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Novel treatments may offer the only chance of survival or an acceptable quality of life. "Drug repurposing is emerging as a drug development strategy.  

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Greetings! The complexity of our immune system is astounding.  Look in the mirror and ask, Who Are We?  Martin Blaser at NYU estimates over 8 million microbial genes to our 23,000 human genes.  Current research is finding a microbial etiology for disease; something we're experiencing first-hand.  If it weren't for the suffering, you might consider the molecular gymnastics going on to keep us alive were fascinating. 

Persistent intracellular bacterial infection compromises the immune system and causes a chronic inflammatory response.[1, 2] Cell-wall-deficient bacteria parasitize nucleated cells in order to escape host defenses, thus contributing to failures of treatment.[3, 4] The concept that intracellular bacteria are protected from the host's immune response was first proposed by Rous in 1916.[5] In an essay on the renin-angiotensin system and the immune response, Smith postulates that unresolved cellular stress is caused by infectious agents, with the deliberate intent to avoid adaptive immune responses.[6] The host immune system has developed many mechanisms to neutralize and remove pathogenic bacteria. In turn, bacteria have developed mechanisms to alter and evade the host immune response.[7] For example, regulation of the vitamin D receptor (VDR) is a common mechanism used in the host defense against pathogens, but certain microbes have been shown to slow innate immune defenses by down-regulating the VDR:

• Mycobacterium tuberculosis down-regulates VDR activity.[8]
• Mycobacterium leprae inhibits VDR activity through down-regulation of CYP27B1 in monocytes.[9]
• Aspergillus fumigates secretes a toxin capable of down-regulating VDR in macrophages.[10]
• Epstein-Barr virus lowers VDR activity.[11]
• HIV completely shuts down VDR activity.[12]
• In VDR knockout mice, a circumstance that closely mimics extreme VDR dysregulation, 1,25-D levels increase by a factor of ten.[13]

Slowing the ability of the VDR to express elements of innate immune function allows intracellular bacteria to persist in the cytoplasm of nucleated cells and increases susceptibility to co-infections that are commonly found in patients with chronic illnesses (e.g., viruses, fungi, parasites and cell-walled bacteria).[14]    

Elevated 1,25(OH)2D is evidence of the dysregulated immune system's attempt to activate the VDR to produce antimicrobial peptides (e.g., cathelicidin) to combat infection.[15] Studies have found elevated 1,25(OH)2D and reduced cathelicidin in chronic diseases:

• Sarcoidosis patients are deficient in cathelicidin despite healthy vitamin D3 levels.[16]
• 1,25(OH)2D is elevated (>60 pg/ml) in 42% of Crohn's patients and the source of the active vitaminD production appears to be the inflamed intestine.[17]
• 1,25(OH)2D is elevated in the synovial fluid of patients with RA.[18]
• Crohn's disease decreases expression of cathelicidin.[19]

1,25(OH)2D is a marker of vitamin D endocrine function.[20] Down-regulation by bacterial ligands may prevent the VDR from expressing the enzymes necessary to keep 1,25(OH)2D in a normal range. Elevated 1,25(OH)2D also reduces VDR competence, suppresses macrophage function, and inhibits the Nuclear Factor kappa-� cytokine pathway, thus further compromising the immune system.[21-23]

  References

1. Quie PG, White JG, Holmes B, Good RA. In Vitro Bactericidal Capacity of Human Polymorphonuclear Leukocytes: Diminished Activity in Chronic Granulomatous Disease of Childhood. J Clin Invest. 1967 Apr;46(4):668-79.
2. Woolard MD, Frelinger JA. Outsmarting the host: bacteria modulating the immune response. Immunol Res. 2008;41(3):188-202.
3. Drevets DA, Leenen PJ, Greenfield RA. Invasion of the central nervous system by intracellular bacteria. Clin Microbiol Rev. Apr 2004;17(2):323-47.
4. Astrauskiene D, Bernotiene E. New insights into bacterial persistence in reactive arthritis. Clin Exp Rheumatol. May-Jun 2007;25(3):470-9.
5. Rous P, Jones F. THE PROTECTION OF PATHOGENIC MICROORGANISMS BY LIVING TISSUE CELLS. J Exp Med. May 1916(23(5)):601-12.
6. Smith G. Angiotensin and systems thinking: wrapping your mind around the big picture. Ochsner J. Spring 2013;11-25(13(1)).
7. Dermine JF, Desjardins M. Survival of intracellular pathogens within macrophages. Protop. 1999;210(1-2):11-24.
8. Xu Y, Xie J, Li Y, et al. Using a cDNA microarray to study cellular gene expression altered by Mycobacterium tuberculosis. Chin Med J (Engl). Jul 2003;116(7):1070-3.
9. Liu PT, Wheelwright M, Teles R, et al. MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy. Nat Med. Jan 2012;18(2):267-73.
10. Coughlan CA, Chotirmall SH, Renwick J, et al. The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis. Am J Respir Crit Care Med. Nov 2012;186(10):999-1007.
11. Yenamandra SP, Lundin A, Arulampalam V, et al. Expression profile of nuclear receptors upon Epstein -- Barr virus induced B cell transformation. Exp Oncol. Jun 2009;31(2):92-6.
12. Haug CJ, Aukrust P, Haug E, M�rkrid L, M�ller F, Fr�land SS. Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab. Nov 1998;83(11):3832-8.
13. Yoshizawa T, Handa Y, Uematsu Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. Aug 1997;16(4):391-6.
14. Marks R, Allegrante JP. Comorbid disease profiles of adults with end-stage hip osteoarthritis. Med Sci Monit. Apr 2002;8(4):CR305-9.
15. Sadeghi K, Wessner B, Laggner U, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. Feb 2006;36(2):361-70.
16. Barna BP, Culver DA, Kanchwala A, et al. Alveolar macrophage cathelicidin deficiency in severe sarcoidosis. J Innate Immun. 2012;4(5-6):569-78.
17. Abreu MT, Kantorovich V, Vasiliauskas EA, et al. Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut. Aug 2004;53(8):1129-36.
18. Mawer EB, Hayes ME, Still PE, et al. Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res. Jul 1991;6(7):733-9.
19. Wang TT, Dabbas B, Laperriere EG, et al. Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. J Biol Chem. Jan 2010;285(4):2227-31.
20. Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci. Sep 209;1173:384-90.
21. Lemire J. 1,25-Dihydroxyvitamin D3--a hormone with immunomodulatory properties. Z Rheumatol. 2000;59 Suppl 1:24-7.
22. Chen Y, Liu W, Sun T, et al. 1,25-Dihydroxyvitamin D Promotes Negative Feedback Regulation of TLR Signaling via Targeting MicroRNA-155-SOCS1 in Macrophages. J Immunol. Apr 2013(190(7)):3687-95.
23. Deb DK, Chen Y, Zhang Z, et al. 1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-kappa B pathway. Am J Physiol Renal Physiol. May 2009(296(5)):F1212-8.

Diet Support Group

Recovery from chronic illness sometimes necessitates a reduction in body weight. If you are in this category, you may need guidance and support. CIR conducts an online dietary group for this purpose. Those who participate receive emails with information related to diets, exercise and weight management. The regular contact provides motivation to get started and incentive to persist if/when the going gets rough. If you would like to join, please send us an email info@chronicillnessrecovery.org. 

I am so pleased to learn about stories of people learning about this treatment and getting on a path to recovery...as I have. ~Flyboy

I appreciate so much the time and consideration you've given to my situation. The advice and support I've receive so far has been such a boon, and I know that I could not be following this path without your help. ~Sunny