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. 1996 May 15;97(10):2324–2331. doi: 10.1172/JCI118675

T cell subsets, epitope mapping, and HLA-restriction in patients with allergic bronchopulmonary aspergillosis.

B Chauhan 1, A p Knutsen 1, P S Hutcheson 1, R G Slavin 1, C J Bellone 1
PMCID: PMC507313  PMID: 8636413

Abstract

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease characterized by Aspergillus fumigatus (Af) colonization, IgE and IgG anti-Af antibodies, pulmonary infiltrates, bronchiectasis, and pulmonary fibrosis. Little is known regarding T cell responses and their role in the pathogenesis of ABPA. To examine T cell reactivity to Af antigens, T cell clones (TCC) specific to the Asp f 1 antigen, an 18-kD protein of Af, were established from the peripheral blood of three ABPA patients. The majority of TCC isolated from ABPA patients, and specific for the Asp f 1 allergen of Af, are IL-4 producing CD4+ cells of the Th2 phenotype. Further analysis in this study revealed that the majority of TCC reacted to mainly two epitopes of Asp f 1, while the remaining TCC reacted to three additional "minor" epitopes. Blocking studies using monoclonal antibodies specific for class II HLA-D region gene products showed that most TCC, 19/21, were restricted by HLA-DR molecules, and the remaining two clones by HLA-DP molecules. The use of a panel of HLA-matched and mismatched EBV-transformed B cells as antigen presenting cells revealed that the HLA-DR restriction was mediated exclusively by either the HLA-DR2 or HLA-DR5 alleles. Genotyping of DRB1 gene products showed that class II presentation for most clones was not restricted to a single allele, representing DRB1 gene products of either HLA-DR2 or DR5. These studies offer insight into the cellular and molecular determinants which contribute to the immunopathophysiology of ABPA.

