Genetic linkage studies and genome wide analysis have provided insights into complex medical diseases. Mycobacterium avium ss. paratuberculosis (MAP) causes Johneâs disease, an important enteric inflammatory disease mostly studied in ruminant animals. MAP is also the putative cause of Crohnâs disease. Moreover, MAP has been linked to other inflammatory diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis and multiple sclerosis. Genetic studies reveal an association between Parkinsonâs disease (PD), leprosy and Crohnâs disease and since discovered, these findings have been considered ââsurprisingââ. Autophagy and ubiquitinâproteosome systems are cellular systems that both fight intracellular pathogens (xenophagy) and maintain cellular protein quality control.
~ Coad Thomas Dow. McPherson Eye Research Institute, University of Wisconsin-Madison, 9431 WIMR, 1111 Highland Avenue, Madison, WI 53705, United States
Chippewa Valley Eye Clinic, 2715 Damon Street, Eau Claire, WI 54701, United States
Received 14 July 2014
Accepted 30 September 2014
Mycobacterium avium ss. paratuberculosis Zoonosis â The HundredYearWar â Beyond Crohnâs Disease
The factitive role of Mycobacterium avium ss. paratuberculosis (MAP) in Crohnâs disease has been debated for more than a century. The controversy is due to the fact that Crohnâs disease is so similar to a disease of MAP-infected ruminant animals, Johneâs disease; and, though MAP can be readily detected in the infected ruminants, it is much more difficult to detect in humans. Molecular techniques that can detect MAP in pathologic Crohnâs specimens as well as dedicated specialty labs successful in culturing MAP from Crohnâs patients have provided strong argument for MAPâs role in Crohnâs disease. Perhaps more incriminating for MAP as a zoonotic agent is the increasing number of diseases with which MAP has been related: Blau syndrome, type 1 diabetes, Hashimoto thyroiditis, and multiple sclerosis. In this article, we debate about genetic susceptibility to mycobacterial infection and human exposure to MAP; moreover, it suggests that molecular mimicry between pro-tein epitopes of MAP and human proteins is a likely bridge between infection and these autoimmune disorders.
Leonardo A. Sechi 1* and CoadThomas Dow2,3
1 Department of Biomedical Sciences, University of Sassari, Sassari, Italy
2 McPherson Eye Research Institute, University ofWisconsin, Madison, WI, USA
3 Chippewa Valley Eye Clinic, Eau Claire, WI, USA
AmĂ©lia M. Sarmento, Universidade
Fernando Pessoa, Portugal
Willem Van Eden, Utrecht University,
Hridayesh Prakash, University of
Leonardo A. Sechi , Department of
Biomedical Sciences, University of
Sassari, Viale San Pietro 43 b, Sassari
Mycobacterium avium subspecies paratuberculosisâAn environmental trigger of type 1 diabetes mellitus
Type 1 diabetes mellitus (T1DM) is an autoimmune disease. The etiology of T1DM is incompletely understood but environmental agent(s) are thought to trigger T1DM in the genetically at-risk. Humans are widely exposed to Mycobacterium avium subspecies paratuberculosis (MAP), a proven multi-host chronic enteric pathogen that is mostly studied in ruminant animals and causes the inflammatory disease paratuberculosis or Johneâs disease. In humans, MAP is the putative cause of Crohnâs disease and has been linked to sarcoidosis, autoimmune thyroiditis, multiple sclerosis and autoimmune diabetes. The role of MAP as a trigger for T1DM was first postulated in 2005; subsequent studies suggest a link. This article discusses MAP, human exposure to MAP, genetic susceptibility to MAP and MAP in human disease including T1DM.~ Coad Thomas Dow. Vol.2, No.1, 88-95 (2012) Journal of Diabetes Mellitus | doi:10.4236/jdm.2012.21014
Type 1 diabetes mellitus (T1DM) is an autoimmune disease. The etiology of T1DM is incompletely understood but environmental agent(s) are thought to trigger T1DM in the genetically at risk. Exposure to cowâs milk early in life is a recognized risk factor in the development of T1DM. Mycobacterium avium ss. paratuberculosis (MAP) is the cause of bovine Johneâs disease and also is thought to act as an immune antigen in Crohnâs disease and other granulomatous diseases. MAP is shed in cowâs milk and has been shown to survive pasteurization. Geneticsusceptibilities, epitope homologies and epidemiologic studies are presented that support MAP as a causative agent of T1DM in the genetically at risk.~ Dow CT.
Med Hypotheses. 2006;67(4):782-5. Epub 2006 Jul 7. journal reference
The plausibility of a causal role of Mycobacterium avium subspecies paratuberculosis (MAP) in Crohnâs disease has gone from controversial to compelling. This century old debate is resolving because of unfolding understanding of shared genetic susceptibilities for Crohnâs and mycobacterial infection in addition to newer laboratory tests to detect MAP which have linked MAP and Crohnâs. Mycobacterial heat shock proteins are associated with a multitude of ââautoimmuneââ diseases, including Type 1 diabetes mellitus (T1DM) and the initiating events of atherosclerosis. These heat shock proteins may come from MAP; this article postulates a causal role for MAP in multipleÂ inflammatory and ââautoimmuneââ diseases.~Thomas Dow C. Med Hypotheses. 2008 Dec;71(6):858-61. Epub 2008 Sep 11. journal reference
Background and Aim of the Work: Â Blau syndrome is an inherited granulomatous inflammatory disorder with clinical findings of uveitis, arthritis, and dermatitis. Although rare, Blau syndrome shares features with the more common diseases sarcoidosis andÂ Crohnâs disease. The clinical findings of Blau syndrome are indistinguishable from juvenile sarcoidosis; the mutations of Blau syndrome are on the same gene of chromosome 16 (CARD15) that confers susceptibility to Crohnâs disease. The product of this gene is part of the innate immune system. Â Mycobacterium avium ss. paratuberculosis (MAP) is the putative cause of Crohnâs disease and has been implicated as a causative agent of sarcoidosis. Methods. Archival tissues of individuals with Blau syndrome were tested for the presence of MAP. Results. DNA evidence of MAP was detected in all of the tissues. Conclusions. This article finds that MAP is present in Blau syndrome tissue and postulates that it has a causal role. The presence of MAP in Blau syndromeâan autosomal dominant, systemic inflammatory diseaseâconnects genetic and environmental aspects of âautoimmuneâ disease.~Dow CT, Ellingson JL. Autoimmune Dis. 2010 Jun 20;2010:127692.