TGF-β upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-α heterozygous mice

Kelly, F. M.; Reddy, Ramesh N.; Roberts, Brian R.; Gangappa, Shivaprakash; Williams, Ifor R.; Gooch, Jennifer

doi:10.1152/ajprenal.90629.2008

Cited by 13 publications

(8 citation statements)

References 26 publications

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“…TLOs contained all of the essential elements for a local immune response and thus might play a role in IgAN progression (23,29,30). Kelly et al revealed that renal TLO neogenesis was associated with matrix accumulation and loss of renal function in a mouse model (31). In our study, we found that high-grade TLOs were significantly associated with an elevated level of serum creatinine and severe glomerular, interstitial, and arterial lesions.…”

Section: Discussionsupporting

confidence: 57%

Renal Interstitial Infiltration and Tertiary Lymphoid Organ Neogenesis in IgA Nephropathy

Pei

Zeng

Han

et al. 2014

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Previous studies have identified inflammatory features that enable the prediction of renal outcome of IgA nephropathy (IgAN); however, validation of these findings is still needed. This prospective study was performed to determine the characteristics of renal interstitial infiltration and tertiary lymphoid organ (TLO) neogenesis in a cohort of Chinese patients with IgAN.Design, setting, participants, & measurements Adult patients with IgAN were recruited into this study from June 2009 to June 2010. Inflammatory cells in renal biopsy tissues were detected by immunohistochemistry and immunofluorescence. Correlations between the density of interstitial inflammatory cells, grades of TLOs, and clinicopathologic features were evaluated. Of 152 eligible patients, 72 (47%) were successfully followed-up by telephone at 30 months after renal biopsy. Twelve patients were classified as the severe group and 60 patients were classified as the stable group, according to the progression of serum creatinine levels during the follow-up period. A comparison of the severity of interstitial infiltration and the frequency of TLO neogenesis between the two groups was performed.Results The accumulation of interstitial inflammatory cells was correlated with decreased renal function, heavy proteinuria, and severe glomerular, interstitial, and arterial lesions in patients with IgAN. TLOs, identified as nodular inflammatory infiltrates containing organized DC-SIGN + , CD4 + , CD8 + , and CD20 + cells, were observed in 37.5% of patients. Patients with high-grade TLOs exhibited a high percentage of mesangial hypercellularity and crescents as well as severe interstitial and arterial lesions. Patients in the severe group exhibited more severe interstitial infiltration and a higher percentage of TLO neogenesis (83.3% versus 33.3%; P=0.001) compared with patients in the stable group.Conclusions As contributors to an active local inflammatory response, the severity of interstitial infiltration and the frequency of TLO neogenesis are correlated with glomerular, interstitial, and arterial lesions as well as IgAN progression.

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Section: Discussionsupporting

confidence: 57%

Renal Interstitial Infiltration and Tertiary Lymphoid Organ Neogenesis in IgA Nephropathy

Pei

Zeng

Han

et al. 2014

Clinical Journal of the American Society of Nephrology

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“…The histological findings of renal TLO formed by infiltrating CD20+ and CD4+ cells support the hypothesis of T helper involvement in physiopathology of IgG4-RD [ 10 ]. The high urinary excretion rate of the active form of TGF-β1 measured in our patient is reported to be crucial for maintaining TLO structure and CD4+ cells activation and plays a role in chronic inflammation and renal fibrosis [ 11 ].…”

Section: Discussionsupporting

confidence: 68%

Azathioprine as successful maintenance therapy in IgG4-related tubulointerstitial nephritis

Pozdzik

Brochériou

Demetter

et al. 2012

Clinical Kidney Journal

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A 65-year-old man presented with a progressive increase in plasma creatinine (PCr). Two years before, diffusion-weighted magnetic resonance imaging had revealed a relapse of immunoglobulin G4 (IgG4)-related autoimmune pancreatitis (AIP) associated with sclerosing cholangitis. Bilateral hypointense renal cortical nodules were also described. Kidney biopsy showed patchy disappearance of tubules, sparse interstitial fibrosis and IgG4+ plasma cells (>30 per high power field) leading to the diagnosis of IgG4-related tubulointerstitial nephritis (TIN). Despite methylprednisolone, PCr and serum IgG4 levels remained elevated. Starting azathioprine (AZA) normalized IgG4 levels, which elicited corticosteroid withdrawal after 17 months. One year later, renal function remains stable. Our clinical observation underlines the importance of biological and radiological long-term follow-up of patients with previous AIP in order to early detect IgG4-related renal involvement. Corticosteroids are the first choice, but in the case of adverse effects or partial remission, AZA could be a useful and safe alternative therapy.

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“…The increase in spleen size is likely due to an expansion of B cells and stromal cells as we reported previously in aged CnAα+/− mice [21]. It is unclear what cell type is responsible for changes in the spleen or if there are any significant phenotypic consequences as a result.…”

Section: Discussionmentioning

confidence: 57%

Nutritional Intervention Restores Muscle but Not Kidney Phenotypes in Adult Calcineurin Aα Null Mice

et al. 2013

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Mice lacking the α isoform of the catalytic subunit of calcineurin (CnAα) were first reported in 1996 and have been an important model to understand the role of calcineurin in the brain, immune system, bones, muscle, and kidney. Research using the mice has been limited, however, by failure to thrive and early lethality of most null pups. Work in our laboratory led to the rescue of CnAα−/− mice by supplemental feeding to compensate for a defect in salivary enzyme secretion. The data revealed that, without intervention, knockout mice suffer from severe caloric restriction. Since nutritional deprivation is known to significantly alter development, it is imperative that previous conclusions based on CnAα−/− mice are revisited to determine which aspects of the phenotype were attributable to caloric restriction versus a direct role for CnAα. In this study, we find that defects in renal development and function persist in adult CnAα−/− mice including a significant decrease in glomerular filtration rate and an increase in blood urea nitrogen levels. These data indicate that impaired renal development we previously reported was not due to caloric restriction but rather a specific role for CnAα in renal development and function. In contrast, we find that rather than being hypoglycemic, rescued mice are mildly hyperglycemic and insulin resistant. Examination of muscle fiber types shows that previously reported reductions in type I muscle fibers are no longer evident in rescued null mice. Rather, loss of CnAα likely alters insulin response due to a reduction in insulin receptor substrate-2 (IRS2) expression and signaling in muscle. This study illustrates the importance of re-examining the phenotypes of CnAα−/− mice and the advances that are now possible with the use of adult, rescued knockout animals.

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TGF-β upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-α heterozygous mice

Cited by 13 publications

References 26 publications

Renal Interstitial Infiltration and Tertiary Lymphoid Organ Neogenesis in IgA Nephropathy

Renal Interstitial Infiltration and Tertiary Lymphoid Organ Neogenesis in IgA Nephropathy

Azathioprine as successful maintenance therapy in IgG4-related tubulointerstitial nephritis

Nutritional Intervention Restores Muscle but Not Kidney Phenotypes in Adult Calcineurin Aα Null Mice

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