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State of the Art. Four Easy Pieces

Interconnections between Tissue Injury, Intermediary Metabolism, Autoimmunity, and Chronic Degeneration

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