Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We observed here that the expression of B lymphocyte chemokine (BLC/CXCL13) was markedly enhanced in the thymus and kidney in aged (NZB x NZW)F1 (BWF1) mice developing lupus nephritis, but not in similarly aged NZB and NZW mice. BLC-positive cells were present in the cellular infiltrates in the target organs with a reticular pattern of staining. CD11b+CD11c+ dendritic cells were increased in the thymus and spleen in aged BWF1 mice and identified as the major cell source for BLC. CD4+ T cells as well as B cells were dramatically increased in the thymus in aged BWF1 mice, whereas no increase was observed in aged NZB and NZW mice. B1/B2 ratio in the thymus was significantly higher than those in the spleen and peripheral blood in aged BWF1 mice. Interestingly, BLC showed preferential chemotactic activity for B1 cells derived from several mouse strains, including nonautoimmune mice. Cell surface CXCR5 expression on B1 cells was significantly higher than that on B2 cells. Thus, aberrant high expression of BLC by myeloid dendritic cells in the target organs in aged BWF1 mice may play a pivotal role in breaking immune tolerance in the thymus and in recruiting autoantibody-producing B cells in the development of murine lupus.
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PMID:Aberrant high expression of B lymphocyte chemokine (BLC/CXCL13) by C11b+CD11c+ dendritic cells in murine lupus and preferential chemotaxis of B1 cells towards BLC. 1141 99

The expression of chemokine receptors on T-cells and chemokine levels in the blood was studied in 23 patients with SLE (ACR criteria), seven patients with rheumatoid arthritis (RA) and in 15 healthy controls using flow cytometry, RT-PCR and ELISA. The cell surface expression of the chemokine receptors CXCR5 and CCR6 was decreased in SLE patients compared with controls (P = 0.051 and P = 0.002, respectively). The decrease of CXCR5 was confined to SLE patients with inactive disease (SLEDAI < 6) compared with active disease (SLEDAI > 6) and controls. CXCR2 and CCR1 were increased in patients with active SLE compared with patients with inactive disease (P = 0.001 and P = 0.01, respectively) and with controls (P = 0.02 and P = 0.053, respectively). The levels of the chemokines MIP-1alpha MCP-1, SDF-1alpha, IP-10 and RANTES were significantly elevated in SLE patients compared with controls. Patients with renal involvement had increased surface expression of CXCR3 and CCR3 (P = 0.04 in both) and a lower level of soluble IP-10 compared with patients without renal disease (P = 0.025) and compared with controls (P = 0.001). The ratio between CCR5 and CCR3 was significantly increased in RA patients compared with SLE patients and controls supporting a Th1 overweight in RA. In conclusion, patients with SLE showed abnormal T-cell expression of several chemokine receptors and levels of soluble chemokines in their plasma/serum.
Lupus 2003
PMID:Abnormal expression of chemokine receptors on T-cells from patients with systemic lupus erythematosus. 1459 26

Chemokines and their receptors are essential in the recruitment and positioning of lymphocytes. To address the question of B cell migration into the inflamed synovial tissue of patients with rheumatoid arthritis (RA), peripheral blood naive B cells, memory B cells and plasma cells were analyzed for cell surface expression of the chemokine receptors CXCR3, CXCR4, CXCR5, CCR5, CCR6, CCR7 and CCR9. For comparison, B cells in the peripheral blood of patients with the autoimmune disease systemic lupus erythematosus (SLE) or with the degenerative disease osteoarthritis (OA) were analyzed. Expression levels of chemokine receptors were measured by flow cytometry and were compared between the different patient groups and healthy individuals. The analysis of chemokine receptor expression showed that the majority of peripheral blood B cells is positive for CXCR3, CXCR4, CXCR5, CCR6 and CCR7. Whereas a small fraction of B cells were positive for CCR5, practically no expression of CCR9 was found. In comparison with healthy individuals, in patients with RA a significant fraction of B cells showed a decreased expression of CXCR5 and CCR6 and increased levels of CXCR3. The downregulation of CXCR5 correlated with an upregulation of CXCR3. In patients with SLE, significant changes in CXCR5 expression were seen. The functionality of the chemokine receptors CXCR3 and CXCR4 was demonstrated by transmigration assays with the chemokines CXCL10 and CXCL12, respectively. Our results suggest that chronic inflammation leads to modulation of chemokine receptor expression on peripheral blood B cells. However, differences between patients with RA and patients with SLE point toward a disease-specific regulation of receptor expression. These differences may influence the migrational behavior of B cells.
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PMID:Differential expression of chemokine receptors on peripheral blood B cells from patients with rheumatoid arthritis and systemic lupus erythematosus. 1620 16

