The binding of autoantibodies (autoAbs) to interferon (IFN)-γ 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-γ autoAbs. We show here that these autoAbs target a major epitope (amino acids 121-131, designated position (P)121-131) in a region crucial for IFN-γ receptor (IFN-γR) activation to impair IFN-γ-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-γ. We generated an epitope-erased variant of IFN-γ (EE-IFN-γ), in which the major neutralizing epitope region was altered. The binding affinity of anti-IFN-γ autoAbs for EE-IFN-γ was reduced by about 40%, as compared to that for IFN-γ1-131. Moreover, EE-IFN-γ activated the IFN-γR downstream signaling pathway ex vivo, irrespectively of anti-IFN-γ autoAbs. In conclusion, we identified a common, crucial B cell epitope that bound to anti-IFN-γ autoAbs in patients, and we propose a molecular-mimicry model for autoAb development. In addition, treatment with EE-IFN-γ might be worth investigating in patients producing anti-IFN-γ autoAbs.
Childhood HAdV-2, HAdV-3 and HAdV-7 infections may exhibit different clinical manifestations. Although HAdV-3 was the most prevalent genotype observed during the 2011 Taiwan outbreak, HAdV-7 caused more severe disease characteristics and outcomes.
examined, suggesting that the absence of functional T cells, rather than specifically CD247, affects NK differentiation. This observation is consistent with data from patients undergoing stem cell transplantation (SCT) in whom the first NK cells to repopulate the periphery have an immature phenotype and are less able to mediate cytotoxicity before T-cell recovery. 8 Interestingly, the ability of peripheral blood NK cells from the CD247-deficient patient to proliferate in mixed lymphocyte cultures in vitro was severely limited (see Fig E3 in this article's Online Repository at www.jacionline.org), but this phenotype could be reversed by IL-2 addition.During differentiation, the ability of NK cells to respond to stimulation is finely tuned in function of the repertoire of inhibitory and activating receptors expressed by each NK cell. 9 Because CD247 deficiency causes decreased expression and function of a range of activating NK receptors, impaired signaling might underlie the partial block of NK cell differentiation and NK cell hyporesponsiveness, which were observed in the CD247deficient patient. Importantly, similar changes in NK cell phenotype and function have not been seen in children with symptomatic congenital human cytomegalovirus (CMV) infection, 10 arguing against the hypothesis that the changes observed in the CD247-deficient patient are a consequence of CMV infection.Our observations have direct implications for the clinical management of immunodeficient patients. Even when not directly fatal, episodes of infectious disease delay transplantation and negatively affect the outcome. Thus, because NK cells play a critical role in antiviral immunity, the potentiation of NK cell function, for example by means of low-dose therapy with IL-2, could be a useful strategy to minimize infections and aid in the management of these patients until SCT.We thank all of the subjects who have contributed blood samples for these studies and Drs M. Lopez-Botet, J. Gil-Herrera, and M. L. Toribio for helpful discussion and advice.
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