Open access

Environmental Triggers of Type 1 Diabetes Mellitus – Mycobacterium Avium Subspecies Paratuberculosis

Written By

Coad Thomas Dow and Leonardo A. Sechi

Submitted: 09 November 2010 Published: 25 November 2011

DOI: 10.5772/20614

From the Edited Volume

Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy

Edited by David Wagner

Chapter metrics overview

2,626 Chapter Downloads

View Full Metrics

1. Introduction

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. In the United States the prevalence of T1DM is increasing and is approximately 1 in 300 by 18 years of age. Research into risk factors for T1DM is an active area with attempts to identify genetic and environmental triggers that could potentially be targeted for intervention (Maahs et al., 2010).

The most important autoimmune diabetes triggering factors are thought to be infectious, dietary, perinatal, and/or psychosocial. Historically, enteroviruses (especially Coxsackie B virus) have been the most commonly regarded infectious triggering agents (Peng & Hagopian, 2006).

Evidence supports the critical role of exogenous factors in the development of T1DM: 1. less than 10% of individuals with HLA-conferred diabetes susceptibility progress to clinical disease, 2. pair-wise concordance of T1DM of less than 40% among monozygotic twins, 3. more than 10-fold difference in the disease incidence among Caucasians living in Europe, (annual rate Macedonia 3.2/100,000 vs. Finland 54/100,000) 4. several-fold increase in the incidence over the last 50 years, and 5. migration studies that indicate disease incidence increases in population groups who have moved from a low-incidence to a high-incidence region. (Knip et al., 2005).

The postulate that MAP plays a causal role in T1DM was presented at the 2005 Colloquium on Paratuberculosis (Dow, 2005) and published in 2006 (Dow, 2006). To understand the rationale of the hypothesis it is necessary to review MAP, the role MAP plays in animal disease and the proposed role MAP has in human disease.

Advertisement

2. Mycobacterium avium ss. paratuberculosis (MAP)

MAP is a gram-positive, acid-fast staining small rod-shaped bacterium. As with members of the Mycobacteriaceae genus, it has a unique cell wall structure rich in complex lipids (fig. 1). The thick and chemically distinctive cell wall of mycobacteria is responsible in large measure for the robust nature of these bacteria, both within the host cell and in the environment. The pathogenic potential of mycobacteria is correlated with their growth rate. Paradoxically, slow-growing mycobacteria are more virulent than fast-growing mycobacteria. With the exception of Mycobacterium leprae (the cause of leprosy in humans), which cannot be cultured in vitro, MAP has the slowest growth rate of pathogenic mycobacteria. After isolation from infected animals and grown under optimal conditions colonies of MAP are typically not visible for 3 months or more (Collins, 2003).

Figure 1.

Electron Microscopy of Mycobacterium avium ss. paratuberculosis (MAP).Image courtesy of Dr. Mike Collins, University of Wisconsin – Madison.

Mycobacterium avium subspecies paratuberculosis (MAP) causes a chronic granulomatous inflammation of the intestines in ruminant animals called Johne’s disease. Mostly studied in dairy cattle, goats and sheep, MAP also causes a chronic inflammation of the intestines in beef cattle and in a wide variety of other domestic and wild ruminants. MAP-induced enteric inflammation has been found in monogastric animals including dogs and pigs as well as four different types of subhuman primates – macaques, baboons, gibbons and cotton-top tamarins’’ (Hermon-Taylor et al., 2000). A majority of the dairy herds in the United States and Europe have infected animals within the herd (Stabel, 1998).

2.1. MAP and human exposure

The article, Evolutionary bottlenecks in the agents for tuberculosis, leprosy and paratuberculosis (Frothingham, 1999), indicates that these parasitic mycobacteria are different from the ‘‘environmental’’ mycobacteria and may reflect opportunities afforded the parasitic mycobacteria by human cohabitation with domesticated animals combined with consolidation of populations. More crowded conditions may have changed tuberculosis, leprosy, and paratuberculosis from sporadic to epidemic diseases.

Mycobacterium avium ss. paratuberculosis (MAP)is present in pasteurized milk (Millar et al., 1996, Ellingson et al., 2005), infant formula made from pasteurized milk (Hruska et al, 2005), surface water (Pickup et al., 2005, Whan et al., 2005, Pickup et al, 2006), soil (Pickup et al., 2005), cow manure ‘‘lagoons’’ that can leach into surface water, cow manure in both solid and liquid forms that is applied as fertilizer to agricultural land (Grewal et al., 2006), and municipal tap water (Collins, 2003), providing multiple routes of transmission to humans. In a recent study in Ohio the DNA of MAP was detected in over 80% of domestic water samples (Beumer et al., 2010).

Normal water treatment processes such as filtration and chlorination amplify rather than eliminate mycobacteria organisms by killing off their competitors (Falkinham, 2003). In addition, mycobacteria organisms grow on tap water pipes (Falkinham & Norton, 2001), in biofilms (Vaerewijck et al., 2005) and on plastic water bottles (Tatchou-Nyamsi-Konig et al., 2009). It is estimated that mycobacteria may be present in drinking water in “massive numbers,” on the level of up to 700,000 or 7 x 105 organisms per liter of water (Falkinham et al., 2001).

Advertisement

3. MAP and human disease – inflammatory bowel disease and sarcoidosis

Beyond Johne’s disease of animals, MAP is the putative cause of the striking similar Crohn’s disease of humans. Although there has been a century-long debate, the role of MAP in Crohn’s has evolved from controversial to compelling (Chamberlin et al., 2007,Feller et al., 2007, Mendoza et al., 2010). The major source of the debate is that conventional methods of detecting bacteria – namely, culture and stain - are largely ineffective in detecting MAP. However, with newer laboratory techniques, primarily PCR, evidence of MAP is readily found in Crohn’s tissues (Chiodini, 1989, McFadden et al, 1987); it can be visualized within the granulomas by in situ hybridization (Sechi, 2001): and, with extreme care and patience, MAP can be grown from the gut and blood of Crohn’s patients (Naser et al., 2004, 2009, Sechi et al., 2005).

MAP has also been reported as a candidate pathogen in the causation irritable bowel syndrome (Scanu et al., 2007) and some suspect that MAP causes the spectrum of inflammatory bowel disease including Crohn’s, ulcerative colitis and irritable bowel syndrome (Pierce, 2010). Irritable bowel syndrome is a widespread abdominal condition that affects about 10 to 15% of people in the industrialized economies of Europe, North America, Australasia, and Japan, with a rising prevalence among the populations in the developing economies of Asia. Some consider irritable bowel syndrome a form fruste of Crohn’s disease (Olbe, 2008).

In addition to inflammatory bowel disease MAP has been historically linked is sarcoidosis; a multi-system inflammatory disease in which DNA evidence of MAP has been found (sporadically) in sarcoid granulomas (el-Zaatari, 1996).

