Control lymphocyte subsets: Can one country's values serve for another's?
2014; Elsevier BV; Volume: 134; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2014.06.030
ISSN1097-6825
AutoresWilson L. Mandala, Jintanat Ananworanich, Tanakorn Apornpong, Stephen J. Kerr, Jenny MacLennan, Celine Hanson, Tanyathip Jaimulwong, Esther N. Gondwe, Howard M. Rosenblatt, Torsak Bunupuradah, Malcolm E. Molyneux, Stephen A. Spector, Chitsanu Pancharoen, Rebecca Gelman, Calman A. MacLennan, William T. Shearer,
Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoReliable interpretation of abnormal immunity depends on an understanding of what constitutes “normal.” We and others have reported that lymphocyte patterns are affected by ethnicity, sex, and environmental factors.1Ananworanich J. Apornpong T. Kosalaraksa P. Jaimulwong T. Hansudewechakul R. Pancharoen C. et al.Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age.J Allergy Clin Immunol. 2010; 126: 1294-1301.e10Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 3Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar Differing exposure to infectious agents, such as malaria, tuberculosis, and cytomegalovirus, could underlie differences in lymphocyte subset patterns in contrasting settings.4Ben-Smith A. Gorak-Stolinska P. Floyd S. Weir R.E. Lalor M.K. Mvula H. et al.Differences between naive and memory T cell phenotype in Malawian and UK adolescents: a role for Cytomegalovirus?.BMC Infect Dis. 2008; 8: 139Crossref PubMed Scopus (30) Google Scholar, 5Weiss G.E. Crompton P.D. Li S. Walsh L.A. Moir S. Traore B. et al.Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area.J Immunol. 2009; 183: 2176-2182Crossref PubMed Scopus (303) Google Scholar, 6Sutherland J.S. Hill P.C. Adetifa I.M. de Jong B.C. Donkor S. Joosten S.A. et al.Identification of probable early-onset biomarkers for tuberculosis disease progression.PLoS One. 2011; 6: e25230Crossref PubMed Scopus (38) Google Scholar In this study we analyzed combined data from 3 studies of healthy children from Thailand,1Ananworanich J. Apornpong T. Kosalaraksa P. Jaimulwong T. Hansudewechakul R. Pancharoen C. et al.Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age.J Allergy Clin Immunol. 2010; 126: 1294-1301.e10Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Malawi,2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar and the United States 3Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar who had used similar standard flow cytometric methods and markers, thus allowing assessment of immune heterogeneity across settings with differences in ethnicity and infectious disease exposure.We used lymphocyte subset data from healthy children aged 0 to 15 years enrolled in our previously published studies1Ananworanich J. Apornpong T. Kosalaraksa P. Jaimulwong T. Hansudewechakul R. Pancharoen C. et al.Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age.J Allergy Clin Immunol. 2010; 126: 1294-1301.e10Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 3Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar; additional Thai subjects less than 2 years of age were recruited to allow comparisons with the youngest children. Exclusion criteria were febrile illness, clinical infection at screening, concomitant medical illnesses potentially resulting in abnormal immunity, or abnormal growth (defined as 97th percentiles of the country's growth chart for Thai and US children or a weight-for-height z score <70% for Malawian children). Rapid HIV diagnostic kits were used with PCR to confirm discordant results. Statistical analyses were performed in a manner similar to previous publications (details are shown in the Methods section in this article's Online Repository at www.jacionline.org).1Ananworanich J. Apornpong T. Kosalaraksa P. Jaimulwong T. Hansudewechakul R. Pancharoen C. et al.Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age.J Allergy Clin Immunol. 