Maternal deprivation, acute respiratory infections and immune regulation
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《美国医学杂志》
Department of Pediatrics and Adolescents Medicine, Tbilisi State Medical University, Georgia
Abstract
Objective. The study was designed to investigate the acute respiratory disease incidence (DI) in deprived infants and test the hypothesis if maternal deprivation effects the processes of immunoregulation in infants. Methods. The prospective study during 1 year in Tbilisi Infant's House was performed. Cohort of 136 infants at age from 1 to 24 months without any congenital abnormalities formed the basic group. The cohort of 136 healthy infants at age 1 to 24 months of the same population living under the maternal care in three shelters of Tbilisi region was randomized as a control. The study included: DI, age of first attack, duration of illness, outcome, plasma immune parameters. Results. The data have demonstrated that maternal deprivation induces a marked increase in the severity of acute respiratory disease among infants. DI was twice as much in deprived children as in control group. Moreover, there was diagnosed the disruption of normal correlations between plasma CD3, CD4 and CD8 in infants under maternal deprivation. Conclusion. Maternal deprivation induces changes in processes of immunoregulation in infants resulted in elevation of acute respiratory DI among them.
Keywords: Maternal deprivation, Children, Immune regulation.
If is now well documented concept that environmental agents, including neonatal stress, maternal care, social interactions, can modify health by disrupting the homeostatic regulatory mechanisms among organ systems.[1],[2] In animals, as it is experimentally confirmed, maternal deprivation can be considered as a stressful stimulus to HPA axis.[3],[4] On the other hand, bidirectorial interactions between the immune and neuroendocrine systems are widely discussed in literature of the last period.[5],[6] Moreover, some authors, testing CNS, have defined the "neuro immunodeficiency syndrome" getting the disruption of regulatory mechanisms among nervous, endocrine and immune systems, resulted in changes in T cell and macrophage maturation.[6],[8] Another previous investigations have shown the negative effect of maternal deprivation on abandoned children's growth and development.[9],[10],[11] Considering the neonates and infants in orphanages, it was tempted to hypothesize, that high morbidity, observed among institutionalized infants was the result of negative effect of maternal deprivation on the immune system of abandoned infants.
The present study was designed to investigate the acute respiratory disease incidence among deprived infants and to test the hypothesis, whether the maternal deprivation affects the immune regulation in abandoned infants.
Material and Methods
The prospective, concurrent cohort study for learning the acute respiratory infections (ARI) incidence took place in Tbilisi Infant's House during one year. The cohort of 136 healthy infants at age from 1 to 24 months without any congenital abnormalities formed the basic group. Another cohort of 136 healthy infants under maternal care of the same belonging to the same population was randomized as a control. The control group was formed in three shelters of Tbilist region. Children were randomized among the healthy population whose mothers agreed on investigation. The ARI incidence, the age of disease first attack, duration of illness, outcome were studied during 1 year. The environmental factors in infant's house (pollution, heating) were better than in shelters. The children compared from basic and control groups were of the same age, with similar physical development, without any congenital abnormalities, all being on formula feeding and immunized. DI was calculated according to Fletcher R.H et. al. methodology[12]. By this method the disease incidence is calculated as DI = A/B, where A-is a number of new cases of infection and B-number of population. In our study A-was number of the new cases of infection among deprived children during one year and B-the whole number of investigated deprived children. The disease incidence in control group was calculated as DI=C/D, where C-was a number of new cases of infection among the children from control group during the observed period and D-a number of children from shelters. The 102 healthy deprived and 102 healthy non-deprived children from observed cohorts were randomized for immune investigation. The following parameters were investigated in blood: total lymphocyte count, number of T-and B-cells, T-cell subpopulations: CD3, CD4, CD8 and CD4/CD8, the concentration of secretory IgA. T-cell subpopulations were measured by the common method with the monoclonal antibodies ("Sorbent", Moscow).
Data were analyzed by Student's t-test as indicated. The comparisons with p<0.05 were considered statistically significant.
