Impact on human health of particulate matter emitted from burnings in the Brazilian Amazon region

OBJECTIVE: To analyze the impact on human health of exposure to particulate matter emitted from burnings in the Brazilian Amazon region. METHODS: This was an ecological study using an environmental exposure indicator presented as the percentage of annual hours (AH%) of PM2.5 above 80 μg/m3. The outcome variables were the rates of hospitalization due to respiratory disease among children, the elderly and the intermediate age group, and due to childbirth. Data were obtained from the National Space Research Institute and the Ministry of Health for all of the microregions of the Brazilian Amazon region, for the years 2004 and 2005. Multiple regression models for the outcome variables in relation to the predictive variable AH% of PM2.5 above 80 μg/m3 were analyzed. The Human Development Index (HDI) and mean number of complete blood counts per 100 inhabitants in the Brazilian Amazon region were the control variables in the regression analyses. RESULTS: The association of the exposure indicator (AH%) was higher for the elderly than for other age groups (β = 0.10). For each 1% increase in the exposure indicator there was an increase of 8% in child hospitalization, 10% in hospitalization of the elderly, and 5% for the intermediate age group, even after controlling for HDI and mean number of complete blood counts. No association was found between the AH% and hospitalization due to childbirth. CONCLUSIONS: The indicator of atmospheric pollution showed an association with occurrences of respiratory diseases in the Brazilian Amazon region, especially in the more vulnerable age groups. This indicator may be used to assess the effects of forest burning on human health.

Plasmodium vivax apical membrane antigen-1: comparative recognition of different domains by antibodies induced during natural human infection

The Apical Membrane Antigen-1 (AMA-1) of Plasmodium sp. has been suggested as a vaccine candidate against malaria. This protein seems to be involved in merozoite invasion and its extra-cellular portion contains three distinct domains: DI, DII, and DIII. Previously, we described that Plasmodium vivax AMA-1 (PvAMA-1) ectodomain is highly immunogenic in natural human infections. Here, we expressed each domain, separately or in combination (DI-II or DII-III), as bacterial recombinant proteins to map immunodominant epitopes within the PvAMA-1 ectodomain. IgG recognition was assessed by ELISA using sera of P. vivax-infected individuals collected from endemic regions of Brazil or antibodies raised in immunized mice. The frequencies of responders to recombinant proteins containing the DII were higher than the others and similar to the ones observed against the PvAMA-1 ectodomain. Moreover, ELISA inhibition assays using the PvAMA-1 ectodomain as substrate revealed the presence of many common epitopes within DI-II that are recognized by human immune antibodies. Finally, immunization of mice with the PvAMA-1 ectodomain induced high levels of antibodies predominantly to DI-II. Together, our results indicate that DII is particularly immunogenic during natural human infections, thus indicating that this region could be used as part of an experimental sub-unit vaccine to prevent vivax malaria. (C) 2008 Elsevier Masson SAS. All rights reserved.

Impact on human health of particulate matter emitted from burnings in the Brazilian Amazon region

OBJECTIVE: To analyze the impact on human health of exposure to particulate matter emitted from burnings in the Brazilian Amazon region. METHODS: This was an ecological study using an environmental exposure indicator presented as the percentage of annual hours (AH%) of PM2.5 above 80 μg/m3. The outcome variables were the rates of hospitalization due to respiratory disease among children, the elderly and the intermediate age group, and due to childbirth. Data were obtained from the National Space Research Institute and the Ministry of Health for all of the microregions of the Brazilian Amazon region, for the years 2004 and 2005. Multiple regression models for the outcome variables in relation to the predictive variable AH% of PM2.5 above 80 μg/m3 were analyzed. The Human Development Index (HDI) and mean number of complete blood counts per 100 inhabitants in the Brazilian Amazon region were the control variables in the regression analyses. RESULTS: The association of the exposure indicator (AH%) was higher for the elderly than for other age groups (β = 0.10). For each 1% increase in the exposure indicator there was an increase of 8% in child hospitalization, 10% in hospitalization of the elderly, and 5% for the intermediate age group, even after controlling for HDI and mean number of complete blood counts. No association was found between the AH% and hospitalization due to childbirth. CONCLUSIONS: The indicator of atmospheric pollution showed an association with occurrences of respiratory diseases in the Brazilian Amazon region, especially in the more vulnerable age groups. This indicator may be used to assess the effects of forest burning on human health.