2010; 126: 1294-1301.e10Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 3Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (273) Google ScholarOf 1399 children enrolled (Thailand, n = 281; Malawi, n = 397; and the United States, n = 721), approximately 50% were male (see Table E1 in this article's Online Repository at www.jacionline.org), and approximately 50% were between 0 and 2 years of age. The Thai and Malawian cohorts were ethnically homogenous; the US cohort had a mix of African American (53%), Hispanic (29%), and Euro-Caucasian (17%) subjects.The following lymphocyte subpopulations were identified as percentages of the lymphocyte gate in all 3 cohorts: T cells (CD3+), CD4+ T cells (CD3+CD4+), CD8+ T cells (CD3+CD8+), B cells (CD19+), and B memory cells (CD19+CD27+). Fig 1 compares cell counts of total T cells, CD4+ T cells, and CD8+ T and B cells by age and country. Graphs representing other cells and percentages are provided online (see Fig E1, Fig E2 in this article's Online Repository at www.jacionline.org).Thai children had higher total T-cell counts compared with the US and Malawian cohorts aged 6 months to 4 years and 0 to 24 months, respectively. Malawian children aged 0 to 5 months had lower total T-cell counts compared with US children. Compared with the US and Thai cohorts, Malawian children aged 0 to 11 and 0 to 17 months, respectively, had lower T-cell percentages.Thai children aged 6 to 11 months had higher CD4+ T-cell counts but a lower percentage of CD4+ T cells compared with US children of the same age group. Compared with US children, Malawian children had lower CD4+ T-cell counts from 0 to 5 months of age and greater CD4+ T-cell counts from 8 to 15 years of age, whereas CD4+ T-cell percentages were lower from 0 to 17 months of age but greater from 8 to 11 years of age. Compared with Thai children, CD4+ T-cell counts were lower in Malawian children aged 0 to 11 and 18 to 24 months of age but greater in those aged 5 to 7 and 12 to 15 years of age. Percentages of CD4+ T cells were similarly lower in Malawian children aged 0 to 12 months of age but consistently higher than those seen in Thai children aged 2 to 15 years of age.Higher CD8+ T-cell counts (birth to 4 years and 8-11 years) and percentages (birth to 18 months and 2-7 years) were observed in Thai compared with US children and also compared with Malawian children for absolute counts from 0 to 17 months and 8 to 11 years and percentages from 0 to 5 months and 8 to 11 years. These values were also higher among Malawian compared with US children for certain age groups (6-17 months for absolute CD8+ T-cell counts and percentages and 2-4 years for percentages only). B-cell and natural killer (NK) cell results are presented in the Results section in this article's Online Repository at www.jacionline.org.In secondary analyses geometric mean ratios were predominantly consistent with the significance results from nonparametric tests, with few apparent sex differences, although the power to detect these differences was limited male (see Table E2 in this article's Online Repository at www.jacionline.org).This analysis of lymphocyte subsets of children from countries within 3 different continents demonstrates a marked heterogeneity in subset patterns of HIV-uninfected children, the extent of which is most marked in children younger than 2 years. The differences in subset patterns might be driven by several factors, including ethnicity, with participants from the 3 countries being of different ethnicities. Previous healthy control studies in Asian and African subjects have reported smaller proportions of CD4+ T-cell subsets and larger proportions of CD8+ T-cell subsets in these populations compared with those observed in populations in the developed world.2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 7Jiang W. Kang L. Lu H.Z. Pan X. Lin Q. Pan Q. et al.Normal values for CD4 and CD8 lymphocyte subsets in healthy Chinese adults from Shanghai.Clin Diagn Lab Immunol. 2004; 11: 811-813PubMed Google Scholar, 8Sagnia B. Ateba Ndongo F. Ndiang Moyo Tetang S. Ndongo Torimiro J. Cairo C. Domkam I. et al.Reference values of lymphocyte subsets in healthy, HIV-negative children in Cameroon.Clin Vaccine Immunol. 