Results
The ARI incidence was studied during 1 year between cohort of deprived (basic group) and non - deprived (control group) children. There were formed three investigative groups: 1st basic group formed 46 deprived and 1st control - 46 non-deprived children at age from 1 to 2 months. 2nd basic group formed 42 deprived and 2nd control group-42 non-deprived children at age from 12 to 13 months and the 3rd group-48 deprived and 48 non-deprived children at age from 24 to 26 months. After first signs of illness the infants were examined daily for clinical signs of disease. The results of investigations are given in table1. It was found the DI in the first as well as in the second basic groups was twice as much as in control groups. The duration of illness was also significantly longer in basic groups, than control (p<0.05). As for the outcome of disease, in the first basic group the hospitalization percent was 45% and in the second-14%, in contrast to control groups, where the hospitalization with ARI was 1,8%. The age of acute respiratory disease's first attack was on an average 2.5 months in infants with maternal deprivationand an average of 6.3 months in the control groups. Most of the cases of infections' first attack were diagnosed in the first basic group, whereas in the second control group the morbidity was the highest.
In order to realize the real mechanism of high morbidity in deprived infants, the blood immune parameters were examined. The total lymphocyte count, as well as a number of T-and B-cells didn't significantly differ between deprived and non-deprived children table2. However, the number of mature T-cells (CD3) decreased in deprived children (p<0.05). There was observed the statistically significant reduction of CD4 (T-helpers) and elevation of CD8 (T-lsuppressors) in the blood of deprived children in contrast to control (p<0.05).
Thus, it has been shown the disruption of normal correlations between T-helper and T-suppressor cells in children with maternal deprivation, which was statistically significant for each investigated groups. In I group CD4/CD8 index was 0.57±0.08 against 1.7±0.01 in control group. In the II group CD4/CD8 index was 0.5±0.002 (2.0±0.05 in control) and in the III group the index was 0.6±0.04 against to control (2.0±0.2).
The concentration of secretory immunoglobulin A was significantly decreased in all investigated groups among deprived children in contrast to control groups (p<0.05).
Discussion
The present study has revealed that maternal deprivation promotes the elevation of acute respiratory disease incidence in infants. As it was noticed above, maternal deprivation of neonatal animals induces changes in the reactivity of the neuroendocrine system, as well as affects susceptibility to immune-mediate diseases.[1],[5],[13] The present study investigations have confirmed, that maternal deprivation in infants affects the plasticity of organism's immune regulation function resulted in elevation of ARI among them. Although the total lymphocyte count, as the number of T-and B-cells did not significantly differ between deprived and non-deprived children, the CD4 and CD8 concentrations were significantly different in investigated groups. The normal correlations between CD4 and CDl8 were also disturbed (0.5-0.6 against 1.7-2.0). The resent data are in conformity with results of several investigations, which suggest that neonatal maternal deprivation among rat pups is leading to changes in T-cell and macrophage maturation.[13],[14] There are interorgan bidirectorial communications between the nervous, endocrine and immune systems, as it was previously discussed. Altered nervous system functions caused by the stress (maternal deprivation) can alter immunity and result in exacerbation of infections or other immune-associated problems. As the relationship between T-cell subpopulations characterizes the process of immune regulation,[15] the authors can suppose, that maternal deprivation alters the normal immune regulation in infants.
As mentioned above, the number of B-cells was normal in deprived children, but because some antigens require the help of T-lymphocytes to activate B-cells, any defect in T-cell function can have an impact on the antibody response.
As to the low concentration of Ig A in the blood of deprived infants, Ig levels are not the equivalent of antibody activity, which can only be assessed in functional assays. However, the low concentration of Ig A paralleled with alternation in T-cells proliferation and maturation may be the problem resulting in functional impairment of immune system in infants with maternal deprivation.
References
1. Lawrence DA, Dongsoo K. Central/peripheral nervous system and immune responses. Toxicology 2000; 142: 19-201.
2. Frank DA, Klass PE, Earls F, Eisenberg L. Infants and Young Children in Orphanages: one view from pediatrics and child psychiatry. Pediatrics 1997; 4: 569-5579.
3. Bhatnagar S, Meaney MI.Hypothalamic-pituitary-adrenal function in chronic intermittently cold-stressed neonatally handled and nonhandled rats. J Neuroendocrinol 1995; 7: 97-10.
