Developmental stages of tertiary lymphoid tissue reflect local injury and inflammation in mouse and human kidneys

Abstract

Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues in chronic inflammatory states and function as sites of priming local immune responses. We previously demonstrated that aged but not young mice exhibited multiple TLTs after acute kidney injury and that TLTs were also detected in human aged and diseased kidneys. However, the forms of progression and the implication for kidney injury remain unclear. To clarify this we analyzed surgically resected kidneys from aged patients with or without chronic kidney disease as well as kidneys resected for pyelonephritis, and classified TLTs into three distinct developmental stages based on the presence of follicular dendritic cells and germinal centers. In injury-induced murine TLT models, the stages advanced with the extent of kidney injury, and decreased with dexamethasone accompanied with improvement of renal function, fibrosis and inflammation. Kidneys from aged patients with chronic kidney disease consistently exhibited more frequent and advanced stages of TLTs than those without chronic kidney disease. Kidneys of patients with pyelonephritis exhibited more frequent TLTs with more advanced stages than aged kidneys. Additionally, TLTs in both cohorts shared similar locations and components, suggesting that TLT formation may not be a disease-specific phenomenon but rather a common pathological process. Thus, our findings provide the insights into biological features of TLT in the kidney and implicate TLT stage as a potential marker reflecting local injury and inflammation. Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues in chronic inflammatory states and function as sites of priming local immune responses. We previously demonstrated that aged but not young mice exhibited multiple TLTs after acute kidney injury and that TLTs were also detected in human aged and diseased kidneys. However, the forms of progression and the implication for kidney injury remain unclear. To clarify this we analyzed surgically resected kidneys from aged patients with or without chronic kidney disease as well as kidneys resected for pyelonephritis, and classified TLTs into three distinct developmental stages based on the presence of follicular dendritic cells and germinal centers. In injury-induced murine TLT models, the stages advanced with the extent of kidney injury, and decreased with dexamethasone accompanied with improvement of renal function, fibrosis and inflammation. Kidneys from aged patients with chronic kidney disease consistently exhibited more frequent and advanced stages of TLTs than those without chronic kidney disease. Kidneys of patients with pyelonephritis exhibited more frequent TLTs with more advanced stages than aged kidneys. Additionally, TLTs in both cohorts shared similar locations and components, suggesting that TLT formation may not be a disease-specific phenomenon but rather a common pathological process. Thus, our findings provide the insights into biological features of TLT in the kidney and implicate TLT stage as a potential marker reflecting local injury and inflammation. see commentary on page 280 see commentary on page 280 Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues that are formed under various pathologic conditions such as autoimmunity and infection.1Sato Y. Yanagita M. Immunology of aging kidney.Nat Rev Nephrol. 2019; 15: 625-640Crossref PubMed Scopus (20) Google Scholar, 2Pitzalis C. Jones G.W. Bombardieri M. Jones S.A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity.Nat Rev Immunol. 2014; 14: 447-462Crossref PubMed Scopus (348) Google Scholar, 3Neyt K. Perros F. GeurtsvanKessel C.H. Hammad H. Lambrecht B.N. Tertiary lymphoid organs in infection and autoimmunity.Trends Immunol. 2012; 33: 297-305Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar TLTs are composed of a hematopoietic compartment, which comprises mostly T and B cells, and stromal components, in particular fibroblasts. The basic functions of TLTs are similar to those of secondary lymphoid organs such as lymph nodes.1Sato Y. Yanagita M. Immunology of aging kidney.Nat Rev Nephrol. 