IgE-expressing B cells are over 1000 times more frequent in the nasal B cell than the peripheral blood B cell population. We have investigated the provenance of these B cells in the nasal mucosa in allergic rhinitis. It is generally accepted that expression of activation-induced cytidine deaminase and class switch recombination (CSR) occur in lymphoid tissue, implying that IgE-committed B cells must migrate through the circulation to the nasal mucosa. Our detection of mRNA for activation-induced cytidine, multiple germline gene transcripts, and ε circle transcripts in the nasal mucosa of allergic, in contrast to nonallergic control subjects, however, indicates that local CSR occurs in allergic rhinitis. The germline gene transcripts and ε circle transcripts in grass pollen-allergic subjects are up-regulated during the season and also when biopsies from allergic subjects are incubated with the allergen ex vivo. These results demonstrate that allergen stimulates local CSR to IgE, revealing a potential target for topical therapies in allergic rhinitis.

Epidemiological studies have suggested inverse associations between allergic diseases and malignancies. As a proof of concept for the capability of immunoglobulin E (IgE) to destruct tumor cells, several experimental strategies have evolved to specifically target this antibody class towards relevant tumor antigens. It could be demonstrated that IgE antibodies specific to overexpressed tumor antigens have been superior to any other immunoglobulin class with respect to antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) reactions. In an alternative approach, IgE nonspecifically attached to tumor cells proved to be a powerful adjuvant establishing tumor-specific immune memory. Active Th2 immunity could also be achieved by applying an oral immunization regimen using mimotopes, i.e. epitope mimics of tumor antigens. The induced IgE antibodies could be cross-linked by live tumor cells leading to tumoricidic mediator release. Thus, IgE antibodies may not only act in natural tumor surveillance, but could possibly also be exploited for tumor control in active and passive immunotherapy settings. Thereby, eosinophils, mast cells and macrophages can be armed with the cytophilic IgE and become potent anti-tumor effectors, able to trace viable tumor cells in the tissues. It is strongly suggested that the evolving new field AllergoOncology will give new insights into the role of IgE-mediated allergy in malignancies, possibly opening new avenues for tumor therapy.

We here demonstrate that mucosal IgE abs in NP tissue are functional and able to activate mast cells; specific IgE abs in NP tissue can be found independently of their presence in serum. We postulate that superantigen-induced polyclonal IgE in airway disease contributes to chronic inflammation by continuously activating mast cells.

Immunoglobulin E is produced by nasal B cells in response to allergen. We have analyzed IgE VH region sequences expressed in the nasal mucosa of patients suffering from allergic rhinitis. VH region sequences were amplified by RT-PCR from IgE+ B cells from nasal biopsies. In two of six patients, sequence analysis clearly demonstrated the presence of closely related IgE+ B cell clones: cells displaying identical signature regions across CDR3/FWR4, indicating a common clonal ancestry, but a mixture of shared and diverse somatic mutations across the VH region. Furthermore, in one of the two patients exhibiting related IgE+ B cell clones, five IgA+ B cell clones, related to the IgE+ B cell family, were also isolated from the patient’s nasal mucosa. This evidence, combined with the local expression of mRNA transcripts encoding activation-induced cytidine deaminase, suggests that local somatic hypermutation, clonal expansion, and class switch recombination occur within the nasal mucosa of allergic rhinitics. The presence of related B cells in the nasal mucosa does not appear to result from the random migration of IgE+ cells from the systemic pool, as analysis of a nonatopic subject with highly elevated serum IgE did not exhibit any detectable VH-Cε transcripts in the nasal mucosa. We have provided evidence that suggests for the first time that the nasal mucosa of allergic rhinitics is an active site for local somatic hypermutation, clonal expansion, and class switch recombination, making it of major significance for the targeting of future therapies.

We show here that the solenoid is maintained by the combination of linker histories and the nonglobular, highly basic "tails" of the core histones, which play only a minor part in the formation of the nucleosome core (Whitlock and Simpson, 1977 . /. Biol. Chem . 252 :6,516-6,520; Lilley and Tatchell, 1977 . Nucleic Acids Res. 4:2,039-2,055 ; and Whitlock and Stein, 1978 . l. Biol . Chem . 253:3,857-3,861) . Polynucleosomes that contain core histories devoid of tails remain substantially unfolded under conditions otherwise favorable for the formation of solenoids. The tails can be replaced by extraneous basic polypeptides and in the presence of the linker histones the solenoid structure is then spontaneously recovered, as judged by a wide variety of structural criteria . The inference is that the core histone tail segments function by providing electrostatic shielding of the DNA charge and at the same time bridging adjacent nucleosomes in the solenoid . Our results carry the further implication that posttranscriptional modifications, such as acetylation of 4E-amino groups, that reduce the positive charge of the core histone tails will tend to destabilize the higher-order structure and could thus render the DNA with which they are associated more readily available for transcription .The polynucleosome chain of chromatin can exist in at least two distinct states: in one the nucleosomes are disposed at regular intervals along an essentially flexible and disordered chain and in the other they form a higher order helix, referred to as the solenoid (4); this state has about six nucleosomes per turn and a pitch in the direction ofthe solenoid axis comparable with the principal dimension (11 rim) of the particles themselves (4-6) . This results in a 50-fold contraction of the DNA relative to the unperturbed double helix . The solenoid must be disrupted during transcription and replication of the DNA . Furthermore, putative promoter sites for selective transcription lie within the size range (up to 240 base pairs) of the DNA segments that link successive nucleosomes ; they could thus be buried in the higher order structure and thereby rendered inaccessible to regulatory proteins. An analysis of factors governing the equilibrium between the solenoid and the extended chain of chromatin is an important step towards an understanding ofthe mechanisms of transcriptional control .The importance of the linker histone (H1 or one of its close analogues) for the formation of the solenoid has been recognized for some time (5,7,8). Chromatin denuded of H1 exists only in the extended state (5, 8); when the H1 is restored, the solenoid structure is regained to an extent proportional to the amount of H1 bound, reaching a limit (for chicken erythrocyte chromatin) at a stoichiometry of two molecules per nucleosome THE JOURNAL OF CELL BIOLOGY " VOLUME 93 MAY 1982 285-297 ©The Rockefeller University Press " 0021-9525/82/05/0285/13 $1 .00 (8) . Furthermore, one can recognize separate roles for the three structural domains of H1, th...