Atypical IgM on T cells predict relapse and steroid dependence in idiopathic nephrotic syndrome

Colucci, Manuela; Carsetti, Rita; Rosado, Maria Manuela; Cascioli, Simona; Bruschi, Maurizio; Candiano, Giovanni; Corpetti, Giorgia; Giardino, Laura; Serafinelli, Jessica; Giannone, Chiara; Rastaldi, Maria Pia; Sitia, Roberto; Emma, Francesco; Vivarelli, Marina

doi:10.1016/j.kint.2019.04.006

Cited by 24 publications

(27 citation statements)

References 32 publications

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“…We thus hypothesized that IgM-RF could exert a direct effect on T-cells. Indeed, the Fcμ receptor is expressed by T-cells in which it mediates the IgM binding with different effects on their functions [21] , [22] , [23] , [24] , [25] , [26] . To test whether IgM-RF could bind to T-cells, we first stained with a fluorescent anti-IgM antibody T-cells isolated from PBMC of healthy donor and cultured in vitro in the presence of both IgM-RF and a control IgM isolated from MM patients.…”

Section: Resultsmentioning

confidence: 99%

“…3 b). This is probably due to the fact that IgM from MM patients are highly sialylated and quickly internalized [ 21 , 22 ], while IgM-RF are not. To confirm this hypothesis, T-cells were incubated with IgM-RF and stained with a fluorescent anti-IgM antibody at different time-points, demonstrating an increase of IgM-positive cells throughout the experiment ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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IgM-Rheumatoid factor confers primary resistance to anti-PD-1 immunotherapies in NSCLC patients by reducing CD137+T-cells

et al. 2020

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Background: ICIs have strongly improved the outcome of NSCLC patients. However, primary and secondary resistance occur during treatment in most of the patients, with several of them developing fast progressions. Autoantibodies can be related with a dysfunctional immune system, although their association with immune-based anti-cancer therapies has never been investigated. Moreover, so far no reliable predictive factor is currently available to aid in treatment selection. CD137 + T-cells are largely known to be the anti-tumor activated effector cells, but they have never been associated with the response to immunotherapies. Methods: Forty-two patients with metastatic NSCLC receiving anti-PD-1 ICIs at Sant'Andrea Hospital and Policlinico Umberto I, from June 2016 to September 2018 were enrolled. Circulating levels of IgM-Rheumatoid Factor were evaluated at baseline and correlated with patients clinical response following the anti-PD-1 treatment. IgM-RF interaction and effect on T-cells in vivo and in vitro were investigated. Findings: IgM-RF in NSCLC patient sera strongly predicted the development of early progression to ICIs. Also, a significant reduction of progression-free survival rate in anti-PD-1 treated patients could be identified when patients were stratified based on IgM-RF positivity and titers. IgM-RF bound preferentially circulating naïve and central memory T-cells and a significant reduction of CD137 + anti-tumor T effector cells was found in IgM-RF positive patients. In addition, a higher percentage of CD137 + T-cells in peripheral blood of NSCLC patients at baseline resulted as a strong independent prognostic factor for a better outcome in terms of PFS and OS after the anti-PD-1 treatment. Furthermore, T-cells exposed to IgM-RF showed a robust defect in their migratory ability in response to CCL19 chemokine. Interpretation: In this study we showed that serum IgM-RF can be regarded as predictive factor for the development of early progression and prognostic factor of a reduced progression-free survival and overall-survival in anti-PD-1 treated NSCLC patients. The ability of IgM-RF to bind naïve and central memory T-cells and impair their migration could make account for the reduction of the tumor-reactive CD137 + T-cells population that may cause a non-effectiveness of these T-cells targeting drugs. Fundings: AIRC, MIUR and Sapienza University of Rome.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

IgM-Rheumatoid factor confers primary resistance to anti-PD-1 immunotherapies in NSCLC patients by reducing CD137+T-cells

et al. 2020

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“…The number of regulatory T cells (those that suppress immune responses) is also reduced in patients with podocytopathies compared with healthy controls and tends to normalize when remission of proteinuria is achieved 79,82,83 . Consistently, renal disorders including podocytopathy with a minimal changes lesion pattern and SSNS are reported in 20% of individuals with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a rare of T cells predisposes patients to steroid dependence 92 ; rituximab can reverse this phenomenon and improve outcomes. Furthermore, B cells may contribute to podocyte injury by other mechanisms; activated antigenspecific B cells can induce FPE and proteinuria through local release of IL-4 in vivo 89 .…”

Section: Syndromic Disordersmentioning

confidence: 85%

Podocytopathies

Kopp

Anders

Suszták

et al. 2020

Nat Rev Dis Primers

301

270

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Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.

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“…Notably, faster memory B-cell reconstitution after treatment was shown to predict nephrotic syndrome relapse (69), and continuous B cell depletion has been proposed as a strategy to maintain disease remission (70). Within the classification limits of a study in a pediatric cohort with unavailable renal pathology assessment, the production of hypo-sialylated IgM antibodies binding to T-cell surface has been reported as a possible mechanism of steroid dependence in idiopathic nephrotic syndrome (71). This work suggests the existence of a pathogenic link between B and T cells in MCD and FSGS, which can be favorably affected by anti-CD20 therapy.…”

Section: Adaptive Immunitymentioning

confidence: 99%

Autoimmunity in Focal Segmental Glomerulosclerosis: A Long-Standing Yet Elusive Association

Podestà

Ponticelli²

2020

Front. Med.

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Focal segmental glomerulosclerosis (FSGS) is a histological term that describes a pathologic renal entity affecting both adults and children, with a wide array of possible underlying etiologies. Podocyte damage with scarring, the hallmark of this condition, leads to altered permeability of the glomerular barrier, which may result in massive proteinuria and relentless renal function deterioration. A definite cause of focal segmental glomerulosclerosis can be confirmed in a minority of cases, while most forms have been traditionally labeled as primary or idiopathic. Despite this definition, increasing evidence indicates that primary forms are a heterogenous group rather than a single disease entity: several circulating factors that may affect glomerular permeability have been proposed as potential culprits, and both humoral and cellular immunity have been implicated in the pathogenesis of the disease. Consistently, immunosuppressive drugs are considered as the cornerstone of treatment for primary focal segmental glomerulosclerosis, but response to these agents and long-term outcomes are highly variable. In this review we provide a summary of historical and recent advances on the pathogenesis of primary focal segmental glomerulosclerosis, focusing on implications for its differential diagnosis and treatment.

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Atypical IgM on T cells predict relapse and steroid dependence in idiopathic nephrotic syndrome

Cited by 24 publications

References 32 publications

IgM-Rheumatoid factor confers primary resistance to anti-PD-1 immunotherapies in NSCLC patients by reducing CD137+T-cells

IgM-Rheumatoid factor confers primary resistance to anti-PD-1 immunotherapies in NSCLC patients by reducing CD137+T-cells

Podocytopathies

Autoimmunity in Focal Segmental Glomerulosclerosis: A Long-Standing Yet Elusive Association

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