stimulation regulates CXCL13 expression, independently from but also in synergy with, TNFα and LTβ. Conversely, on epithelial cells, IL22Rα engagement increases CXCL12 production but not CXCL13. This effect is direct, as treatment of isolated stromal and epithelial cells with recombinant IL22 in vitro was sufficient to induce CXCL13 and CXCL12 production by gp38+ stromal cells and EPCAM+ epithelial cells respectively. This dual impairment in chemokine expression is responsible for the reduced B cell accumulation, aberrant follicle maturation and lack of autoantibody production observed in both KO and anti-IL22 treated.
Conclusions Here we describe for the first time the functional connection between expression of IL22, aberrant chemokine production and autoantibody response in TLO associated autoimmune diseases such as SS.
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Disclosure of Interest None declared