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* Department of Cancer Immunology and AIDS and Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston MA 02115.;
Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.;
C. W. Bill Young Department of Defense Marrow Donor Program, Georgetown University, Kensington, MD 20895;
Department of Pathology, State University of New York Upstate Medical University, Syracuse, NY 13210;
¶ Department of Immunology, Roswell Park Cancer Institute Buffalo, NY 14263; and
|| Division of Pathology and Laboratory Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
We identified and characterized an HLA-A1 aberrant allele (A*0118N) resulting from a novel molecular mechanism; this allele was present in an unusually informative family with a near identical parental HLA haplotype (c d) differing only by one nucleotide substitution in one HLA-A allele, A*0118N, of the maternal HLA haplotype (c) and not of the paternal HLA haplotype (a). Although serologic HLA typing showed a "blank," DNA molecular HLA typing detected a HLA-A*0118N allele. Sequence based typing identified the substitution of guanine by cytosine at the nucleotide position 215, which resulted in the replacement of arginine by proline at position 48 of the HLA-A1 H chain. The loss of surface protein expression was also found by FACS analysis. Isoelectric-focusing analysis detected a HLA-A H chain with a unique isoelectric-focusing pattern, which does not associate with the L chain (
2-microglobulin). These results suggest that the residue 48-containing interaction site on the 
1 domain plays a critical role in the association between HLA class I H chain and 2-microglobulin. Functional studies showed that the T cells of the propositus (HLA haplotypes c d) carrying this null allele recognized its wild-type counterpart, HLA-A*010101, in her HLA-identical son that carries the HLA-A*0101 heterodimer. This is the first example of the generation of cytotoxic T cells in the absence of proliferation of CD4+ T cells (mixed lymphocyte culture) and the description of an aberrant allele, A*0118N, that may behave as a minor histocompatibility Ag, with implications in allorecognition by cytolytic T cells in solid organ and stem cell transplantation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Public Health Service Grants HL29583 and HL59838 from the National Heart, Lung and Blood Institute and CA67108 from the National Cancer Institute, National Institutes of Health..
2 I.A., Z.C.W., J.Z., and M.F.-V. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Edmond J. Yunis, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail address: edmond_yunis{at}dfci.harvard.edu or Dr. Marcelo Fernandez-Vina, Division of Pathology and Laboratory Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. E-mail: mfernand{at}mdanderson.org
4 Abbreviations used in this paper: B-LCL, B lymphoblastoid cell line; 2m, 2-microglobulin; CML, cell-mediated lysis; FWS, flow washing system; IEF, isoelectric focusing.
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