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Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses.

Immunoglobulin E (IgE) isotype antibodies are associated with atopic disease, namely allergic rhinitis, asthma and atopic dermatitis, but are also involved in host immune defence mechanisms against parasitic infection. The commitment of a B cell to isotype class switch to an IgE-producing cell is a tightly regulated process, and our understanding of the regulation of IgE-antibody production is central to the prevention and treatment of atopic disease. Both those that are presently in use and potential future therapies to prevent IgE-mediated disease take advantage of our existing knowledge of the specific mechanisms that are required for IgE class switching.

Background: We recently described a murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). The skin lesions in these mice were characterized by a dermal infiltrate consisting of eosinophils and T cells and by increased expression of the T H 2 cytokines IL-4 and IL-5. Epicutaneous sensitization induces a rise in the levels of serum total IgE and OVA-specific antibodies, further indicating that it elicits a predominantly T H 2 response. Objective: This study was undertaken to assess the roles of T cells, B cells, and CD40L-CD40 interactions in AD. Methods: Mice with targeted gene deletions were sensitized with OVA. Histologic and immunohistochemical examinations, as well as measurements of IL-4 mRNA, were performed on OVA-sensitized skin. Total and antigen-specific serum IgE levels were determined. Results: RAG2 –/– mice, which lack both T and B cells, did not exhibit cellular infiltration, induction of dermal IL-4 mRNA, or elevation of serum IgE after OVA sensitization; all of these features were present in B-cell–deficient IgH –/– mice. T-cell receptor α –/– mice did not display cellular infiltration, IL-4 mRNA expression, or increased IgE levels after OVA sensitization, but these responses were elicited in T-cell receptor δ –/– mice after sensitization. Absence of CD40 had no effect on these responses. Conclusion: These results suggest that αβ T cells, but not γδ T cells, B cells, or CD40L-CD40 interactions, are critical for skin inflammation and the T H 2 response in AD. (J Allergy Clin Immunol 2001;107:359-66.)

Background Many receptors rely on the appropriate activation of nuclear factor (NF) κB to induce cellular function. This process depends critically on the phosphorylation of the inhibitor of NF-κB (IκB) by the IκB kinase. This targets IκB for ubiquitination and degradation, allowing NF-κB to translocate to the nucleus, where it can direct transcription. Hypomorphic human mutations affecting one IκB kinase component, the NF-κB essential modulator (NEMO), result in impaired signaling from receptors required for ectodermal development and immune function. Male subjects with these mutant NEMO molecules have an X-linked syndrome known as ectodermal dysplasia with immunodeficiency, which is characterized by severe infections, with herpesviruses, bacteria, and mycobacterial susceptibility. Objective We sought to genetically and biochemically characterize a patient with a mutant NEMO molecule without ectodermal abnormalities. Methods We evaluated NEMO in a patient who had immunodeficiency and atypical mycobacterial infection but normal ectoderm. Results We identified a novel NEMO mutant causing immunodeficiency without ectodermal dysplasia. The mutation, which altered the exon 9 splice site, was present in cells of ectodermal and hematopoetic origin and resulted in a heterogeneous mixture of mutant and wild-type cDNA species. Immunologic function was variably impaired, with reduced CD40-induced B-cell proliferation, partially reduced NF-κB p65 nuclear translocation, and variable Toll-like receptor–induced TNF production. This variability might be explained by an inconsistent ratio of mutant to wild-type NEMO. The lack of any ectodermal phenotype, however, suggested a separation in the hematopoetic and ectodermal function of NEMO that leads to NF-κB activation. Conclusion Mutation of the gene encoding NEMO can result in immunodeficiency without ectodermal dysplasia.

Background: A substantial body of evidence exists to support the pivotal role of IL-13 in the pathogenesis of bronchial asthma. We recently found that a variant of the IL13 gene (Arg110Gln) is genetically associated with bronchial asthma, which is concordant with animal experiments using IL-13 in the development of asthma. Objective: To address whether the Gln110 variant of IL13 influences IL-13 function, contributing to the pathogenesis of bronchial asthma, we studied the functional properties of the variant. Methods: We generated 2 types of recombinant IL-13 proteins, the amino acids of which at 110 were arginine or glutamine, and analyzed the binding affinities with the IL-13 receptors, as well as the stability of the proteins. We further compared the relationship between the genotype and serum levels of IL-13. Results: The variant showed a lower affinity with the IL-13 receptor α2 chain, a decoy receptor, causing less clearance. The variant also demonstrated an enhanced stability in both human and mouse plasma. We further identified that asthmatic patients homozygous for the Gln110 variant have higher serum levels of IL-13 than those without the variant. Conclusion: These results suggested that the variant might act as a functional genetic factor of bronchial asthma with a unique mechanism to upregulate local and systemic IL-13 concentration in vivo. (J Allergy Clin Immunol 2002;109:980-7.)