immunology today, October 1980

74 tained a m i x t u r e of these m o n o c l o n a l l y derived factors. T h e s e findings, therefore, open the w a y for a detailed analysis of the possible structural and biological relationships b e t w e e n antigen-specific and non-specific i m m u n o r e g u l a t o r y factors p r o d u c e d simultaneously d u r i n g antigen sensitization. Finally, T-cell h y b r i d o m a s allow a kind of structural analysis which was impossible with conventionally derived factors. For example, T a u s s i g and H o l t i m a n 2° were able to show, by internal labeling of h y b r i d o m a s p r o d u c i n g sheep-erythrocyte-specific SF a n d S D S - p o l y a c r y l a m i d e gel etectrophoresis analysis, that the factor consisted of two polypeptide chains in non-covalent association. T h e large subunit (85,000 d a h o n s ) p o s s e s s e d the a n t i g e n - b i n d i n g a c t i v i t y whereas a smaller subunit (25,000 daltons) expressed M H C d e t e r m i n a n t s . In a more recent study 2~, it was shown, by analysis of the intracellular p r o d u c t s as well as the secreted product of an SFKLn-producing h y b r i d cell line, that the a n t i g e n - b i n d i n g and t h e / - J - b e a r i n g molecules present in the SF are i n d e p e n d e n t l y synthesized in the c y t o p l a s m and are secreted as an associated form of the two molecules. F u r t h e r m o r e , it was shown that this association is r e q u i r e d for antigenReferences I Tada, T., Taniguchi, M. and Okumura, K. (1977) Progr. Immunol. 3, 369 2 Taniguchi, M. and Tokuhisa, T. (1980) J. Exp. Med. 151,517 3 Waltenbaugh, C., Th6ze, J., Kapp, J. A. and Benacerraf, B. (t977) J. Exp. Med. 146, 970 4 Germain, R. N., Th6ze, J., Kapp, J. A. and Benacerraf, B. (1978) J. Exp. Med. 147, 123 5 Sy, M.-S., Dietz, M. H., Germain, R. N., Benacerraf, B. and Greene, M. I. (1980)J. Exp. Med. 151, 1183 6 Perry, L. L., Benacerraf, B. and Greene, M. I. (1978) J. Irnmunol. 121, 2144 7 Hirai, Y. and Nisonoff, A. (1980) J. Exp. Med. 151, 1213 8 Tada, T., Takemori, T., Okumura, K., Nonaka, M. and Tokuhisa, T. (1978)J. Exp. Med. 147,446 9 Woodland, R. and Cantor, H. (1978) Eur. J. lmmunol. 8, 600 10 Janeway, C. A., Bert, D. L. and Shen, F.-W. (1980) Eur. J. Immunol. 10, 231 11 Takatsu, K., Tominaga, A. and Hamaoka, T. (1980) J. lmmunol. 124, 2414 12 Kontiainen, S., Simpson, E., Bohrer, E., Beverley, P. C. L., Herzenberg, L. A., Fitzpatrick, W. C., Vogt, P., Torano, A., McKenzie, I. F. C. and Feldmann, M. (1978) Nature (London) 274,477

specific biological activity. It w o u l d be of interest to test whether the I - J + molecule, in the absence of the a n t i g e n - b i n d i n g c o m p o n e n t , w o u l d be capable of exerting antigen-non-specific irnmunoregulatory activity. T h e i n f o r m a t i o n a b o u t the t w o - s u b u n i t structure of antigen-specific SF 2°,21 is interesting in view of the finding that allogeneic effect factor, the first T cellderived i m m u n o r e g u l a t o r y I y m p h o k i n e found to express Ia d e t e r m i n a n t s 22,23, also consists of two subunits 24. T h e r e is no doubt, therefore, that the study of h y b r i d cell lines p r o d u c i n g i m m u n o r e g u l a t o r y factors will bring m u c h nearer the solution of some of the most basic questions about the structure and function of these factors. I thank Dr David H. Katz for constant support and encouragement and Keith L. Dunn for typing this manuscript. This is publication number 187 from the Department of Cellular and Developmental Immunology and publication number 2198 from the Immunology Departments, Scripps Clinic and Research Foundation, La Jolla, California. I am a recipient of an American Cancer Society, Inc. Faculty Research AwardJFRA-17. AMNON ALTMAN Department of Cellular and Developmental Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037, U.S.A.

