Defective Leukocyte Fungicidal Activity in End-Organ Resistance to 1,25-Dihydroxyvitamin D

Abstract

ABSTRACT. Recent studies have shown 1,25(OH)zD~ receptor-mediated modulation of leukocyte proliferation, differentiation, and function. We examined the phagocytosis and killing of microorganisms by neutrophils and monocytes from five patients of three families with hereditary resistance to 1,25(OH)2D3. Phagocytosis of microorganisms by patients' neutrophils and monocytes was normal. However, defective neutrophil killing activity toward Candida albicans (30-40% of controls) was found in all patients. The killing of Staphylococcus aureus was normal. The neutrophil chemiluminescence, nitroblue tetrazolium (NBT) dye reduction, and the generation of superoxide ions and hydrogen peroxide by neutrophils and monocytes after induction by either soluble stimuli or zymozan particles, did not differ from those in controls. The neutrophil myeloperoxidase activity was also normal. Monocytes obtained from two patients of different families before long-term calcium infusion therapy and after they became normocalcemic, demonstrated a similar impaired fungicidal activity toward Saccharomyces cerevisiae, indicating that hypocalcemia itself was not the cause of the killing defect. However, the addition of the Ca+2 ionophore A23187 (1 p M ) to the test medium restored the monocyte fungicidal activity to normal. As patients' neutrophil cytosolic free calcium concentration was similar to that in controls, it is suggested that 1,25-(OH)2D3 exerts its effect on leukocyte function by a putative receptor-mediated regulation of subcellular calcium localization which may be important for fungicidal activity. (Pediatr Res 25276-279, 1989) Abbreviations 1,25(OH)zD3, 1,25-dehydroxyvitamin D3 TPA, 12-0-tetra-decanoyl-phorbol-13-acetate f-met-leu-phe, N-formyl-L-methionyl-L-phenylalanine NBT, nitroblue-tetrazolium Recently, it has been shown that receptors for 1,25-(OH)2D3, the hormonal form of vitamin D3, are present in cellular components of the immune system and that specific functional receptors for 1 ,25-(OH)2D3 mediate the effects of 1 ,25-(OH)2D3

The Use of 1α,25-Dihydroxyvitamin D3 as an Anticancer Agent

“…1,25D enhances the protective effects of the innate immune response. Individuals who are vitamin D deficient [ 60 ] and those with inactivating mutations in the gene encoding VDR show defects in responses towards infectious agents [ 61 ]. Tiosano and colleagues examined the immune status of fifteen hereditary vitamin-D resistant patients that have a truncated VDR, which is unable to bind 1,25D and devoid of function.…”

Vitamin-D-Dependent Rickets Type 2

“…Patients with loss-of-function VDR mutations provide the ultimate tool to understand the importance of the VDR, and over the years many of the extra-intestinal claims attributed to vitamin D were examined. Etzioni et al [21], the consulting pediatric immunologist at our institute, showed that other than slightly impaired phagocytosis and Candida killing, the immune system functions normally in the absence of VDR effect. Endocrine glands, including the pancreatic β-cell, respond normally to routinely used stimuli, provided that serum calcium is normal [22].…”

Antimicrobial implications of vitamin D

“…137 In animal studies, Cantorna et al 138 demonstrated that 1,25-D 3 may reduce the prevalence of opportunistic infections such as candidiasis. metabolism and precluding this crucial step.…”