Elsevier

Clinical Immunology

Volume 113, Issue 1, October 2004, Pages 14-18
Clinical Immunology

Short Analytical Review
DNaseI in pathogenesis of systemic lupus erythematosus

https://doi.org/10.1016/j.clim.2004.05.009Get rights and content

Abstract

The aberrant activation of lymphocytes causes autoimmune diseases. Although there are many candidate molecules that are involved in the pathogenesis of autoimmune diseases, it still remains unclear how immunological tolerance is disturbed in each autoimmune disease. Recently, we discovered two patients suffering from systemic lupus erythematosus (SLE) with a defect in the DNaseI gene locus. According to immunological and genetic analysis, we hypothesize that defective antigen clearance, especially accumulation of nucleosomal antigens, is responsible for the development of SLE. In this article, we review the pathogenesis of SLE from the view of defective self-antigen clearance due to low DNaseI activity.

Introduction

Autoimmune diseases are caused by a breakdown of immunological tolerance against self-antigens [1]. Many papers have shown that a variety of molecules or cells regulate the induction or maintenance of immunological tolerance [2], [3], [4]. However, the essential regulators that are deficient in each autoimmune disease remain unknown [1], [4].

Systemic lupus erythematosus (SLE) is typical of systemic autoimmune diseases and is associated with the production of a variety of autoantibodies, including anti-nuclear antibodies (ANA), directed against naked DNA, entire nucleosomes, and ribonucleoprotein components of the spliceosome complex [1], [5], [6]. The amount of serum anti-double strand (ds) DNA antibodies is in parallel with the clinical evidence of SLE disease activity [7], [8], [9], although the contribution of anti-nucleosomal antibodies to the pathogenesis of SLE remains unknown. We recently discovered two DNaseI-deficient SLE patients with very high serum titers of anti-dsDNA antibodies [10]. Naiperi et al. [11] has independently reported that DNaseI-deficient mice also developed a SLE-like syndrome. These two findings indicate that clearance of nucleosomes from the body is crucial for the development of SLE. Here, we review the relationships between defective clearance of nuclear antigens due to low DNaseI activity and the pathogenesis of SLE.

Section snippets

The genetic basis for susceptibility to SLE

Over the last decade, several studies using gene knockout technology have revealed that the disruption of several genes caused SLE-like syndrome in mice [3], [4], [6]. Based on the function of these genes, the causes of SLE can be classified into two categories: impairment of immunological tolerance and defective clearance of autoantigens. The impairment of immunological tolerance might induce SLE by two mechanisms. First, the threshold for lymphocyte activation becomes low by mutations in

DNaseI in the pathogenesis of SLE

DNaseI, which is the major nuclease present in serum and urine, has been thought to be a key molecule in the pathophysiology of SLE for several reasons. First, dsDNA is a predominant autoantigen in SLE patients [1]. Secondly, DNaseI from bovine pancreas destroys the antigenicity of DNA. Lastly, the serum activity of DNaseI is often low in SLE patients [26]. The implication of DNaseI in SLE was strongly supported by the report that DNaseI-deficient mice developed a SLE like syndrome, namely, the

Mechanisms of SLE induction by DNaseI mutations

As discussed above, nuclear antigens, including DNA, have been suggested to have crucial roles in the pathogenesis of SLE. Nevertheless, it remains unclear how anti-nucleosome specific lymphocytes contribute to the progression of SLE. One explanation is that anti-nucleosome antibodies cross-react with self-antigens and damage tissues expressing such antigens [27], [28]. Indeed, one recent report has shown that anti-dsDNA antibodies cross-react with NMDA and cause SLE encephalitis [29].

DNaseI for the treatment of SLE

The studies of DNaseI in SLE have suggested that the elimination of DNA–protein complexes is a critical step for the prevention of autoimmune disease. Therefore, DNaseI is expected to be useful for the treatment of SLE. Macanovic et al. [39] have reported that injection of recombinant DNaseI reduces the autoimmune response in spontaneously lupus-prone mice. In addition, to increase the potency of DNaseI, Pan et al. [40] generated hyperactive and actin-resistant variants, which digested DNA much

References (41)

  • P. Marrack et al.

    Autoimmune disease: why and where it occurs

    Nat. Med

    (2001)
  • K. Yasutomo

    Pathological lymphocyte activation by defective clearance of self-ligands in systemic lupus erythematosus

    Rheumatology (Oxford)

    (2003)
  • M.C. Hochberg

    Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus

    Arthritis Rheum

    (1997)
  • P. Davis et al.

    Correlation between levels of DNA antibodies and clinical disease activity in SLE

    Ann. Rheum. Dis

    (1977)
  • A.J. Swaak et al.

    Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus

    Ann. Rheum. Dis

    (1986)
  • E.J. ter Borg et al.

    Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study

    Arthritis Rheum

    (1990)
  • K. Yasutomo et al.

    Mutation of DNASE1 in people with systemic lupus erythematosus

    Nat. Genet

    (2001)
  • M. Napirei et al.

    Features of systemic lupus erythematosus in Dnase1-deficient mice

    Nat. Genet

    (2000)
  • T.L. O'Keefe et al.

    Hyperresponsive B cells in CD22-deficient mice

    Science

    (1996)
  • H.W. Tsui et al.

    Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene

    Nat. Genet

    (1993)

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