13 Taniguchi, M. and Miller, J. F. A. P. (1978) J. Exp. Med. 148, 373 14 Taussig, M. J., Corvalfin, J. R. F., Binns, R. M. and Holliman, A. (1979) Nature (London) 277,305 15 Hewin,J. and Liew, F. Y. (1979) Eur. J. ImmunoL 9, 572 16 Watanabe, T., Kimoto, M., Maruyama, S., Kishimoto, T. and Yamamura, Y. (1978) J. Immunol. 121, 2113 17 Neauport-Sautes, C., Rabourdin-Combe, C. and Fridman, W. (1979) Nature (London) 277,656 18 Schrader, J. W., Arnold, B. and Clark-Lewis, I. (1980) JVature (London) 283, 197 19 Katz, D. H., Cardenas, J. M., Bechtold, T. E. and Ahman, A. J. Exp. Med. (in press) 20 Taussig, M. J. and Holliman, A. (1979) Nature (London) 277, 3O8 21 Taniguchi, M., Takei, I. and Tada, T. (1980) Nature (London) 283,227 22 Armerding, D. and Katz, D. H. (1974) J. Exp. Med. 140, 19 23 Armerding, D., Sachs, D. H. and Katz, D. H. (1974) J. Exp. Med. 140, 1717 24 Armerding, 1)., Eshhar, Z. and Katz, D. H. (1977)J. Immunol. 119, 1468

Antigen specificity in food allergies F o o d allergy is a b o o m subject with rapidly e x p a n d i n g clinical horizons. Clinicians have long recognized skin rashes due to such things a s . s t r a w b e r r i e s a n d shellfish, but it is now suggested that c o m m o n foods can provoke i m m u n o l o g i c a l reactions in m a n y o r g a n systems, causing diseases in w h i c h allergy has not been hitherto seriously considered, across a range e x t e n d i n g even to m e n t a l disease. T h e clinical claims vary from the well-substantiated to the fanciful. Historically, clinical observation usually precedes scientific u n d e r s t a n d i n g - J e n n e r ' s observation on vaccination is a classical e x a m p l e - and there is now a need for a sound scientific base for clinical observa© Elsevier/North-Holland Biomedical Press 1980

tions of food allergy. Until very recently it has been considered a fringe subject u n w o r t h y of serious immunological investigation a n d studies therefore have been few. Soothill's a d m i r a b l e work on the role of cow's milk in c h i l d h o o d e c z e m a and a s t h m a has stood alone 1. T h e position is changing, however, and basic studies are b e g i n n i n g to appear. Foods are c o m m o n causes of anaphylaxis, but the responsible antigens have rarely been characterized. Clinicians working in this field talk of milk and egg allergy as c o m m o n problems, with no knowledge of which c o m p o n e n t of egg or milk is the allergen. In some cases it is not the food itself but an additive. T a r -