4. Ladd CO, Ownes MI, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 1996; 137: 1212-1
5. Marc AT, Teunis, Cobi J. Heijnen, Frans Sluyter, Joost M Bakkar, Anne-Marie M.W. Van Dam, Maalen Hof et al. Maternal deprivation of rat pups increases clinical symptoms of experimental autoimmune encephalomyelities a adult age. J Neuroimmunology 2002; 133: 30-33
6. Korneva EA. Nervous System and Immunity/ru/. J Vestnik AMS of USSR 19; 11: 76-4
7. Evsee VA., Magaeva SV. Neurogenic Immunodeficiency/ru/ J Vestnik AMS of USSR 19; 11: 5-91.
8. Lisianii NI. Neuroimmune connections and their Role in Secondary Immunodeficiency Syndrome Patogenesis/ru/. J Immunologia i Allergia 1999; 23: 41-46.
9. Gogberashvili KJ, Pagava KI. Bubuteishvili A; Beridze KV, Abashidze GA. The Influence of Psychoemotional Deprivation on the Health of Children in Orphanages/in georgian/. Workshop Series of TSMU 1999; 35: 70-74
10. Gogberashivili KJ, Chigladze T. Adeishvili M. Psycho-Motor Development of Infants Suffering from Maternal Deprivation. Workshop Series of TSMS 2003; 39: 91
11. Gogberashvili K, Pagava K, Melkadze T, Berelashvili N, Aznaurashvili K. The Development Quotient of Children in Orphanages Suffering from Maternal Deprivation J GMN, Tbilisi 2003; 7 (100,101): 73-75.
12. Fletcher RH, Fletcher SW, Wagner EH. Clinical Epidemiology. The Essentials/ru/. Moscow: Media Spera 1999; 266-267
13. Workel JO, Oitzl MS, Fluttert M, Lesscher H, Karssen A, de Kloet ER. Differential and age-dependent effects of maternal deprivation on the hypothalamic-pituitary-adrenal axis of Brown Norway Rats from youth to senescence. J Neuroendocrinol 2001; 13 (7): 569-0
14. Coe CL; Lubach GR; Ershler WE; Klopp RG. Influence of early rearing on lymphocyte proliferation responses in juvenile rhesus monkeys. Brain Behav Immun 1999; 3: 47-60
15. Petrov RB, Khaitov RM; Pinegin BV. (ru). Immunodiagnosis of Immunodeficiency. J Immunologia 1997; 4: 4-7.(Gogberashvili K)
Abstract
Objective. The study was designed to investigate the acute respiratory disease incidence (DI) in deprived infants and test the hypothesis if maternal deprivation effects the processes of immunoregulation in infants. Methods. The prospective study during 1 year in Tbilisi Infant's House was performed. Cohort of 136 infants at age from 1 to 24 months without any congenital abnormalities formed the basic group. The cohort of 136 healthy infants at age 1 to 24 months of the same population living under the maternal care in three shelters of Tbilisi region was randomized as a control. The study included: DI, age of first attack, duration of illness, outcome, plasma immune parameters. Results. The data have demonstrated that maternal deprivation induces a marked increase in the severity of acute respiratory disease among infants. DI was twice as much in deprived children as in control group. Moreover, there was diagnosed the disruption of normal correlations between plasma CD3, CD4 and CD8 in infants under maternal deprivation. Conclusion. Maternal deprivation induces changes in processes of immunoregulation in infants resulted in elevation of acute respiratory DI among them.
Keywords: Maternal deprivation, Children, Immune regulation.
If is now well documented concept that environmental agents, including neonatal stress, maternal care, social interactions, can modify health by disrupting the homeostatic regulatory mechanisms among organ systems.[1],[2] In animals, as it is experimentally confirmed, maternal deprivation can be considered as a stressful stimulus to HPA axis.[3],[4] On the other hand, bidirectorial interactions between the immune and neuroendocrine systems are widely discussed in literature of the last period.[5],[6] Moreover, some authors, testing CNS, have defined the "neuro immunodeficiency syndrome" getting the disruption of regulatory mechanisms among nervous, endocrine and immune systems, resulted in changes in T cell and macrophage maturation.[6],[8] Another previous investigations have shown the negative effect of maternal deprivation on abandoned children's growth and development.[9],[10],[11] Considering the neonates and infants in orphanages, it was tempted to hypothesize, that high morbidity, observed among institutionalized infants was the result of negative effect of maternal deprivation on the immune system of abandoned infants.
