Calculating the etiology of systemic lupus erythematosus.

Abstract

UNLABELLED:

Objective was to clarify the etiology and pathogenesis of systemic lupus erythematosus (SLE). Drug-induced lupus (DIL) and SLE are both found in humans, are exacerbated by the same viruses or drugs, and they are both more common in slow acetylators. Thus, DIL can be used as a model for SLE and the Adhami equation of DIL can be applied to SLE. Polyamines are the only possible link between the viral and amine hypotheses of SLE pathogenesis. Based on the Adhami equation, polyamines can explain the actual annual incidence of SLE in the general population. Putrescine is a very weak SLE-causing agent, while spermine and spermidine contribute equally in triggering SLE. The positively charged polyamines bind to negatively charged internucleosomal DNA and change its conformation from B (non-immunogenic) to Z (immunogenic). This is the major contribution of polyamines in triggering SLE. The other effects of polyamines are only secondary. Apoptosis is a necessary step in SLE pathogenesis, because it causes the internucleosomal fragmentation of DNA and exposes Z-DNA to the immune system (due to cell death). The next step is the production of anti-DNA antibodies, followed by other SLE phenomena. Polyamines not only cause SLE, but they are also important in sustaining the disease. Other endogenous and exogenous amines have additive effects with polyamines and may contribute in exacerbating SLE. When SLE is in the active phase, polyamine levels are higher as compared to remissions. Fluctuations in polyamine levels due to diet, metabolic factors, infections, intestinal flora, etc. or the presence of other amines may explain the course of SLE, characterized by remissions and exacerbations. Acetylcysteine is a drug that can be completely metabolized to acetyl groups. As such, this drug is proposed as the ideal acetyl donor for the acetylation of polyamines and other SLE-triggering compounds. Clinical trials will be necessary to test the role of acetylcysteine in the etiologic treatment of SLE.

CONCLUSIONS:

Changes in DNA conformation by polyamines are the first step in SLE pathogenesis. Many genetic and environmental factors may increase or decrease the effects or levels of polyamines, causing SLE exacerbations or remissions. Viruses and other infectious agents may cause SLE by producing polyamines or by increasing the levels of endogenous polyamines. The major autoimmune diseases are characterized by remissions and exacerbations and not by a continuously progressive course, as commonly believed. Consequently, they are not sustained by internal vicious cycles, but by the initial triggering agent(s). While the conventional treatment of autoimmune disorders is important in minimizing tissue damage, the neutralization of their etiology may be important in curing and preventing autoimmunity.

• Authors: Eftim Adhami
• Journal: Medical hypotheses (Med Hypotheses) Vol. 62 Issue 2 Pg. 237-46 ( 2004) ISSN: 0306-9877 [Print] United States
• PMID: 14962634 (Publication Type: Journal Article)

Chemical References

• Polyamines
• Spermine
• Spermidine
• Putrescine

Topics

• Animals
• Autoimmunity (immunology)
• Humans
• Lupus Erythematosus, Systemic (chemically induced, etiology, immunology)
• Models, Immunological
• Polyamines (immunology)
• Putrescine
• Spermidine
• Spermine