Modeling the interplay between land use, bioenergy production and climate change

Land use has become a force of global importance, considering that 34% of the Earth’s ice-free surface was covered by croplands or pastures in 2000. The expected increase in global human population together with eminent climate change and associated search for energy sources other than fossil fuels can, through land-use and land-cover changes (LUCC), increase the pressure on nature’s resources, further degrade ecosystem services, and disrupt other planetary systems of key importance to humanity. This thesis presents four modeling studies on the interplay between LUCC, increased production of biofuels and climate change in four selected world regions. In the first study case two new crop types (sugarcane and jatropha) are parameterized in the LPJ for managed Lands dynamic global vegetation model for calculation of their potential productivity. Country-wide spatial variation in the yields of sugarcane and jatropha incurs into substantially different land requirements to meet the biofuel production targets for 2015 in Brazil and India, depending on the location of plantations. Particularly the average land requirements for jatropha in India are considerably higher than previously estimated. These findings indicate that crop zoning is important to avoid excessive LUCC. In the second study case the LandSHIFT model of land-use and land-cover changes is combined with life cycle assessments to investigate the occurrence and extent of biofuel-driven indirect land-use changes (ILUC) in Brazil by 2020. The results show that Brazilian biofuels can indeed cause considerable ILUC, especially by pushing the rangeland frontier into the Amazonian forests. The carbon debt caused by such ILUC would result in no carbon savings (from using plant-based ethanol and biodiesel instead of fossil fuels) before 44 years for sugarcane ethanol and 246 years for soybean biodiesel. The intensification of livestock grazing could avoid such ILUC. We argue that such an intensification of livestock should be supported by the Brazilian biofuel sector, based on the sector’s own interest in minimizing carbon emissions. In the third study there is the development of a new method for crop allocation in LandSHIFT, as influenced by the occurrence and capacity of specific infrastructure units. The method is exemplarily applied in a first assessment of the potential availability of land for biogas production in Germany. The results indicate that Germany has enough land to fulfill virtually all (90 to 98%) its current biogas plant capacity with only cultivated feedstocks. Biogas plants located in South and Southwestern (North and Northeastern) Germany might face more (less) difficulties to fulfill their capacities with cultivated feedstocks, considering that feedstock transport distance to plants is a crucial issue for biogas production. In the fourth study an adapted version of LandSHIFT is used to assess the impacts of contrasting scenarios of climate change and conservation targets on land use in the Brazilian Amazon. Model results show that severe climate change in some regions by 2050 can shift the deforestation frontier to areas that would experience low levels of human intervention under mild climate change (such as the western Amazon forests or parts of the Cerrado savannas). Halting deforestation of the Amazon and of the Brazilian Cerrado would require either a reduction in the production of meat or an intensification of livestock grazing in the region. Such findings point out the need for an integrated/multicisciplinary plan for adaptation to climate change in the Amazon. The overall conclusions of this thesis are that (i) biofuels must be analyzed and planned carefully in order to effectively reduce carbon emissions; (ii) climate change can have considerable impacts on the location and extent of LUCC; and (iii) intensification of grazing livestock represents a promising venue for minimizing the impacts of future land-use and land-cover changes in Brazil.

