IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

Genetic factors are known to strongly influence susceptibility to allergic inflammation. The Th2 cytokine IL-13 is a central mediator of allergy and asthma, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13+2044G→A is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044G→A on the functional properties of IL-13 by directly comparing the activity of WT IL-13 and IL-13 R130Q on primary human cells involved in the effector mechanisms of allergic inflammation. Our results show that IL-13 R130Q was significantly more active than WT IL-13 in inducing STAT6 phosphorylation and CD23 expression in monocytes and hydrocortisone-dependent IgE switching in B cells. Notably, IL-13 R130Q was neutralized less effectively than WT IL-13 by an IL-13Rα2 decoy. Decreased neutralization of the minor variant could contribute to its enhanced in vivo activity. Neither IL-13 variant was able to engage T cells, which suggests that increased allergic inflammation in carriers of IL13+2044A depends on enhanced IL-13–mediated Th2 effector functions rather than increased Th2 differentiation. Collectively, our data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy

Cytokine Profiles in Human Immunodeficiency Virus-Infected Children Treated With Highly Active Antiretroviral Therapy

ABSTRACT: CONTEXT: There have been few longitudinal studies of cytokine production in neonatally acquired HIV-1 infection and none in Asian or Chinese children. OBJECTIVE: To determine whether monitoring cytokine production could contribute to the better management of pediatric patients with HIV-1 infection. SETTING: Clinical Immunology Laboratory and Pediatrics Department, University Hospital, Hong Kong. PATIENTS: Ten Asian and 2 Eurasian children infected with HIV-1 by mother-to-child transmission were followed for up to 5 years while on treatment with highly active antiretroviral therapy (HAART). MAIN OUTCOME MEASURES: Numbers of unstimulated and mitogen-activated cytokine-secreting cells (IFN-gamma, interleukin [IL]-2, IL-4, IL-6, IL-10, IL-12, and TNF-alpha) were measured by ELISPOT assay at frequent intervals, and correlations were sought with CD4+ and CD8+ cell counts and viral loads. RESULTS: Mitogen-stimulated IL-2-secreting cells were directly associated with recovery of CD4+ cells. Correlations with viral load were found for Con A-induced IFN-gamma, Con A-induced IL-4, and unstimulated IL-10, suggesting that these cytokines were either suppressed by high virus levels or that higher cytokine levels suppressed virus. IFN-gamma, IL-2-, IL-4-, and IL-12-secreting cells induced by PHA, Con A, and/or SAC tended to increase for the first 3–4 years of treatment but declined thereafter. CONCLUSIONS: Alterations in cytokine profiles were not associated with adverse clinical events and there was little evidence to indicate that monitoring cytokine enzyme-linked immunospots (ELISPOTs) could contribute to pediatric patient management. INTRODUCTION: With the advent of highly active antiretroviral therapy (HAART), human immunodeficiency virus type 1 (HIV-1) can be controlled for prolonged periods,[1] although the virus cannot be eliminated[2] and treatment failures occur due to development of drug-resistant mutations.[3] Chronic immune hyperactivation and raised T-cell turnover due to continued viral replication and antigenic stimulation are present even after HAART has decreased the viral load to undetectable levels.[4] Both proinflammatory and regulatory cytokines are produced during chronic immune stimulation. Proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha), contribute to tissue pathology, especially in the brain,[5] and can induce transcription of latent HIV-1.[6,7] Type 2 or regulatory cytokines, such as IL-4, IL-6, and IL-10, can suppress type 1 cytokines and induce polyclonal B-cell activation,[8] lymphomagenesis,[9] autoantibody production,[10] and manifestations of allergy.[11] Type 1 cytokines, such as IL-12, interferon (IFN) gamma, and IL-2, are important for antiviral cell-mediated immunity.[12] During the long course of HIV-1 infection, type 2 cytokines gradually come to predominate over type 1 cytokines,[13–16] although this finding is not universally accepted.[17] There have been few studies of in vitro cytokine production in neonatally acquired HIV-1 infection in Asian or Chinese children. The enzyme-linked immunospot (ELISPOT) system for measuring unstimulated or mitogen-activated cytokine secreting cells has not been evaluated in this context. We wished to know whether monitoring cytokine production in addition to CD4+ cell counts and viral load could provide additional useful information in pediatric patients with HIV-1 infection being treated with HAART. We hoped to identify cytokine profiles that are characteristic of either clinical improvement or disease progression, so that manipulation towards the desirable profile might be attempted