The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses.
In patients with celiac disease, inflammatory T cell responses to HLA-DQ2-bound gluten peptides are thought to cause disease. Two types of HLA-DQ2 molecules exist, termed HLA-DQ2.5 and HLA-DQ2.2. Whereas HLA-DQ2.5 predisposes to celiac disease, HLA-DQ2.2 does not. We now provide evidence that the disease-associated HLA-DQ2.5 molecule presents a large repertoire of gluten peptides, whereas the non-disease-associated HLA-DQ2.2 molecule can present only a subset of these. Moreover, gluten presentation by HLA-DQ2 homozygous antigen-presenting cells was superior to presentation by HLA-DQ2/non-DQ2 heterozygous antigen-presenting cells in terms of T cell proliferation and cytokine secretion. Gluten presentation by HLA-DQ2.5/2.2 heterozygous antigen-presenting cells induced intermediate T cell stimulation. These results correlated with peptide binding to the antigen-presenting cells. Finally, we demonstrate that HLA-DQ trans dimers formed in HLA-DQ2.5/2.2 heterozygous individuals have properties identical with HLA-DQ2.5 dimers. Our findings explain the strongly increased risk of disease development for HLA-DQ2.5 homozygous and HLA-DQ2.2/2.5 heterozygous individuals, and they are indicative of a quantitative model for disease development, where HLA-DQ expression and the available number of T cell-stimulatory gluten peptides are critical limiting factors. This model may have important implications for disease prevention.
Vader
Willemijn
W
Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, E3-Q, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Stepniak
Dariusz
D
Kooy
Yvonne
Y
Mearin
Luisa
L
Thompson
Allan
A
van Rood
Jon J
JJ
Spaenij
Liesbeth
L
Koning
Frits
F
D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology*; D004247:DNA / Q000235:genetics; D019281:Dimerization; D018628:Gene Dosage; D005983:Glutens / Q000276:immunology* / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D011485:Protein Binding; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology*
D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D005983:Glutens; D004247:DNA