Development of immunoglobulin lambda-chain-positive B cells, but not editing of immunoglobulin kappa-chain, depends on NF-kappaB signals.
ABSTRACT By genetically ablating IkappaB kinase (IKK)-mediated activation of the transcription factor NF-kappaB in the B cell lineage and by analyzing a mouse mutant in which immunoglobulin lambda-chain-positive B cells are generated in the absence of rearrangements in the locus encoding immunoglobulin kappa-chain, we define here two distinct, consecutive phases of early B cell development that differ in their dependence on IKK-mediated NF-kappaB signaling. During the first phase, in which NF-kappaB signaling is dispensable, predominantly kappa-chain-positive B cells are generated, which undergo efficient receptor editing. In the second phase, predominantly lambda-chain-positive B cells are generated whose development is ontogenetically timed to occur after rearrangements of the locus encoding kappa-chain. This second phase of development is dependent on NF-kappaB signals, which can be substituted by transgenic expression of the prosurvival factor Bcl-2.
Article: Deletion of the immunoglobulin kappa chain intron enhancer abolishes kappa chain gene rearrangement in cis but not lambda chain gene rearrangement in trans.[show abstract] [hide abstract]
ABSTRACT: Immunoglobulins (Ig) secreted from a plasma cell contain either kappa or lambda light chains, but not both. This phenomenon is termed isotypic kappa-lambda exclusion. While kappa-producing cells have their lambda chain genes in germline configuration, in most lambda-producing cells the kappa chain genes are either non-productively rearranged or deleted. To investigate the molecular mechanism for isotypic kappa-lambda exclusion, in particular the role of the Ig kappa intron enhancer, we replaced this enhancer by a neomycin resistance (neoR) gene in embryonic stem (ES) cells. B cells heterozygous for the mutation undergo V kappa-J kappa recombination exclusively in the intact Ig kappa locus but not in the mutated Ig kappa locus. Homozygous mutant mice exhibited no rearrangements in their Ig kappa loci. However, splenic B cell numbers were only slightly reduced as compared with the wild-type, and all B cells expressed lambda chain bearing surface Ig. These findings demonstrate that rearrangement in the Ig kappa locus is not essential for lambda gene rearrangement. We also generated homozygous mutant mice in which the neoR gene was inserted at the 3' end of the Ig kappa intron enhancer. Unexpectedly, mere insertion of the neoR gene showed some suppressive effect on V kappa-J kappa recombination. However, the much more pronounced inhibition of V kappa-J kappa recombination by the replacement of the Ig kappa intron enhancer suggests that this enhancer is essential for V kappa-J kappa recombination.The EMBO Journal 07/1993; 12(6):2329-36. · 9.20 Impact Factor
Article: Rearrangement of mouse immunoglobulin kappa deleting element recombining sequence promotes immune tolerance and lambda B cell production.[show abstract] [hide abstract]
ABSTRACT: The recombining sequence (RS) of mouse and its human equivalent, the immunoglobulin (Ig) kappa deleting element (IGKDE), are sequences found at the 3' end of the Ig kappa locus (Igk) that rearrange to inactivate Igk in developing B cells. RS recombination correlates with Ig lambda (Iglambda) light (L) chain expression and likely plays a role in receptor editing by eliminating Igk genes encoding autoantibodies. A mouse strain was generated in which the recombination signal of RS was removed, blocking RS-mediated Igk inactivation. In RS mutant mice, receptor editing and self-tolerance were impaired, in some cases leading to autoantibody formation. Surprisingly, mutant mice also made fewer B cells expressing lambda chain, whereas lambda versus kappa isotype exclusion was only modestly affected. These results provide insight into the mechanism of L chain isotype exclusion and indicate that RS has a physiological role in promoting the formation of lambda L chain-expressing B cells.Immunity 03/2008; 28(2):161-70. · 21.64 Impact Factor
Article: Prevalence of nutritional wasting in populations: building explanatory models using secondary data.[show abstract] [hide abstract]
ABSTRACT: To understand how social context affects the nutritional status of populations, as reflected by the prevalence of wasting in children under 5 years of age from Africa, Latin America, and Asia; to present a systematic way of building models for wasting prevalence, using a conceptual framework for the determinants of malnutrition; and to examine the feasibility of using readily available data collected over time to build models of wasting prevalence in populations. Associations between prevalence of wasting and environmental variables were examined in the three regions. General linear mixed models were fitted using anthropometric survey data for countries within each region. Low birth weight (LBW), measles incidence, and access to a safe water supply explained 64% of wasting variability in Asia. In Latin America, LBW and survey year explained 38%; in Africa, LBW, survey year, and adult literacy explained 7%. LBW emerged as a predictor of wasting prevalence in all three regions. Actions regarding women's rights may have an effect on the nutritional status of children since LBW seems to reflect several aspects of the conditions of women in society. Databases have to be made compatible with each other to facilitate integrated analysis for nutritional research and policy decision-making. In addition, the validity of the variables representing the conceptual framework should be improved.Bulletin of the World Health Organisation 02/2002; 80(4):282-91. · 4.64 Impact Factor