The Roles of Vitamin D Binding Protein in Human Immune Function

Authors:
Bethel KP, Clement RJ, Sands NA

 

Abstract:

The recent proliferation of published studies outlining the role of vitamin D in the prevention of many diseases associated with a weakened immune system has brought to light the importance of monitoring the serum levels of 25(OH) vitamin D. (1)  Specifically, the direct correlation of vitamin D levels in the human serum with increased levels of cathelicidin and the potentiating role cathelicidin plays in the immune response to infections, cancer, autoimmune disease, and especially acute viral infections. (2) While research into vitamin D needs to continue, the importance of vitamin D binding protein (VDBP) has been demonstrated to have synergistic yet independent functions in the human immune system. (3) This article will outline the emerging role of VDBP in the field of immunology.

 

Method:

A review of the scientific literature pertaining to vitamin D binding protein and its derivatives identified in human serum and produced in the laboratory.

 

Results:

Vitamin D binding protein, also known as Gc-protein, is a group of isoform proteins with O-linked glycans.  The dominant isoform of VDBP are non-glycosylated 656 Da proteins produced mainly in the liver. (4) Vitamin D binding protein participates in liver cell stability and regeneration through calcium-dependent interaction with the megalin/gp330 receptor. (5) There are four important roles VDBP has in humans.  It binds circulating vitamin D for transport and storage, it is the most important scavenger of extracellular G-actin, it enhances the chemotactic activity of C5a for neutrophils in inflammation, and it activates macrophages through GaINAc-modified Gc-protein. (6) Additionally, low levels of VDBP have been found to correlate with multiple organ failure sepsis, and non-survival in fulminant liver failure and traumatic liver failure. (7) The non-glycosylated isoform of VDBP is able to mask the presence of endotoxins by 20%. (7) Therapy with VDBP may increase survival in trauma, sepsis and fulminant liver failure. (7)

The function of VDBP is independent of the hormone actions of 1,25(2OH) vitamin D and it has limited impact on the extracellular pool of 1,25(OH) vitamin D. (8) Vitamin D binding protein has virtually no impact on the distribution, uptake, activation profile, or biological potency of the hormone vitamin D. (8) Vitamin D binding protein is not affected by race or adiposity the way vitamin D levels are affected. (9) The serum levels of VDBP are decreased by trauma, septic infections, and chronic or acute liver diseases. (10) The normal levels of serum VDBP are 350-50 mg/L and low levels below 80 mg/L yield a positive and negative mortality predictive value 85% and 43% respectively. (11)

While vitamin D binding protein is a primary macrophage activating factor, several glycosylated isoforms have more potent and specific macrophage activating properties. (12) The most potent serum macrophage activation factor (MAF) is produced by a series of glycosylation reactions performed by the B-cells and T-cells. (13) Vitamin D-MAF as a potent adjuvant activity for immunization and healthy serum levels of MAF prevent tumours from being able to transplant into mice. (14) Other roles for VDBP derived MAF have been described, including an anti-angiogenesis function through blocking VEGF-induced angiogenesis.(15)

Laboratory derived MAF from serum VDBP has the advantage of activating macrophages and not being deglycosylated by N-acetylgalactosaminidase enzymes (NaGaLase) produced by cancer cells and infectious bacteria, viruses and fungi.(16) The clinical dose required to have a sustained systemic activation of macrophages in 100 mcg injected weekly.(16) A novel MAF (Gc-MAF) can be produced in the lab with cancer specific activity that targets undifferentiated cancer cells better than well differentiated cancer cells.(17) Several prospective clinical trials of treatment of cancer and HIV with Gc-MAF have been reported and three trials with metastatic colon, breast and prostate cancer have provided 100% remission rate beyond the five years since Gc-MAF treatment.(16)(17)(18)

 

Discussion:

The scientific and clinical experience with VDBP and Gc-MAF are very encouraging. Several clinical trials are underway in The Bahamas at the Immune Augmentation Therapy Centre to reproduce and confirm the current clinic studies, as well as to answer several clinical questions that have not yet been reported in the scientific literature about VDBP and Gc-MAF. If you would like to enroll any clients with cancer or immune suppression in a trial with Gc-MAF, please click here to contact us.

