Trends in Immunology

Trends in Immunology

Volume 26, Issue 11, November 2005, Pages 572-579
Journal home page for Trends in Immunology

Autoimmunity special issue
SLE: translating lessons from model systems to human disease

https://doi.org/10.1016/j.it.2005.08.013Get rights and content

Systemic lupus erythematosus (SLE, lupus) results from immune-mediated damage to multiple organs. Its pathogenesis should be viewed as a series of steps, beginning with impaired immune regulation that permits self-reactive T–B-cell activation, which results in the production of autoantibodies. Activated T and B cells then infiltrate tissues, which along with autoantibody and immune complex deposition, triggering local events that ultimately cause organ damage. Although improved understanding of early autoimmune events might open up avenues for disease prevention, future investigations must focus on the mechanisms of end-organ damage in model systems and how to translate this knowledge into human disease. Understanding the mechanisms of each pathogenetic step would provide a rational basis for the development of disease stage-specific diagnostic markers and treatments.

Section snippets

The challenge

Systemic lupus erythematosus (SLE) is the most heterogeneous autoimmune disease that affects multiple organs [1]. The disease progresses through four broad stages, that is, the presence of autoantibodies against a variety of ubiquitous self-antigens, deposition of autoantibodies and immune complexes in tissues, development of tissue inflammation and finally, tissue damage and fibrosis. Although there has been a marked improvement in five-year survival from <50% in the 1950s to >90% in the

Heterogeneity of SLE: different animal models represent its various stages and subsets

Although clinical criteria have helped clinicians in making the diagnosis of SLE, the marked heterogeneity in disease expression has posed a difficulty in clearly defining the disease and formulating mechanistic investigations. Consequently, many investigators have turned toward animal models, which develop a homogeneous disease recapitulating the serological and histopathological features of SLE [4]. Examples of such models include the (NZBxNZW)F1 (BWF1), MRL-MpJ and NZM.2410 mouse strains.

Up

Tracing the steps of the pathogenesis of SLE

The clinical syndrome, known as human lupus, might actually encompass several diseases that have similar clinical features, yet with different mechanisms of pathogenesis. Here, we envision the natural course and pathogenesis of SLE as a series of steps that are narrated in the following working roadmap (Figure 3). It is hoped that a better understanding of this roadmap will facilitate the development of treatment strategies that can block the progression of disease at each step in most patients.

Step 1: insufficient immune regulation in SLE – harnessing the capacity of inhibitory or suppressor T cells to suppress lupus

Otherwise healthy, non-autoimmune mice can be induced to develop antibodies to DNA and mild nephritis by in vivo stimulation of the Th cells that are capable of promoting autoantibody production [9]. These animals, however, completely recover from such an episode of autoimmunity, despite persistent exposure to autoreactive Th cells. Recovery from disease in these mice correlates temporally with the appearance of certain CD8+ T, CD4+CD25+ T and natural killer T (NKT) cells that are capable of

Step 2: activation of autoreactive T and B cells

Strikingly, impairments in almost every step of the immune response occur in SLE. As narrated in the following substeps, vigorous attempts are underway to characterize these impairments in animal models and to translate this knowledge into human disease.

Step 3: autoantibodies can cause SLE lesions

Although patients with SLE have autoantibodies against several different specificities, they are usually restricted to a recurring set of autoantigens. Such restricted polyclonality might be related to a unique case of molecular mimicry, whereby variable regions of autoantibodies contain shared T-cell epitopes [56]. Thus, T cells stimulated by a peptide derived from one autoantibody can stimulate several different B cells that express the shared epitope 20, 56. The importance of these

Step 4: tissue inflammation and disease activity

Although ample evidence supports a pathogenic role for autoantibodies, it is unclear how they cause the myriad lesions of lupus. Multiple mechanisms have been proposed. For example, certain murine anti-DNA antibodies interact with antigens in glomerular basement membrane or hippocampal neurons, thus initiating death or dysfunction of local cells, such as podocytes or neurons, respectively 59, 60. The autoantibody and immune complex deposition triggers the activation of the complement cascade,

Step 5: tissue fibrosis and organ damage

Results of repeated kidney biopsies in SLE patients and longitudinal analysis of renal pathology in BWF1 mice suggest that lupus nephritis progresses generally from focal glomerular infiltration to diffuse proliferative glomerulonephritis to glomerulosclerosis and eventually to tubulo-interstitial fibrosis [65]. Some models and patients, however, have only localized renal inflammation 8, 9, 22, whereas others have marked inflammation but not much renal fibrosis, and still others have severe

Synthesis

Parallel developments in human disease observations and animal model investigations have helped in tracing some pathogenetic steps that lead to the manifestations of lupus. Some observations made in animal models are already being translated into human clinical trials. However, past experience has taught us that a rush to clinical trials must not occur without a full realization that the biological basis by which an intervention might suppress disease in an animal model might not be

Acknowledgements

I am supported by grants from the NIH/NIAMS and NIDDK (AR47322, DK69282 and AR50797). I thank Robert Kimberly sincerely for suggestions.

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