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Beckman Center for Molecular Medicine, Stanford University, Stanford, California
Correspondence and requests for reprints should be addressed to Lawrence Steinman, M.D., Professor of Neurology and Neurological Sciences and Pediatrics, Chairman, Interdepartmental Program in Immunology, Beckman Center for Molecular Medicine, Stanford University, Stanford, CA 94305. E-mail: steinman{at}stanford.edu
ABSTRACT
Four questions are posed: (1) Can tissue damage itself provoke autoimmunity? (2) Can genetic mutations of key structures produce tissue pathology and thus provoke autoimmunity? (3) Can acute immune damage produce tissue degeneration without further hallmarks of an immune response? (4) Can intermediary metabolism modulate immune damage to tissues? Four answers are given: (1) Tissue injury itself may lead to autoimmunity. Both innate and adaptive immunity may arise as a response to tissue injury, and the immune attack can further damage tissue. (2) Genetic mutations can lead to an immune response indistinguishable from autoimmunity, exemplified from Duchenne's Muscular Dystrophy and X-linked adrenoleukodystrophy. (3) Chronic immune damage may lead to tissue degeneration, with or without further hallmarks of an immune response. Variations on this theme, including inverse scenarios, are also possible: Inborn errors of metabolism may lead to tissue damage that may provoke an adaptive and or innate immune response. The immune response might further damage tissue. (4) Finally, perturbations of intermediary metabolism may modulate the immune response, controlling the extent of immune-mediated damage. Examples are taken from perturbations in the cholesterol pathway that influence the characteristics of the immune response, and with tryptophan metabolites that modulate autoimmunity and graft rejection. Inflammatory, degenerative, and autoimmune neurological disease will be discussed in terms of their implications for pathogenic mechanisms underlying chronic obstructive pulmonary disease.
Key Words: adrenoleukodystophy • Alzheimer's Disease • chronic obstructive pulmonary disease • Duchenne's Muscular Dystrophy • multiple sclerosis
Finding myself, knowledgeable about neurological diseases, and asked to lecture to a group of distinguished experts on lung diseases at a conference on chronic obstructive pulmonary disease (COPD), I chose to make some extrapolations from my area of knowledge. I decided to describe lessons we have learned from our current understanding of (1) neurodegenerative diseases, exemplified by Alzheimer's Disease; of (2) autoimmune diseases of the nervous system, exemplified by multiple sclerosis; and of (3) two genetic disorders of the nervous system and muscle, adrenoleukodsystrophy and Duchenne's muscular dystrophy. These lessons may well be applicable to understanding conditions like COPD.
Peter Atkins, in the introduction to his magnificent book Atkins' Molecules (1), mentions "the sense of sheer joy of seeing interconnections and explanations, the sense of delight in seeing why nature is the way it is, and the sense of understanding why a little change can have profound consequences." I organize this brief summation of my talk, delivered in June, 2005 in the magnificent village of Aspen, around a series of questions and brief answers. I hope to reveal my own joy in making some interconnections between some phenomena that occur in the realm of diseases of the nervous system, in the hope that the lessons might be applied to understanding COPD.
1. CAN TISSUE DAMAGE ITSELF PROVOKE AUTOIMMUNITY?
One potential trigger for autoimmunity is microbial infection. Microbial infection can provoke an inflammatory response with activation of aspects of both innate and adaptive immunity. Microbes share short peptide sequences that are identical to peptide sequences in self-antigens that are known epitopes for triggering autoimmunity. We have studied the peptide sequence p84-102 of myelin basic protein extensively. We first demonstrated in 1988 that this sequence is capable of inducing experimental autoimmune encephalomyelitis, known as EAE, in the SJL mouse (2, 3). Several microbes share this sequence, and have preserved the anchor residues for binding to the major histocompatibility complex and the key contact residues for T cell receptors recognizing MBPp84-102, as well as the main contact sites with antibodies recognizing this fragment of myelin basic protein (4, 5) (Table 1). This implies that an immune response to such peptide sequences on the microbes in Table 1 might trigger an immune response against myelin, since the structure that is recognized is identical. Parenthetically, one might ask what immunologists are talking about when they separate the world of "self" from the world of "non-self." There are no boundaries between these worlds of "self" and "non-self," when one looks at chemical structures and sequences.
