4e.eE.,.9/A.A.'A.. . . ,.,. ........ ...-.... .'.' ,., .... because the onset and progression of the disease is markedly delayed. Taken together, these results demon- strate that IL-4 is critical to the development of MAIDS. The mechanism by which IL-4 mediates its effects in the development of the disease is not clear. Infection with the LP-BM5 virus causes a switch from a Thl to a Th2 response with progression of the dis- ease (2). This may be due to superantigen activity expressed by virus-infected B cells (10) that stimulate aberrant IL-4 production in T cells. A mouse line that expresses high amounts of IL-4 derived from a transgene shows a variety of immunological abnormal- ities, including a deficient proliferative re- sponse of T cells to the mitogen concanava- lin A (11). Furthermore, Th2 cytokine re- sponses are dependent on IL-4 production (12). Thus, other Th2 cytokines that have been shown to be significantly reduced in IL-4-/- mice, such as IL-5, IL-9, IL-10, and IL-6 (13), may also be involved in the development of MAIDS. This could be test- ed by reconstituting infected IL-4-/- mice or by infecting mice deficient in other cyto- kines. Although human immunodeficiency virus (HIV) and the murine leukemia virus causing MAIDS represent different types of retroviruses, some of the features of the diseases are similar, such as lymphoadenop- athy, B cell hyperactivity, T cell immuno- deficiency, and development of certain tu- mor cells at the late stage of the disease (1, 14). Furthermore, a shift from a Thl to a Th2 response and a high serum immuno- globulin E level have been reported for HIV-infected patients (15). These findings suggest that IL-4 as well as other Th2-related cytokines may be crucial to the development of T cell dysfunction induced by the two different viruses. Thus, understanding the role of IL-4 in the development of MAIDS may provide insight into the mechanisms causing dysregulated cytokine production and generalized T cell immunodeficiency found in human acquired immunodeficiency syndrome. REFERENCES AND NOTES 1. H. C. Morse Ill et al., AIDS 6, 607 (1992); P. Jolicoeur, FASEB J. 5, 2398 (1991); D. E. Mosier, R. A. Yetter, H. C. Morse Ill, J. Exp. Med. 165, 1737 (1987). 2. R. T. Gazzinelli etal., J. Immunol. 148,182 (1992). 3. M. Kopf et al., Nature 362, 245 (1993). 4. S. K. Chattopadhyay, H. C. Morse Ill, M. Makino, S. K. Ruscetti, J. W. Hartley, Proc. NatI. Acad. Sci. U.S.A. 86, 3862 (1989). 5. 0. Kanagawa, unpublished observations. 6. R. C. Budd etal., J. Immunol. 138, 3120 (1987); L. M. Bradley, D. D. Duncan, S. Tonkonogy, S. Swain, J. Exp. Med. 174, 547 (1991). 7. G. Muralidhar, S. Koch, M. Hasas, S. Swain, J. Exp. Med. 175,1589 (1992). 8. S. Gayama and 0. Kanagawa, unpublished data. 9. J. W. Hartley, T. N. Fredrickson, R. A. Yetter, M. Makino, H. C. Morse Ill, J. Virol. 63, 1223 (1989); M. Makino, W. F. Davidson, T. N. Fredrickson, J. W. Hartley, H. C. Morse Ill, Immunogenetics 33, 242 345 (1991); M. Huang, C. Simard, P. Jolicoeur, J. Virol. 66, 2398 (1992). 10. A. W. Hugin, M. S. Vacchio, H. C. Morse Ill, Science 252, 424 (1991). 11. R. I. Tepper et al., Cell 62, 457 (1990). 12. S. L. Swain, A. D. Weinberg, M. English, G. Huston, J. Immunol. 145, 3796 (1990); G. Le- Gros, S. Z. Ben-Sasson, R. Seder, F. D. Finkel- man, W. E. Paul. J. Exp. Med. 172, 921 (1990). 13. M. Kopf, unpublished data. 14. A. S. Fauci, Science 239, 617 (1988). 15. D. R. Lucey, R. A. Zajac, G. P. Melcher, C. A. 16. 17. 18. Butzin, R. N. Boswell, AIDS Res. Hum. Retrovi- ruses6, 427 (1990); M. Clerici and G. M. Shearer, Immunol. Today 14, 107 (1993). 0. Kanagawa et al., J. Immunol. 149, 9 (1992). V. Glisen, R. Crkvenjakov, C. Byus, Biochemistry 13, 2633 (1974). We thank N. Noben, R. Lamers, M. Kosco-Vilbois, K. Sydel, and J. Shimizu for helpful comments and suggestions. Supported by National Institutes of Health grant A130803. 