Derecho penal y la obligación de investigar y sancionar graves violaciones de derechos humanos y el derecho internacional humanitario -especial referencia a la sentencia de la corte constitucional colombiana c-579/13-

En el presente trabajo se analiza la obligación de investigar graves violaciones de Derechos Humanos y Derecho Internacional Humanitario, a la luz de la sentencia de la Corte Constitucional Colombiana referente a la constitucionalidad del Marco Jurídico para la paz. De la aparente remisión que hace la Corte Constitucional a la Corte Interamericana de Derechos Humanos sobre el deber de investigar graves violaciones de Derechos Humanos y de Derecho Internacional Humanitario se concluye que la Corte Constitucional propone como premisa mayor una obligación que surge de una interpretación extensiva de la Convención Interamericana. De la misma forma, se estudia el tratamiento indebido del derecho aplicable a las amnistías e indultos, que se relaciona con la necesidad de evitar cualquier tipo de impunidad, cuyo concepto sirve para esclarecer cuáles son los estándares que se quiere proteger. Por último, se analiza el contexto al que se pretende aplicar dicha obligación, es decir, la justicia transicional, proponiendo un modelo interpretativo de los fines de la pena, y su aplicación por medio de la favorabilidad penal, para la justicia transicional, que sea acorde a la interpretación de la Convención Interamericana.

Coupling Virus-Induced Gene Silencing to Exogenous Green Fluorescence Protein Expression Provides a Highly Efficient System for Functional Genomics in Arabidopsis and across All Stages of Tomato Fruit Development

Since the advent of the postgenomic era, efforts have focused on the development of rapid strategies for annotating plant genes of unknown function. Given its simplicity and rapidity, virus-induced gene silencing (VIGS) has become one of the preeminent approaches for functional analyses. However, several problems remain intrinsic to the use of such a strategy in the study of both metabolic and developmental processes. The most prominent of these is the commonly observed phenomenon of ""sectoring"" the tissue regions that are not effectively targeted by VIGS. To better discriminate these sectors, an effective marker system displaying minimal secondary effects is a prerequisite. Utilizing a VIGS system based on the tobacco rattle virus vector, we here studied the effect of silencing the endogenous phytoene desaturase gene (pds) and the expression and subsequent silencing of the exogenous green fluorescence protein (gfp) on the metabolism of Arabidopsis (Arabidopsis thaliana) leaves and tomato (Solanum lycopersicum) fruits. In leaves, we observed dramatic effects on primary carbon and pigment metabolism associated with the photobleached phenotype following the silencing of the endogenous pds gene. However, relatively few pleiotropic effects on carbon metabolism were observed in tomato fruits when pds expression was inhibited. VIGS coupled to gfp constitutive expression revealed no significant metabolic alterations after triggering of silencing in Arabidopsis leaves and a mild effect in mature green tomato fruits. By contrast, a wider impact on metabolism was observed in ripe fruits. Silencing experiments with an endogenous target gene of interest clearly demonstrated the feasibility of cosilencing in this system; however, carefully constructed control experiments are a prerequisite to prevent erroneous interpretation.

Paleoamerican Morphology in the Context of European and East Asian Late Pleistocene Variation: Implications for Human Dispersion Into the New World

Early American crania show a different morphological pattern from the one shared by late Native Americans. Although the origin of the diachronic morphological diversity seen on the continents is still debated, the distinct morphology of early Americans is well documented and widely dispersed. This morphology has been described extensively for South America, where larger samples are available. Here we test the hypotheses that the morphology of Early Americans results from retention of the morphological pattern of Late Pleistocene modern humans and that the occupation of the New World precedes the morphological differentiation that gave rise to recent Eurasian and American morphology. We compare Early American samples with European Upper Paleolithic skulls, the East Asian Zhoukoudian Upper Cave specimens and a series of 20 modern human reference crania. Canonical Analysis and Minimum Spanning Tree were used to assess the morphological affinities among the series, while Mantel and Dow-Cheverud tests based on Mahalanobis Squared Distances were used to test different evolutionary scenarios. Our results show strong morphological affinities among the early series irrespective of geographical origin, which together with the matrix analyses results favor the scenario of a late morphological differentiation of modern humans. We conclude that the geographic differentiation of modern human morphology is a late phenomenon that occurred after the initial settlement of the Americas. Am J Phys Anthropol 144:442-453, 2011. (c) 2010 Wiley-Liss, Inc.

