Maturation of blood cells
Differentiation is the process by which subsets of a family of cells are formed from parent, or ‘stem’ cells by the acquisition of specific functions. It is of particular importance in haemopoiesis, the process by which blood cells are formed, and the consequent development of T-lymphocytes. Differentiation is a gradual process with cells passing through various stages before achieving maturity, and is stimulated by various growth factors. Apoptosis is a mechanism of programmed cell death, which occurs as a response to an external factor or the withdrawal of a growth factor. It is an important part of cell differentiation for both the immune system and haemopoiesis as it culls excess cells to maintain a suitable subset balance. The enzymes concerned in breaking apart DNA fragmentation during apoptosis are endonucleases.
DS individuals have been found to have an unusual presence of immature myeloid cells (found in the earliest stages of haemopoiesis) in peripheral blood circulation associated with low levels of zinc plasma (Trubiani et al, 1996a, 1996b). Both pieces of research found that six months of zinc therapy induced the disappearance of the immature myeloid cells, but the authors offer different possible explanations:
that zinc is required for the process of programmed cell suicide: “ The results here show that zinc therapy in Down’s patients induces cell death of undifferentiated and ineffective myeloid cells, recovering a mechanism related to cellular differentiation of the haemopoietic system” (1996a)
- that zinc is required for normal cell differentiation: “Since leukocytes contain high levels of zinc and this level varies with cell maturity, being lowest in the most immature cells, we suggest that low plasma zinc levels in DS subjects could be responsible for a reduced rate of myeloid differentiation resulting in accumulation and in escape from the bone marrow of immature cells reaching the peripheral blood” (1996b)
These reasons are not mutually exclusive and most likely zinc supplementation is supporting both processes (Trubiani et al, 1996a).
A paper was published the following year, by essentially the same researchers (Antonucci et al, 1997), which evaluated the presence of apoptosis in the peripheral blood cells in DS subjects before and after six months of zinc supplementation. It was found that there were signs of programmed cell death before the zinc treatment, which decreased in all the patients following supplementation. The authors state that endonucleases are inhibited by normal plasma zinc concentrations and suggest that in DS individuals low levels of plasma zinc activate the endonucleases. Zinc therapy would therefore inhibit the apoptotic process leading to a decrease in the number of apoptotic cells.
It would appear that programmed cell suicide is happening at an inappropriately high rate in mature DS peripheral blood cells. This author believes that when combined with the weakened cell maturation process discussed above these findings represent a serious decrease in the numbers of healthy, efficient blood cells in circulation, and the apparent success in treating this deficiency with zinc has important implications for supporting DS people’s health. Murphy et al (1995) found that DS spleens are markedly missing T cells “suggesting the inefficient release of mature T cells from the DS thymus to the DS spleen”. Could this lack of mature T cells be related to a poor rate of stem cell maturation? Or to a rapid destruction of healthy, mature cells by a high rate of apoptosis? Or both? How does this confusion of the cell differentiation process relate to the 10 to 20 times higher risk DS people have of developing myeloid leukaemia (Milunsky et al, 1970)? The question must also be asked as to why these scientists found that zinc deficiency appears to reduce programmed cell death in immature cells and promote it in mature cells. It is unfortunate that at present one group of investigators has done all the research and it is hoped that in the future other scientists will pick up the baton.