Advertisement

4. Genetics and T1DM

Early studies indicated that the HLA region on chromosome 6p21 (commonly termed IDDM1, for insulin-dependent diabetes mellitus locus) is a critical susceptibility locus for T1DM (Nerup et al., 1974, Singal & Blajchman, 1973). A comprehensive review of the genetics of T1DM is beyond the scope of this chapter; instead, we will focus on genes that appear to be permissive to MAP (CARD15 and SLC11A1) and then to MAP and T1DM specifically (SLC11A1). Though we will focus on these genes, it is short sighted to expect that only one or two genes affect the susceptibility of humans to mycobacterial infections and autoimmune disease. Gene-gene interaction (epistasis) is known with regard to tuberculosis susceptibility (de Wit et al., 2010). For instance, there seems to be a role for vitamin D as well as the VDR gene (vitamin D receptor) (Hayes et al., 2003, Motohashi et al., 2003). In addition to regulation of bone and mineral metabolism, Vitamin D is a potent modulator of the immune system (Zella & DeLuca, 2003). Vitamin D activity occurs via the VDR. VDR is part of the steroid receptor super-family and is widely expressed in many cell types including lymphocytes, macrophages and the insulin producing pancreatic beta-cells (Hayes et al, 2003). Vitamin D and VDR, have been implicated in the susceptibility of TIDM: VDR gene polymorphisms have been described in TIDM in Taiwanese (Chang et al., 2000), Indian Asians (McDermot et al., 1997), Germans (Pani et al., 2000), Spaniards (Marti et al., 2004), Japanese (Ban et al., 2001) and Croatians (Skrabic et al., 2003). Additionally, calcitriol – the hormonal form of vitamin D – prevents or markedly suppress experimental TIDM (Deluca & Cantorna, 2001) and is active against tuberculosis (Jo, 2010).

4.1. Genetics – CARD15

The CARD15 gene is part of the ancestral innate immune system that senses and eliminates bacteria (Girardin et al., 2003, Hugot et al., 2002, Inohara et al., 2003); it is part of the newly recognized, larger CATERPILLER gene family that acts as sensors to detect pathogens and regulates inflammatory and apoptotic responses (Ting & Davis, 1985). Defects in the CARD15 gene are associated with Crohn’s disease susceptibility (Hampe et al., 2002). In 2005, Sechi reported that more than 70 percent of people in Sardinia with Crohn's disease carry at least one of the susceptibility-associated NOD 2/CARD 15 alleles and were infected with MAP.

Insights into genetic susceptibility and MAP infection can be found in a rare inflammatory disease, Blau syndrome. Blau syndrome is an inherited granulomatous inflammatory disorder with clinical findings of uveitis, arthritis, and dermatitis (Blau, 1985). Although rare, Blau syndrome has been of interest in current medical literature because of the discovery that places its genetic defect on the same Crohn’s susceptibility CARD15 gene (Hampe et al., 2002, Miceli-Richard et al., 2001). Linkage studies have placed the gene on chromosome 16; originally referred to as the NOD2 gene, it is now known as the CARD15 gene (Hugot et al., 2002). The Blau syndrome susceptibility component of the CARD15 gene is at the nucleotide binding site domain (Hampe et al., 2002, Wang et al., 2002) while the Crohn’s susceptibility is at the N-terminal leucine-rich repeat domain (Hugot et al., 2002, Lesage et al., 2002). The CARD15 gene is part of the ancestral innate immune system that senses and eliminates bacteria (Girardin et al., 2003, Inohara et al., 2003).

The clinical findings of Blau syndrome are one and the same as juvenile sarcoidosis; and, indeed, de novo CARD15 defects are consistently found in cases of sporadic juvenile sarcoidosis – Blau syndrome (Kanazawa et al., 2005, Rose et al., 2005). For these reasons - the clinical appearance of sarcoidosis and a shared genetic susceptibility with Crohn’s - it was proposed that MAP could have a role in Blau syndrome. The following results were presented at the 2005 Colloquium on Paratuberculosis (Dow) and published in 2010 (Dow & Ellingson, 2010):

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 syndrome—an autosomal dominant, systemic inflammatory disease—connects genetic and environmental aspects of “autoimmune” disease.

The complexity of genetic susceptibility and microbial infection can be reflected in these two diseases (Crohn’s and Blau), both having polymorphisms of the CARD15 gene. The proposed etiopathology is that with adequate MAP exposure, an individual with SNPs within one CARD15 location (nucleotide binding domain) will exhibit Blau syndrome and if the SNPs are within another location of the same gene (leucine-rich-repeat domain) they exhibit Crohn’s disease. CARD15 defects of the leucine--rich-repeat domain, result in an aggressive phenotype of Crohn’s disease (Lacher et al., 2010). Adding to the complexity is that there are several susceptibility genes associated with Crohn’s (Franke et al., 2010).

4.2. Genetics - SLC11A1

One additional gene associated with Crohn’s susceptibility is the SLC11A1 gene (Sechi et al., 2006). Natural resistance-associated macrophage protein 1 (NRAMP1) is now strictly referred to as SLC11A1 (solute carrier 11a1). The gene that encodes for this protein is recognized as having a role in the susceptibility of humans and animals to a number of infections, including mycobacterial infections, and is associated with a number of autoimmune diseases as well. In human beings, the SLC11A1 gene is located on chromosome 2q35. It encodes an integral membrane protein of 550 amino acids that is expressed exclusively in the lysosomal compartment of monocytes and macrophages (Canonne-Hergaux et al., 1999).

The product of the SLC11A1 gene modulates the cellular environment in response to activation by intracellular pathogens by acidifying the phagosome thus killing the pathogen (Lapham et al., 2004). As such, it plays a role in host innate immunity (Wyllie et al., 2002). Mutation of SLC11A1 impairs phagosome acidification yielding a permissive environment for the persistence of intracellular bacteria (Hackam et al., 1998).

Advertisement

5. SLC11A1 in infectious and autoimmune disease

Sarcoidosis, the previously mentioned systemic disease associated with MAP, is also associated with polymorphisms of the SLC11A1 gene (Dubaniewicz et al., 2005). Susceptibility to mycobacterial diseases tuberculosis, leprosy and Buruli’s ulcer are associated with polymorphism of the SLC11A1 gene (Stienstra et al., 2006). Similar polymorphisms are associated with Johne’s disease (paratuberculosis) in cattle (Ruiz-Larrañaga et al., 2010), goats (Korou et al., 2010), and sheep (Purdie et al., 2011). When researchers at the Belgium Pasteur Institute developed a murine model for MAP infection, they created an SLC11A1 defect mouse (Roupie et al., 2008).

Given the pivotal roles that SLC11A1 plays in innate immunity, it is not surprising that the relationship between polymorphisms in SLC11A1 and a number of mycobacterial as well as autoimmune diseases has been explored (Blackwell et al, 2003). Associations have been found with leprosy (Hatta et al., 2010), tuberculosis (Bellamy et al., 1998), rheumatoid arthritis (Ates et al., 2009), visceral leishmaniasis (Mohamed et al., 2004), multiple sclerosis (Kotze et al., 2001, Gazouli et al., 2008b), inflammatory bowel disease (Gazouli et al., 2008a, Kotlowski et al., 2008, Sechi et al., 2006) and type 1 diabetes mellitus (Paccagnini et al., 2009, Takahashi et al., 2004).

Advertisement

6. MAP and Type 1 diabetes

Type 1 diabetes mellitus (T1DM) is an autoimmune disease manifest by progressive T cell-mediated autoimmune destruction of insulin-producing beta cells in the pancreatic islets of Langherans (Eisenbarth, 1986). Dow in 2005 postulated a causative role for MAP in the T1DM, Sechi in 2007 found the DNA of MAP in the blood of autoimmune (type 1) patients but not non-autoimmune (type 2) diabetics (Rosu et al., 2009, Sechi, et al., 2007, 2008). Sechi also found an association of polymorphisms of the SLC11a1 gene and MAP in T1DM patients (Paccagnini et al., 2009).

While it may be intuitive to envision an occult presence of MAP as an infective agent producing a granulomatous lesion of Crohn’s or sarcoidosis; it is broader divide to assign a role for MAP in T1DM. The link connecting MAP and T1DM comes from the concept of molecular mimicry: protein elements of the pathogen “look like” elements of the host to a degree that immune responses directed at the pathogen also attack the host.

