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Defective leukocyte fungicidal activity in end-organ resistance to 1,25-dihydroxyvitamin D
A Etzioni1, Z Hochberg, S Pollak
1Department of Pediatrics, Rambam Medical Center, Faculty of Medicine, Haifa, Israel.
Abstract:
Recent studies have shown 1,25(OH)2D3 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 microM) 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.
Insights
Hereditary vitamin D resistance impairs neutrophil fungicidal activity against Candida albicans. This defect is linked to 1,25(OH)2D3 receptor-mediated calcium regulation, not hypocalcemia.
Area of Science:
- Immunology
- Endocrinology
- Cell Biology
Background:
- Vitamin D (1,25(OH)2D3) influences leukocyte function via its receptor.
- Hereditary vitamin D resistance presents challenges in understanding these mechanisms.
Purpose of the Study:
- To investigate the phagocytosis and microbicidal activity of neutrophils and monocytes in patients with hereditary vitamin D resistance.
- To determine the role of calcium in the observed leukocyte dysfunction.
Main Methods:
- Assessed phagocytosis and killing of Candida albicans and Staphylococcus aureus by patient and control leukocytes.
- Measured neutrophil chemiluminescence, NBT reduction, superoxide and hydrogen peroxide generation, and myeloperoxidase activity.
- Evaluated monocyte fungicidal activity with and without calcium ionophore A23187.
Main Results:
- Patients exhibited normal phagocytosis but defective neutrophil killing of Candida albicans.
- Killing of Staphylococcus aureus and other measured leukocyte functions were normal.
- Monocyte fungicidal activity was impaired but restored by calcium ionophore, independent of serum calcium levels.
Conclusions:
- 1,25(OH)2D3 receptor signaling is crucial for effective fungicidal activity in neutrophils and monocytes.
- The mechanism involves receptor-mediated regulation of intracellular calcium localization, impacting leukocyte function.