B lymphocyte chemoattractant (BLC/CXCL13) is ectopically and highly expressed in the target organs such as the thymus and kidney in aged (NZB x NZW)F1 (BWF1) mice, a murine model for SLE. Ectopic expression of BLC/CXCL13 was attributed to mature myeloid DCs infiltrating in the target organs. DCs were also increased in the peripheral blood in aged BWF1 mice and differentiated into BLC/CXCL13-producing DCs in the presence of TNF-alpha or IL-1beta, but not IFN-alpha or IFN-gamma. BLC/CXCL13 expression in mature myeloid DCs was confirmed in bone marrow derived-DCs generated in vitro in the presence of GM-CSF and TNF-alpha. B1 cells expressed higher level of CXCR5 and migrated towards BLC/CXCL13 much better than B2 cells. B1 cells failed to home to the peritoneal cavity and preferentially recruited to the target organs in aged BWF1 mice developing lupus nephritis. B1, but not B2 cells possessed a potent antigen presenting activity in allo-MLR and activated autologous thymic CD4 T cells in the presence of IL-2. CXCR5+ CD4 T cells were also increased in aged BWF1 mice and they enhanced IgG production by B1 cells in vitro. These results suggest a possible involvement of aberrant B1 cell trafficking in activation of autoreactive CD4 T cells and autoantibody production in the target organs during the development of lupus, providing a new insight for the pathogenesis of B1 cells in lupus.
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PMID:Aberrant B1 cell trafficking in a murine model for lupus. 1712 21

The weakly estrogenic organochlorine pesticide chlordecone can accelerate the development of systemic lupus erythematosus (SLE) in ovariectomized (NZBxNZW)F1 mice, with a shortened time to appearance of autoantibodies and disease similar to that produced by treatment with the sex hormone 17beta-estradiol (E2). It is unclear whether chlordecone and E2 share the same pathways in mediating this effect. The effects of chlordecone and E2 treatment on splenic germinal center (GC) and marginal zone B cells were examined. Both chlordecone and E2 activated splenic B cells and enhanced GC reactions, as shown by upregulated protein expression of GL7, CXCR5, and CXCR4. Both treatments increased B-cell bcl-2 and shp-1 gene expression and enhanced ICAM-1 and VCAM-1 protein levels in GC B cells. Chlordecone reduced total B cell and GC B-cell apoptosis without affecting proliferation, another feature shared by E2 treatment. However, chlordecone treatment did not alter the composition of splenic B-cell subsets in marked contrast to the decrease in transitional B cells and increase in marginal zone B cells seen in E2-treated mice. The differences in effects between chlordecone and E2 indicate that chlordecone is not functioning simply as an estrogen mimic with respect to effects on the immune system. Similarities in the effects of chlordecone and E2 on specific immune functions, such as diminished apoptosis in GC B cells, may provide valuable clues regarding key events in the acceleration of autoimmunity by E2, chlordecone, and other agents.
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PMID:Acceleration of autoimmunity by organochlorine pesticides: a comparison of splenic B-cell effects of chlordecone and estradiol in (NZBxNZW)F1 mice. 1757 64

