Elsevier

Medical Hypotheses

Volume 79, Issue 2, August 2012, Pages 136-137
Medical Hypotheses

Still’s disease and the mitochondrion: The other face of an old friend?

https://doi.org/10.1016/j.mehy.2012.04.009Get rights and content

Abstract

Although Still’s disease has been first described more than one century ago, it still appears as an orphan entity, which should be separated from the other auto-inflammatory diseases (AID). The main reason to individualize Still’s disease among the AID is the absence of any genetic predisposition. Recently, the human mitochondria have been clearly implicated in the systemic inflammation that is observed during the innate immune response. After various types of cellular injuries, including infections, the release of “Damage-Associated Molecular Patterns” (DAMPs) from mitochondria can recruit circulating polymorphonuclear neutrophils (PMNs), monocytes and macrophages, along with the activation of NLRP3 inflammasome. Flares of Still’s disease usually mimic systemic bacterial infections, with high levels of PMNs, but no evidence of circulating bacteria. Ubiquitous and usually benign viruses, such as human herpes virus 6 (HHV-6), appear capable of inducing mitochondrial damages. Such a phenomenon could in turn initiate the flares of Still’s disease, thereafter persisting as an inappropriate and self-perpetuating reaction to an endogenous bacterial vestige, the mitochondrion itself.

Introduction

When, in 1896, George Frederic Still first identified the disease that now bears his name, he based his description on consistent clinical findings: a specific aspect of joint manifestations (elastic, fusiform and symmetrical joint swelling), diffuse lymphadenopathy and splenomegaly [1]. By themselves, these manifestations permitted to distinguish this newly described disease from other forms of chronic rheumatic diseases of the child, and particularly from juvenile rheumatoid arthritis.

Subsequently, Still’s disease kept its peculiar place in the spectrum of juvenile idiopathic arthritides (JIA), due to an evolution marked by prolonged inflammatory attacks, sometimes ongoing beyond childhood, separated by free intervals, with intermittent fever, skin lesions, serous exsudates, and delayed osteo-articular destructive lesions, along with the possibility of severe complications (macrophage activation, AA amyloidosis) [2], [3].

Once its difference recognized, Still’s disease became at the same time a kind of orphan disease. Despite many common features with infectious diseases, all searches for a bacterial or viral origin remained so far negative, even though some infections can simulate Still’s disease, at the beginning [4].

Still’s disease most probably reflects a disorder of the innate immunity, without evidence of auto-immunity, and shares many similarities with auto-inflammatory diseases (AID) [5].

Section snippets

Hypothesis

In the absence of any familial aggregation, the integration of Still’s disease into the group of monogenic AIDs faces an important obstacle to overcome [6], [7], [8]. Taking this point into account, it seemed difficult to ignore the major progresses that have been made in the field of pro-inflammatory cellular pathways. In particular, it was really tempting to examine the possible implication of mitochondrial metabolism, since concordant works recently stressed the role played by mitochondria

Conclusion

The hypothesis of an ambiguous role played by mitochondria – an old friendly symbion reconverting itself as an aggressive enemy – could be the unexpected explanation of both start and autonomous increase of the inflammatory burst that is currently registered in Still’s disease. After a cellular – mitochondrial? – injury, whatever the cause, the systemic circulation of DAMPs could act as a potent stimulus on the innate immunity, whose persistent and abnormal activation should be explained by a

Conflict of interest statement

None declared.

Acknowledgments

The authors are indebted to Dr. Jamel Elbenna for his very helpful comments. They also thank Mrs. Hélène Grimot and Mr. Robert de Ferrer for her kind assistance in writing this manuscript.

References (15)

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