Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection

Abstract

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection.

Kidney Inflammation, Injury and Regeneration

“…This Special Issue covers research articles that investigated the molecular mechanisms of inflammation [1][2][3] and injury [4,5] during different renal pathologies and renal regeneration [6], diagnostics using new biomarkers [7][8][9], and the effects of different stimuli like medication or bacterial components on isolated renal cells or in vivo models [10][11][12], all of which were summarized in a very simplified manner. Furthermore, this Special Issue contains important reviews that dealt with the current knowledge of cell death and regeneration [13,14], inflammation [15][16][17][18], and the molecular mechanisms of kidney diseases [19][20][21][22].…”

“…Furthermore, others introduced a kidney injury test for the noninvasive monitoring of IgA nephropathy progression [9]. Schiffer and co-workers described CXCL13 blood levels as a biomarker in T-cell-mediated rejection [8]. The marker correlates with B-cell involvement and might help to identify patients with a more severe clinical course of rejection [8].…”

“…Schiffer and co-workers described CXCL13 blood levels as a biomarker in T-cell-mediated rejection [8]. The marker correlates with B-cell involvement and might help to identify patients with a more severe clinical course of rejection [8]. Others demonstrated that that specific IL-18 genotypes may play a role in the etiology and progression of renal cell carcinoma and serve as useful early detection biomarkers.…”

Noninvasive Identification of Core Gene Biomarkers in Patients with Acute Kidney Transplant Rejection

“…On the other hand, TCMR is characterized by lymphocytic in ltration of the renal tubules, interstitium and arterial intima [27] . Zoghby et al proved that TCMR is one of the most important and serious complications occurring in the renal transplant patients and it will cause graft loss and permanent impairment of graft function if not early diagnosis [28] . Therefore, we found that both ABMR and TCMR are equally essential for renal transplant patients which need to early detection and treatment.…”

Graph-based description of tertiary lymphoid organs at single-cell level

“…While the success and great potential of ML is undisputed, there is still a rationale to consider approaches of manually curated features according to domain-specific knowledge as they may help to biologically understand the result and consequently increase the acceptance by medical experts. Methods broadly considered by pathologists are descriptive, purely density-based, or include spatial characteristics by distance metrics [33,34]. In contrast, graphbased concepts could include complex neighborhood characteristics [35][36][37][38][39][40][41].…”