The present study was designed to investigate the acute respiratory disease incidence among deprived infants and to test the hypothesis, whether the maternal deprivation affects the immune regulation in abandoned infants.
Material and Methods
The prospective, concurrent cohort study for learning the acute respiratory infections (ARI) incidence took place in Tbilisi Infant's House during one year. The cohort of 136 healthy infants at age from 1 to 24 months without any congenital abnormalities formed the basic group. Another cohort of 136 healthy infants under maternal care of the same belonging to the same population was randomized as a control. The control group was formed in three shelters of Tbilist region. Children were randomized among the healthy population whose mothers agreed on investigation. The ARI incidence, the age of disease first attack, duration of illness, outcome were studied during 1 year. The environmental factors in infant's house (pollution, heating) were better than in shelters. The children compared from basic and control groups were of the same age, with similar physical development, without any congenital abnormalities, all being on formula feeding and immunized. DI was calculated according to Fletcher R.H et. al. methodology[12]. By this method the disease incidence is calculated as DI = A/B, where A-is a number of new cases of infection and B-number of population. In our study A-was number of the new cases of infection among deprived children during one year and B-the whole number of investigated deprived children. The disease incidence in control group was calculated as DI=C/D, where C-was a number of new cases of infection among the children from control group during the observed period and D-a number of children from shelters. The 102 healthy deprived and 102 healthy non-deprived children from observed cohorts were randomized for immune investigation. The following parameters were investigated in blood: total lymphocyte count, number of T-and B-cells, T-cell subpopulations: CD3, CD4, CD8 and CD4/CD8, the concentration of secretory IgA. T-cell subpopulations were measured by the common method with the monoclonal antibodies ("Sorbent", Moscow).
Data were analyzed by Student's t-test as indicated. The comparisons with p<0.05 were considered statistically significant.
Results
The ARI incidence was studied during 1 year between cohort of deprived (basic group) and non - deprived (control group) children. There were formed three investigative groups: 1st basic group formed 46 deprived and 1st control - 46 non-deprived children at age from 1 to 2 months. 2nd basic group formed 42 deprived and 2nd control group-42 non-deprived children at age from 12 to 13 months and the 3rd group-48 deprived and 48 non-deprived children at age from 24 to 26 months. After first signs of illness the infants were examined daily for clinical signs of disease. The results of investigations are given in table1. It was found the DI in the first as well as in the second basic groups was twice as much as in control groups. The duration of illness was also significantly longer in basic groups, than control (p<0.05). As for the outcome of disease, in the first basic group the hospitalization percent was 45% and in the second-14%, in contrast to control groups, where the hospitalization with ARI was 1,8%. The age of acute respiratory disease's first attack was on an average 2.5 months in infants with maternal deprivationand an average of 6.3 months in the control groups. Most of the cases of infections' first attack were diagnosed in the first basic group, whereas in the second control group the morbidity was the highest.
In order to realize the real mechanism of high morbidity in deprived infants, the blood immune parameters were examined. The total lymphocyte count, as well as a number of T-and B-cells didn't significantly differ between deprived and non-deprived children table2. However, the number of mature T-cells (CD3) decreased in deprived children (p<0.05). There was observed the statistically significant reduction of CD4 (T-helpers) and elevation of CD8 (T-lsuppressors) in the blood of deprived children in contrast to control (p<0.05).
Thus, it has been shown the disruption of normal correlations between T-helper and T-suppressor cells in children with maternal deprivation, which was statistically significant for each investigated groups. In I group CD4/CD8 index was 0.57±0.08 against 1.7±0.01 in control group. In the II group CD4/CD8 index was 0.5±0.002 (2.0±0.05 in control) and in the III group the index was 0.6±0.04 against to control (2.0±0.2).
The concentration of secretory immunoglobulin A was significantly decreased in all investigated groups among deprived children in contrast to control groups (p<0.05).