2011; 18: 790-795Crossref PubMed Scopus (25) Google Scholar, 9Amatya R. Vajpayee M. Kaushik S. Kanswal S. Pandey R.M. Seth P. Lymphocyte immunophenotype reference ranges in healthy Indian adults: implications for management of HIV/AIDS in India.Clin Immunol. 2004; 112: 290-295Crossref PubMed Scopus (28) Google Scholar, 10Likanonsakul S. Wasi C. Thepthai C. Sutthent R. Louisirirotchanakul S. Chearskul S. et al.The reference range of CD4+ and CD8+ T-lymphocytes in healthy non-infected infants born to HIV-1 seropositive mothers; a preliminary study at Siriraj Hospital.Southeast Asian J Trop Med Public Health. 1998; 29: 453-463PubMed Google Scholar However, ethnic differences alone might not account for all subset differences because variations within specific ethnic groups have also been reported.2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 8Sagnia B. Ateba Ndongo F. Ndiang Moyo Tetang S. Ndongo Torimiro J. Cairo C. Domkam I. et al.Reference values of lymphocyte subsets in healthy, HIV-negative children in Cameroon.Clin Vaccine Immunol. 2011; 18: 790-795Crossref PubMed Scopus (25) Google Scholar, 11Lugada E.S. Mermin J. Kaharuza F. Ulvestad E. Were W. Langeland N. et al.Population-based hematologic and immunologic reference values for a healthy Ugandan population.Clin Diagn Lab Immunol. 2004; 11: 29-34PubMed Google Scholar, 12Embree J. Bwayo J. Nagelkerke N. Njenga S. Nyange P. Ndinya-Achola J. et al.Lymphocyte subsets in human immunodeficiency virus type 1-infected and uninfected children in Nairobi.Pediatr Infect Dis J. 2001; 20: 397-403Crossref PubMed Scopus (47) Google Scholar Environmental factors, particularly prevalent infectious diseases, might affect cellular phenotypic patterns.13Duramad P. Tager I.B. Holland N.T. Cytokines and other immunological biomarkers in children's environmental health studies.Toxicol Lett. 2007; 172: 48-59Crossref PubMed Scopus (75) Google ScholarThe high median B-cell counts observed in Malawian children in younger age groups, which have been reported in other African cohorts,8Sagnia B. Ateba Ndongo F. Ndiang Moyo Tetang S. Ndongo Torimiro J. Cairo C. Domkam I. et al.Reference values of lymphocyte subsets in healthy, HIV-negative children in Cameroon.Clin Vaccine Immunol. 2011; 18: 790-795Crossref PubMed Scopus (25) Google Scholar, 12Embree J. Bwayo J. Nagelkerke N. Njenga S. Nyange P. Ndinya-Achola J. et al.Lymphocyte subsets in human immunodeficiency virus type 1-infected and uninfected children in Nairobi.Pediatr Infect Dis J. 2001; 20: 397-403Crossref PubMed Scopus (47) Google Scholar might be associated with malaria, which is prevalent in Malawi but less common in Thailand and absent in the United States. Children living in malaria-endemic areas are known to exhibit expansion of atypical memory B cells, which are thought to be driven by parasite antigens and could have beneficial immune-modulating effects for the host.14Weiss G.E. Crompton P.D. Li S. Walsh L.A. Moir S. Traore B. et al.Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area.J Immunol. 2009; 183: 2176-2182Crossref PubMed Scopus (72) Google Scholar In contrast, Thailand is a dengue-endemic area, with most Thai children being dengue seropositive by 5 years of age,15Dejnirattisai W. Duangchinda T. Lin C.L. Vasanawathana S. Jones M. Jacobs M. et al.A complex interplay among virus, dendritic cells, T cells, and cytokines in dengue virus infections.J Immunol. 2008; 181: 5865-5874Crossref PubMed Scopus (68) Google Scholar which could explain the pattern of higher CD4+ and CD8+ T-cell and NK cell counts observed in Thai children. As a likely confounding factor, participants in all 3 cohorts were screened for HIV, and those who were HIV seropositive were not included in the analysis. It is also possible that the prominent CD8+ T cells and NK cells seen in Thai children could result partly from air pollution.13Duramad P. Tager I.B. Holland N.T. Cytokines and other immunological biomarkers in children's environmental health studies.Toxicol Lett. 2007; 172: 48-59Crossref PubMed Scopus (75) Google Scholar The cause underlying the diversity between cohorts still remains speculative and deserves further investigation. Limitations to