2019; 15: 625-640Crossref PubMed Scopus (20) Google Scholar, 2Pitzalis C. Jones G.W. Bombardieri M. Jones S.A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity.Nat Rev Immunol. 2014; 14: 447-462Crossref PubMed Scopus (348) Google Scholar, 3Neyt K. Perros F. GeurtsvanKessel C.H. Hammad H. Lambrecht B.N. Tertiary lymphoid organs in infection and autoimmunity.Trends Immunol. 2012; 33: 297-305Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar TLTs have the potential to initiate adaptive immune responses and produce large amounts of proinflammatory cytokines. Additionally, some TLTs develop germinal centers, unique structures in which B cells proliferate rapidly and undergo class switching, resulting in the generation of antibody-secreting plasma cells. Besides these functional similarities, TLTs and secondary lymphoid organs also rely on related molecules for their development, including the homeostatic CXC chemokine ligand 13 (CXCL13) and retinoic acid.1Sato Y. Yanagita M. Immunology of aging kidney.Nat Rev Nephrol. 2019; 15: 625-640Crossref PubMed Scopus (20) Google Scholar, 2Pitzalis C. Jones G.W. Bombardieri M. Jones S.A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity.Nat Rev Immunol. 2014; 14: 447-462Crossref PubMed Scopus (348) Google Scholar, 3Neyt K. Perros F. GeurtsvanKessel C.H. Hammad H. Lambrecht B.N. Tertiary lymphoid organs in infection and autoimmunity.Trends Immunol. 2012; 33: 297-305Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 4Ansel K.M. Ngo V.N. Hyman P.L. et al.A chemokine-driven positive feedback loop organizes lymphoid follicles.Nature. 2000; 406: 309-314Crossref PubMed Scopus (923) Google Scholar, 5van de Pavert S.A. Oliver B.J. Goverse G. et al.Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation.Nat Immunol. 2009; 10: 1193-1199Crossref PubMed Scopus (206) Google Scholar The role of TLT in the host organ is context-dependent and can be beneficial or detrimental.1Sato Y. Yanagita M. Immunology of aging kidney.Nat Rev Nephrol. 2019; 15: 625-640Crossref PubMed Scopus (20) Google Scholar, 2Pitzalis C. Jones G.W. Bombardieri M. Jones S.A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity.Nat Rev Immunol. 2014; 14: 447-462Crossref PubMed Scopus (348) Google Scholar, 3Neyt K. Perros F. GeurtsvanKessel C.H. Hammad H. Lambrecht B.N. Tertiary lymphoid organs in infection and autoimmunity.Trends Immunol. 2012; 33: 297-305Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar In patients with rheumatoid arthritis, for instance, multiple TLTs develop in the synovium and generate pathogenic autoantibodies such as anti-cyclic citrullinated protein → peptide antibodies, which are used as a specific, diagnostic, and prognostic marker of rheumatoid arthritis.6Nielen M.M. van der Horst A.R. van Schaardenburg D. et al.Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis.Ann Rheum Dis. 2005; 64: 1199-1204Crossref PubMed Scopus (156) Google Scholar, 7Avouac J. Gossec L. Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review.Ann Rheum Dis. 2006; 65: 845-851Crossref PubMed Scopus (363) Google Scholar, 8Humby F. Bombardieri M. Manzo A. et al.Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium.PLoS Med. 2009; 6: e1Crossref PubMed Scopus (305) Google Scholar, 9Ge C. Tong D. Liang B. et al.Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage.JCI Insight. 2017; 2: 93688Crossref PubMed Scopus (26) Google Scholar In contrast, during infections, TLTs are induced as an integral part of anti-pathogen immunity at local site, though a failure to eradicate a pathogen can lead to the development of autoimmunity. In a previous study, we found that aged but not young mice developed multiple renal TLTs after acute kidney injury.10Sato Y. Mii A. Hamazaki Y. et al.Heterogeneous lymphoid tissues in the Insight. PubMed Scopus Google Scholar TLTs a of renal and inflammation. The TLT with renal function and of proinflammatory such as and Y. Mii A. Hamazaki Y. et al.Heterogeneous lymphoid tissues in the Insight. PubMed Scopus Google Scholar Additionally, of cells as well as