One of the proposed links is the mimicry of mycobacterial heat shock protein of MAP (HSP65) and pancreatic glutamic acid decarboxylase(GAD) (Dow, 2006).

Advertisement

7. Molecular mimicry/ heat shock proteins - HSP65

Molecular mimicry has long been implicated as a mechanism by which microbes can induce autoimmunity (Oldstone, 1987, Raska & Weigl, 2005). Rheumatic fever is the classic example for molecular mimicry between an infecting agent—Streptococcus pyogenes (group A streptococcus) and a related autoimmune disease in humans (Guilherme et al., 2005, Kaplan & Svec, 1964, Kirvan et al., 2003). The disease is characterized by damage to the heart, joints, and the central nervous system (Sydenham’s chorea). The activity of the host’s immune system against the streptococcus generates a cross-recognition to human tissue causing an autoimmune reaction. Heart damage is the most serious consequence and is present in 30 to 45% of the cases - mostly causing damage to the heart valves.

Heat shock proteins (HSPs) are produced in response to environmental stress. They act in a protective capacity helping cells survive stressful conditions and promoting recovery (Parsell & Lindquist, 1993). During an active immune response to infection, both the host and the microorganisms synthesize HSPs. The increased expression of both self and infective stress proteins and the extensive sequence homology between microbial and human HSP (50–80% amino acid homology of mycobacterial HSP65 versus human HSP60) have led to the concept that HSPs are involved in the etiology and pathogenesis of many immune mediated disorders (Lamb & Young, 1990). Mycobacterial HSPs have been found in a myriad of autoimmune diseases (Jarjour et al., 1991). For example, the mycobacterial 65 kDa HSP has been implicated in the pathogenesis of rheumatoid arthritis (Moudgil et al.,1997, Quayle et al., 1992), autoimmune hepatitis (Miyata et al.,1995), primary biliary cirrhosis (Vilagut et al.,1997) and scleroderma (Danieli et al., 1992). HSP65 is implicated in multiple vasculitis-associated systemic autoimmune diseases such as Kawasaki disease (Yokota et al., 1993), Behcet’s disease (Direskeneli & Saruhan-Direskeneli, 2003) and Takayasu’s arteritis (Aggarwal et al., 1996).

Advertisement

8. Molecular mimicry and Type 1 diabetes mellitus

Individuals at-risk for T1DM produce anti-GAD antibodies. HSP65 was first associated with T1DM via GAD in 1990 (Jones et al., 1990). Mycobacteria produce HSP65 in response to stress. There is marked homology between mycobacterial HSP65 and human HSP60 (Jindal et al., 1989). Epitope homology between MAP/human HSP60/65 and pancreatic glutamic acid decarboxylase (GAD) likely triggers the anti-GAD antibodies that secondarily destroy the pancreas (Jones et al., 1993).

Mycobacterial HSP65 provides a well-described diabetogenic peptide, p277 (Liang et al., 2010). The critical role of immunity against hsp65 and its T-cell epitope, p277 was proven in two different experimental animal model systems: the spontaneous diabetes that develops in the diabetes model NOD (non-obese diabetic) mice, and the autoimmune diabetes induced by a very low dose of the toxin streptozotocin (STZ). Pre-diabetic NOD mice manifest spontaneous antibody formation and T cell responses to hsp60 and to peptide p277 prior to the onset of diabetes (Birk et al., 1996, Elias et al., 1990, Elias et al., 1991). A single administration of the peptide p277 conjugated to carrier molecules can induce diabetes in C57BL/6 mice and in other strains not genetically prone to develop diabetes (Elias et al., 1995). Conversely, a single injection of unconjugated peptide p277 in NOD mice could arrest the diabetogenic autoimmune process, even when it was advanced (Elias et al., 1991, Elias & Cohen, 1994, Elias & Cohen, 1995). Additionally, administration of peptide p277 could prevent the development of autoimmune diabetes induced by very low dose of STZ in 57BL/KsJ mice strain (Elias & Cohen, 1996).

Advertisement

9. T1DM and milk

We now have come full circle regarding MAP, exposure to MAP, MAP in animal and human disease, epitope homology between mycobacterial HSP65 (particularly p277) and pancreatic GAD. The observation regarding risk of T1DM and early life exposure to milk warrants discussion.

Several studies indicate an association between early exposure to dietary cow’s milk and an increased risk of TIDM. (Akerblom & Knip, 1998, Gerstein, 1994; Gimeno & deSouza, 1997). These studies were prompted by the observation that children at risk for TIDM who were breast fed exclusively for more than six months were less likely to have TIDM later in life than similar risk children who were weaned onto cow’s milk-based formula at an earlier age. This observation spawned a large study, the TRIGR study: Trial to Reduce IDDM in the Genetically at Risk (Akerblom et al., 2010). The postulate is that there is something about cow’s milk protein that is an immunologic trigger for TIDM and that breaking the protein with hydrolysis may eliminate the trigger. The TRIGR study is an ongoing, 17-country study enlisting 6200 infants who are genetically at risk to develop TIDM. Children weaned early from breastfeeding are randomized into two groups; one receiving traditional cow’s milk-based formula and the other receiving formula in which the protein has been hydrolyzed. A recent, smaller but somewhat parallel study shows that exposure to the hydrolyzed infant formula resulted in lessened incidence of T1DM (Knip et al., 2010). Antibodies against specie specific MAP proteins were found in Sardinian children involved in the TRIGR study (Sechi, personal communication) As previously mentioned, viable MAP has been found in infant formula powder (Hruska et al., 2005).

Advertisement

10. MAP and other autoimmune disease – thyroiditis and multiple sclerosis

Two recent articles link MAP to autoimmune (Hashimoto’s) thyroiditis. The same molecular mimicry principle is suggested as the link between MAP (HSP65) and the organ-specific autoantigens of thyroiditis (D'Amore et al., 2010, Sisto et al., 2010). Another recent article implicates MAP in multiple sclerosis. Molecular mimicry and SLC11A1 associations are germane here as well (Cossu et al., 2011, Gazouli et al., 2008b).

11. MAP – the future

While evidence mounts that MAP is, indeed, a zoonotic agent, what policies and interventions might be employed to address curtailing MAP and the effects of its persistence in individuals? Presently, sound farm management practices and stringent culling are considered the best means to reduce the spread of MAP from animal to animal, as well as from farm to farm (Tavornpanich et al., 2008). However, because such practices have yet to eliminate MAP from food animals, other preventive or curative measures are needed. Industry has made an attempt to assess the risk of a positive MAP/Crohn’s association (Groenendaal & Zagmutt, 2008).

TASF is a Swiss-based international forum for Transmissible Animal Diseases and Food Safety. TASF acknowledges the uncertainties of the zoonotic potential of MAP for Crohn’s disease. TASF suggests that “… a decision by food safety regulators to exercise the “precautionary principle”, label MAP as a potential zoonotic agent, and adopt measures to limit as much as possible the levels of MAP contamination of raw milk and meat would go far to protect the coming generations of children from MAP exposure, possible infection, and potentially Crohn’s disease.” (TAFS, white paper, 2009).