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We have recently developed large scale microarrays to detect autoantibodies to lipids and to proteins and peptides (10, 11). There are many microbial lipids that are identical with lipids or cross-reactive with lipids in the myelin sheath. Such anti-lipid antibodies to a microbe can exacerbate clinical paralysis in EAE. Taken together, it is clear that immune responses to microbial peptides and microbial lipids can modulate autoimmune disease, culminating at times in organ-specific tissue damage. There is no reason to doubt that such similar scenarios could be in play for microbial infections in the lung, which might lead to tissue damage and induction of COPD. Microbial infection may therefore be a key trigger for COPD.
2. CAN GENETIC MUTATIONS OF KEY STRUCTURES LEADING TO TISSUE PATHOLOGY PROVOKE AUTOIMMUNITY?
Two examples from the field of neurology exemplify how a mutation in a structural gene can provoke an intense inflammatory reaction. In Duchenne's Muscular Dystrophy, caused by mutations in the structural protein of muscle known as dystrophin, there are inflammatory foci with T cells, macrophages, and B cells at the site of muscle degeneration (12). In children with X-linked adrenoleukodystrophy there is an intense inflammatory demyelinating neuropathology in the brain, with many features of acute disemminated encephalomyelitis and multiple sclerosis. The disease is caused by a mutation in ABCD1, a peroxisomal membrane protein (ALDP) that is part of a small family of related peroxisomal membrane proteins (13, 14). The parallels with these situations, and with 
1-antitrypsin deficiency leading to the develop of pulmonary emphysema with other associated inflammatory vasculitides (15), emphasize how disorders, genetic or epigenetic, in structural genes can lead to inflammation and even autoimmunity.
3. CAN ACUTE IMMUNE DAMAGE PRODUCE TISSUE DEGENERATION WITH OR WITHOUT FURTHER HALLMARKS OF AN IMMUNE RESPONSE?
There are examples of what M. B. A. Oldstone refers to as "hit and run" damage, where a microbial infection can instigate tissue damage, and after the eradication of the microbe, tissue damage persists, though evidence of the virus is absent (9). There may be a parallel in diseases like Alzheimer's Disease, and even in multiple sclerosis, when we views silent lesions of chronic MS. In both of these situations there are no classical signs of inflammation in the brain, and yet immunohistochemistry and analysis of gene transcripts reveals some of the hallmarks of an immune reaction including inflammatory cytokines like tumor necrosis factor, complement, and immunoglobulin Fc receptors (16–18). In COPD, similar hints of an earlier inflammatory response are present, based on recent microarray work from Golpon and coworkers (19).
4. CAN INTERMEDIARY METABOLISM MODULATE IMMUNE DAMAGE TO TISSUES?
We have been studying the remarkable role of statins, inhibitors of the enzyme HMG-CoA reductase, in the cholesterol pathway (20). Remarkably, statins modulate autoimmune activity, down-regulating the class II major histocompatibility complex molecules, co-stimulatory molecules, and Th1 cytokines, while pushing the immune response toward Th2. All these effects are reversed when mevalonate is given, thus alleviating the block induced with statins. In early clinical trials in multiple sclerosis, statins have shown promise of reducing disease activity (21). Remarkably, perturbations in isoprenoid metabolism caused by a deficiency of the enzyme mevalonate kinase produce a syndrome with periodic fevers, elevation in immunoglobulin D, and autoimmune phenomena like arthralgias (22, 23). Recent research from our lab indicates that catabolites of the essential amino acid tryptophan are also able to modulate autoimmunity (24). The kynurenines, breakdown products of tryptophan, induce a Th2 shift and suppress paralytic disease in an animal model of multiple sclerosis, much like the statins are able to do. Kynurenines decrease inflammation and in turn reduce expression of class II major histocompatibility molecules on microglial cells, and co-stimulatory molecules on T cells that infiltrate the brain (24). It is striking that amino acid metabolism, as well as cholesterol metabolism, can have enormous effects on the development of autoimmune disease. Clearly intermediary metabolism may have the capacity to influence chronic conditions like COPD.
These four easy pieces, where I have tried to connect certain unusual observations and place them in a context relevant to COPD, provide a basis for further experimentation that may help elucidate the basis of this lung disease, and even point toward novel therapy.
ACKNOWLEDGMENTS
The author thanks the organizers of the Aspen Lung Conference for the opportunity to meet leaders in the field. He learned a great amount of exciting new information.
FOOTNOTES
Conflict of Interest Statement: L.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form March 17, 2006; accepted in final form March 27, 2006)
REFERENCES
This article has been cited by other articles:
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  M. G. Cosio, M. Saetta, and A. Agusti Immunologic Aspects of Chronic Obstructive Pulmonary Disease N. Engl. J. Med., June 4, 2009; 360(23): 2445 - 2454. [Full Text] [PDF]
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