Adult-onset immunodeficiency in Thailand and Taiwan

Abstract

Background: Autoantibodies against interferon-γ are associated with severe disseminated opportunistic infection, but their importance and prevalence are unknown.

Methods: We enrolled 203 persons from sites in Thailand and Taiwan in five groups: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection (group 1); 45 patients with another opportunistic infection, with or without nontuberculous mycobacterial infection (group 2); 9 patients with disseminated tuberculosis (group 3); 49 patients with pulmonary tuberculosis (group 4); and 48 healthy controls (group 5). Clinical histories were recorded, and blood specimens were obtained.

Results: Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-γ in normal cells. High-titer anti-interferon-γ autoantibodies were detected in 81% of patients in group 1, 96% of patients in group 2, 11% of patients in group 3, 2% of patients in group 4, and 2% of controls (group 5). Forty other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte-macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering.

Conclusions: Neutralizing anti-interferon-γ autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research; ClinicalTrials.gov number, NCT00814827.).

Figures

Figure 1. Common Disease Manifestations in Patients with Anti–Interferon-γ Autoantibodies

Panel A shows osteomyelitis (arrow) due to infection with Cryptococcus neoformans. Panel B shows a disseminated Mycobacterium abscessus infection. Panel C shows neutrophilic dermatosis.

Figure 2. Anti–Interferon-γ Autoantibody Concentrations in 203 Participants, According to Study Group

Interferon-γ autoantibodies were measured with the use of Luciferase Immunoprecipitation Systems. The dashed line is the estimated 99th percentile for the combined control groups of patients with pulmonary tuberculosis (group 4) and healthy controls (group 5), estimated with the use of the lognormal distribution. Participants with concentrations exceeding the 99th percentile were classified as autoantibody-positive.

Figure 3. Biologic Activity of Autoantibodies In Vitro, According to Flow Cytometric Analysis of Interferon-γ–Induced Signal Transducer and Activator of Transcription 1 (STAT1) Phosphorylation

Panel A shows inhibition of STAT1 phosphorylation in plasma specimens from patients with disseminated opportunistic infections and anti–interferon-γ autoantibodies. The solid line indicates the median value for patients who were positive for autoantibodies, and the dashed line indicates the median for patients who were negative for autoantibodies. The P value, based on the Wilcoxon rank-sum test, is for the difference in median phosphorylation values between autoantibody-positive and autoantibody-negative patients. Panel B shows that anti–interferon-γ blocking activity is conferred by interferon-γ–specific IgG but is absent from IgG depleted over an interferon-γ column in three patients with anti–interferon-γ autoantibodies. Total IgG was evaluated in control participant 203, who did not have anti–interferon-γ autoantibodies.