CXCR3 and mEPCR Expression in Renal Tissue of Pediatric SLE Patients
Nesrine Mohamed Radwan;
Abstract
Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies against components of cell nucleus, due to failure to control the auto-reactive T, B, and antigen-presenting cells and the local activation of the complement system. The mean age of diagnosis in pSLE at diagnosis is 12 to 13 years. The etiology of SLE includes both genetic and environmental factors with female sex strongly influencing the pathogenesis. Renal involvement occurs in 40–70% of all SLE patients and is considered to be the major cause of morbidity, hospital admissions and mortality.
In LN nearly all kidney compartments are affected. Renal manifestations range from asymptomatic hematuria or proteinuria, acute nephritic syndrome, nephrotic syndrome and nephritic nephrotic syndrome. The diagnosis of lupus nephritis is based on the kidney histopathology, while the outcome is based on laboratory data.
Therapeutic strategy for SLE nephritis distinguishes two distinct phases, which are based on histological classification of LN using different immune suppressive treatment. The first phase is the induction phase, which aims to control disease activity and induce remission. While the second phase is the maintenance phase, which aims is to avoid relapses and control the disease by limiting inflammation and damage.
The chemokines are a subgroup of cytokines that mediate cell migration and chemotaxis of the circulating leukocytes and other cells to sites of inflammation. There are four subfamilies of chemokines including CCL, CXCL, CX3CL, and CL. Inflammatory chemokine receptors such as CCR5, CXCR3, and CCR4 are expressed in inflamed tissues by resident and infiltrating cells upon stimulation by pro-inflammatory cytokines or during contact with pathogenic agents.
CXCR3 is a G protein–coupled receptor that binds and is activated by IFN-γ-inducible chemokines of the CXC family (CXCL9, CXCL10, and CXCL11). It is expressed on several immune cell types, among which are natural killer cells, plasmacytoid, myeloid dendritic cells, B cells and activated T cells. Such activation causes recruitment of inflammatory cells to inflamed tissues. The frequency of infiltrating CXCR3- positive cells correlates with the degree of renal dysfunction and is an indicator of progressive renal diseases. Accordingly, this makes CXCR3 to be considered as a novel potential diagnostic and therapeutic target in progressive glomerular diseases, as IgA nephropathy, lupus nephritis, and membranoproliferative glomerulonephritis.
Circulating CD4+CXCR3+ T cells are used to correlate with disease activity of different autoimmune diseases such as Rheumatoid Arthritis and Systemic Lupus Erythematosus. It represents a marker of acute inflammation where Th1 cells recruited to the inflammatory sites expresses CXCR3. The level of circulating CD4+CXCR3+ in relation to SLE disease activity determined by SLEDAI, lymphocytic count and 24 hours urinary protein is controversial.
LN is strongly influenced by the vascular homeostasis. However its effect was never mentioned in ISN/RPS 2003 pathologic classification; but recent murine data based on microarray analysis suggested that endothelial activation is a feature shared by progressive glomerulosclerosis.
With the focus on the endothelium surface; a membrane protein with both anti-inflammatory and anti-thrombotic properties was demonstrated, which is the membrane endothelial protein C receptor (mEPCR). It regulates the conversion of protein C to activated protein C by presenting it to the thrombin–thrombomodulin complex. It is considered to be a predictor of poor outcome. Against what was expected increase expression is associated with poor response to treatment.
Our study was an exploratory cross sectional case control study conducted on 45 patients with SLE following up at the Allergy and Immunology clinic in Children’s Hospital, Ain Shams University. Our studied SLE patients were divided into two subgroups: Group I A: 25 patients having Lupus nephritis and whose Paraffin blocks of renal biopsies were available at the archives files of Pathology department of Ain Shams Specialized Hospital. These patients were selected for examining their renal biopsies for the expression of the tissue markers CXCR3+ and mEPCR using the Immunohistochemistry stain. This group of patients was also subjected to assessment of serum CD4+CXCR3+ expression using flowcytometry. Group I B: were 20 patients who were only subjected to serum sampling of CD4+CXCR3+ expression by flowcytometry. Group II: were 45 age and sex matched controls who were subjected to serum sampling of CD4+CXCR3+ expression using flowcytometry. We divided our patients with LN into 2 subgroups; proliferative LN (classes III and IV) and non-proliferative (class II).
