Four previously healthy homosexual men contracted Pneumocystis carinii pneumonia, extensive mucosal candidiasis, and multiple viral infections. In three of the patients these infections followed prolonged fevers of unknown origin. In all four cytomegalovirus was recovered from secretions. Kaposi's sarcoma developed in one patient eight months after he presented with esophageal candidiasis. All patients were anergic and lymphopenic; they had no lymphocyte proliferative responses to soluble antigens, and their responses to phytohemagglutinin were markedly reduced. Monoclonal-antibody analysis of peripheral-blood T-cell subpopulations revealed virtual elimination of the Leu-3 / helper/inducer subset, an increased percentage of the Leu-2 + suppressor/cytoxic subset, and an increased percentage of cells bearing the thymocyte-associated antigen T10. The inversion of the T/ helper to suppressor/cytotoxic ratio suggested that cytomegalovirus infection was an important factor in the pathogenesis of the immunodeficient state. A high level of exposure of male homosexuals to cytomegalovirus-infected secretions may account for the occurrence of this immune deficiency.

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Diesel exhaust particles (DEP) have been implicated in the increased incidence of allergic airway disorders. We investigated the effects of DEP on localized immunoglobulin production by performing nasal challenges with varying doses of DEP and analyzing the local immune response in nasal lavages obtained before and after. A significant rise in nasal IgE but not IgG, IgA, IgM, or albumin was observed in subjects 4 d after challenge with 0.30 mg DEP, equivalent to exposure on an average Los Angeles day. Direct evidence for DEP-enhanced local production of IgE was that challenge increased the number of IgE-secreting cells in lavage fluid from < 1 in 2,000,000 to > 1 in 100,000 but did not alter the number of IgA-secreting cells. There was a concomitant increase in epsilon mRNA production in the lavage cells. Additionally, DEP altered the relative amounts of five different epsilon mRNAs generated by alternative splicing, mRNAs that code for different IgE proteins. These results show that DEP exposure in vivo causes both quantitative and qualitative changes in local IgE production. The implication is that natural exposure to DEP may result in increased expression of respiratory allergic disease. (J. Clin.

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Allergic reactions to the beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are a major factor limiting their use. Immediate hypersensitivity reactions to penicillins depend on the presence of preformed allergic (IgE) antibodies to several penicillin determinants. These materials can be used in in-vivo skin testing to exclude those patients at risk for immediate or accelerated allergic reactions. The cephalosporins have not had their relevant determinants defined as related to allergic reactions. The results of in-vivo challenges of patients with IgE to penicillin suggest the incidence of reactivity of cephalosporins in patients allergic to penicillin is less than generally appreciated. The monocyclic beta-lactam antibiotic, aztreonam (a monobactam), failed to show cross-reactivity with penicillin antibodies, because immune reactivity toward the monobactam was directed against side chain rather than nuclear determinants. On the other hand, the new bicyclic carbapenem beta-lactam drugs, represented by imipenem, showed extensive in-vivo cross-reactivity with penicillins.

Human mast cells and basophils that express the high-affinity immunoglobulin E (IgE) receptor, Fcε receptor 1 (FcεRI), have key roles in allergic diseases. FcεRI cross-linking stimulates the release of allergic mediators 1 . Mast cells and basophils co-express FcγRIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with FcεRI can block FcεRI-mediated reactivity 2-4 . Here we designed, expressed and tested the human basophil and mast-cell inhibitory function of a novel chimeric fusion protein, whose structure is γ Hinge-CHγ2-CHγ3-15aa linker-CHε2-CHε3-CHε4. This Fcγ-Fcε fusion protein was expressed as the predicted 140-kD dimer that reacted with anti-human ε-and γ-chain specific antibodies. Fcγ-Fcε bound to both human FcεRI and FcγRII. It also showed dose-and time-dependent inhibition of antigen-driven IgE-mediated histamine release from fresh human basophils sensitized with IgE directed against NIP (4-hydroxy-3-iodo-5-nitrophenylacetyl). This was associated with altered Syk signaling. The fusion protein also showed increased inhibition of human anti-NP (4-hydroxy-3-nitropheny-lacetyl) and anti-dansyl IgE-mediated passive cutaneous anaphylaxis in transgenic mice expressing human FcεRIα. Our results show that this chimeric protein is able to form complexes with both FcεRI and FcγRII, and inhibit mast-cell and basophil function. This approach, using a Fcγ-Fcε fusion protein to co-aggregate FcεRI with a receptor containing an immunoreceptor tyrosinebased inhibition motif, has therapeutic potential in IgE-and FcεRI-mediated diseases.Allergen aggregation of IgE bound to FcεRI induces release of preformed mediators and synthesis of later acting leukotrienes and chemokines from mast cells and basophils 5 . This process has a major role in many of human diseases such as asthma, allergic rhinitis, chronic urticaria, angioedema and anaphylaxis. FcεRI aggregation induces release of preformed mediators and synthesis of later-acting leukotrienes, chemokines and cytokines 5 . The FcεRI is a heterotetramer consisting of a single IgE-binding α-subunit, a β-subunit and two disulfidelinked γ-subunits. The β and γ-subunit cytoplasmic tails each contain a conserved immunoreceptor tyrosine-based activation motif (ITAM). Cross-linking FcεRI via IgE bound to multivalent antigen activates tyrosine phosphorylation of ITAMs, thereby initiating downstream signaling 6 . Mast cells and basophils co-express FcγRIIb, which contains two extracellular immunoglobulin-like loops and a single conserved immunoreceptor tyrosinebased inhibition motif (ITIM) within its cytoplasmic tail 7 . FcγRIIb may co-aggregate with Correspondence should be addressed to A.S.; email: asaxon@mednet.ucla.edu. D.Z. and C.L.K. contributed equally to this study. Competing interests statementThe authors declare competing financial interests: see the website (http://medicine.nature.com) for details. FcεRI under physiologic conditions. It is hypothesized that when FcγRIIb aggregates, it induces inhibitory...

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