Systemic lupus erythematosus or SLE is an autoimmune disease which is characterized as producing autoantibodies against the antigens like histones, RNA and DNA. The organs and tissues of the brain, kidney, skin, joints and cardiovascular areas are mostly susceptible to this disease. Lupus Nephritis or LN is a specific complication of SLE which leads to the mortality of SLE patients. LN results when the macrophages are activated or when the autoantibodies are accumulated in the glomerulus or during the proliferation of cells or when extracellular matrix proteins, pro-inflammatory chemokines and pro-inflammatory cytokines are produced. These autoantibodies ultimately are involved in causing tubule interstitial inflammation, fibrosis and tubular damage.
Lupus Nephritis is considered as the most severe form of SLE. The treatment for LN is based on its severity and hence the research on the Biomarkers of LN will aid in evaluating the disease activity, risky patients for kidney damage and in identifying the therapies to improve the outcomes. Genome wide association studies and linkage analysis were utilized for selecting the lupus susceptibility and genetic variation analysis has shown many loci that are susceptible to lupus. The collective influence of these loci justifies for disease inheritance of LN. The epigenetic and genetic variations might result in the altered levels of Biomarker proteins like cytokines of serum and urine of LN patients and autoantibodies. This article discusses the proteomics and genetic biomarkers concomitant with the pathogenesis and susceptibility of LN.
Genetic variations related to Lupus Nephritis
The disease severity of LN is found to be associated with the alleles of the susceptibility genes. There are certain kidney specific genes which make the patients to be sensitive to LN autoimmunity. High throughput genotyping technology helps in searching for genetic polymorphisms in SLE and LN. Production of autoantibodies, traits of lupus and nephritis are linked to histocompatibility complex. The human leukocyte antigens like DR2, HLA-B8, HLA-DR and HLA-DQA alleles are observed to be associated with African-American LN patients and Italian LN patients. The mutants of Fc? receptor (FcYR) IIA and IIIA are related to SLE and LN. FcYR IIA genes are seen as factors responsible for SLE and LN disease susceptibility and proved that Fc receptor plays vital role in the clinical outcome of LN.
The variant of FcYR IIIA called V158F and FcYR IIA/R131 have an increase in risk for LN, which indicates that polymorphism in these alleles might create susceptibility factor for LN and SLE. Transcriptomic and microarray analysis of the genome has identified that 567 genes are differentially expressed in the glomeruli of MRL/lpr mice with LN. The expression of Mdm2 gene homolog in the kidneys and spleen of lupus mice was higher compared to that of in healthy mice. The stimulation of Mdm2 enhances the autoantibodies and expand the plasma cell number leading to immune complex disease in mice. Developing antagonists to Mdm2 might lead to the exploration of therapeutic ability against LN. The NZM lupus mice lacking the STAT4 gene developed nephritis and most of them died due to lower levels of anti-dsDNA Abs. Another study identified that programmed cell death 1 gene or PDCD1gene is a susceptibility marker for LN. In African and Caucasian populations, pentraxin CRP gene was found to be related to SLE nephritis. Alu insertion/deletion in ACE gene and polymorphism in M235T in AGT gene were associated with LN. The DD genotype of ACE gene was considered as a valuable marker to enhance the risk for LN. Polymorphism in MCP-1 and low frequency of ITGAM gene were found to be associated with LN.
Epigenetic regulation of LN
Epigenetic factors also influence LN disease and they constitute the factors which regulate the expression of genes not causing any alterations in the DNA sequence. These factors include DNA methylation, microRNA regulation and histone modification.
Methylation of regulatory regions of DNA will lead to inactivation while demethylation will lead to activation of transcription. The DNA fragments that are demethylated in the SLE patient serum could generate antiDNA antibodies to participate in the pathophysiology of SLE and LN. Hypomethylation was vital for apoptotic DNA to trigger autoimmune disease in mice generating large amounts of anti-dsDNA Abs.
The nucleosomes from apoptotic cells accumulate in the circulation and help in triggering B cells to transform into autoantibody releasing plasma cells. These cells lead to the formation of polyclonal immune complex and glomerulonephritis in the kidney. Histone modification occurs during LN inflammatory reaction. Disease activity was found to be stimulated by histone acetylation as well.
The expression of microRNAs has been a new tool for diagnosing LN and for identifying treatment options for LN. The higher expression of miR-142-3p and miR-181a as well as lower expression of miR-106a, miR-17, miR-20a, miR-343-3p, miR-223, miR-203 and miR-92a was seen in SLE patients.
Serum protein markers for LN
The highly sensitive serum marker for LN activity was anti-C1q antibody rather than other traditional markers. Glomerular proteome array analysis and high throughput autoantigen microarray could identify antibodies like anti-chromatin, anti-RNP, anti-Ro and anti-DNA which were associated with SLE and LN disease activity. The protein content of proliferation inducing ligand or APRIL in serum and intra renal regions were found to be initiating resistance to treatment. Hence, APRIL could stand as a potential biomarker for identifying the LN cases that are difficult to treat.
Urine Biomarkers for LN
Mean baseline urine MCP-1 levels were used for measuring the intensity of LN and the class of LN. Another new Biomarker for LN includes urinary levels of TNF-like weak inducer of apoptosis.
Yajuan Li, Xiangdong Fang, Quan -Zhen Li. Biomarker Profiling for Lupus Nephritis. Genomics Proteomics Bioinformatics 11 (2013) 158-165.
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