Preliminary studies with a probiotic of the Dietzia species have been shown effective in treating clinically ill adult cows with Johne’s disease and in preventing Johne’s in calves (Click & VanKampen, 2009, 2010). The use of Dietzia has also been suggested for individuals with inflammatory bowel disease (Click, 2011). Vaccines are effective in reducing the incidence of clinical Johne’s disease (Kormendy, 1994; van Schaik et al., 1996) and attenuate pre-existing infection (Gwozdz et al., 2000). However, such whole killed vaccines do not eliminate subclinical MAP infection or its persistence in the gut. Additionally, about half of the animals receiving whole killed MAP vaccines become false positive using the conventional tuberculin skin test diagnostic for bovine tuberculosis (Mackintosh et al., 2005, Muskens et al., 2002). DNA vaccination may have an interesting application: Sechi et al., (2006) showed that lambs vaccinated with plasmids encoding mycobacterial antigens produced a Th1 immune response similar to that generated by natural infection by MAP. Moreover, lambs vaccinated with DNA mycobacterial antigens (expecially HSP65) were protected against MAP infection. Additionally, the unfolding knowledge regarding susceptibility polymorphism of genes such as the SLC11a1 gene described in this chapter may lead to breeding practices that would limit MAP infection in breeding lines thus keeping it from the human food chain.

In humans with MAP-associated disease recognition of both the need to treat as an infectious disease as well as the need to avoid further exposure is paramount. Aggressive anti-mycobacterial treatment has had beneficial effect in those who can tolerate the treatment (Borody et al., 2007, Hermon-Taylor, 2002). Vaccines against MAP for use in humans are being advocated and prototypes are being developed (Bull et al., 2007).

12. Conclusion

The controversy regarding MAP and human disease has been going for a century and will likely continue for a long time. T1DM has only recently been added to the discussion - and controversy. In addition to the human toll to individuals with T1DM, the dollar cost is extreme; the burden is passed along to all of society in the form of higher insurance premiums and taxes, reduced earnings, and reduced standard of living. Each year T1DM costs this country $14.4 billion (11.5–17.3) in medical costs and lost income. Were the disease eliminated by therapeutic intervention, an estimated $10.6 billion (7.2–14.0) incurred by a new cohort and $422.9 billion (327.2–519.4) incurred by the existing number of T1DM patients over their lifetime would be avoided (Tao et al., 2010). This alone should elevate the discussion, draw resources and bring a sense of urgency to the MAP/T1DM connection.

