ABSTRACT
Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)ßR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTα1ß2/LTßR pathway in TLS-associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis.
Subject(s)
Interleukin-7/metabolism , Lymphangiogenesis , Lymphatic Vessels/immunology , Lymphotoxin alpha1, beta2 Heterotrimer/immunology , Lymphotoxin alpha1, beta2 Heterotrimer/metabolism , Tertiary Lymphoid Structures/immunology , Animals , Gene Expression Regulation , Inflammation , Interleukin-7/genetics , Interleukin-7/immunology , Lymphatic Vessels/metabolism , Lymphotoxin alpha1, beta2 Heterotrimer/genetics , Mice , Salivary Glands/immunology , Signal Transduction/genetics , Signal Transduction/immunology , Tertiary Lymphoid Structures/pathologyABSTRACT
Children who suffer with cerebral palsy (CP) have a significant chance of developing scoliosis during their early years and adolescence. The behavior of this scoliosis is closely associated with the severity of the CP disability and unlike idiopathic scoliosis, it continues to progress beyond skeletal maturity. Conservative measures may slow the progression of the curve, however, surgery remains the only definitive management option. Advances in surgical technique over the last 50 years have provided methods to effectively treat the deformity while also reducing complication rates. The increased risk of surgical complications with these complex patients make decisions about treatment challenging, however with careful pre-operative optimization and post-operative care, surgery can offer a significant improvement in quality of life. This review discusses the development of scoliosis in CP patient, evaluates conservative and surgical treatment options and assesses post-operative outcome.
ABSTRACT
The series of events leading to tertiary lymphoid organ (TLO) formation in mucosal organs following tissue damage remain unclear. Using a virus-induced model of autoantibody formation in the salivary glands of adult mice, we demonstrate that IL-22 provides a mechanistic link between mucosal infection, B-cell recruitment, and humoral autoimmunity. IL-22 receptor engagement is necessary and sufficient to promote differential expression of chemokine (C-X-C motif) ligand 12 and chemokine (C-X-C motif) ligand 13 in epithelial and fibroblastic stromal cells that, in turn, is pivotal for B-cell recruitment and organization of the TLOs. Accordingly, genetic and therapeutic blockade of IL-22 impairs and reverses TLO formation and autoantibody production. Our work highlights a critical role for IL-22 in TLO-induced pathology and provides a rationale for the use of IL-22-blocking agents in B-cell-mediated autoimmune conditions.
