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-We hypothesize that iodine allergy is an immune response to iodinated autologous proteins generated in vivo from iodine-containing organic and inorganic chemicals. In this report, effects of protein iodination on elicitogenic activity in guinea pig iodine allergy model and iodinated protein antigen generation in vitro from iodine-containing chemicals were investigated.Active cutaneous anaphylaxis (ACA) and delayed-type hypersensitivity (DTH) tests were performed in guinea pigs immunized with iodine. The amount of iodine (I 2 ) reacted to proteins for giving them an eliciting activity of ACA was ≥0.15 µmol for 1 mg of albumin. DTH reactions were provoked by intradermal injection of 10 6 PECs reacted with ≥0.075 µmol of I 2 . I 2 was generated from a potassium iodide (KI) solution or iodinated contrast media by UV light irradiation. X-ray irradiation of KI and iodinated contrast media in the presence of protein resulted in the generation of iodinated protein antigens. The generation of iodinated protein antigens was inhibited in the presence of reducing agents. Therefore, it is noteworthy that iodine allergy of the present hypothesis is dependent on reactive oxygens. By presenting these ex vivo and in vitro data, we discuss the possibilities for the generation of iodinated protein antigens in vivo.

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It has generally been thought that iodine allergy is cross-sensitive to various iodine-containing chemicals. However, this concept seems to deviate from the immunological principle that immune recognition is specific. To solve this contradiction, we hypothesize that iodine allergy is an immunological reaction to iodinated autologous proteins produced in vivo by iodination reaction from various iodine-containing chemicals. Antisera to iodine were obtained from guinea pigs immunized subcutaneously with iodine-potassium iodide solution emulsified in complete Freund's adjuvant (CFA). The specificity of guinea pig anti-iodine antiserum was determined by enzyme-linked immunosorbent assay (ELISA) inhibition experiments using microplates coated with iodinated guinea pig serum albumin (I-GSA). Antibody activities were inhibited by I-GSA, diiodo-L-tyrosine, and thyroxine, but not by potassium iodide, monoiodo-L-tyrosine, 3,5,3'-triiodothyronine, monoiodo-L-histidine, or diiodo-L-histidine, or by ionic or non-ionic iodinated contrast media. The results that antigen recognition of anti-iodine antibody is specific to iodinated protein support our hypothesis. While protein iodination usually takes place both at histidine residues as well as at tyrosine residues, only iodinated tyrosine acted as an antigenic determinant and no antibody activities to iodinated histidine were detected in our experimental iodine allergy model.

Healthy volunteers, who were receiving intravenous injections of cefclidin (CFCL) with frequent concomitant use of fluorescein (F) and oxybuprocain (O) in the eyes for measurement of ocular tension, developed drug eruptions at the high frequency of 66.7%. The injection of CFCL alone induced the eruptions at an incidence of 2.8%. The cause of this high eruption rate was thought to be the simultaneous treatment with F and/or O. Therefore, we conducted experiments with CFCL-induced generalized rash (GR) in guinea pigs. Guinea pigs treated with F and O during both the phases of immunization and intraperitoneal elicitation developed CFCL rashes at a high frequency. This CFCL-rash was augmented by the treatment with F during either phase, but not by the treatment with O. Skin testing induced delayed type hypersensitivity (DTH) reaction to O in some animals, but the DTH to F was not induced in animals immunized with F in complete Freund's adjuvant. Furthermore, F augmented rashes induced not only by CFCL but also by other beta-lactam antibiotics such as cefsulodin and sulbenicillin. Accordingly, it is likely that F played a dominant role in the high incidence of drug eruptions during the volunteer trials with measurement of ocular tension.