Correspondence

Autoimmune Diseases

N Engl J Med 2001; 345:1707-1708December 6, 2001

Article

To the Editor:

The review of autoimmunity by Davidson and Diamond (Aug. 2 issue)1 leaves many points open for debate. The field has never properly come to grips with the question of whether antibodies can damage or impair intact cells by binding to antigens within their cytoplasm. The Ro antigen is cytoplasmic. Is it really proved that antibodies to Ro “bind to the conducting system in the . . . heart, causing complete heart block”?

Without any qualifying remarks, the statement that “cardiac ischemia and necrosis cause heart-specific autoreactivity and myocarditis” is misleading. Dressler's syndrome is an uncommon complication of myocardial infarction. The vast majority of cases of myocardial infarction do not result in autoimmunity, nor do burns, severe tissue trauma, or most infections, unless the host has a particular set of susceptibility genes, which are present in only a small number of persons. Susceptibility genes must also be present in animal models in which tissue damage leads to autoimmunity.

The “danger hypothesis” has been oversold. On the one hand, massive tissue damage and infection do not generally trigger autoimmunity. On the other hand, the repeated intravenous administration of pure, deaggregated, endotoxin-free mouse antibodies almost inevitably provokes the formation of antimouse antibodies. If it did not do so, we would be using mouse monoclonal antibodies as therapeutic agents much more often than we do. Self-tolerance is alive and well.

Finally, the authors state that “the incidence of disease declines as the distance from regions where the disease is endemic increases.” Surely this is a truism. How could it be otherwise?

James W. Goding, M.D., Ph.D.
Monash Medical School, Prahran 3181, Australia
goding@med.monash.edu.au

1 References

1. 1

   Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001;345:340-350
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Dr. Goding's chief point seems to be that there are many areas of ignorance and controversy regarding autoimmune diseases. With this, we certainly agree. As for the particular issues he raises: first, anti-Ro antibodies have been shown to destroy the atrioventricular node in the fetal, not the maternal, heart; they have not been shown to bind directly to the conducting system. Second, we hope we did not imply that all tissue injury leads to autoimmunity and autoimmune disease. We cited an animal study in which T cells from animals subjected to myocardial ischemia were adoptively transferred into a normal animal and caused myocarditis. This example served to demonstrate that autoreactivity can arise in the absence of foreign antigen. We hope we have stated clearly that autoimmunity and autoimmune disease, whatever the trigger, arise only in a susceptible host.

It is clear that there are many ways to induce autoimmunity; one of them is through the presence of a proinflammatory microenvironment. We are not aware that we advanced the so-called danger hypothesis as a unifying theory of autoimmunity. This hypothesis will become useful when we know the molecular identity of the danger signal, the receptor or receptors to which it binds, and the ways in which cell function is then altered. At that point, we will have a mechanistic explanation. At this point, there is still much to be learned about autoimmunity.

Anne Davidson, M.D.
Betty Diamond, M.D.
Albert Einstein College of Medicine, Bronx, NY 10461
diamond@aecom.yu.edu

Citing Articles (1)

Citing Articles

1. 1

   Marc Gotkine, Peter G. E. Kennedy, Israel Steiner. (2010) Post infectious CNS disorders: towards a unified approach. Journal of Neurology 257:12, 1963-1969
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