Spectrum of Kidney Disorders Associated with T-Cell Immunoclones

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.

Keywords: STAT3; T-cell receptor; autoimmune disorders; immunoclones; large granular lymphocytic leukemia; renal fibrosis.

Figure 1

Flow-chart of the study. TIC, T-cell immunoclone; TCUS, T-cell clone of unknown significance; FSGS, focal and segmental glomerulosclerosis; MN, membranous nephropathy; GN, glomerulonephritis. * One patient had both acute interstitial nephropathy and immune-mediated glomerulopathy.

Figure 2

Kidney pathology. (A) Acute interstitial nephropathy with polymorphic infiltration of inflammatory cells and interstitial edema (Masson’s trichroma). (B) Interstitial granuloma (Masson’s trichroma). (C–E) Glomerulonephritis with CD3+ T-cells’ endocapillary proliferation ((C) Masson’s trichroma staining, (D) Jones’ staining, (E) CD3+ immunostaining in brown). (F) Membranous nephropathy with extra-capillary cell proliferation (Masson’s trichroma).

Figure 3

Phospho-STAT3 immunostaining. (A,B) Representative cases of pSTAT3 staining in renal fibrosis showing nuclear expression in some lymphocytes and endothelial cells (A ×150 and B ×100). (C,D) Representative cases of pSTAT3 staining in a liver sample expressed by numerous lymphocytes and hepatocytes (C ×200) or highlighting the intra-sinusoidal T-LGL infiltrate (D ×150). (E,F) Representative cases of pSTAT3 staining in inflammatory fibrosis tissue (E ×100) and sarcoidosis-like lymph node (F ×150) showing nuclear expression mostly in reactive lymphocytes (D) and histiocytes (F) as well as in endothelial cells.