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Review
. 2005 Nov;26(11):572-9.
doi: 10.1016/j.it.2005.08.013. Epub 2005 Sep 9.

SLE: Translating Lessons From Model Systems to Human Disease

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Free PMC article
Review

SLE: Translating Lessons From Model Systems to Human Disease

Ram Raj Singh. Trends Immunol. .
Free PMC article

Erratum in

  • Trends Immunol. 2006 Feb;27(2):59-60

Abstract

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.

Figures

Figure 1
Figure 1
Autoimmunity is common in the general population, whereas autoimmune diseases are rare. The presence of self-reactive T and B cells and autoantibodies is common in the general population. Only a small percentage of these individuals develop inflammatory disease and this is generally self-limiting. Some of these individuals, however, develop a more persistent but mild and usually localized, autoimmune disease, which is referred to as undifferentiated autoimmune or connective tissue disease. Finally, a small percentage of patients develop a full-blown autoimmune syndrome, such as SLE. The determinants of disease progression from the initiation of autoimmunity to full-blown disease expression can include the loss of suppressor mechanisms and the gain of pathogenic factors.
Figure 2
Figure 2
Major stages of disease progression in SLE (e.g. lupus nephritis). The disease course can be envisioned in two broad stages, namely (1) benign and (2) pathological autoimmunity. Each of these broad stages can be further sub-classified into two stages; the benign autoimmunity stage into the stage of (a) autoantibody development and of (b) autoantibody and immune complex deposition in tissues, and the pathological autoimmunity stage into stages of (2i) (df) inflammation and (2ii) (gi) fibrosis. (a) Anti-nuclear antibody in the serum of an SLE patient, detected by an indirect immunofluorescence assay using Hep-2 cells; stained nuclei appear green/yellow. (b) Glomerular (GI) and tubular (Tb) deposition of IgG, detected by a direct immunofluorescence assay; stained tissues appear pale green. (c–i) Renal histology in (c,f–h) periodic acid-Schiff (PAS), (d,e) hematoxylin and eosin (H&E) (i) and Masson’s trichrome stained sections. (c) Normal glomerulus and Tb. (d–f) Stages of renal inflammation in sections showing localized glomerular inflammation [focal glomerulonephritis (FGN)] in (d), diffuse proliferative glomerulonephritis (DPGN) with inflammatory cell infiltration and proliferation of glomerular cells in (e) and intense perivascular infiltration (PVI) in (f). (g–i) Stages of renal fibrosis in sections showing glomerulosclerosis (GS) (i.e. extracellular matrix deposition in glomeruli) in (g), fibrous crescent (FC) (i.e. periglomerular fibrosis) in (h) and advanced glomerular fibrosis with scarring (GF), dilated atrophic tubules (TA) and tubulo-interstitial fibrosis (TIF) (fibrosis in the interstitium of kidneys with loss of tubules) in (i). The disease course might serially progress from the steps (a) to (i) in some animal models, such as BWF1 mice. In other models, however, the disease might be limited to early steps, for example, BALB/c mice immunized with a DNA surrogate peptide develop steps (a) and (b) but have no inflammation (c) [7] and BALB/c mice injected with pristane develop steps (a) and (b) and have limited glomerular inflammation (d) [8,22]. In some other models, the disease advances further but exhibits predominance of one of the other steps, for example, MRL-lpr mice develop massive glomerular (e) and interstitial (f) inflammation but have generally limited glomerulosclerosis and fibrotic changes, whereas NZM.2410 mice develop profound glomerulosclerosis (g) without much glomerular inflammation [10]. These different animal models might represent different subsets or stages of human SLE.
Figure 3
Figure 3
Roadmap to disease development and progression in SLE. According to our working model, the lupus disease progresses through a series of steps: (1) immune dysregulation and (2) immunity against self generally occur long before the onset of the first symptoms that are manifestations of (3) autoimmune ‘invasion’ and (4) consequent inflammation. The autoimmune disease up to this stage is generally amenable to correction by the defenses of the body or by anti-inflammatory or immunosuppressive treatments. (5) Some patients, however, exhibit impaired tissue response to inflammation or have local or systemic factors that perpetuate tissue fibrosis and organ damage. The patients at stage (5) and beyond generally do not respond to currently available treatments.
Figure 4
Figure 4
Inhibitory and suppressor mechanisms that protect from the development of pathological autoimmunity. (a) Lupus-prone BWF1 and (b) normal CWF1 mice were immunized with anti-DNA antibody V-region peptides and monitored for the development of anti-DNA antibodies (and disease). Most T-cell lines generated from immunized BWF1 mice are CD4+ Th cells that promote anti-DNA antibody formation in vitro [9]. By contrast, although CWF1 mice develop CD4+ Th cells during initial immunizations, most T-cell lines, including CD8+ cells, CD4+CD25+Treg cells and NKT cells, generated from CWF1 mice recovering from disease suppress anti-DNA antibody production by lupus (BWF1) B cells [9,19,20]. Abbreviation: CTLs, cytotoxic T lymphocytes.

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