Anti–IFN-γ autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia

Abstract

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.

A 38-year-old woman with necrotising cervical lymphadenitis due to Histoplasma capsulatum

“…In our patient none of her alleles were present homozygously. She had the HLA types: A*02/A*31, B*53:01:01/B*57, C*04:01:01/C*18:01, DQA1*01:02:01/DQA1*03:03:01, DQB1*02:02/DQB1*06, and DRB1*09/DRB1*13:02:01, so no overlap was seen with the HLA types in the previous studies [ 2 , 3 ].…”

“…In a large study in patients with adult-onset immunodeficiency due to IFN-γ autoantibodies from Taiwan, limited HLA allele polymorphism was observed and HLA types A*11:01, B*40:01, DRB1*16:02, and DQB1*05:02 were found to be overrepresented [ 3 ]. In a follow-up study also including patients from Thailand the association with DRB1*16:02 and DQB1*05:02 was confirmed while also DRB1*15:02 was found to be associated [ 2 ]. In our patient none of her alleles were present homozygously.…”

“…These autoantibodies directed against IFN-γ are thought to arise due to the 100% homology between peptides of the IFN-γ protein and the Aspergillus spp Noc2 proteins [ 1 ], which can be recognised by persons with certain haplotypes. A few HLA haplotypes have been found to be associated with the development of IFN-γ autoantibodies [ 2 , 3 ], and these are mainly found in Asians, thus explaining why the IFN-γ autoantibodies are almost exclusively found in individuals from Asia or Asian descent [ 4 – 6 ]. We describe the first case of a patient from African descent that developed a severe opportunistic infection due to the presence of IFN-γ autoantibodies.…”

Cellular and Molecular Defects Underlying Invasive Fungal Infections—Revelations from Endemic Mycoses

“…Similar observations were also reported in Hong Kong and Taiwan (190, 192, 194, 195). HLA class II molecules HLA-DRB1*15:02–HLA-DQB1*05:01 and HLA-DRB1*16:02–HLA-DQB1*05:02 are specifically associated with anti-IFN-γ autoantibodies and NTM (196, 197). The high frequency of such alleles in Southeast Asia might account for the relatively high prevalence this condition in the Asian population.…”

Simultaneous disseminated infections with intracellular pathogens: an intriguing case report of adult-onset immunodeficiency with anti-interferon-gamma autoantibodies

“…Neutralizing anti-IFNγ autoantibodies mimic congenital defects of this pathway and have been identified as a rare cause of an immunodeficiency associated with disseminated NTM disease. Predominantly occurring in patients aged 30 to 50 years of Asian origin, a strong association of anti-IFNγ autoantibodies to certain human leukocyte antigen (HLA) class II molecules has been found [ 18 , 19 ]. The etiology of anti-IFNγ autoantibody formation remains unclear and in addition to a failure of self-tolerance, cross-reactivity reactions between infectious agents and host proteins have been discussed [ 8 , 9 ].…”