Deficient Regulatory T Cell Activity and Low Frequency of IL-17-Producing T Cells Correlate with the Extent of Cardiomyopathy in Human Chagas' Disease

Background: Myocardium damage during Chagas' disease results from the immunological imbalance between pro-and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease. Methodology/Principal Findings: First, we observed CD4(+)IL-17(+) T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-alpha, IFN-gamma and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4(+)IL-17(+) cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4(+)CD25(+) regulatory T cells. However, CD4(+)CD25(+) T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN-gamma levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = -0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500). Conclusion/Significance: These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-gamma and TNF-alpha is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation.

Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative

Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a "roadmap" for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH.

Na 1 Nachlass Max Horkheimer, 690 - Materialien zu Forschungsprojekten über Antisemitismus u.a. (p. IX 157 - IX 163.1-9)

"Beitrag des Instituts für Sozialforschung zu dem Forschungsprojekt über Autorität" (3.1.1951). Typoskript, 5 Blatt; "Reactions to the Antisemitic Incidents in January 1960. A Pilot Study in Frankfurt am Main. Summary of Procedure and Results" (1960). Typoskript, 6 Blatt (= Alt.Sig. IX 234.13 a); "Proposal for International Study of Anti-Semitism" (1960):; 1. American Jewish Committee: Luncheon Meeting, May 25, 1960, Typoskript, 2 Blatt; 2. American Jewish Committee, Institute of Human Relations: "The JDA Agencies and Germany" (17.5.1960). Als Typoskript vervielfältigt, 32 Blatt; Exzerpte aus Werken über Antisemitismus, Literaturlisten (etwa 1933-46):; 1. Everett R. Clinchy, Typoskript, 1 Blatt; 2. Paul K. Hatt, Typoskript, 3 Blatt; 3. John Moffat Mecklin, Typoskript, 3 Blatt; 4. Conrad Henry Moehlman, Typoskript, 4 Blatt; 5. Maurice Samuel, Typoskript, 5 Blatt; 6. Milton Steinberg, Typoskript, 2 Blatt; 7. "General Literature on Antisemitism", Liste, Typoskript mit handschriftlichen Ergänzungen, 1 Blatt; 8. "Bibliography" zum Judentum, 15 Blatt; 9. Literaturliste, handschriftliche Notizen, 9 Blatt; 10. Literaturliste, eigenhändige Notizen von Max Horkheimer, 1 Blatt; 11. Literaturliste, 1 Blatt; 12. Zitate zum Judentum aus Zeitschriften, 1 Blatt; Memorandum zum Antisemitismus (1944-48):; 1. S. Andhil Fineberg: "Notes on 'A Mask for Privilege' by Carey McWilliams", als Typoskript vervielfältigt, 4 Blatt; Carey McWilliams: "Memorandum" (8.5.1948), Typoskript, 3 Blatt; Lawrence Bloomgarden und S.A. Fineberg: "In Reply to Carey McWilliams Memorandum of May 8th", Typoskript, 3 Blatt; 2. Rundbriefe der American Jewish Sociological Society, 1944, als Typoskript vervielfältigt, 4 Blatt; 3. Bericht über einen Vortrag von Wladimir Eliasberg über Antisemitismus, Typoskript, 1 Blatt; Abschriften und Übersetzungen aus Zeitungsartikeln über Antisemitismus (1939-43):; 1. "A Note on Anti-Semitism", aus: The New Statesman and Nation (13.3.1939), Typoskript, 7 Blatt; 2. Abschriften aus deutschen und englischen Zeitungen, 1939, Typoskript, 1 Blatt; 3. "A Homility of the Bishop of Cremona" (Übersetzung aus: Osservatore Romano) 1939. Typoskript, 18 Blatt; Veröffentlichungen über Antisemitismus, Vorurteil, Demagogie (1941-63):; 1. Earl Raab und Seymour M. Lipset: "Prejudice and Society", Freedom Pamphlet Anti-Defamation League of B'nai B'rith (New York 1963), 48 Seiten; 2. Committee on Education, Training and Research in Race Relations of the University of Chicago: Bulletin, Nr. 1, 30.6.1948, 55. Seiten; 3. Solomon Andhil Fineberg: "Checkmate for Rabble-Rousers. What to Do When the Demagogue Comes to Town", Sonderdruck aus Commentary, Vol. 2, 1946 und eine Broschüre, 20 Seiten; 4. Kurt Lewin: "A new Approach to Old Problems", aus: Congress Week, 19.1.1945, 2 Blatt; 5. Eric A. Johnston: "Intolerance", New York, 11.1.1945, Heft, 8 Blatt; 6. Philip Wylie: "Memorandum on Anti-Semitism", aus: American Mercury, Januar 1945, 5 Blatt; 7. S.I. Hayakawa: "Race and Words", aus: Common Sense, Juli 1943, 3 Blatt; 8. David Riesman: "The Politics of Persecution". Als Typoskript vervielfältigt, 21 Blatt; 9. James P. Gifford, Frank D. Schroth, Maximilian Moss, Edward A. Richards, Samuel J. Levinson, Thomas G. Grace: "Anti-Semitism. It's Causes and Cures", New York, 1941, 30 Seiten;