13 May 1993; accepted 26 July 1993 HLA-DPB1 Glutamate 69: A Genetic Marker of Beryllium Disease Luca Richeldi, Rosa Sorrentino, Cesare Saltini* Chronic beryllium disease (CBD) is a lung disorder related to beryllium exposure and is characterized by the accumulation in the lung of beryllium-specific CD4+ major histocom- patibility complex (MHC) class Il-restricted T lymphocytes. Evaluation of MHC class 11 genes in 33 CBD cases and 44 controls has shown a negative association with HLA- DPB1 *0401 (P < 0.001) and a positive association with HLA-DPB1 *0201 (P < 0.05) alleles, which differ at residues 36, 55 to 56, and 69 of the P, chain. Among CBD cases, 97 percent expressed the HLA-DPB13*0201-associated glutamic acid (unaffected popu- lation, 30 percent; P < 0.001) at residue 69, a position involved in susceptibility to autoimmune disorders. This suggests that HLA-DP has a role in conferring susceptibility and that residue 69 of HLA-DPB1 could be used in risk assessment for CBD. Exposure to metals such as Co, Al, Ti, Zr, and Be is associated with a variety of chron- ic disorders of the lung (1). CBD is a hypersensitivity lung disorder caused by ex- posure to Be that is not strictly dependent on Be concentration (2). As predicted by its immunopathologic features, CBD is maintained by an accumulation of large numbers of Be-specific CD4' T cells in patient lungs (3). In this context, CBD could be used as a model to test the relation between environmental and immunoge- netic factors in occupation-related diseases. T cell clones from CBD patient lungs are MHC class II-restricted, that is, they only respond to Be in association with MHC class II molecules on the surface of the antigen-presenting cell (3). Genes of the MHC class II (HLA-DR, -DQ, and -DP) that are associated with susceptibility to autoimmune disorders (4) are likely candi- dates as susceptibility genes to CBD. This hypothesis is supported by the observations that MHC class II genes are involved in T cell responses to metals such as Ni and Au L. Richeldi, Postgraduate School of Cardiorespiratory Physiopathology, Universities of Roma and Modena, Italy. R. Sorrentino, Department of Experimental Medicine, University of L'Aquila, and Department of Cellular and Developmental Biology, University La Sapienza, Roma, Italy. C. Saltini, Institute of Tuberculosis and Respiratory Diseases, University of Modena, USL 16 Modena and Postgraduate School of Cardiorespiratory Physiopa- thology, Universities of Roma and Modena, Italy. *To whom correspondence should be addressed. SCIENCE * VOL. 262 * 8 OCTOBER 1993 (5), and they play a key role in susceptibil- ity to experimental hypersensitivity to Be and other metals (6). We tested this concept, after a prelimi- nary analysis of a small sample of patients that did not show strong associations with HLA-DR or HLA-DQ genes, by evaluating the association of the HLA-DP gene with CBD in a group of 33 CBD individuals and a group of 44 Be-exposed unaffected indi- viduals (7). Frequencies of the HLA-DPB1 alleles in the Be-exposed unaffected group were similar to those of the normal popula- tion (8), regardless of the race composition of the group. The HLA-DPB1*0201 and *0401 allele frequencies in the total popu- lation sample were similar to those in Cau- casians alone [percent of total population sample unaffected, *0201 (10%), *0401 (48%); Caucasians unaffected, *0201 (11%), *0401 (52%); P > 0.2, compared with published populations (8)] (9). In contrast, allelic frequencies in the CBD case group were biased. The frequency of the DPB1 *0201 allele was increased [CBD, 30%; unaffected, 10%; x2 = 9.94, P = 0.0016, Bonferroni corrected P < 0.05 (19 alleles)]. Conversely, the frequency of the DPB1*0401 allele was decreased (CBD, 14%; unaffected, 48%; x2 = 19.79, P = 0.00001, corrected P < 0.001). When we evaluated the phenotypic frequencies, we observed a similar bias (DPB1*0201: CBD, 52%; unaffected, 18%; corrected P < 0.05; DPB1*0401: CBD, 27%; unaffected, 68%; corrected P < 0.01), indicating that, as in on February 1, 2015 www.sciencemag.org Downloaded from on February 1, 2015 www.sciencemag.org Downloaded from on February 1, 2015 www.sciencemag.org Downloaded from