In LN nearly all kidney compartments are affected. Renal manifestations range from asymptomatic hematuria or proteinuria, acute nephritic syndrome, nephrotic syndrome and nephritic nephrotic syndrome. The diagnosis of lupus nephritis is based on the kidney histopathology, while the outcome is based on laboratory data.
Therapeutic strategy for SLE nephritis distinguishes two distinct phases, which are based on histological classification of LN using different immune suppressive treatment. The first phase is the induction phase, which aims to control disease activity and induce remission. While the second phase is the maintenance phase, which aims is to avoid relapses and control the disease by limiting inflammation and damage.
The chemokines are a subgroup of cytokines that mediate cell migration and chemotaxis of the circulating leukocytes and other cells to sites of inflammation. There are four subfamilies of chemokines including CCL, CXCL, CX3CL, and CL. Inflammatory chemokine receptors such as CCR5, CXCR3, and CCR4 are expressed in inflamed tissues by resident and infiltrating cells upon stimulation by pro-inflammatory cytokines or during contact with pathogenic agents.
CXCR3 is a G protein–coupled receptor that binds and is activated by IFN-γ-inducible chemokines of the CXC family (CXCL9, CXCL10, and CXCL11). It is expressed on several immune cell types, among which are natural killer cells, plasmacytoid, myeloid dendritic cells, B cells and activated T cells. Such activation causes recruitment of inflammatory cells to inflamed tissues. The frequency of infiltrating CXCR3- positive cells correlates with the degree of renal dysfunction and is an indicator of progressive renal diseases. Accordingly, this makes CXCR3 to be considered as a novel potential diagnostic and therapeutic target in progressive glomerular diseases, as IgA nephropathy, lupus nephritis, and membranoproliferative glomerulonephritis.
Circulating CD4+CXCR3+ T cells are used to correlate with disease activity of different autoimmune diseases such as Rheumatoid Arthritis and Systemic Lupus Erythematosus. It represents a marker of acute inflammation where Th1 cells recruited to the inflammatory sites expresses CXCR3. The level of circulating CD4+CXCR3+ in relation to SLE disease activity determined by SLEDAI, lymphocytic count and 24 hours urinary protein is controversial.
LN is strongly influenced by the vascular homeostasis. However its effect was never mentioned in ISN/RPS 2003 pathologic classification; but recent murine data based on microarray analysis suggested that endothelial activation is a feature shared by progressive glomerulosclerosis.
With the focus on the endothelium surface; a membrane protein with both anti-inflammatory and anti-thrombotic properties was demonstrated, which is the membrane endothelial protein C receptor (mEPCR). It regulates the conversion of protein C to activated protein C by presenting it to the thrombin–thrombomodulin complex. It is considered to be a predictor of poor outcome. Against what was expected increase expression is associated with poor response to treatment.
Our study was an exploratory cross sectional case control study conducted on 45 patients with SLE following up at the Allergy and Immunology clinic in Children’s Hospital, Ain Shams University. Our studied SLE patients were divided into two subgroups: Group I A: 25 patients having Lupus nephritis and whose Paraffin blocks of renal biopsies were available at the archives files of Pathology department of Ain Shams Specialized Hospital. These patients were selected for examining their renal biopsies for the expression of the tissue markers CXCR3+ and mEPCR using the Immunohistochemistry stain. This group of patients was also subjected to assessment of serum CD4+CXCR3+ expression using flowcytometry. Group I B: were 20 patients who were only subjected to serum sampling of CD4+CXCR3+ expression by flowcytometry. Group II: were 45 age and sex matched controls who were subjected to serum sampling of CD4+CXCR3+ expression using flowcytometry. We divided our patients with LN into 2 subgroups; proliferative LN (classes III and IV) and non-proliferative (class II).
Other data
| Title | CXCR3 and mEPCR Expression in Renal Tissue of Pediatric SLE Patients | Other Titles | معدل تعبير مستقبل CXCR3و mEPCRفى أنسجة الكلى للمرضى الأطفال المصابين بالذئبة الحمراء | Authors | Nesrine Mohamed Radwan | Issue Date | 2015 |
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