Basal Immunoglobulin Signaling Actively Maintains Developmental Stage in Immature B Cells

In developing B lymphocytes, a successful V(D)J heavy chain (HC) immunoglobulin (Ig) rearrangement establishes HC allelic exclusion and signals pro-B cells to advance in development to the pre-B stage. A subsequent functional light chain (LC) rearrangement then results in the surface expression of IgM at the immature B cell stage. Here we show that interruption of basal IgM signaling in immature B cells, either by the inducible deletion of surface Ig via Cre-mediated excision or by incubating cells with the tyrosine kinase inhibitor herbimycin A or the phosphatidylinositol 3-kinase inhibitor wortmannin, led to a striking “back-differentiation” of cells to an earlier stage in B cell development, characterized by the expression of pro-B cell genes. Cells undergoing this reversal in development also showed evidence of new LC gene rearrangements, suggesting an important role for basal Ig signaling in the maintenance of LC allelic exclusion. These studies identify a previously unappreciated level of plasticity in the B cell developmental program, and have important implications for our understanding of central tolerance mechanisms

Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1Anaef naïve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation

The role of parental achievement goals in predicting autonomy-supportive and controlling parenting

Although autonomy-supportive and controlling parenting are linked to numerous positive and negative child outcomes respectively, fewer studies have focused on their determinants. Drawing on achievement goal theory and self-determination theory, we propose that parental achievement goals (i.e., achievement goals that parents have for their children) can be mastery, performance-approach or performance-avoidance oriented and that types of goals predict mothers' tendency to adopt autonomy-supportive and controlling behaviors. A total of 67 mothers (aged 30-53 years) reported their goals for their adolescent (aged 13-16 years; 19.4 % girls), while their adolescent evaluated their mothers' behaviors. Hierarchical regression analyses showed that parental performance-approach goals predict more controlling parenting and prevent acknowledgement of feelings, one autonomy-supportive behavior. In addition, mothers who have mastery goals and who endorse performance-avoidance goals are less likely to use guilt-inducing criticisms. These findings were observed while controlling for the effect of maternal anxiety

Conflito trabalho-família, auto eficácia parental e estilos parentais percebidos em pais e mães da cidade de Talca no Chile

The relationship between levels of work-family conflict, parental self-efficacy and perceived parenting styles in a group of 43 school children and both working parents is analyzed, controlling for socio-demographic variables. Also, gender differences are identified in the variables and the relationship between them in relation to the number of children. Three instruments were applied to the sample for measuring the referred variables. A significant and negative relationship is observed between levels of work-family conflict and parental self-efficacy (r = -0.484, P <0.001). The authoritarian parenting style has greater association with self-efficacy (r = 0.301, P = 0.005). A significant and negative relationship between self-efficacy and number of children (r = -0.257, P = 0.017) is reported. Finally, it is concluded that women have greater work-family conflict than men.Se analiza la relación existente entre los niveles de conflicto trabajo-familia, autoeficacia parental y estilos parentales percibidos en un grupo de 43 niños estudiantes y ambos padres trabajadores, controlando las variables sociodemográficas. Así mismo, se identifican las diferencias por género en las variables, y la relación que existe entre ellas con respecto al número de hijos. A la muestra le fueron aplicados tres instrumentos de medición de las variables referidas. Se observa una relación significativa y negativa entre los niveles de conflicto trabajo-familia y la autoeficacia parental (r= -0,484; p<0,001). El estilo parental autoritario presenta mayor asociación con autoeficacia (r=0,301; p=0,005). Se reporta una relación significativa y negativa entre autoeficacia y número de hijos (r=-0,257; p=0,017). Finalmente se reporta que las mujeres presentan mayor conflicto trabajo-familia que los hombres.Analisa-se a relação existente entre os níveis de conflito trabalho-família, auto eficácia parental e estilos parentais percebidos em um grupo de 43 crianças estudantes de pais trabalhadores, controlando as variáveis sociodemográficas. Assim mesmo, identificam-se as diferenças por gênero nas variáveis, e a relação que existe entre elas com respeito ao número de filhos. Foram aplicados à mostra três instrumentos de medição das variáveis referidas. Observa-se uma relação significativa e negativa entre os níveis de conflito trabalho-família e a auto eficácia parental (r= -0,484; p<0,001). O estilo parental autoritário apresenta maior associação com autoeficácia (r=0,301; p=0,005). Reporta-se uma relação significativa e negativa entre autoeficácia e número de filhos (r=-0,257; p=0,017). Finalmente reporta-se que as mulheres apresentam maior conflito trabalho-família que os homens

Parents' and teachers' beliefs about adolescents: Effects of sex and experience

Three studies examine beliefs that parents and teachers have about adolescents. A distinction is made between category-based beliefs (concerning adolescents as a group) and target-based beliefs (concerning individual adoles cents). In Study 1, 90 late elementary and junior high school teachers indicated degree of agreement with a set of category-based statements about adolescents. Parents of early adolescents in Study 2 (N=1272) responded to category- and target-based statements. Study 3 compares the responses of teachers in Study 1 and parents in Study 2. Both teachers and parents endorsed beliefs that adolescence is difficult, and that adults can have an impact. Compared to fathers, mothers believed more in difficulty and in the negative effects of biological change on behavior. Parents of daughters believed adolescence is more difficult than parents of sons. Among teachers, amount of experience with adolescents was positively associated with the belief that adolescence is a difficult period of life. For parents, the effect of amount of experience was mixed. Experience had a greater impact on the category-based beliefs of teachers than parents. Possible influences on the origins and modification of beliefs are discussed .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45275/1/10964_2005_Article_BF01537078.pd

Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios⁺ T cells and autoantibodies

Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1ᴬⁿᵃᵉᶠ, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1ᴬⁿᵃᵉᶠ mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios⁺ PD-1⁺ CD4⁺ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1ᴬⁿᵃᵉᶠ is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1ᴬⁿᵃᵉᶠ naïve CD4⁺ T cells. CD44 expression, CD4⁺ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1ᴬⁿᵃᵉᶠMtorᶜʰⁱⁿᵒ double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1ᴬⁿᵃᵉᶠ T cell dysregulation

Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity.

Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1-binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation-induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity