Type 1 and Type 2 Cytokine Imbalance in Acute Respiratory Syncytial Virus Bronchiolitis

Abstract

We examined the in vivo immune response of infants to natural respiratory syncytial virus (RSV) infection through analysis of cytokine levels in nasal lavage fluid and stimulated peripheral blood mononuclear cells. Eighty-eight babies with at least one parent with atopy and asthma were prospectively studied through their first winter. Twenty-eight infants had an upper respiratory tract infection where RSV was detected, of whom nine developed signs of acute bronchiolitis. Nasal lavage specimens were assayed for interferon-gamma, interleukin (IL)-4, IL-10, and IL-12 and the RSV load determined by quantitative polymerase chain reaction. Messenger RNA (mRNA) was extracted from stimulated peripheral blood mononuclear cells and interferon-gamma, IL-4, IL-12, and IL-18 mRNA levels determined by polymerase chain reaction. Cytokine profiles were analyzed in relation to clinical outcome. The IL-4/interferon-gamma ratio for infants with acute bronchiolitis was elevated in nasal lavage fluid on both Days 1-2 (p = 0.014) and Days 5-7 (p = 0.001) of the illness compared with infants with upper respiratory tract infection alone. Those with acute bronchiolitis demonstrated a higher IL-10/IL-12 ratio (p = 0.0015) on Days 1-2. IL-18 mRNA levels were reduced (p = 0.019) and the IL-4/interferon-gamma ratio elevated (p = 0.01) in stimulated peripheral blood mononuclear cells from infants with acute bronchiolitis. There was no difference in initial RSV load. These data strongly implicate excess type 2 and/or deficient type 1 immune responses in the pathogenesis of RSV bronchiolitis.

Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor deficient mice

“…The role of IFNγ has also been explored in the HRSV mouse challenge model [47][48][49] and has been detected in lung tissue in response to acute infection with virulent PVM J3666 [50; Table 3]. IFNγ has also been associated with a "Th1/ Th2 imbalance" [51,52], and has been implicated in a variety of pathologic outcomes related to hRSV infection, including prolonged respiratory dysfunction [53], and the exaggerated inflammatory response to an earlier parenteral vaccine formulation [54,55]. The IFNγR−/− mice used in this study, originally developed by Huang and colleagues [56] have a phenotypically normal immune system, but when challenged, demonstrate increased susceptibility to vaccinia virus, listeria and mycobacteria species despite normal cytotoxic and T helper cell responses.…”

The role of Th17 and Treg responses in the pathogenesis of RSV infection

“…Arguments for an imbalance in the Th1 and Th2 responses during severe RSV infections were indeed provided by some studies, demonstrating on the one hand a Th2 predominance with increased IL-4 concentrations in serum or nasopharyngeal aspirates of RSV infected children and on the other hand a decreased Th1 response with decreased IFN-γ concentrations in serum or nasopharyngeal aspirates (12,(18)(19)(20). An increased IL-4/IFN-γ ratio correlated with an increased severity of the infection (12).…”

Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection

“…Severe RSV disease in infants has been associated with Th-2-type immune responses (13). Prematurity is the greatest risk factor for severe RSV disease in infants.…”