this study include some differences in the details of the flow cytometric methodologies used by the 3 countries and possible variation in the nutritional status of the participants.In conclusion, this study highlights that distinct patterns of lymphocyte subsets exist between populations from different countries with different ethnicities and exposed to different environmental and nutritional factors. Therefore population-specific healthy control subject reference ranges for different lymphocyte subsets should be developed for the diagnosis and monitoring of immunologic disorders. Reliable interpretation of abnormal immunity depends on an understanding of what constitutes “normal.” We and others have reported that lymphocyte patterns are affected by ethnicity, sex, and environmental factors.1Ananworanich J. Apornpong T. Kosalaraksa P. Jaimulwong T. Hansudewechakul R. Pancharoen C. et al.Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age.J Allergy Clin Immunol. 2010; 126: 1294-1301.e10Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 3Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar Differing exposure to infectious agents, such as malaria, tuberculosis, and cytomegalovirus, could underlie differences in lymphocyte subset patterns in contrasting settings.4Ben-Smith A. Gorak-Stolinska P. Floyd S. Weir R.E. Lalor M.K. Mvula H. et al.Differences between naive and memory T cell phenotype in Malawian and UK adolescents: a role for Cytomegalovirus?.BMC Infect Dis. 2008; 8: 139Crossref PubMed Scopus (30) Google Scholar, 5Weiss G.E. Crompton P.D. Li S. Walsh L.A. Moir S. Traore B. et al.Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area.J Immunol. 2009; 183: 2176-2182Crossref PubMed Scopus (303) Google Scholar, 6Sutherland J.S. Hill P.C. Adetifa I.M. de Jong B.C. Donkor S. Joosten S.A. et al.Identification of probable early-onset biomarkers for tuberculosis disease progression.PLoS One. 2011; 6: e25230Crossref PubMed Scopus (38) Google Scholar In this study we analyzed combined data from 3 studies of healthy children from Thailand,1Ananworanich J. Apornpong T. Kosalaraksa P. Jaimulwong T. Hansudewechakul R. Pancharoen C. et al.Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age.J Allergy Clin Immunol. 2010; 126: 1294-1301.e10Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Malawi,2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar and the United States 3Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar who had used similar standard flow cytometric methods and markers, thus allowing assessment of immune heterogeneity across settings with differences in ethnicity and infectious disease exposure. We used lymphocyte subset data from healthy children aged 0 to 15 years enrolled in our previously published studies1Ananworanich J. Apornpong T. Kosalaraksa P. Jaimulwong T. Hansudewechakul R. Pancharoen C. et al.Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age.J Allergy Clin Immunol. 2010; 126: 1294-1301.e10Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 3Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar; additional Thai subjects less than 2 years of age were recruited to allow comparisons with the youngest children. Exclusion criteria were febrile illness, clinical infection at screening, concomitant medical illnesses potentially resulting in abnormal immunity, or abnormal growth (defined as 97th percentiles of the country's growth chart for Thai and US children or a weight-for-height z score <70% for Malawian children). Rapid HIV diagnostic kits were used with PCR to confirm discordant results. Statistical analyses were performed in a manner similar to previous publications (details are shown in the Methods section in this article's Online Repository at www.jacionline.org).1Ananworanich J. Apornpong T. Kosalaraksa P. Jaimulwong T. Hansudewechakul R. Pancharoen C. et al.Characteristics of lymphocyte subsets in HIV-infected, long-term nonprogressor, and healthy Asian children through 12 years of age.J Allergy Clin Immunol. 2010; 126: 1294-1301.e10Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 3Shearer W.T. Rosenblatt H.M. Gelman R.S. Oyomopito R. Plaeger S. Stiehm E.R. et al.Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.J Allergy Clin Immunol. 2003; 112: 973-980Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar Of 1399 children enrolled (Thailand, n = 281; Malawi, n = 397; and the United States, n = 721), approximately 50% were male (see Table E1 in this article's Online Repository at www.jacionline.org), and approximately 50% were between 0 and 2 years of age. The Thai and Malawian cohorts were ethnically homogenous; the US cohort had a mix of African American (53%), Hispanic (29%), and Euro-Caucasian (17%) subjects. The following lymphocyte subpopulations were identified as percentages of the lymphocyte gate in all 3 cohorts: T cells (CD3+), CD4+ T cells (CD3+CD4+), CD8+ T cells (CD3+CD8+), B cells (CD19+), and B memory cells (CD19+CD27+). Fig 1 compares cell counts of total T cells, CD4+ T cells, and CD8+ T and B cells by age and country. Graphs representing other cells and percentages are provided online (see Fig E1, Fig E2 in this article's Online Repository at www.jacionline.org). Thai children had higher total T-cell counts compared with the US and Malawian cohorts aged 6 months to 4 years and 0 to 24 months, respectively. Malawian children aged 0 to 5 months had lower total T-cell counts compared with US children. Compared with the US and Thai cohorts, Malawian children aged 0 to 11 and 0 to 17 months, respectively, had lower T-cell percentages. Thai children aged 6 to 11 months had higher CD4+ T-cell counts but a lower percentage of CD4+ T cells compared with US children of the same age group. Compared with US children, Malawian children had lower CD4+ T-cell counts from 0 to 5 months of age and greater CD4+ T-cell counts from 8 to 15 years of age, whereas CD4+ T-cell percentages were lower from 0 to 17 months of age but greater from 8 to 11 years of age. Compared with Thai children, CD4+ T-cell counts were lower in Malawian children aged 0 to 11 and 18 to 24 months of age but greater in those aged 5 to 7 and 12 to 15 years of age. Percentages of CD4+ T cells were similarly lower in Malawian children aged 0 to 12 months of age but consistently higher than those seen in Thai children aged 2 to 15 years of age. Higher CD8+ T-cell counts (birth to 4 years and 8-11 years) and percentages (birth to 18 months and 2-7 years) were observed in Thai compared with US children and also compared with Malawian children for absolute counts from 0 to 17 months and 8 to 11 years and percentages from 0 to 5 months and 8 to 11 years. These values were also higher among Malawian compared with US children for certain age groups (6-17 months for absolute CD8+ T-cell counts and percentages and 2-4 years for percentages only). B-cell and natural killer (NK) cell results are presented in the Results section in this article's Online Repository at www.jacionline.org. In secondary analyses geometric mean ratios were predominantly consistent with the significance results from nonparametric tests, with few apparent sex differences, although the power to detect these differences was limited male (see Table E2 in this article's Online Repository at www.jacionline.org). This analysis of lymphocyte subsets of children from countries within 3 different continents demonstrates a marked heterogeneity in subset patterns of HIV-uninfected children, the extent of which is most marked in children younger than 2 years. The differences in subset patterns might be driven by several factors, including ethnicity, with participants from the 3 countries being of different ethnicities. Previous healthy control studies in Asian and African subjects have reported smaller proportions of CD4+ T-cell subsets and larger proportions of CD8+ T-cell subsets in these populations compared with those observed in populations in the developed world.2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 7Jiang W. Kang L. Lu H.Z. Pan X. Lin Q. Pan Q. et al.Normal values for CD4 and CD8 lymphocyte subsets in healthy Chinese adults from Shanghai.Clin Diagn Lab Immunol. 