GENETICS OF SYSTEMIC LUPUS ERYTHEMATOSUS: Clinical Implications

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Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. The clinical features are well-known: production of autoantibodies, immune complex–mediated end-organ damage, arthritis, and serositis. The mechanistic pathways implicated in this disease have also been partly elucidated. Consistent defects in immune complex clearance, B-cell tolerance, and T-cell function have been demonstrated. It is also thought that the major histocompatibility complex (MHC) plays a role in the genetic susceptibility to this disorder. Finally, gender is probably the single biggest determinant of susceptibility. Because the pathophysiology of SLE is well-understood, it has become the model for the study of polygenic susceptibility factors in autoimmunity.

Recent advances in understanding the complex genetics of SLE may lead to improved therapy for this disease. The discovery of cytokine dysregulation paves the way for new biologic strategies, and the improved understanding of the mechanism underlying the association of complement deficiencies with SLE has led to the use of specific replacement strategies. These are the two most concrete examples of intervention directed at a known genetic susceptibility factor; however, it is possible to imagine interventions directed at aberrant apoptotic pathways or dysfunctional tolerance pathways.

This article defines the goals of understanding the genetic susceptibility factors in SLE, the strategies that are currently being used, and our current level of understanding. Finally, a few specific examples of novel interventions are described.

Section snippets

Single Gene Effects

The traditional goal of genetic analysis is to identify the single gene implicated in the disease under study. It is anticipated that after the identification of the gene, the disease would either become a candidate for gene therapy or identification of the gene would lead to specific therapy directed at the defective biochemical pathway. Although gene therapy has been shown to be effective in the rare adenosine deaminase deficiency,10, 13 this type of intervention has yet to fulfill its

Association Studies

There are two main methods to identify genetic susceptibility factors in polygenic disorders: association studies and linkage analysis. Association studies examine the frequency of a mutation or polymorphism in the affected population and compare the frequency to that seen in a matched control population. In the past, restriction fragment length polymorphisms were often used, but most laboratories now use polymerase chain reaction–based techniques to identify the specific mutation,

CURRENT UNDERSTANDING OF THE GENETICS OF SYSTEMIC LUPUS ERYTHEMATOSUS

The pathophysiology is better established for SLE than for any other autoimmune disease with the possible exception of ankylosing spondylitis. The genetic factors identified in SLE to date include genes known to affect immune complex clearance, genes implicated in tolerance, MHC genes, and genes regulating inflammation. This section reviews our current understanding of the genetic contributions to the development of SLE.

Human Studies

The current strategies for the treatment of SLE have not changed dramatically over the past 20 years, although they have been significantly refined, and the mortality and morbidity statistics suggest overall improvement.168 Nevertheless, the dominant strategy remains global immunosuppression with glucocorticoids or antiproliferative agents such as cyclophosphamide. Many new clinical trials are exploring variations on this theme to optimize the antiautoimmunity effect and minimize the

FUTURE OPTIONS

The main direct benefit of genetic analysis of SLE is a greater understanding of its etiopathogenesis. This has already led to the development and testing of new strategies directed at immune complex clearance, tolerance, apoptosis, and cytokine regulation. It is hoped that these new biologic strategies have a more specific effect on the disease process compared with global immunosuppression.

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      Citation Excerpt :

      There is an interaction between gene susceptibility, hormonal influences and some environmental triggers, which induce antibody production and the consequent inflammatory response leading to the induction and maintenance of the disease. The genetic component in SLE pathogenesis was first suggested by the evident concordance between monozygotic twins in 24–69% compared to 1–5% in dizygotic twins,4,5 and also by the different prevalence in various ethnic groups. Some rare genetic mutations associated with familial SLE-like disease, transmitted in a Mendelian fashion, have been identified but these account for only 1–2% of cases.

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    Address reprint requests to Kathleen E. Sullivan, MD, PhD, Division of Immunologic and Infectious Diseases, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104

    *

    Division of Immunologic and Infectious Diseases, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

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