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Selected References

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  1. Arruda L. K., Mann B. J., Chapman M. D. Selective expression of a major allergen and cytotoxin, Asp f I, in Aspergillus fumigatus. Implications for the immunopathogenesis of Aspergillus-related diseases. J Immunol. 1992 Nov 15;149(10):3354–3359. [PubMed] [Google Scholar]
  2. Arruda L. K., Platts-Mills T. A., Longbottom J. L., el-Dahr J. M., Chapman M. D. Aspergillus fumigatus: identification of 16, 18, and 45 kd antigens recognized by human IgG and IgE antibodies and murine monoclonal antibodies. J Allergy Clin Immunol. 1992 Jun;89(6):1166–1176. doi: 10.1016/0091-6749(92)90301-h. [DOI] [PubMed] [Google Scholar]
  3. Boguniewicz M., Schneider L. C., Milgrom H., Newell D., Kelly N., Tam P., Izu A. E., Jaffe H. S., Bucalo L. R., Leung D. Y. Treatment of steroid-dependent asthma with recombinant interferon-gamma. Clin Exp Allergy. 1993 Sep;23(9):785–790. doi: 10.1111/j.1365-2222.1993.tb00367.x. [DOI] [PubMed] [Google Scholar]
  4. Carballido J. M., Carballido-Perrig N., Terres G., Heusser C. H., Blaser K. Bee venom phospholipase A2-specific T cell clones from human allergic and non-allergic individuals: cytokine patterns change in response to the antigen concentration. Eur J Immunol. 1992 Jun;22(6):1357–1363. doi: 10.1002/eji.1830220605. [DOI] [PubMed] [Google Scholar]
  5. Del Prete G. F., De Carli M., Mastromauro C., Biagiotti R., Macchia D., Falagiani P., Ricci M., Romagnani S. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest. 1991 Jul;88(1):346–350. doi: 10.1172/JCI115300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Del Prete G., Maggi E., Parronchi P., Chrétien I., Tiri A., Macchia D., Ricci M., Banchereau J., De Vries J., Romagnani S. IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol. 1988 Jun 15;140(12):4193–4198. [PubMed] [Google Scholar]
  7. Del Prete G., Maggi E., Romagnani S. Human Th1 and Th2 cells: functional properties, mechanisms of regulation, and role in disease. Lab Invest. 1994 Mar;70(3):299–306. [PubMed] [Google Scholar]
  8. Gajewski T. F., Fitch F. W. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4245–4252. [PubMed] [Google Scholar]
  9. Goodfriend L., Choudhury A. M., Klapper D. G., Coulter K. M., Dorval G., Del Carpio J., Osterland C. K. Ra5G, a homologue of Ra5 in giant ragweed pollen: isolation, HLA-DR-associated activity and amino acid sequence. Mol Immunol. 1985 Aug;22(8):899–906. doi: 10.1016/0161-5890(85)90076-8. [DOI] [PubMed] [Google Scholar]
  10. Hanifin J. M., Schneider L. C., Leung D. Y., Ellis C. N., Jaffe H. S., Izu A. E., Bucalo L. R., Hirabayashi S. E., Tofte S. J., Cantu-Gonzales G. Recombinant interferon gamma therapy for atopic dermatitis. J Am Acad Dermatol. 1993 Feb;28(2 Pt 1):189–197. doi: 10.1016/0190-9622(93)70026-p. [DOI] [PubMed] [Google Scholar]
  11. Higgins J. A., Thorpe C. J., Hayball J. D., O'Hehir R. E., Lamb J. R. Overlapping T-cell epitopes in the group I allergen of Dermatophagoides species restricted by HLA-DP and HLA-DR class II molecules. J Allergy Clin Immunol. 1994 May;93(5):891–899. doi: 10.1016/0091-6749(94)90383-2. [DOI] [PubMed] [Google Scholar]
  12. Karr R. W., Panina-Bordignon P., Yu W. Y., Lanzavecchia A. Antigen-specific T cells with monogamous or promiscuous restriction patterns are sensitive to different HLA-DR beta chain substitutions. J Immunol. 1991 Jun 15;146(12):4242–4247. [PubMed] [Google Scholar]
  13. Knutsen A. P., Mueller K. R., Hutcheson P. S., Slavin R. G. Serum anti-Aspergillus fumigatus antibodies by immunoblot and ELISA in cystic fibrosis with allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1994 May;93(5):926–931. doi: 10.1016/0091-6749(94)90387-5. [DOI] [PubMed] [Google Scholar]
  14. Knutsen A. P., Mueller K. R., Levine A. D., Chouhan B., Hutcheson P. S., Slavin R. G. Asp f I CD4+ TH2-like T-cell lines in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1994 Aug;94(2 Pt 1):215–221. doi: 10.1016/0091-6749(94)90043-4. [DOI] [PubMed] [Google Scholar]
  15. Kurup V. P., Choi H., Resnick A., Kalbfleisch J., Fink J. N. Immunopathological response of C57BL/6 and C3H/HeN mice to Aspergillus fumigatus antigens. Int Arch Allergy Appl Immunol. 1990;91(2):145–154. doi: 10.1159/000235106. [DOI] [PubMed] [Google Scholar]
  16. Kurup V. P., Mauze S., Choi H., Seymour B. W., Coffman R. L. A murine model of allergic bronchopulmonary aspergillosis with elevated eosinophils and IgE. J Immunol. 1992 Jun 15;148(12):3783–3788. [PubMed] [Google Scholar]
  17. Lundgren M., Persson U., Larsson P., Magnusson C., Smith C. I., Hammarström L., Severinson E. Interleukin 4 induces synthesis of IgE and IgG4 in human B cells. Eur J Immunol. 1989 Jul;19(7):1311–1315. doi: 10.1002/eji.1830190724. [DOI] [PubMed] [Google Scholar]
