Sandeep Sampangi1, Xiangju Wang2, Kenneth W Beagley3, Travis Klein3, Sadia Afrin1, Helen Healy4, Ray Wilkinson5, Andrew J Kassianos1. 1. Conjoint Renal Laboratory, Pathology Queensland, Brisbane, Australia Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. 2. Conjoint Renal Laboratory, Pathology Queensland, Brisbane, Australia. 3. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. 4. Conjoint Renal Laboratory, Pathology Queensland, Brisbane, Australia Department of Renal Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia. 5. Conjoint Renal Laboratory, Pathology Queensland, Brisbane, Australia Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia Medical School, University of Queensland, Brisbane, Australia.
Abstract
BACKGROUND: Descriptions of inflammatory cells infiltrating the human kidney rarely mention B cells, other than in the specific scenario of transplantation. In these reports, B cells are localized almost exclusively within the kidney tubulointerstitium where they are ideally placed to interact with proximal tubule epithelial cells (PTEC). We have previously shown that activated PTEC down-modulate autologous T lymphocyte and dendritic cell function. In this report, we extend these prior studies to describe PTEC-B cell interactions. METHODS: Stimulated B cells were cultured in the absence or presence of activated autologous human PTEC and monitored for proliferation, surface antigen expression, cytokine secretion and antibody (Ab) production. RESULTS: PTEC decreased B cell proliferative responses, whilst B cells cultured in the presence of PTEC displayed decreased levels of CD27, a marker of plasma B cells and memory cells. Interestingly, autologous PTEC also significantly decreased the number of B cells secreting both IgG and IgM and overall levels of Ab production. Transwell studies demonstrated that this modulation was primarily contact-dependent, and blocking studies with anti-PD-L1 led to partial restoration in Ab production. Further blocking studies targeting soluble HLA-G (sHLA-G) and IDO, two other immunoinhibitory molecules also up-regulated in our activated PTEC, demonstrated minor restoration of Ab responses. DISCUSSION: We report, for the first time, that PTEC are also able to modulate autologous B-cell phenotype and function via complex contact-dependent (PD-L1), soluble (sHLA-G) and intracellular (IDO) factors. We hypothesize that such mechanisms may have evolved to maintain peripheral immune-homeostasis, especially within the inflammatory milieu that exists within many kidney diseases.
BACKGROUND: Descriptions of inflammatory cells infiltrating the human kidney rarely mention B cells, other than in the specific scenario of transplantation. In these reports, B cells are localized almost exclusively within the kidney tubulointerstitium where they are ideally placed to interact with proximal tubule epithelial cells (PTEC). We have previously shown that activated PTEC down-modulate autologous T lymphocyte and dendritic cell function. In this report, we extend these prior studies to describe PTEC-B cell interactions. METHODS: Stimulated B cells were cultured in the absence or presence of activated autologous human PTEC and monitored for proliferation, surface antigen expression, cytokine secretion and antibody (Ab) production. RESULTS: PTEC decreased B cell proliferative responses, whilst B cells cultured in the presence of PTEC displayed decreased levels of CD27, a marker of plasma B cells and memory cells. Interestingly, autologous PTEC also significantly decreased the number of B cells secreting both IgG and IgM and overall levels of Ab production. Transwell studies demonstrated that this modulation was primarily contact-dependent, and blocking studies with anti-PD-L1 led to partial restoration in Ab production. Further blocking studies targeting soluble HLA-G (sHLA-G) and IDO, two other immunoinhibitory molecules also up-regulated in our activated PTEC, demonstrated minor restoration of Ab responses. DISCUSSION: We report, for the first time, that PTEC are also able to modulate autologous B-cell phenotype and function via complex contact-dependent (PD-L1), soluble (sHLA-G) and intracellular (IDO) factors. We hypothesize that such mechanisms may have evolved to maintain peripheral immune-homeostasis, especially within the inflammatory milieu that exists within many kidney diseases.
Authors: V Foschi; D Bortolotti; A F Doyle; V Stratigou; L Stephens; P Trivedi; R Rinaldi; M Padovan; A Bortoluzzi; L Lightstone; T D Cairns; M Botto; T H Cook; R Rizzo; M Govoni; M C Pickering Journal: Lupus Date: 2019-07-10 Impact factor: 2.911
Authors: Becker M P Law; Ray Wilkinson; Xiangju Wang; Katrina Kildey; Kurt Giuliani; Kenneth W Beagley; Jacobus Ungerer; Helen Healy; Andrew J Kassianos Journal: J Am Soc Nephrol Date: 2019-06-11 Impact factor: 10.121
Authors: Xiangju Wang; Ray Wilkinson; Katrina Kildey; Jeremy Potriquet; Jason Mulvenna; Richard J Lobb; Andreas Möller; Nicole Cloonan; Pamela Mukhopadhyay; Andrew J Kassianos; Helen Healy Journal: J Extracell Vesicles Date: 2017-04-21
Authors: Xiangju Wang; Ray Wilkinson; Katrina Kildey; Jacobus P J Ungerer; Michelle M Hill; Alok K Shah; Ahmed Mohamed; Mriga Dutt; Jeffrey Molendijk; Helen Healy; Andrew J Kassianos Journal: J Extracell Vesicles Date: 2021-02-16