Spectrum of Kidney Disorders Associated with T-Cell Immunoclones.

Alexis Piedrafita,Dominique Chauveau,David Ribes,Julie Belliere,Loïc Ysebaert,Antoine Huart,Stéphanie Lagarde,Camille Laurent,Lucie Oberic,Nais Prades,Arnaud Del Bello,Stanislas Faguer,Jean-Baptiste Rieu,François Vergez,Nassim Kamar,Magali Colombat

doi:10.3390/jcm11030604

Abstract

Large granular T-cell leukemia is a clonal hematological condition often associated with autoimmune disorders. Whether small-sized T-cell clones that are otherwise asymptomatic can promote immune kidney disorders remains elusive. In this monocentric retrospective cohort in a tertiary referral center in France, we reviewed characteristics of 29 patients with T-cell clone proliferation and autoimmune kidney disorders. Next-generation sequencing of the T-cell receptor of circulating T-cells was performed in a subset of patients. The T-cell clones were detected owing to systematic screening (mean count 0.32 × 109/L, range 0.13–3.7). Strikingly, a common phenotype of acute interstitial nephropathy was observed in 22 patients (median estimated glomerular filtration rate at presentation of 22 mL/min/1.73 m2 (range 0–56)). Kidney biopsies showed polymorphic inflammatory cell infiltration (predominantly CD3+ T-cells, most of them demonstrating positive phospho-STAT3 staining) and non-necrotic granuloma in six cases. Immune-mediated glomerulopathy only or in combination with acute interstitial nephropathy was identified in eight patients. Next-generation sequencing (n = 13) identified a major T-cell clone representing more than 1% of the T-cell population in all but two patients. None had a mutation of STAT3. Twenty patients (69%) had two or more extra-kidney autoimmune diseases. Acute interstitial nephropathies were controlled with corticosteroids, cyclosporin A, or tofacitinib. Thus, we showed that small-sized T-cell clones (i.e., without lymphocytosis) undetectable without specific screening are associated with various immune kidney disorders, including a previously unrecognized phenotype characterized by severe inflammatory kidney fibrosis and lymphocytic JAK/STAT activation.

Highlights

The development of new molecular diagnosis tools, including multicolor flow cytometry, polymerase chain reaction of the T-cell receptor (TCR), and next-generation sequencing, has provided new opportunities to refine the phenotypes and molecular mechanisms of immune disorders of unknown origin
We reported two cases of inflammatory renal fibrosis associated with a small-sized T-cell clone [13]
Next-generation sequencing of the TCR CDR3 region, and pathology analyses, we showed that LGL proliferation and immunoclones are associated with various immune kidney disorders, including relapsing inflammatory kidney fibrosis with granulomatosis

Summary

Introduction

The development of new molecular diagnosis tools, including multicolor flow cytometry, polymerase chain reaction of the T-cell receptor (TCR), and next-generation sequencing, has provided new opportunities to refine the phenotypes and molecular mechanisms of immune disorders of unknown origin. This approach helped to relate large granular lymphocytic leukemia (LGL), a condition frequently associated with autoimmune diseases, with a clonal or oligoclonal proliferation of cytotoxic T-cells [1]. T-cells is observed in most if not all LGL clones and is driven by acquired mutations of the STAT3 or very rarely STAT5b genes in 5% to 30% of patients [3,4,5]. STAT3 mutations are considered a secondary event during clonal expansion, but LGL can evolve and progress because of persistent antigenic drive, even if STAT3 is not mutated [4]

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