References

  1. 1. Aggarwal A. Chag M. Sinha N. Naik S. 1996 Takayasu’s arteritis: Role of Mycobacterium tuberculosis and its 65 kDa heat shock protein. Int J Cardiol 1996 55 1 49 .
  2. 2. Akerblom H. K. 2010 The TRIGR Study Group. The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up. Diabetologia. 2010 Dec 12.
  3. 3. Akerblom H. K. Knip M. 1998 Putative environmental factors in Type 1 diabetes. Diabetes Metab Rev 1998 14 1 31 .
  4. 4. Ates O. Dalyan L. Musellim B. Hatemi G. Turker H. Ongen G. Hamuryudan V. Topal-Sarikaya A. 2009 NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis. Int J Immunogenet 2009; 36 15 19
  5. 5. Ban Y. Taniyama M. Yanagawa T. Yamada S. Maruyama T. Kasuga A. et al. 2001 Vitamin D receptor initiation codon polymorphism influences genetic susceptibility to type 1 diabetes mellitus in the Japanese population. BMC Med Genet 2001 2:7 [Epub 2001 June 25].
  6. 6. Bellamy R. Ruwende C. Corrah T. Mc Adam K. P. Whittle H. C. Hill A. V. 1998 Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998; 338 640 644
  7. 7. Beumer A. King D. Donohue M. Mistry J. Covert T. Pfaller S. 2010 Detection of Mycobacterium avium subsp. paratuberculosis in drinking water and biofilms by quantitative PCR. Appl Environ Microbio 2010 Nov 76 21 7367 70 . Epub 2010 Sep 3.
  8. 8. Birk O. S. Elias D. Weiss A. S. Rosen A. van-der Zee. R. Walker M. D. Cohen I. R. 1996 NOD mouse diabetes: the ubiquitous mouse hsp60 is a beta-cell target antigen of autoimmune T cells. J Autoimmun. 1996 Apr;9 2 159 66 .
  9. 9. Blackwell J. M. Searle S. Mohamed H. White J. K. 2003 Divalentcation transport and susceptibility to infectious and autoimmune disease: Continuation of the Ity/Lsh/Bcg/Nramp1/ Slc11a1 gene story. Immunol Lett 2003 85 2 197 .
  10. 10. Blau B. 1985 Familial granulomatous arthritis, iritis, and rash, Journal of Pediatrics, 107 5 689 693 , 1985.
  11. 11. Borody T. J. Bilkey S. Wettstein A. R. Leis S. Pang G. Tye S. 2007 Anti-mycobacterial therapy in Crohn’s disease heals mucosa with longitudinal scars. Dig Liver Dis. 2007 May 39 5 438 44 . Epub 2007 Mar 21.
  12. 12. Bull T. J. Gilbert S. C. Sridhar S. Linedale R. Dierkes N. Sidi-Boumedine K. Hermon-Taylor J. 2007 A novel multi-antigen virally vectored vaccine against Mycobacterium avium subspecies paratuberculosis. PLoS One. 2007 Nov 28 2(11):e1229 .
  13. 13. Canonne-Hergaux F. Gruenheid S. Govoni G. Gros P. 1999 The Nramp1 protein and its role in resistance to infection and macrophage function. Proc Assoc Am Physicians 1999; 111 283 289
  14. 14. Chamberlin W. Borody T. Naser S. 2007 MAP-associated Crohn’s disease MAP, Koch’s postulates, causality and Crohn’s disease. Dig Liver Dis 39 792 794 .
  15. 15. Chang T. J. Lei H. H. Yeh J.I. et al. 2000 Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population. Clin Endocrinol (Oxf) 2000 52 5 575 .
  16. 16. Chiodini R. J. 1989 Crohn’s disease and the mycobacterioses: a review and comparison of two disease entities. Clin Microbiol Rev 1989; 2 90 117
  17. 17. Click R. E. Van Kampen C. L. 2010 Assessment of Dietzia subsp. C79793-74 for treatment of cattle with evidence of paratuberculosis. Virulence. 2010 May-Jun 1 3 145 55 .
  18. 18. Click R. E. Van Kampen C. L. 2009 Short communication: progression of Johne’s disease curtailed by a probiotic. J Dairy Sci. 2009 Oct 92 10 4846 51 .
  19. 19. Click R. E. 2011 Successful treatment of asymptomatic or clinically terminal bovine Mycobacterium avium subspecies paratuberculosis infection (Johne’s disease) with the bacterium Dietzia used as a probiotic alone or in combination with dexamethasone: Adaption to chronic human diarrheal diseases. Virulence. 2011 Mar 1;2(2).
  20. 20. Cossu D. Cocco E. Paccagnini D. Masala S. Ahmed N. et al. 2011 Association of Mycobacterium avium subsp. paratuberculosis with Multiple Sclerosis in Sardinian Patients. PLoS ONE 6(4): e18482. doi:10.1371/journal.pone.0018482
  21. 21. Collins M. T. 2003 International Handbook of Foodborne Pathogens Edited by Marianne D. Miliotis and Jeffrey W. Bier CRC Press 2003
  22. 22. Collins M. T. 2003 Paratuberculosis: review of present knowledge. Acta Vet Scand 44 217 221 .
  23. 23. D’Amore M. Lisi S. Sisto M. Cucci L. Dow C. T. 2010 Molecular identification of Mycobacterium avium subspecies paratuberculosis in an Italian patient with Hashimoto’s thyroiditis and Melkersson-Rosenthal syndrome. J Med Microbiol. 2010 Jan 59(Pt 1):137 139 -9
  24. 24. Danieli M. G. Candela M. Ricciatti A. M. et al. 1992 Antibodies to mycobacterial 65 kDa heat shock protein in systemic sclerosis (scleroderma). J Autoimmun 5 4 443 5 .
  25. 25. Deluca H. F. Cantorna M. T. 2001 Vitamin D: its role and uses in immunology. FASEB J 2001 15 14 2579
  26. 26. de Wit E. van der Merwe L. van Helden P. D., Hoal E. G. 2010 Gene-gene interaction between tuberculosis candidate genes in a South African population. Mamm Genome. 2010 Aug 27.
  27. 27. Direskeneli H. Saruhan-Direskeneli G. 2003 The role of heat shock proteins in Behcet’s disease. Clin Exp Rheumatol 2003 21(Suppl. 30):S44 8 .
  28. 28. Dow C. T. 2005 Paratuberculosis and Type I Diabetes-Mapping the TRIGR- In: Proceedings of the 8th International Colloquium on Paratuberculosis. August 2005, Denmark: Copenhagen; Available from:http://www.paratuberculosis.org/pubs/proc8/abst3b_o20.htm
  29. 29. Dow C. T. 2006 Paratuberculosis and Type I diabetes: is this the trigger? Med Hypotheses. 2006 67 4 782 . Epub 2006 Jul 7
  30. 30. Dow C. T. Ellingson J. L. 2010 Detection of Mycobacterium avium ss. Paratuberculosis in Blau Syndrome Tissues. Autoimmune Dis. 2010 Jun 20 2010:127692.
  31. 31. Dubaniewicz A. Jamieson S. E. Dubaniewicz-Wybieralska M. Fakiola M. Nancy Miller. E. Blackwell J. M. 2005 Association between SLC11A1 (formerly NRAMP1) and the risk of sarcoidosis in Poland. Eur J Hum Genet. 2005 Jul 13 7 829 34 .
  32. 32. Eisenbarth G. S. 1986 Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med 1986 314 21 1360 .
  33. 33. Elias D. Markovits D. Reshef T. van der Zee R. Cohen I. R., Cohen I. R. 1990 Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci U S A. 1990 Feb 87 4 1576 80 .
  34. 34. Elias D. Reshef T. Birk O. S. van der Zee R. Walker M. D., Reshef T., Birk O. S., van der Zee R., Walker M. D., Cohen I. R. 1991 Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci U S A. 1991 Apr 15 88 8 3088
  35. 35. Elias D. Marcus H. Reshef T. Ablamunits V. Cohen I. R. 1995 Induction of diabetes in standard mice by immunization with the 277 peptide of a 60-kDa heat shock protein. Eur J Immunol. 1995 Oct 25(10):2851-7.
  36. 36. Elias D. Cohen I. R. 1994 Peptide therapy for diabetes in NOD mice. Lancet. 1994 Mar 19 343 8899 704 .
  37. 37. Elias D. Cohen I. R. 1995 Treatment of autoimmune diabetes and insulitis in NOD mice with heat shock protein 60 peptide 277 Diabetes. 1995 Sep 44(9):1132-8.
  38. 38. Elias D. Cohen I. R. 1996 The hsp60 peptide 277 arrests the autoimmune diabetes induced by the toxin streptozotocin. Diabetes. 1996 Sep 45(9):1168-72.
  39. 39. Ellingson J. L. Anderson J. L. Koziczkowski J. J. Radcliff R. P. Sloan S. J. Allen S. E. Sullivan N. M. 2005 Detection of viable Mycobacterium avium subsp. paratuberculosis in retail pasteurized whole milk by two culture methods and PCR. J Food Prot. 2005 May 68 5 966 72 .