Effects of birth order and sibling sex composition on human capital investment in children in India

The paper explores the effects of birth order and sibling sex composition on human capital investment in children in India using the Indian Human Development Survey (IHDS). Endogeneity of fertility is addressed using instruments and controlling for household fixed effects. Family size effect is also distinguished from the sibling sex composition effect. Previous literature has often failed to take endogeneity into account and shows a negative birth order effect for girls in India. Once endogeneity of fertility is addressed, there is no evidence for a negative birth order effect or sibling sex composition effect for girls. Results show that boys are worse off in households that have a higher proportion of boys specifically when they have older brothers.

HLA-G expression during preimplantation human embryo development.

HLA-G is a nonclassical class I major histocompatibility complex molecule with a restricted pattern of expression that includes the placental extravillus cytotrophoblast cells in direct contact with maternal tissues. Circumstantial evidence suggests that HLA-G may play a role in protection of the semiallogeneic human fetus. We examined whether HLA-G is expressed during the critical period of preimplantation human development and whether expression of this molecule could be correlated with the cleavage rate of embryos. Using reverse transcription PCR on surplus human embryos and unfertilized oocytes from patients undergoing in vitro fertilization we detected HLA-G heavy chain mRNA in 40% of 148 of blastocysts tested. The presence of HLA-G mRNA was also detected in unfertilized oocytes and in early embryos, but not in control cumulus oophorus cells. beta 2-Microglobulin mRNA was also found in those embryos expressing HLA-G. In concordance with our mRNA data, a similar proportion of embryos stained positive for HLA-G utilizing a specific monoclonal antibody. Interestingly, expression of HLA-G mRNA was associated with an increased cleavage rate, as compared to embryos lacking HLA-G transcript. Thus, HLA-G could be a functional homologue of the mouse Qa-2 antigen, which has been implicated in differences in the rate of preimplantation embryo development. To our knowledge, the presence of HLA-G mRNA and protein in human preimplantation embryos and oocytes has not been reported previously. The correlation of HLA-G mRNA expression with cleavage rate suggests that this molecule may play an important role in human pre-embryo development.

