Immunoglobulin heavy chain (IgH) variable region exons are assembled from VH, D and JH gene segments in developing B lymphocytes. Within the 2.7 megabase (Mb) mouse IgH locus (IgH), V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Herein, we report a key IgH V(D)J recombination regulatory region, termed InterGenic Control Region-1 (IGCR1), that lies between the VH and D clusters. Functionally, IGCR1 employs CTCF looping/insulator factor binding elements and, correspondingly, mediates IgH loops containing distant enhancers. IGCR1 promotes normal B cell development and balances antibody repertoires by inhibiting transcription and rearrangement of DH-proximal VHs and promoting rearrangement of distal VHs. IGCR1 maintains ordered and lineage-specific VH(D)JH recombination, respectively, by suppressing VH joining to Ds not joined to JHs and VH to DJH joins in thymocytes. IGCR1 also is required to allow feedback regulation and allelic exclusion of proximal VH to DJH recombination. Our studies elucidate a long-sought IgH V(D)J recombination control region and implicate a new role for the generally expressed CTCF protein.
The RAG1/RAG2 endonuclease ("RAG") initiates the V(D)J
recombination reaction that assembles Ig heavy
(IgH) and light (IgL) chain variable
region exons from germline gene segments to generate primary antibody
repertoires1.
IgH V(D)J assembly occurs in progenitor (pro-) B cells
followed by that of IgL in precursor (pre-) B cells. Expression
of IgH μ and IgL (Igκ or Igλ) chains generates IgM,
which is expressed on immature B cells as the B cell antigen-binding receptor
("BCR"). Rag expression can continue in
immature B cells2, allowing
continued Igκ V(D)J recombination that replaces the
initial VκJκ exon with one that generates a new
specificity3–5. This “receptor
editing” process, which also can lead to Igλ
V(D)J recombination and expression3,6,7, provides a mechanism whereby antigen-encounter
at the Rag-expressing immature B cell stage helps shape
pre-immune BCR repertoires. As the major site of post-natal B cell development,
the bone marrow is the principal location of primary Ig
repertoire diversification in mice. Here, we report that early B cell
development also occurs within the mouse intestinal lamina propria (LP), where
the associated V(D)J recombination/receptor editing processes modulate primary
LP Ig repertoires. At weanling age in normally housed mice, the
LP contains a population of Rag-expressing B lineage cells that
harbor intermediates indicative of ongoing V(D)J recombination and which contain
cells with pro-B, pre-B, and editing phenotypes. Consistent with LP-specific
receptor editing, Rag-expressing LP B-lineage cells have
similar VH repertoires, but significantly different
Vκ repertoires, compared to those of
Rag2-expressing BM counterparts. Moreover, colonization of
germ-free mice leads to an increased ratio of
Igλ-expressing versus
Igκ-expressing B cells specifically in the LP. We
conclude that B cell development occurs in the intestinal mucosa, where it is
regulated by extra-cellular signals from commensal microbes that influence gut
Ig repertoires.
Ten large European cities provided data on daily air pollution as well as mortality from respiratory and cardiovascular mortality. We used Poisson autoregressive models that controlled for trend, season, influenza epidemics, and meteorologic influences to assess the short-term effects of air pollution at each city. We then compared and pooled the city-specific results in a meta-analysis. The pooled relative risks of daily deaths from cardiovascular conditions were 1.02 [95% confidence interval (CI) = 1.01-1.04] for a 50 microg/m3 increment in the concentration of black smoke and 1.04 (95% CI = 1.01-1.06) for an increase in sulfur dioxide levels in western European cities. For respiratory diseases, these figures were 1.04 (95% CI = 1.02-1.07) and 1.05 (95% CI = 1.03-1.07), respectively. These associations were not found in the five central European cities. Eight-hour averages of ozone were also moderately associated with daily mortality in western European cities (relative risk = 1.02; 95% CI = 1.00-1.03 for cardiovascular conditions and relative risk = 1.06; 95% CI = 1.02-1.10 for respiratory conditions). Nitrogen dioxide did not show consistent relations with daily mortality. These results are similar to previously published data and add credence to the causal interpretation of these associations at levels of air pollution close to or lower than current European standards.
Pregnant women who received H1N1 influenza vaccine were less likely to give birth preterm, and gave birth to heavier infants. The findings support US vaccine policy choices to prioritize pregnant women during the 2009 influenza A (H1N1) pandemic.
In this large, geographically diverse population, A(H1N1)pdm09 infection increased the risk for hospitalization during pregnancy. Late initiation of antiviral treatment was also associated with an increased risk for hospitalization.
Signaling downstream of the T cell receptor (TCR) is directly regulated by the dose and affinity of peptide antigen. The strength of TCR signaling drives a multitude of T cell functions from development to differentiation. CD8 T cells differentiate into a diverse pool of effector and memory cells after activation, a process that is critical for pathogen clearance and is highly regulated by TCR signal strength. T cells rapidly alter their gene expression upon activation. Multiple signaling pathways downstream of the TCR activate transcription factors, which are critical for this process. The dynamics between proximal TCR signaling, transcription factor activation and CD8 T cell function are discussed here. We propose that inducible T cell kinase (ITK) acts as a rheostat for gene expression. This unique regulation of TCR signaling by ITK provides a possible signaling mechanism for the promotion of a diverse T cell repertoire in response to pathogen.
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