  40. 40. el -Zaatari F. A. k. Naser S. A. Markesich D. C. Kalter D. C. Engstand L. Graham D. Y. 1996 Identification of Mycobacterium avium complex in sarcoidosis. Journal of Clinical Microbiology, 34 9 2240 2245 , 1996.
  41. 41. Falkinham J. O. I. I. I. 2003 Factors influencing the chlorine susceptibility of Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium scrofulaceum. Applied and environmental microbiology 2003, 69:5685 9 .
  42. 42. Falkinham J. O. III Norton C. D. Le Chevallier M. W. 2001 Factors influencing numbers of Mycobacterium avium, Mycobacterium intracellulare, and other Mycobacteria in drinking water distribution systems. Applied and environmental microbiology 2001, 67:1225-1231.
  43. 43. Feller M. Huwiler K. Stephan R. Altpeter E. Shang A. Furrer H. Pfyffer G. E. Jemmi T. Baumgartner A. Egger M. 2007 Mycobacterium avium subspecies paratuberculosis and Crohn’s disease: a systematic review and meta-analysis. Lancet Infect Dis 7 607 613 .
  44. 44. Franke A. et al. 2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010 Dec 42 12 1118 25 .
  45. 45. Frothingham R. 1999 Evolutionary bottlenecks in the agents of tuberculosis, leprosy, and paratuberculosis. Med Hypotheses 1999 52 2 95
  46. 46. Gazouli M. Atsaves V. Mantzaris G. Economou M. Nasioulas G. Evangelou K. Archimandritis A. J. Anagnou N. P. 2008a Role of functional polymorphisms of NRAMP1 gene for the development of Crohn’s disease. Inflamm Bowel Dis 2008; 14 1323 1330
  47. 47. Gazouli M. Sechi L. Paccagnini D. Sotgiu S. Arru G. et al. 2008b NRAMP1 polymorphism and viral factors in Sardinian multiple sclerosis patients. Can J Neurol Sciences 35 491 494 .
  48. 48. Gerstein H. C. 1994 Cow’s milk exposure and Type I diabetes mellitus. A critical overview of the clinical literature. Diabetes Care 1994; 17 1 13 9 .
  49. 49. Gimeno S. G. de Souza J. M. 1997 DM and milk consumption. A case-control study in Sao Paulo, Brazil. Diabetes Care 1997 20 8 1256 .
  50. 50. Girardin S. E. Hugot J. P. Sansonetti P. J. 2003 Lessons from Nod2 studies: towards a link between Crohn’s disease and bacterial sensing, Trends in Immunology, 24 12 652 658 , 2003.
  51. 51. Grewal S. K. Rajeev S. Sreevatsan S. Michel F. C. Jr 2006 Persistence of Mycobacterium avium subsp. paratuberculosis and other zoonotic pathogens during simulated composting, manure packing, and liquid storage of dairy manure. Appl Environ Microbiol 72 565 574 .
  52. 52. Groenendaal H. Zagmutt F. J. 2008 Scenario analysis of changes in consumption of dairy products caused by a hypothetical causal link between Mycobacterium avium subspecies paratuberculosis and Crohn’s disease.J Dairy Sci. 2008 Aug 91 8 3245 58 .
  53. 53. Guilherme L. Faé K. Oshiro S. E. Kalil J. 2005 Molecular pathogenesis of rheumatic fever and rheumatic heart disease. Expert Rev Mol Med. 2005 Dec 8;7 28 1 15 .
  54. 54. Gwozdz J. M. Thompson K. G. Manktelow B. W. Murray A. West D. M. 2000 Vaccination against paratuberculosis of lambs already infected experimentally with Mycobacterium avium subspecies paratuberculosis. Aust Vet J. 2000 78 560 .
  55. 55. Hackam D. J. Rotstein O. D. Zhang W. Gruenheid S. Gros P. Grinstein S. 1998 Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J Exp Med 1998 188 2 351 .
  56. 56. Hampe J. Grebe J. Nikolaus S. et al. 2002 Association of NOD2 (CARD 15) genotype with clinical course of Crohn’s disease: a cohort study, Lancet, 359 9318 1661 1665 , 2002.
  57. 57. Hatta M. Ratnawati Tanaka. M. Ito J. Shirakawa T. Kawabata M. 2010 NRAMP1/SLC11A1 gene polymorphisms and host susceptibility to Mycobacterium tuberculosis and M. leprae in South Sulawesi, Indonesia. Southeast Asian J Trop Med Public Health. 2010 Mar 41 2 386 94 .
  58. 58. Hayes C. E. Nashold F. E. Spach K. M. Pedersen L. B. 2003 The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand) 2003. 49 2 277 300 [Review].
  59. 59. Hermon-Taylor J. Bull T. J. Sheridan J. M. Cheng J. Stellakis M. L. et al. 2000 Causation of Crohn’s disease by Mycobacterium avium subspecies paratuberculosis. Can J Gastroenterol 14 521 539 .
  60. 60. Hermon-Taylor J. 2002 Treatment with drugs active against Mycobacterium avium subspecies paratuberculosis can heal Crohn’s disease: more evidence for a neglected public health tragedy. Dig Liver Dis. 2002 Jan 34 1 9 12 .
  61. 61. Hilborn E. D. Covert T. C. Yakrus M. A. Harris S. I. Donnelly S. F. Rice E. W. Toney S. Bailey S. A. Stelma G. N. Jr 2006 Persistence of nontuberculous mycobacteria in a drinking water system after addition of filtration treatment. Applied and environmental microbiology 2006, 72:5864-5869.
  62. 62. Hruska K. Bartos M. Kralik P. Pavlik I. 2005 Mycobacterium avium subsp. paratuberculosis in powdered infant milk: paratuberculosis in cattle- the public health problem to be solved. Vet. Med. 0 Czech, 2005 50, (8); 327 335
  63. 63. Hugot J. P. Chamaillard M. Zouali H. et al. 2001 Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease, Nature, 411 6837 599 603 , 2001.
  64. 64. Inohara N. Ogura Y. Fontalba A. et al. 2003 Host recognition of bacterial muramyl dipeptide mediated through NOD2: implications for Crohn’s disease, Journal of Biological Chemistry, 278 8 5509 5512 , 2003.
  65. 65. Jarjour W. N. Jeffries B. D. Davis J. S. 4th et al. 1991 Autoantibodies to human stress proteins. A survey of various rheumatic and other inflammatory diseases. Arthritis Rheum 1991 34 9 1133 .
  66. 66. Jindal S. Dudani A. K. Singh B. Harley C. B. Gupta R. S. 1989 Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Mol Cell Biol 1989 9 5 2279 .
  67. 67. Jo E. K. 2010 Innate immunity to mycobacteria: vitamin D and autophagy. Cell Microbiol. 2010 Aug 12 8 026 35 . Epub 2010 Jun 14.
  68. 68. Jones D. B. Hunter N. R. Duff G. W. 1990 Heat-shock protein 65 as a beta cell antigen of insulin-dependent diabetes. Lancet. 1990 Sep 8 336 8715 583 .
  69. 69. Kanazawa N. Okafuji I. Kambe N. et al. 2005 Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-B activation: common genetic etiology with Blau syndrome, Blood, 105 3 1195 1197 , 2005.
  70. 70. Kaplan M. H. S. V. E. C. K. H. 1964 Immunologic relation of streptococcal and tissue antigens. III. Presence in human sera of streptococcal antibody cross-reactive with heart tissue. Association with streptococcal infection, rheumatic fever, and glomerulonephritis. J Exp Med. 1964 Apr 1;119:65166.
  71. 71. Kirvan C. A. Swedo S. E. Heuser J. S. Cunningham M. W. 2003 Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med. 2003 Jul 9 7 914 20 .
  72. 72. Knip M. Virtanen S. M. Seppä K. Ilonen J. Savilahti E. Vaarala O. Reunanen A. Teramo K. Hämäläinen A. M. Paronen J. Dosch H. M. Hakulinen T. Akerblom H. K. 2010 Dietary intervention in infancy and later signs of beta-cell autoimmunity. Finnish TRIGR Study Group. N Engl J Med. 2010 Nov 11;363 20 1900 8
  73. 73. Kormendy B. 1994 The effect of vaccination on the prevalence of paratuberculosis in large dairy herds. Vet Microbiol. 1994 41 117 .
  74. 74. Korou L. M. Liandris E. Gazouli M. Ikonomopoulos J. 2010 Investigation of the association of the SLC11A1 gene with resistance/sensitivity of goats (Capra hircus) to paratuberculosis. Vet Microbiol. 2010 Aug 26;144(3-4):353-8. Epub 2010 Jan 28.
  75. 75. Kotlowski R. Bernstein C. N. Silverberg M. S. Krause D. O. 2008 Population-based case-control study of alpha 1-antitrypsin and SLC11A1 in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 2008; 14 1112 1117
  76. 76. Kotze M. J. de Villiers J. N. Rooney R. N. Grobbelaar J. J. Mansvelt E. P. Bouwens C. S. Carr J. Stander I. du Plessis. L. 2001 Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects. Blood Cells Mol Dis 2001; 27 44 53
  77. 77. Knip M. Veijola R. Virtanen S. M. Hyöty H. Vaarala O. Akerblom H. K. 2005 Environmental triggers and determinants of type 1 diabetes. KnipM.VeijolaR.VirtanenS. M.HyötyH.VaaralaO.AkerblomH. K. (2005) Environmental triggers and determinants of type 1 diabetes. Diabetes. 2005 Dec 54 Suppl 2:S125-36. . 2005 Dec 54 Suppl 2:S125 36 .
  78. 78. Lacher M. Helmbrecht J. Schroepf S. Koletzko S. Ballauff A. Classen M. Uhlig H. Hubertus J. Hartl D. Lohse P. von Schweinitz. D. Kappler R. 2010 NOD2 mutations predict the risk for surgery in pediatric-onset Crohn’s disease. J Pediatr Surg. 2010 Aug 45 8 1591 7 .
  79. 79. Lamb J. R. Young D. B. 1990 cell recognition of stress proteins. A link between infectious and autoimmune disease. Mol Biol Med 1990 7 4 311
  80. 80. Lapham A. S. Phillips E. S. Barton C. 2004 (2004 ) Transcriptional control of Nramp1: a paradigm for the repressive action of c-Myc. Biochem Soc Trans 2004 32(Pt 6):1084 6 .
  81. 81. Lesage S. Zouali H. C´ezard J. P. et al. 2002 CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease, American Journal of Human Genetics, 70 4 845 857 , 2002.
  82. 82. Liang J. Aihua Z. Yu W. Yong L. Jingjing L. 2010 HSP65 serves as an immunogenic carrier for a diabetogenic peptide 277 inducing anti-inflammatory immune response in NOD mice by nasal administration. Vaccine. 2010 Apr 26;28(19):3312-7. Epub 2010 Mar 10.
  83. 83. Maahs D. M. West N. A. Lawrence J. M. Mayer-Davis E. J. 2010 Epidemiology of type 1 diabetes. Endocr Metab Clin North Am, 2010 Sep 39 3 481 97 .
  84. 84. Mackintosh C. G. Labes R. E. Griffin J. F. 2005 The effect of Johne’s vaccination on tuberculin testing in farmed red deer (Cervus elaphus). N Z Vet J. 2005 53:216 22
  85. 85. Marti G. Audi L. Esteban C. et al. 2004 Association of vitamin D receptor gene polymorphism with type 1 diabetes mellitusin two Spanish populations. Med Clin (Barc) 2004 123 8 286 [in Spanish].
  86. 86. Mc Dermott M. F. Ramachandran A. Ogunkolade B. W. Aganna E. Curtis D. Boucher B. J. et al. 1997 Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians. Diabetologia 1997 40 8 971 .
  87. 87. Mc Fadden J. J. Butcher P. D. Chiodini R. Hermon-Taylor J. 1987 Crohn’s disease-isolated mycobacteria are identical to M. para, as determined by DNA probes that distinguish between mycobacterial species. J Clin Microbiol 1987; 25 796 801 .
  88. 88. Mendoza J. L. San-Pedro A. Culebras E. Cíes R. Taxonera C. Lana R. Urcelay E. de la Torre F. Picazo J. J., Díaz-Rubio M. 2010 High prevalence of viable Mycobacterium avium subspecies paratuberculosis in Crohn’s disease. World J Gastroenterol. 2010 Sep 28 16 36 4558
  89. 89. Miceli-Richard C. Lesage S. Rybojad M. et al. 2001 CARD15 mutations in Blau syndrome, Nature Genetics, 29 1 19 20 , 2001.
  90. 90. Millar D. Ford J. Sanderson J. Withey S. Tizard M. et al. 1996 IS900 PCR to detect Mycobacterium paratuberculosis in retail supplies of whole pasteurized cows’ milk in England and Wales. Appl Environ Microbiol 1996 62 3446 .
  91. 91. Miyata M. Kogure A. Sato H. et al. 1995 Detection of antibodies to 65 KD heat shock protein and to human superoxide dismutase in autoimmune hepatitis-molecular mimicry between 65 KD heat shock protein and superoxide dismutase. Clin Rheumatol 1995 14 6 673 .
  92. 92. Motohashi Y. Yamada S. Yanagawa T. et al. 2003 Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes. J Clin Endocrinol Metab. 2003 88 7 3137 .
  93. 93. Moudgil K. D. Chang T. T. Eradat H. et al. 1997 Diversification of T cell responses to carboxy-terminal determinants within the 65 kD heat-shock protein is involved in regulation of autoimmune arthritis. J Exp Med 1997 185 7 1307 .
  94. 94. Muskens J. van Zijderveld F. Eger A. Bakker D. 2002 Evaluation of the long-term immune response in cattle after vaccination against paratuberculosis in two Dutch dairy herds. Vet Microbiol. 2002 86 269 .
  95. 95. Naser S. A. Ghobrial G. Romero C. Valentine J. F. 2004 Culture of Mycobacterium avium subspeciesparatuberculosis from the blood of patients with Crohn’s disease. Lancet. 2004 Sep 18-24 364(9439):1039-44.
  96. 96. Naser S. A. Collins M. T. Crawford J. T. Valentine J. F. Culture of Mycobacterium avium subspecies paratuberculosis (MAP) from the Blood of Patients with Crohn’s disease: A Follow-Up Blind Multi Center Investigation. The Open Inflammation Journal, 2009 2009 2 22 23
  97. 97. Nerup J. Platz P. Andersen O. O. Christy M. Lyngsoe J. 1974 HL-A antigens and diabetes mellitus. Lancet. 2 864 866 .
  98. 98. Olbe L. 2008 2008. Concept of Crohn’s disease being conditioned by four main components, and irritable bowel syndrome being an incomplete Crohn’s disease. Scand J Gastroenterol, 43 234 241 .
  99. 99. Oldstone M. B. 1987 Molecular mimicry and autoimmune disease. Cell 1987 50 6 819 .
  100. 100. Paccagnini D. Sieswerda L. Rosu V. Masala S. Pacifico A. Gazouli M. Ikonomopoulos J. Ahmed N. Zanetti S. Sechi L. A. 2009 Linking chronic infection and autoimmune diseases: Mycobacterium avium subspecies paratuberculosis, SLC11A1 polymorphisms and type-1 diabetes mellitus. PLoS One. 2009 Sep 214(9):e7109.
  101. 101. Pani M. A. Knapp M. Donner H. Braun J. Baur M. P. Usadel K. H. et al. 2000 Vitamin D receptor allele combinations influencegenetic susceptibility to type 1 diabetes in Germans. Diabetes 2000;49 3 504 7 .
  102. 102. Parsell D. A. Lindquist S. 1993 The function of heat shock proteins in stress tolerance: Degradation and reactivation of damaged proteins. Annu Rev Genet 1993 27 437 .
  103. 103. Peng H. Hagopian W. 2006 Environmental factors in the development of Type 1 diabetes. Rev Endocr Metab Disord. 2006 Sep 7 3 149 62 . Review.
  104. 104. Pickup R. W. Rhodes G. Arnott S. Sidi-Boumedine K. Bull T. J. et al. 2005 Mycobacterium avium subsp. paratuberculosis in the catchment area and water of the River Taff in South Wales, United Kingdom, and its potential relationship to clustering of Crohn’s disease cases in the city of Cardiff. Appl Environ Microbiol 71 2130 2139 .
  105. 105. Pickup R. W. Rhodes G. Bull T. J. Arnott S. Sidi-Boumedine K. et al. 2006 Mycobacterium avium subsp. paratuberculosis in lake catchments, in river water abstracted for domestic use, and in effluent from domestic sewage treatment works: diverse opportunities for environmental cycling and human exposure. Appl Environ Microbiol 2006 72 4067 .
  106. 106. Purdie A. C. Plain K. M. Begg D. J. de Silva K. Whittington R. J. 2011 Candidate gene and genome-wide association studies of Mycobacterium avium subsp. paratuberculosis infection in cattle and sheep: A review. Comp Immunol Microbiol Infect Dis. 2011 Jan 7.
  107. 107. Quayle A. J. Wilson K. B. Li S. G. et al. 1992 Peptide recognition, T cell receptor usage and HLA restriction elements of human heat-shock protein (hsp) 60 and mycobacterial 65 kDa hspreactive T cell clones from rheumatoid synovial fluid. Eur J Immunol 1992;22 5 1315 22 .
  108. 108. Raska M. Weigl E. 2005 Heat shock proteins in autoimmune diseases. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2005 149 2 243 .