immunology today, October 1980

trazine, a yellow colouring substance common in processed foods, crossreacts with salicylates, and can cause problems in some patients with aspirin-induced asthma. Soybean products are also c o m m o n in processed foods and they too can cause food allergy. The recent identification of a specific allergen in a patient with severe soybean allergy is thus a significant advance 2. The patient had angio-oedema and urticaria after eating several types of legume but the most violent reactions were to soybean products. Once, as a post-partum patient in hospital, she ate a h a m b u r g e r that had been cooked in soya oil, and 10 minutes later had a severe anaphylactic reaction with facial swelling and difficulty in b r e a t h i n g a n d swallowing that required emergency treatment including oxygen. After testing her infant's soya food preparation she had a particularly severe reaction in which she lost consciousness. Skin testing revealed reactions to several varieties of bean but responses to soybean and commercially produced Kunitz soybean trypsin inhibitor (SBTI), a well-characterized polypeptide , were particularly striking. Purified SBTI gave a strong reaction in normal skin previously sensitized with the patient's serum. O n gel filtration with 'Bio-Gei P60' more than 97% of this material eluted in a single peak that con-' tained the trypsin inhibitory and skin test activity. The protein was homogeneous by cellulose acetate electrophoresis with a molecular weight of 20,000 to 21,000. W i t h SBTI as the ligand, binding of IgE from the serum was detectable by radioallergosorbent testing (RAST) at a dilution of 1:64. Addition of SBTI to serum during the IgE binding phase produced inhibition at concentrations as low as 3 ng ml -~. Binding was unaffected by other agents thus proving its specificity for SBTI. Two other patients with soybean allergy had no response to SBTI (by R A S T ) although one reacted to whole soybean. These findings indicate that SBTI is a specific allergen in h u m a n beings. Clearly there are other antigens in soybean and some patients may react with a non-IgE mechanism. The authors suggest that proteinase inhibitors may be important in food allergy because they have a low molecular weight and are resistant to acid p H and proteolytic degradation, which would be conducive to their rapid absorption and interaction with the immune system in an intact form. The maior importance of this work is the demonstration that a well-characterized molecule is a food allergen but in addition it establishes that food allergy to soybean can occur, even if it is rare. It is now common practice to put patients, including infants with milk allergies, on food substitutes that often include soy protein 'milk', and it should be recognized that this product can also produce allergic problems. This should not be common, however, and goat's milk would be an alternative for the patient who is sensitive to both cow's milk and soyprotein. Migraine affects about 20% of the population and a

75 recent survey has shown that it is responsible for more time lost in industry than is industrial action. Conventional therapy is not very effective and there has been strong clinical evidence that food allergy plays a part in this condition. M y own experience is that about 70% of migraine patients can be virtually cured by avoidance of certain foods which can be detected on an empirical basis by elimination diets. H a r d evidence that immunological factors are involved and that food allergy does indeed play a part in migraine has now been provided in an important paper by Munro, Carini, Brostoff and Zilkna 3. 33 patients were studied by elimination diets. Foods which provoked migraine were identified in 23 patients (70%) and elimination of these foods resulted in relief of symptoms within 2 weeks. At the end of the study R A S T to a battery of foods was carried out and there was a good correlation between high R A S T titres and the clinically relevant foods. Patients in whom dietary factors were not identified tended to have low R A S T tltres. Foods tested included milk, cheese, egg, chocolate, tea, tomato, coffee, shellfish, orange, fish, wheat, rice and apple. The predictive value of R A S T assays was then tested in 26 patients. 23 of the 26 responded tavourably (relief from migraine) to withdrawal of the foods to which specific titres in the R A S T assay were high. Avoidance of allergic foods led to a fall in specific IgE. Total igE levels did not predict food allergy. The high levels of specific IgE suggest that type-I hypersensitivity plays an important role in the production of migraine and that oral sodium cromoglycate should protect against antigen-induced mast cell histamine release. There is some evidence that sodium cromoglycate will protect against single antigen challenges, and it m a y therefore have a limited but important role in protecting migraine patients fi'om the results of occasional dietary lapses. The authors speculate that the initial specific allergic reaction may increase the permeability of the gut mucosa and allow other dietary antigens to be absorbed. This may explain why patients tend to have high lgE levels to several foods. Migraine is an episodic disease with natural remissions, and some patients can stop their elimination diet after several months without relapse. Perhaps keeping to a strict elimination diet allows the gut to retain its integrity, or strict avoidance of the allergen over several months allows the immune response to subside. There are still many unanswered questions, but we now have clear evidence that food allergy plays an important part in migraine. RONALI) FINN

Department of Medicine, Royal Liverpool Hospital, Liverpool, U.K

References 1 Atherton, D. J., Soothill, J. F., Sewell, M., Wells, R. S. and Chilvers, C. E. D. (1978) Lancetvol. no. 401 2 Moroz, L. A. and Yang, W. H. (1980) N. Engl. J: Med. 302, 1126 3. Munro, ,]., Carini, C., Brostoff, J. and Zilkha, K. (1980) Lancet ii; 1