Recent studies have revealed new populations of T/B cells, including central/effector memory, follicular T cells and CXCR3+ or CXCR4+ B cells. In the present study, changes in these populations of CD4+ T cells were examined on the basis of the expression of CD62L, CCR7 and CXCR5 in patients with systemic lupus erythematosus (SLE) in relation to CCL21 and CXCL10. Changes in CXCR3+, CXCR4+ and CXCR5+ B cells were also examined. CD62L and various chemokine receptors were examined by flow cytometry analysis using monoclonal antibodies, and CCL21 and CXCL10 were examined by sandwich enzyme-linked immunosorbent assay. In patients with SLE, a decrease of naive T cells and an increase in the ratio of activated effector memory T cells were associated with an increase of CCL21 and CXCL10 in serum, although the correlation was not significant. An increase in the ratio of CXCR3+ B cells was also recognized. These results suggest that naive T cells are transferred to lymphoid tissue by CCL21, and that effector memory T cells are activated by CXCL10. It is also suggested that B cells responsive to follicular helper T cells tend to migrate to inflammatory tissue.
Lupus 2008 Jan
PMID:Striking alteration of some populations of T/B cells in systemic lupus erythematosus: relationship to expression of CD62L or some chemokine receptors. 1808 80

Intrarenal B cell infiltrates resembling secondary lymphoid tissue have been found in several forms of inflammatory kidney disease. Their role in renal inflammation is not well defined, perhaps because B cell clusters have been regarded as a single entity while being quite heterogeneous. Therefore we characterized intrarenal lymphoid clusters of 32 patients diagnosed with lupus nephritis and 16 with ANCA associated nephritis. We identified four increasingly organized levels of intrarenal aggregates from scattered B cells to highly compartmentalized B cell clusters with central follicular dendritic cell networks. Most B cells displayed a mature non-antibody producing phenotype with antigen presenting ability. In regions of B cell infiltration, expression of the lymphoid chemokine BCA-1 was found in cells of a dendritic-like morphology and most B cells expressed the corresponding receptor CXCR5. Biopsies containing B cells had significantly higher levels of BCA-1 mRNA expression compared to those without, suggesting a role of BCA-1 and CXCR5 for B cell infiltration into the kidney. Our study proposes a new classification of B cell clusters in lupus and ANCA associated nephritis which might help to study the function of intrarenal B cell clusters in a more differentiated manner.
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PMID:Analysis and classification of B-cell infiltrates in lupus and ANCA-associated nephritis. 1852 26

Lupus is an Ab-mediated autoimmune disease. One of the potential contributors to the development of systemic lupus erythematosus is a defect in naturally occurring CD4(+)CD25(+) regulatory T cells. Thus, the generation of inducible regulatory T cells that can control autoantibody responses is a potential avenue for the treatment of systemic lupus erythematosus. We have found that nasal administration of anti-CD3 mAb attenuated lupus development as well as arrested ongoing lupus in two strains of lupus-prone mice. Nasal anti-CD3 induced a CD4(+)CD25(-)latency-associated peptide (LAP)(+) regulatory T cell that secreted high levels of IL-10 and suppressed disease in vivo via IL-10- and TFG-beta-dependent mechanisms. Disease suppression also occurred following adoptive transfer of CD4(+)CD25(-)LAP(+) regulatory T cells from nasal anti-CD3-treated animals to lupus-prone mice. Animals treated with nasal anti-CD3 had less glomerulonephritis and diminished levels of autoantibodies as measured by both ELISA and autoantigen microarrays. Nasal anti-CD3 affected the function of CD4(+)ICOS(+)CXCR5(+) follicular helper T cells that are required for autoantibody production. CD4(+)ICOS(+)CXCR5(+) follicular helper T cells express high levels of IL-17 and IL-21 and these cytokines were down-regulated by nasal anti-CD3. Our results demonstrate that nasal anti-CD3 induces CD4(+)CD25(-)LAP(+) regulatory T cells that suppress lupus in mice and that it is associated with down-regulation of T cell help for autoantibody production.
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PMID:Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+ CD25- LAP+ regulatory T cell and is associated with down-regulation of IL-17+ CD4+ ICOS+ CXCR5+ follicular helper T cells. 1894 Nov 93

Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Costimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (T(FH) cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of T(FH) cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F(1) mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in T(FH) cells and GC B cells as well as an overall decrease in the frequency of ICOS(+) T cells. Coculture experiments of Ag-primed B cells with CXCR5(+) or CXCR5(-) T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the T(FH) cell pool is an important mechanism by which ICOS regulates Ab production.
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PMID:B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. 1915 89

Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor gamma chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T(FH)), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5(+) T(FH) but instead was produced broadly by ICOS(+) CD4(+) splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.
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PMID:A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. 1916 19


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