 

Citations:

  1. Bikie DD, “Vitamin D and immune function: understanding common pathways” Curr Osteoporos Rep. 2009 Jul;7(2):58-63
  2. Yuk JM, Shin DM, Lee HM, Yang CS, Jin HS, Kim KK, Lee SH, Kim JM, Jo EK, “Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin” Cell Host Microbe. 2009 Sep 17;6(3):231-43
  3. Chkri M et al, “Production of human macrophages with potent antitumoral properties (MAK) by culture of monocytes in the presence of GM-CSF and 1,25-dihydroxy vitamin D3.” Anticancer Res. 1992 Nov-Dec;12(6B):2257-60
  4. Christiansen M et al, “Protein chemical characterization of Gc-gobulin (vitamin D-binding protein) isoforms; Gc-f1, Gc-s, and Gc-2.” Biochem Biophys Acta. 2007 Apr; 1774(4):481-92
  5. Gressner OA et al, “Gc-globulin (vitamin D binding protein) is synthesized and secreted by hepatocytes and internalized by hepatic stellate cells through Ca2+ dependent interaction with megalin/gp330 receptor.” Clinica ChimiceActa 2008 Apr 390;1-2:28-37
  6. Nagasawa H et al, “Gc-protein (vitamin D-binding protein): Gc genotyping and GcMAF precursor activity.” Anticancer Res. 2005 Nov-Dec; 25(6A):3689-95
  7. Jorgensen CS et al, “Large-scale purification and characterization of non-glycosylated Gc-protein (vitamin D binding protein) from plasma fraction IV.” Biotechnol Appl Biochem. 2006 Apr;44(pt1):35-44
  8. Zella LA et al, “Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo.” Endocrinology. 2008 Jul;149(7):3656-67
  9. Winters SJ et al, “Influence of obesity on vitamin D-binding protein and 25-hydroxy vitamin D levels in African and white women.” Metabolism. 2009 Apr;58(4):438-42
  10. Schiodt FV et al, “Increased turnover of Gc-protein in patients with hepatic encephalopathy.” Scand J Gastroenterol. 2001 Sep;36(9):998-1003
  11. Schiodt FV et al, “Gc-globulin and prognosis in acute liver failure.” Liver Transpl. 2005 Oct;11(10):1223-7
  12. Homma S et al, “Vitamin D-binding protein (group-specific component) is the sole serum protein required for macrophage activation after treatment of peritoneal cells with lyso-phosphatidylcholine.” Immunol Cel Biol. 1993 Aug;71(pt4):249-57
  13. Yamamoto N et al, “Conversion of vitamin D3 binding protein (group-specific component) to a macrophage activating factor by stepwise action of beta-galactosidase of B-celss and sialidase of T-cells.” J Immunol. 1993 Sep 1;151(5):2794-802
  14. Yamamoto N et al, “Structurally well-defined macrophage activating factor derived from vitamin D3-binding protein has a potent adjuvant activity for immunization.” Immunol Cell Biol. 1998 Ju;76(3):237-44
  15. Kallunte S et al, “Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-MAF.”  Angiogenesis. 2005;8(4):349-60
  16. Yamamoto N et al, “Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein derived macrophage activating factor, Gc-MAF.” Cancer Immunol Immunotherapy 2008;57:1007-16
  17. Yamamoto N et al, “Immunotherapy of metastatic breast cancer patients with vitamin D-bindng protein-derived macrophage activating factor (GcMAF).” Int J Cancer. 2008;122:461-467
  18. Yamamoto N, Suyama H, Yamamoto N “Immunotherapy for prostate cancer with Gc protein-derived macrophage activating factor, GcMAF.” Transl Oncol.2008 Jul;1(2):65-72

 

If you are interested in clinical options for GcMAF with Dr. Bethel, Please read more information in our Treatment section.