Up-regulation of CX3CR1 on tonsillar CD8-positive cells in patients with IgA nephropathy

Abstract

Although tonsillectomy are used as therapeutic options to prevent chronic renal failure in IgA nephropathy (IgAN) patients, the relationship between IgAN and tonsils is not fully proved by basic research. Recently, circulating CX3CR1-positive cells were reportedly involved in promoting hematuria in patients with IgAN. In this study, we focused on the expression of CX3CR1 in tonsillar mononuclear cells in IgAN patients. Immunohistological analysis revealed greater distribution of CX3CR1-positive cells in the inter-follicular area of tonsils in IgAN patients than in non-IgAN patients. CX3CR1-positive cells were also found in the affected renal glomerulus of IgAN patients. Flow cytometric analysis revealed the expression of CX3CR1 on tonsillar CD8-positive cells to be significantly higher in IgAN patients. CpG-oligodeoxynucleotides enhanced the expression in IgAN patients. The chemotactic response of tonsillar mononuclear cells to fractalkine was significantly higher in IgAN patients. Expression of CX3CR1 on peripheral blood CD8-positive cells in IgAN patients was significantly higher, and decreased after tonsillectomy, along with the disappearance of hematuria. These results suggest that hyper-immune response to microbial DNA enhanced the expression of CX3CR1 on tonsillar CD8-positive cells in IgAN patients, followed by the migration of the cells to renal lesions via blood circulation, resulting in the development of hematuria.

T lymphocytes in IgA nephropathy (Review)

“…The chemotactic response of tonsillar mononuclear cells to fractalkine was significantly higher in patients with IgAN. The expression of CX3CR1 in the peripheral blood CD8 + cells in patients with IgAN was significantly higher and decreased after tonsillectomy, along with the disappearance of hematuria (24). Taken together, the aforementioned studies suggest that CD8 + T cells might be one of the exacerbating factors in patients with IgAN.…”

“…However, additional reports also revealed that the strong polarization of Th1 in IgAN, and the advantage of Th1 is associated with the development of renal injury in IgAN (20)(21)(22)(23). In a recent study, the upregulation of CX3CR1 + CD8 + T cells in the tonsils was found in patients with IgAN (24). Taken together, these findings revealed that T lymphocytes play an important role in the development of IgAN.…”

The epipharynx-kidney axis triggers glomerular vasculitis in immunoglobulin A nephropathy

“…Notably, Otaka et al demonstrated the upregulation of CX3CR1 on tonsillar CD8+ T cells in patients with IgAN and postulated that a hyper-immune response to microbial DNA enhanced the expression of CX3CR1 on CD8+ T cells in the interfollicular area of palatine tonsils, followed by migration of the cells to renal lesions via the blood circulation, eventually resulting in the development of hematuria [8]. Given that epipharyngeal CD8+ T cells, as a part of NALT, behave in similar fashion to tonsillar interfollicular CD8+ T cells, we postulate that the upregulation of fractalkine/ CX3CR1 interactions related to epipharyngitis may play a crucial role in glomerular vasculitis, resulting in worsening hematuria.…”

“…Immunoglobulin A (IgA) deposition in the glomerular mesangium is the histological hallmark of IgA nephropathy (IgAN) and has led to extensive research on mucosaassociated lymphoid tissue (MALT) since the initial recognition of this disease approximately 50 years ago. MALT governs mucosal immunity and, in particular, the palatine tonsils (organized MALT) [1][2][3][4][5][6][7][8][9][10] and the gut-associated lymphatic tissue [11][12][13][14][15][16][17][18][19] have drawn significant interest.…”

CX3CL1/CX3CR1 Axis, as the Therapeutic Potential in Renal Diseases: Friend or Foe?

“…CX3CL1 is mainly produced by glomerular endothelial cells and the tubular epithelium and can be detected in many other cells, such as podocytes, mesangial cells, renal tumor cells and stromal cells [ 14 - 16 ]. CX3CR1 is a G-protein coupled receptor that is expressed on CD8 + T lymphocytes [ 17 ], mast cells [ 18 ], Natural Killer (NK) cells [ 19 ], Dendritic Cells (DCs) [ 20 ], platelets [ 21 ], renal cancer cells [ 22 ], vascular smooth cells [ 23 ], tubular cells [ 24 ] mesenchymal cells [ 25 ], and monocytes/macrophages [ 26 , 27 ]. After CX3CL1 conjugates with CX3CR1, the CX3CL1/CX3CR1 axis can initiate a cascade via several signaling pathways in the kidney, including ROS/MAPKS, Raf/MEK1/2-ERK1/2-Akt/PI3K, and nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NF-kB).…”