Novel disease severity factors in systemic lupus erythematosus: A profile of mannose binding lectin gene polymorphisms, nephrin autoantibodies and brain-reactive autoantibodies

Abstract

The aim of this post graduate thesis is to study novel disease severity factors in Systemic Lupus Erythematosus (SLE) relating to infections, and involvement of the kidney and brain. Although the pathogenesis of SLE is not fully understood, the management of SLE has dramatically improved over the last decade with use of various therapeutic agents. Lupus patients are now expected to live longer compared to those of earlier days. However, the number of hospitalizations of lupus patients is still significant. The predominant causes of hospitalizations were infections and major organ complications. It is reasonable to conclude that more lupus patients are seen with infections because of the use of immunosuppressive drugs in lupus management. In innate defense mechanisms, complement proteins are generally well regarded, as a??important proteinsa?? against pathogens. They also play a role in clearance of immune complexes and complement deficiencies are associated with SLE. Mannose Binding Lectin (MBL) is from the lectin pathway of complement system. Its deficiencies were associated with infections in both children and adults. It was also interesting to note that MBL plays an important role against infections in patients on immunosuppressive therapy. We therefore studied the different variants of genotypes and haplotypes of MBL, especially structural mutants and MBL low-producing haplotypes, to determine its predisposition to infection. Recurrent infections worsen disease severity in lupus patients on immunosuppressive therapy.Proper management of lupus patients on immunosuppressive drugs can reduce the disease severity and increase the survival rate of lupus patients. However organ damages are still significant morbidity and mortality issues facing lupus patients. Among many suggested mechanisms causing organ-system damages, autoantibodies against structural systems in the kidneys and brain are thought to play important roles. However it is not clear how these autoantibodies are involved in the pathogenesis of such organ involvement. The significant finding of renal involvement in lupus is proteinuria, which is widely been used as a diagnostic, prognostic and disease-monitoring tool in the management of lupus nephritis. Recently a monoclonal antibody (mAb 5-1-6), which caused immediate transient and massive proteinuria in animal models upon intravenous injection, was reported as targeting against nephrin, a structural protein of slit diaphragm. We therefore studied nephrin autoantibodies in lupus patients to determine the role these autoantibodies play in disease severity in lupus nephritis patients. The role of brain reactive autoantibodies in lupus has been studied. However no significant autoantibodies that can be used in diagnosis and management of neuropsychiatric lupus are yet defined. We looked into autoantibodies against the neuronal membrane proteins in unselected lupus patients to determine their roles in neuropsychiatric lupus and disease severity. Together with those finding (genetic MBL variants with protein deficiencies, anti-nephrin antibodies and brain reactive autoantibodies), the damage index in SLE patients (SLICC/ACR score) were studied if these factors predispose to severity in Systemic Lupus Erythematosus. The structural MBL mutant alleles and MBL low-producing promoter haplotypes are found to be associated SLE and correlated with infections during immunosuppressive therapy. Anti-nephrin antibodies are highly associated with lupus disease, but their association with renal involvement was seen only in lupus mouse models. Brain Reactive Autoantibodies are highly associated with lupus patients and correlated with psychosis or seizure disorders. The data suggests that the MBL variants play a role in SLE pathogenesis and the usefulness of anti-nephrin antibodies and BRAA need further exploration before their clinical usefulness can be determined.