Discussion
The present study has revealed that maternal deprivation promotes the elevation of acute respiratory disease incidence in infants. As it was noticed above, maternal deprivation of neonatal animals induces changes in the reactivity of the neuroendocrine system, as well as affects susceptibility to immune-mediate diseases.[1],[5],[13] The present study investigations have confirmed, that maternal deprivation in infants affects the plasticity of organism's immune regulation function resulted in elevation of ARI among them. Although the total lymphocyte count, as the number of T-and B-cells did not significantly differ between deprived and non-deprived children, the CD4 and CD8 concentrations were significantly different in investigated groups. The normal correlations between CD4 and CDl8 were also disturbed (0.5-0.6 against 1.7-2.0). The resent data are in conformity with results of several investigations, which suggest that neonatal maternal deprivation among rat pups is leading to changes in T-cell and macrophage maturation.[13],[14] There are interorgan bidirectorial communications between the nervous, endocrine and immune systems, as it was previously discussed. Altered nervous system functions caused by the stress (maternal deprivation) can alter immunity and result in exacerbation of infections or other immune-associated problems. As the relationship between T-cell subpopulations characterizes the process of immune regulation,[15] the authors can suppose, that maternal deprivation alters the normal immune regulation in infants.
As mentioned above, the number of B-cells was normal in deprived children, but because some antigens require the help of T-lymphocytes to activate B-cells, any defect in T-cell function can have an impact on the antibody response.
As to the low concentration of Ig A in the blood of deprived infants, Ig levels are not the equivalent of antibody activity, which can only be assessed in functional assays. However, the low concentration of Ig A paralleled with alternation in T-cells proliferation and maturation may be the problem resulting in functional impairment of immune system in infants with maternal deprivation.
References
1. Lawrence DA, Dongsoo K. Central/peripheral nervous system and immune responses. Toxicology 2000; 142: 19-201.
2. Frank DA, Klass PE, Earls F, Eisenberg L. Infants and Young Children in Orphanages: one view from pediatrics and child psychiatry. Pediatrics 1997; 4: 569-5579.
3. Bhatnagar S, Meaney MI.Hypothalamic-pituitary-adrenal function in chronic intermittently cold-stressed neonatally handled and nonhandled rats. J Neuroendocrinol 1995; 7: 97-10.
4. Ladd CO, Ownes MI, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 1996; 137: 1212-1
5. Marc AT, Teunis, Cobi J. Heijnen, Frans Sluyter, Joost M Bakkar, Anne-Marie M.W. Van Dam, Maalen Hof et al. Maternal deprivation of rat pups increases clinical symptoms of experimental autoimmune encephalomyelities a adult age. J Neuroimmunology 2002; 133: 30-33
6. Korneva EA. Nervous System and Immunity/ru/. J Vestnik AMS of USSR 19; 11: 76-4
7. Evsee VA., Magaeva SV. Neurogenic Immunodeficiency/ru/ J Vestnik AMS of USSR 19; 11: 5-91.
8. Lisianii NI. Neuroimmune connections and their Role in Secondary Immunodeficiency Syndrome Patogenesis/ru/. J Immunologia i Allergia 1999; 23: 41-46.
9. Gogberashvili KJ, Pagava KI. Bubuteishvili A; Beridze KV, Abashidze GA. The Influence of Psychoemotional Deprivation on the Health of Children in Orphanages/in georgian/. Workshop Series of TSMU 1999; 35: 70-74
10. Gogberashivili KJ, Chigladze T. Adeishvili M. Psycho-Motor Development of Infants Suffering from Maternal Deprivation. Workshop Series of TSMS 2003; 39: 91
11. Gogberashvili K, Pagava K, Melkadze T, Berelashvili N, Aznaurashvili K. The Development Quotient of Children in Orphanages Suffering from Maternal Deprivation J GMN, Tbilisi 2003; 7 (100,101): 73-75.
12. Fletcher RH, Fletcher SW, Wagner EH. Clinical Epidemiology. The Essentials/ru/. Moscow: Media Spera 1999; 266-267
13. Workel JO, Oitzl MS, Fluttert M, Lesscher H, Karssen A, de Kloet ER. Differential and age-dependent effects of maternal deprivation on the hypothalamic-pituitary-adrenal axis of Brown Norway Rats from youth to senescence. J Neuroendocrinol 2001; 13 (7): 569-0
14. Coe CL; Lubach GR; Ershler WE; Klopp RG. Influence of early rearing on lymphocyte proliferation responses in juvenile rhesus monkeys. Brain Behav Immun 1999; 3: 47-60
15. Petrov RB, Khaitov RM; Pinegin BV. (ru). Immunodiagnosis of Immunodeficiency. J Immunologia 1997; 4: 4-7.(Gogberashvili K)