Expression of CXCL12 receptors in B cells from Mexican Mestizos patients with systemic lupus erythematosus

Abstract

BackgroundSystemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by B-cell hyper-reactivity and the production of pathogenic anti-nuclear-directed auto-antibodies (Abs). B-cell ontogeny is partly dependent on the CXCL12/CXCR4 axis for which the contribution to SLE pathogenesis remains unclear. CXCR7, the novel receptor for CXCL12, is differentially expressed among memory B-cell subsets. However, its biological role in SLE remains to be explored.MethodsRelative CXCR4 and CXCR7 expression levels were compared by quantitative PCR in leukocytes from blood samples of 41 Mexican Mestizos patients with SLE and 45 ethnicity-matched healthy subjects. Intracellular and membrane expression of both receptors was analyzed by flow cytometry in naive and Ab-secreting B cells. B-cell responsiveness to CXCL12 was investigated using Transwell-based chemotaxis assays. Data were analyzed using the Kruskal-Wallis test for comparisons of values amongst healthy controls and patients with inactive or active SLE, and non-parametrically using the Mann–Whitney U-test for multiple comparisons and unpaired samples. Correlations were determined by Spearman’s ranking.ResultSLE leukocytes displayed reduced levels of CXCR4 and CXCR7 transcripts. In SLE patients, a significant defect in CXCR4 expression was detected at the surface of naive and Ab-secreting B cells, associated with an abnormal intracellular localization of the receptor. CXCR7 predominantly localized in cytosolic compartments of B cells from healthy and SLE individuals. Disease activity did not impact on these expression patterns. Altered receptor compartmentalization correlated with an impaired CXCL12-promoted migration of SLE B cells.ConclusionsOur data highlight a down-regulation of CXCL12 receptors on circulating B cells from SLE patients that likely influences their migratory behavior and distribution.

Infection of Female BWF1 Lupus Mice with Malaria Parasite Attenuates B Cell Autoreactivity by Modulating the CXCL12/CXCR4 Axis and Its Downstream Signals PI3K/AKT, NFκB and ERK

“…This increase in CXCR4 expression may be due to the occurrence of inflammation in lupus mice. In contrast, another study reported that CXCR4 expression on circulating B cells was significantly lower in SLE patients than in healthy controls and that this decrease in CXCR4 expression could be due to changes in the proportion of B cell subsets or variations in expression levels within a subset [ 22 ]. Strikingly, our study demonstrated that lupus mice infected with live malaria parasite exhibit a restored surface expression of CXCR4 on B cells.…”

“…In patients with SLE, an up-regulation of CXCR4 has been reported, suggesting that the CXCR4/CXCL12 axis might be a therapeutic target for SLE patients with kidney and/or central nervous system involvement [ 21 ]. Inversely, a previous investigation revealed a down-regulation of the CXCL12 receptor (CXCR4) in circulating B cells from SLE patients, leading to their altered migratory behavior and distribution of the B cell compartment [ 22 ]. The signaling cascades involving PI3K/AKT, MAPKs (ERK, JNK, p38) and the regulation of NF-κB nuclear translocation (IκBs) are critically involved in B cell differentiation and the production of autoantibodies during SLE disease progression [ 23 ].…”

Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus

“…All patients fulfilled the revised American College of Rheumatology (ACR) 1997 classification criteria for SLE. Disease activity was evaluated by SLEDAI-2000 criteria (mean 11.7, range [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Peripheral blood samples from 18 age and gender-matched healthy volunteers (17 female, one male; mean age 27 ± 3 years, range 23-32 years) were collected as controls.…”

“…9,[11][12][13][14] Although overexpression of CXCR4 on B cells has been reported both in a lupus mouse model and in SLE patients, 15,16 contradictory results have also been reported. 17 Recently, it has been demonstrated that CXCR4 is crucial for the pathogenesis of murine lupus. 8 Heightened CXCR4 levels in lupus mice were found to prolong B cell survival and promote migration of these cells to end-organs via CXCL12 gradients.…”

CXCR4 in Central and Peripheral Lymphoid Niches – Physiology, Pathology and Therapeutic Perspectives in Immune Deficiencies and Malignancies

“…The contribution of the CXCL12/CXCR4 signaling axis to many aspects of physiology and pathology has been increasingly appreciated (Figure 1 & 2). Deregulations of CXCR4 signaling and/or expression are associated with several disorders including lymphoid and autoimmune diseases, solid tumours and immune defects [15,[200][201][202][203]. Therefore, interference with the CXCL12/CXCR4 interaction or modulation of CXCR4 expression and/or activity is potentially interesting in the treatment of diseases with loss or gain of function of CXCR4.…”