2004; 11: 811-813PubMed Google Scholar, 8Sagnia B. Ateba Ndongo F. Ndiang Moyo Tetang S. Ndongo Torimiro J. Cairo C. Domkam I. et al.Reference values of lymphocyte subsets in healthy, HIV-negative children in Cameroon.Clin Vaccine Immunol. 2011; 18: 790-795Crossref PubMed Scopus (25) Google Scholar, 9Amatya R. Vajpayee M. Kaushik S. Kanswal S. Pandey R.M. Seth P. Lymphocyte immunophenotype reference ranges in healthy Indian adults: implications for management of HIV/AIDS in India.Clin Immunol. 2004; 112: 290-295Crossref PubMed Scopus (28) Google Scholar, 10Likanonsakul S. Wasi C. Thepthai C. Sutthent R. Louisirirotchanakul S. Chearskul S. et al.The reference range of CD4+ and CD8+ T-lymphocytes in healthy non-infected infants born to HIV-1 seropositive mothers; a preliminary study at Siriraj Hospital.Southeast Asian J Trop Med Public Health. 1998; 29: 453-463PubMed Google Scholar However, ethnic differences alone might not account for all subset differences because variations within specific ethnic groups have also been reported.2Mandala W.L. MacLennan J.M. Gondwe E.N. Ward S.A. Molyneux M.E. MacLennan C.A. Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.J Allergy Clin Immunol. 2010; 125: 203-208Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 8Sagnia B. Ateba Ndongo F. Ndiang Moyo Tetang S. Ndongo Torimiro J. Cairo C. Domkam I. et al.Reference values of lymphocyte subsets in healthy, HIV-negative children in Cameroon.Clin Vaccine Immunol. 2011; 18: 790-795Crossref PubMed Scopus (25) Google Scholar, 11Lugada E.S. Mermin J. Kaharuza F. Ulvestad E. Were W. Langeland N. et al.Population-based hematologic and immunologic reference values for a healthy Ugandan population.Clin Diagn Lab Immunol. 2004; 11: 29-34PubMed Google Scholar, 12Embree J. Bwayo J. Nagelkerke N. Njenga S. Nyange P. Ndinya-Achola J. et al.Lymphocyte subsets in human immunodeficiency virus type 1-infected and uninfected children in Nairobi.Pediatr Infect Dis J. 2001; 20: 397-403Crossref PubMed Scopus (47) Google Scholar Environmental factors, particularly prevalent infectious diseases, might affect cellular phenotypic patterns.13Duramad P. Tager I.B. Holland N.T. Cytokines and other immunological biomarkers in children's environmental health studies.Toxicol Lett. 2007; 172: 48-59Crossref PubMed Scopus (75) Google Scholar The high median B-cell counts observed in Malawian children in younger age groups, which have been reported in other African cohorts,8Sagnia B. Ateba Ndongo F. Ndiang Moyo Tetang S. Ndongo Torimiro J. Cairo C. Domkam I. et al.Reference values of lymphocyte subsets in healthy, HIV-negative children in Cameroon.Clin Vaccine Immunol. 2011; 18: 790-795Crossref PubMed Scopus (25) Google Scholar, 12Embree J. Bwayo J. Nagelkerke N. Njenga S. Nyange P. Ndinya-Achola J. et al.Lymphocyte subsets in human immunodeficiency virus type 1-infected and uninfected children in Nairobi.Pediatr Infect Dis J. 2001; 20: 397-403Crossref PubMed Scopus (47) Google Scholar might be associated with malaria, which is prevalent in Malawi but less common in Thailand and absent in the United States. Children living in malaria-endemic areas are known to exhibit expansion of atypical memory B cells, which are thought to be driven by parasite antigens and could have beneficial immune-modulating effects for the host.14Weiss G.E. Crompton P.D. Li S. Walsh L.A. Moir S. Traore B. et al.Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area.J Immunol. 2009; 183: 2176-2182Crossref PubMed Scopus (72) Google Scholar In contrast, Thailand is a dengue-endemic area, with most Thai children being dengue seropositive by 5 years of age,15Dejnirattisai W. Duangchinda T. Lin C.L. Vasanawathana S. Jones M. Jacobs M. et al.A complex interplay among virus, dendritic cells, T cells, and cytokines in dengue virus infections.J Immunol. 2008; 181: 5865-5874Crossref PubMed Scopus (68) Google Scholar which could explain the pattern of higher CD4+ and CD8+ T-cell and NK cell counts observed in Thai children. As a likely confounding factor, participants in all 3 cohorts were screened for HIV, and those who were HIV s
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