Allorecognition of an HLA-A*01 aberrant allele by an HLA identical family member carrying the HLA-A*0101 allele.
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 (beta(2)-microglobulin). These results suggest that the residue 48-containing interaction site on the alpha(1) domain plays a critical role in the association between HLA class I H chain and beta(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.
Almeciga
Ingrid
I
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston MA 02115, USA.
Wang
Zhigang Charles
ZC
Zúñiga
Joaquin
J
Fernandez-Viña
Marcelo
M
Clavijo
Olga
O
Araujo
Hugo
H
Romero
Viviana
V
Henry
John
J
Ferrone
Soldano
S
Yunis
Edmond J
EJ
D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005192:Family Health; D005260:Female; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D001613:beta 2-Microglobulin / Q000378:metabolism
D015234:HLA-A Antigens; D001613:beta 2-Microglobulin