Innovation in leadership development

In the light of the financial crisis and the radically changed conditions in the market place, international leadership development is facing new demands. The Danish-based International Leadership Institute Mannaz has researched the new conditions in collaboration with the Institute of Executive Development in the United States. The research, conducted in 2008 and 2009, combines, in an innovative way, quantitative and qualitative inputs, from both current and future perspectives, from some 111 senior Corporate Executives, Heads of Human Resources and of Learning and Organisational Development in large international corporations headquartered in Europe and the United States; together with the thoughts of some 50 experienced practitioners involved in executive coaching as well as in designing, developing and facilitating leadership development programmes. Also we include a section summarising the key findings from recently published research from other leadership development surveys. Conclusions reveal that the crisis has propelled a long-awaited decline of the traditional classroom-based educational approach to leadership development. Instead, effective leadership development is suggested to build on experiential learning approaches rooted in real life, real time and allowing for more immediate impact and providing for considerably higher relevance and motivation. Coaching, leaders teaching leaders, stretch assignments, action learning, peer networking, customer insights and selective use of technology are seen as important contributors to the leadership development process going forward.

IL-10-producing Regulatory B Cell Development in Human Autoimmune Disease

B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of costimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of “regulatory B cells” has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported with interleukin-10 (IL-10) being the most studied. IL-10-producing regulatory B cells predominantly localize within a rare CD1dhiCD5+ B cell subset in mice and the CD24hiCD27+ B cell subset in adult humans. This specific IL-10-producing subset of regulatory B cells have been named “B10 cells” to highlight that the regulatory function of these rare B cells is primarily mediated by IL-10, and to distinguish them from other regulatory B cell subsets that regulate immune responses through different mechanisms. B10 cells have been studies in a variety of animal models with autoimmune disease and clinical settings of human autoimmunity. There are many unsolved questions related to B10 cells including their surface phenotype, their origin and development in vivo, and their role in autoimmunity.

In Chapter 3 of this dissertation, the role of the B cell receptor (BCR) in B10 cell development is highlighted. First, the BCR repertoire of mouse peritoneal cavity B10 cells is examined by single cell sequencing; peritoneal cavity B10 cells have clonally diverse germline BCRs that are predominantly unmutated. Second, mouse B10 cells are shown to have higher frequencies of λ+ BCRs compared to non-B10 cells which may indicate the involvement of BCR light chain editing early in the process of B10 cell development in vivo. Third, human peripheral blood B10 cells are examined and are also found to express higher frequencies of λ chains compared to non-b10 cells. Therefore, B10 cell BCRs are clonally diverse and enriched for unmutated germline sequences and λ light chains.

In Chapter 4 of this dissertation, B10 cells are examined in the healthy developing human across the entire age range of infancy, childhood and adolescence, and in a large cohort of children with autoimmunity. The study of B10 cells in the developing human documents a massive transient expansion during middle childhood when up to 30% of blood B cells were competent to produce IL-10. The surface phenotype of pediatric B10 cells was variable and reflective of overall B cell development. B10 cells down-regulated CD4+ T cell interferon-gamma (IFN-γ) production through IL-10-dependent pathways and IFN-γ inhibited whereas interleukin-21 (IL-21) promoted B cell IL-10 competency in vitro. Children with autoimmunity had a contracted B10 cell compartment, along with increased IFN-γ and decreased IL-21 serum levels compared to age-matched healthy controls. The decreased B10 cell frequencies and numbers in children with autoimmunity may be partially explained by the differential regulation of B10 cell development by IFN-γ and IL-21 and alterations in serum cytokine levels. The age-related changes of the B10 cell compartment during normal human development provide new insights into immune tolerance mechanisms involved in inflammation and autoimmunity.

These studies collectively demonstrate that BCR signals are the most important early determinant of B10 cell development in vivo, that human B10 cells are not a surface phenotype defined developmental B cell subset but a functionally defined regulatory B cell subset that regulates CD4+ T IFN-γ production through IL-10-dependent pathways and that human B10 cell development can be regulated by soluble factors in vivo such as the cytokine milieu. The findings of these studies provide new insights into immune tolerance mechanisms involved in human autoimmunity and the potent effects of IL-21 on human B cell IL-10 competence in vitro open new horizons in the development of autologous B10 cell-based therapies as an approach to treat human autoimmune disease in the future.