  18. Maggi E., Parronchi P., Manetti R., Simonelli C., Piccinni M. P., Rugiu F. S., De Carli M., Ricci M., Romagnani S. Reciprocal regulatory effects of IFN-gamma and IL-4 on the in vitro development of human Th1 and Th2 clones. J Immunol. 1992 Apr 1;148(7):2142–2147. [PubMed] [Google Scholar]
  19. Marsh D. G., Freidhoff L. R., Ehrlich-Kautzky E., Bias W. B., Roebber M. Immune responsiveness to Ambrosia artemisiifolia (short ragweed) pollen allergen Amb a VI (Ra6) is associated with HLA-DR5 in allergic humans. Immunogenetics. 1987;26(4-5):230–236. doi: 10.1007/BF00346517. [DOI] [PubMed] [Google Scholar]
  20. Marsh D. G., Zwollo P., Huang S. K., Ghosh B., Ansari A. A. Molecular studies of human response to allergens. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):459–470. doi: 10.1101/sqb.1989.054.01.055. [DOI] [PubMed] [Google Scholar]
  21. Marshall K. W., Liu A. F., Canales J., Perahia B., Jorgensen B., Gantzos R. D., Aguilar B., Devaux B., Rothbard J. B. Role of the polymorphic residues in HLA-DR molecules in allele-specific binding of peptide ligands. J Immunol. 1994 May 15;152(10):4946–4957. [PubMed] [Google Scholar]
  22. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  23. O'Hehir R. E., Eckels D. D., Frew A. J., Kay A. B., Lamb J. R. MHC class II restriction specificity of cloned human T lymphocytes reactive with Dermatophagoides farinae (house dust mite). Immunology. 1988 Aug;64(4):627–631. [PMC free article] [PubMed] [Google Scholar]
  24. O'Hehir R. E., Mach B., Berte C., Greenlaw R., Tiercy J. M., Bal V., Lechler R. I., Trowsdale J., Lamb J. R. Direct evidence for a functional role of HLA-DRB1 and -DRB3 gene products in the recognition of Dermatophagoides spp. (house dust mite) by helper T lymphocytes. Int Immunol. 1990;2(9):885–892. doi: 10.1093/intimm/2.9.885. [DOI] [PubMed] [Google Scholar]
  25. Olson R. R., Reuter J. J., McNicholl J., Alber C., Klohe E., Callahan K., Siliciano R. F., Karr R. W. Acidic residues in the DR beta chain third hypervariable region are required for stimulation of a DR(alpha, beta 1*0402)-restricted T-cell clone. Hum Immunol. 1994 Nov;41(3):193–200. doi: 10.1016/0198-8859(94)90036-1. [DOI] [PubMed] [Google Scholar]
  26. Parronchi P., Macchia D., Piccinni M. P., Biswas P., Simonelli C., Maggi E., Ricci M., Ansari A. A., Romagnani S. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4538–4542. doi: 10.1073/pnas.88.10.4538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Patterson R., Greenberger P. A., Lee T. M., Liotta J. L., O'Neill E. A., Roberts M., Sommers H. Prolonged evaluation of patients with corticosteroid-dependent asthma stage of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1987 Nov;80(5):663–668. doi: 10.1016/0091-6749(87)90285-5. [DOI] [PubMed] [Google Scholar]
  28. Paul W. E., Seder R. A. Lymphocyte responses and cytokines. Cell. 1994 Jan 28;76(2):241–251. doi: 10.1016/0092-8674(94)90332-8. [DOI] [PubMed] [Google Scholar]
  29. Roebber M., Hussain R., Klapper D. G., Marsh D. G. Isolation and properties of a new short ragweed pollen allergen, Ra6. J Immunol. 1983 Aug;131(2):706–711. [PubMed] [Google Scholar]
  30. Sharma S., Mehta S., Morgan J., Maizel A. Molecular cloning and expression of a human B-cell growth factor gene in Escherichia coli. Science. 1987 Mar 20;235(4795):1489–1492. doi: 10.1126/science.3547651. [DOI] [PubMed] [Google Scholar]
  31. Slavin R. G., Bedrossian C. W., Hutcheson P. S., Pittman S., Salinas-Madrigal L., Tsai C. C., Gleich G. J. A pathologic study of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1988 Apr;81(4):718–725. doi: 10.1016/0091-6749(88)91044-5. [DOI] [PubMed] [Google Scholar]
  32. Stern L. J., Brown J. H., Jardetzky T. S., Gorga J. C., Urban R. G., Strominger J. L., Wiley D. C. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994 Mar 17;368(6468):215–221. doi: 10.1038/368215a0. [DOI] [PubMed] [Google Scholar]
  33. Wierenga E. A., Snoek M., Bos J. D., Jansen H. M., Kapsenberg M. L. Comparison of diversity and function of house dust mite-specific T lymphocyte clones from atopic and non-atopic donors. Eur J Immunol. 1990 Jul;20(7):1519–1526. doi: 10.1002/eji.1830200717. [DOI] [PubMed] [Google Scholar]
  34. Wierenga E. A., Snoek M., de Groot C., Chrétien I., Bos J. D., Jansen H. M., Kapsenberg M. L. Evidence for compartmentalization of functional subsets of CD2+ T lymphocytes in atopic patients. J Immunol. 1990 Jun 15;144(12):4651–4656. [PubMed] [Google Scholar]
  35. van Neerven R. J., van de Pol M. M., Wierenga E. A., Aalberse R. C., Jansen H. M., Kapsenberg M. L. Peptide specificity and HLA restriction do not dictate lymphokine production by allergen-specific T-lymphocyte clones. Immunology. 1994 Jul;82(3):351–356. [PMC free article] [PubMed] [Google Scholar]

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