부산대학교 도서관

The binding of autoantibodies (autoAbs) to interferon (IFN)-[gamma] in people with mycobacterial diseases has become an emerging medical concern. Many patients display specific human leukocyte antigen (HLA) class II haplotypes, which suggests that a common T cell-dependent and B cell-dependent mechanism might underlie the production of specific anti-IFN-[gamma] autoAbs. We show here that these autoAbs target a major epitope (amino acids 121-131, designated position (P)[sub.121-131]) in a region crucial for IFN-[gamma] receptor (IFN-[gamma]R) activation to impair IFN-[gamma]-mediated activities. The amino acid sequence of this epitope is highly homologous to a stretch in the Noc2 protein of Aspergillus spp., which was cross-reactive with autoAbs from patients. Rats immunized with Aspergillus Noc2 developed antibodies that reacted with human IFN-[gamma]. We generated an epitope-erased variant of IFN-[gamma] (EE-IFN-[gamma]), in which the major neutralizing epitope region was altered. The binding affinity of anti-IFN-[gamma] autoAbs for EE-IFN-[gamma] was reduced by about 40%, as compared to that for IFN-[gamma][sub.1-131]. Moreover, EE-IFN-[gamma] activated the IFN-[gamma]R downstream signaling pathway ex vivo, irrespectively of anti-IFN-[gamma] autoAbs. In conclusion, we identified a common, crucial B cell epitope that bound to anti-IFN-[gamma] autoAbs in patients, and we propose a molecular-mimicry model for autoAb development. In addition, treatment with EE-IFN-[gamma] might be worth investigating in patients producing anti-IFN-[gamma] autoAbs.
Author(s): Chia-Hao Lin [1, 2]; Chih-Yu Chi [1, 3, 4]; Han-Po Shih [1]; Jing-Ya Ding [1]; Chia-Chi Lo [1]; Shang-Yu Wang [1, 5]; Chen-Yen Kuo [1, 6]; Chun-Fu Yeh [1, [...]