  109. 109. Rose C. D. Doyle T. M. Mc Ilvain-Simpson G. et al. 2005 Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis, Journal of Rheumatology,32 2 373 375 , 2005.
  110. 110. Rosu V. Ahmed N. Paccagnini D. Gerlach G. Fadda G. Hasnain S. E. Zanetti S. Sechi L. A. 2009 Specific immunoassays confirm association of Mycobacterium avium Subsp. paratuberculosis with type-1 but not type-2 diabetes mellitus. PLoS One. 2009;4(2):e4386 . Epub 2009 Feb 10.
  111. 111. Roupie V. Rosseels V. Piersoel V. Zinniel D. K. Barletta R. G. Huygen K. 2008 Genetic resistance of mice to Mycobacterium paratuberculosis is influenced by Slc11a1 at the early but not at the late stage of infection. Infect Immun. 2008 May 76 5 2099 105 . Epub 2008 Feb 19.
  112. 112. Ruiz-Larrañaga O. Garrido J. M. Manzano C. Iriondo M. Molina E. Gil A. Koets A. P. Rutten V. P. Juste R. A. Estonba A. 2010 Identification of single nucleotide polymorphisms in the bovine solute carrier family 11 member 1 (SLC11A1) gene and their association with infection by Mycobacterium avium subspecies paratuberculosis. J Dairy Sci. 2010 Apr 93 4 1713 21
  113. 113. Scanu A. M. Bull T. J. Cannas S. Sanderson J. D. Sechi L. A. Dettori G. Zanetti S. Hermon-Taylor J. 2007 Mycobacterium avium subspecies paratuberculosis infection in cases of irritable bowel syndrome and comparison with Crohn’s disease and Johne’s disease: common neural and immune pathogenicities. J Clin Microbiol. 2007 Dec 45 12 3883 90
  114. 114. Sechi L. A. Mura M. Tanda F. Lissia A. Solinas A. Fadda G. Zanetti S. 2001 Identification of Mycobacterium avium subsp. paratuberculosis in biopsy specimens from patients with Crohn’s disease identified by in situ hybridization. J Clin Microbiol. 2001 Dec 39 12 4514 7 .
  115. 115. Sechi L. A. Scanu A. M. Molicotti P. Cannas S. Mura M. Dettori G. Fadda G. Zanetti S. 2005 Detection and Isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn’s disease in Sardinia. Am J Gastroenterol. 2005 Jul 100 7 1529 36 .
  116. 116. Sechi L. A. Ruehl A. Ahmed N. Usai D. Paccagnini D. Felis G. E. Zanetti S. 2007 Mycobacterium avium subspecies paratuberculosis infects and multiplies in enteric glial cells. World J Gastroenterol. 2007 Nov 21;13 43 5731 5 .
  117. 117. Sechi L. A. Gazouli M. Sieswerda L. E. Molicotti P. Ahmed N. Ikonomopoulos J. Scanu A. M. Paccagnini D. Zanetti S. 2006 Relationship between Crohn’s disease, infection with Mycobacterium avium subspecies paratuberculosis and SLC11A1 gene polymorphisms in Sardinian patients. World J Gastroenterol. 2006 Nov 28;12 44 7161 4 .
  118. 118. Sechi L. A. Paccagnini D. Salza S. Pacifico A. Ahmed N. Zanetti S. 2008 Mycobacterium avium subspecies paratuberculosis bacteremia in type 1 diabetes mellitus: an infectious trigger? Clin Infect Dis. 2008 Jan 1;46 1 148 9 . No abstract available.
  119. 119. Sechi L. A. Rosu V. Pacifico A. Fadda G. Ahmed N. Zanetti S. 2008 Humoral immune responses of type 1 diabetes patients to Mycobacterium avium subsp. paratuberculosis lend support to the infectious trigger hypothesis. (2008) Clin Vaccine Immunol. 2008 Feb 15 2 320 6 . Epub 2007 Dec 12.
  120. 120. Sechi L. A. Mara L. Cappai P. Frothingam R. Ortu S. Leoni A. Ahmed N. Zanetti S. 2006 Immunization with DNA vaccines encoding different mycobacterial antigens elicits a Th1 type immune response in lambs and protects against Mycobacterium avium subspecies paratuberculosis infection. Vaccine. 2006 Jan 16 24 3 229
  121. 121. Singal D. P. Blajchman M. A. Histocompatibility 1973 (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes. 22 429 432 .
  122. 122. Sisto M. Cucci L. D’Amore M. Dow T. C. Mitolo V. Lisi S. 2010 Proposing a relationship between Mycobacterium avium subspecies paratuberculosis infection and Hashimoto’s thyroiditis. Scand J Infect Dis. 2010 Oct 42 10 787 90 .
  123. 123. Skrabic V. Zemunik T. Situm M. Terzic J. 2003 2003) Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in the Dalmatian population. Diabetes Res Clin Pract 2003 59 1 31 .
  124. 124. Stabel J. R. 1998 Johne’s disease: a hidden threat. J Dairy Sci. 1998 Jan 81 1 283 8 . Review.
  125. 125. Stienstra Y. van der Werf T.S. Oosterom E. Nolte I. M. van der Graaf W.T Etuaful S. Raghunathan P.L Whitney E.A Ampadu E. O., Asamoa K. Klutse E. Y., te Meerman G. J., Tappero J. W. Ashford D. A. van der Steege G. 2006 Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorphism. Genes Immun. 2006 Apr 7 3 185 9 .
  126. 126. Takahashi K. Satoh J. Kojima Y. Negoro K. Hirai M. Hinokio Y. Kinouchi Y. Suzuki S. Matsuura N. Shimosegawa T. Oka Y. 2004 Promoter polymorphism of SLC11A1 (formerly NRAMP1) confers susceptibility to autoimmune type 1 diabetes mellitus in Japanese. Tissue Antigens. 2004 Mar 63 3 231 6 .
  127. 127. Tao B. Pietropaolo M. Atkinson M. Schatz D. Taylor D. 2010 Estimating the cost of type 1 diabetes in the U.S.: a propensity score matching method. PLoS One. 2010 Jul 9;5(7):e11501.
  128. 128. Tatchou-Nyamsi-Konig J. A. Dailloux M. Block J. C. 2009 Survival of Mycobacterium avium attached to polyethylene terephtalate (PET) water bottles. J Appl Microbiol 2009, 106:825 832 .
  129. 129. Ting J. P. Y. Davis B. K. 2005 CATERPILLER: a novel gene family important in immunity, cell death, and diseases, Annual Review of Immunology, 23 387 414 , 2005. E
  130. 130. Tavornpanich S. Johnson W. O. Anderson R. J. Gardner I. A. 2008 Herd characteristics and management practices associated with seroprevalence of Mycobacterium avium subspecies paratuberculosis infection in dairy herds. Am. J. Vet. Res. 69 904 911 .
  131. 131. Vaerewijck M. J. Huys G. Palomino J. C. Swings J. Portaels F. 2005 Mycobacteria in drinking water distribution systems: ecology and significance for human health. FEMS Microbiol Rev 2005, 29:911-934.
  132. 132. van Schaik G. Kalis C. H. Benedictus G. AA Dijkhuizen Huirne. R. B. 1996 Cost-benefit analysis of vaccination against paratuberculosis in dairy cattle. Vet Rec. 1996 139 624 .
  133. 133. Vilagut L. Pares A. Vinas O. et al. 1992 Antibodies to mycobacterial 65 kD heat shock protein cross-react with the main mitochondrial antigens in patients with primary biliary cirrhosis. Eur J Clin Invest 1997 27 8 667 .
  134. 134. Wang X. Kuivaniemi H. Bonavita G. et al. 2002 CARD15 mutations in familial granulomatosis syndromes: a study of the original Blau syndrome kindred and other families with large-vessel arteritis and cranial neuropathy, Arthritis and Rheumatism, 46 11 3041 3045 , 2002
  135. 135. Whan L. Ball H. J. Grant I. R. Rowe M. T. 2005 Occurrence of Mycobacterium avium subsp. paratuberculosis in untreated water in Northern Ireland. Appl Environ Microbiol 2006 71 7107 .
  136. 136. Wyllie S. Seu P. Goss J. A. 2002 The natural resistance-associatedmacrophage protein 1 Slc11a1 (formerly Nramp1) and iron metabolism in macrophages. Microbes Infect 2002 4 3 351
  137. 137. Yokota S. Tsubaki S. Kuriyama T. et al. 1993 Presence in Kawasaki disease of antibodies to mycobacterial heatshock protein HSP65 and autoantibodies to epitopes of human HSP65 cognate antigen. Clin Immunol Immunopathol 1993 67 163 .
  138. 138. Zella J. B. De Luca H. F. 2003 Vitamin D and autoimmune diabetes. J Cell Biochem 2003 88 2 216

Written By

Coad Thomas Dow and Leonardo A. Sechi

Submitted: 09 November 2010 Published: 25 November 2011