dexamethasone TLT formation and renal Y. Mii A. Hamazaki Y. et al.Heterogeneous lymphoid tissues in the Insight. PubMed Scopus Google Scholar these not we that formation of TLTs in the diseased kidneys for the Y. Mii A. Hamazaki Y. et al.Heterogeneous lymphoid tissues in the Insight. PubMed Scopus Google Y. Yanagita M. in the a of fibrosis and 2017; PubMed Scopus Google Scholar TLTs were also detected in aged human with a similar to those of Y. Mii A. Hamazaki Y. et al.Heterogeneous lymphoid tissues in the Insight. PubMed Scopus Google Scholar In to aged human TLTs were in kidneys of patients with J. et and of in and Full Text Full Text PDF PubMed Scopus Google Scholar renal J. et in chronic for a local A. 2005; PubMed Scopus Google D. The role of lymphoid in PubMed Scopus Google Scholar and in G. M. et and lymphoid organ in Nephrol. 2014; PubMed Scopus Google Scholar However, the of TLTs in human kidney is D. B cells and lymphoid organs in renal Full Text Full Text PDF PubMed Scopus Google Scholar and is on their in and of the for this may be that of the of renal TLT on a of patients or TLTs from kidney which not be to renal In though renal an in the of kidney and prognostic of such as A. et prognostic value of in kidney from the Nephrol. PubMed Scopus Google Scholar the of renal is to chronic kidney disease of the for such as is that the of TLTs our of the of TLTs in human kidneys. TLTs develop a that to their Y. Yanagita M. Immunology of aging kidney.Nat Rev Nephrol. 2019; 15: 625-640Crossref PubMed Scopus (20) Google Scholar, 2Pitzalis C. Jones G.W. Bombardieri M. Jones S.A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity.Nat Rev Immunol. 2014; 14: 447-462Crossref PubMed Scopus (348) Google Scholar, 3Neyt K. Perros F. GeurtsvanKessel C.H. Hammad H. Lambrecht B.N. Tertiary lymphoid organs in infection and autoimmunity.Trends Immunol. 2012; 33: 297-305Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar The and of TLTs and their developmental stages a for of TLTs in human kidneys. To the extent of TLT not in human and the the and disease also unclear. In this study, we analyzed surgically resected human kidney from patients with pyelonephritis, infection is a of TLT development in various Y. Yanagita M. Immunology of aging kidney.Nat Rev Nephrol. 2019; 15: 625-640Crossref PubMed Scopus (20) Google Scholar, 2Pitzalis C. Jones G.W. Bombardieri M. Jones S.A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity.Nat Rev Immunol. 2014; 14: 447-462Crossref PubMed Scopus (348) Google Scholar, 3Neyt K. Perros F. GeurtsvanKessel C.H. Hammad H. Lambrecht B.N. Tertiary lymphoid organs in infection and autoimmunity.Trends Immunol. 2012; 33: 297-305Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar and found multiple TLTs developed in human pyelonephritis kidneys. with the from aged patients and the aged murine we have Y. Mii A. Hamazaki Y. et al.Heterogeneous lymphoid tissues in the Insight. PubMed Scopus Google Scholar we provide that TLT formation is a common pathogenic that distinct developmental stages of we a for TLTs in human kidneys based on the developmental stages and that the TLT stages were with the of kidney injury in mice and and be after TLTs into advanced is a of TLT development in various Y. Yanagita M. Immunology of aging kidney.Nat Rev Nephrol. 2019; 15: 625-640Crossref PubMed Scopus (20) Google Scholar, 2Pitzalis C. Jones G.W. Bombardieri M. Jones S.A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity.Nat Rev Immunol. 2014; 14: 447-462Crossref PubMed Scopus (348) Google Scholar, 3Neyt K. Perros F. GeurtsvanKessel C.H. Hammad H. Lambrecht B.N. Tertiary lymphoid organs in infection and autoimmunity.Trends Immunol. 2012; 33: 297-305Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar but TLTs in human kidneys not To we of kidneys surgically of The features of these patients are in We that kidneys of the patients with pyelonephritis exhibited and with and in some acute pyelonephritis with of of which are findings in B. of chronic Dis. Full Text Full Text PDF PubMed Scopus Google B. of acute Dis. 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