Abstract
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) mutation. Patients are susceptible to severe enterovirus infections. The underlying mechanism remains unknown. BTK is involved in toll-like receptors pathway, which initiates antiviral responses including interferon (IFN) productions. To demonstrate type I and III IFN productions in dendritic cells of XLA patients is decreased in response to oral poliovirus vaccine (OPV) but not H1N1 virus. Monocyte-derived dendritic cells (MoDCs) were derived from nine XLA patients aged 22-32 years old and 23 buffy coats from Hong Kong Red Cross blood donors. LFM-A13 was used to inhibit BTK. OPV Sabin type 1 and H1N1 influenza virus were used to stimulate MoDCs with RPMI as mock stimulation. The antiviral cytokine productions and phenotypic maturation of MoDCs were determined 24 h post-stimulation. OPV RNA was determined at 0, 6, 12, and 24 h post-stimulation. Upon OPV stimulation, IFN-α2, IFN-β, and IFN-λ1 productions in MoDCs from XLA patients and BTK-inhibited MoDCs of healthy controls were significantly lower than that from healthy controls. Whereas upon H1N1 stimulation, the IFN-α2, IFN-β, and IFN-λ1 productions were similar in MoDCs from XLA patients, BTK-inhibited MoDCs of healthy controls and healthy controls. The mean fluorescent intensities (MFI) of CD83, CD86, and MHC-II in MoDCs from XLA patients in response to OPV was similar to that in response to mock stimulation, while the MFI of CD83, CD86, and MHC-II were significantly higher in response to H1N1 stimulation than that in response to mock stimulation. Whereas, the MFI of CD83, CD86, and MHC-II in MoDCs of healthy controls were significantly higher in response to both OPV and H1N1 stimulation compared to that in response to mock stimulation. Production of type I and III IFN in response to OPV was deficient in MoDCs from XLA patients, but was normal in response to H1N1 due to deficient BTK function. Moreover, phenotypic maturation of MoDCs from XLA patients was impaired in response to OPV but not to H1N1. These selective impairments may account for the unique susceptibility of XLA patients toward severe enterovirus infections.
Highlights
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations of Bruton’s tyrosine kinase (BTK) (1, 2)
Cytokines produced upon oral poliovirus vaccine (OPV) stimulation from the monocyte-derived dendritic cells (MoDCs) of XLA patients, BTK-inhibited MoDCs and MoDCs of healthy controls were measured at 24 h post-stimulation
IFN-α2, IFN-β, IFN-λ1, and interferon gamma-induced protein 10 (IP-10) productions were lower in MoDCs from XLA patients compared to that from healthy controls upon OPV stimulation (Figure 3)
Summary
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations of Bruton’s tyrosine kinase (BTK) (1, 2). XLA patients typically suffer from recurrent respiratory infections caused by encapsulated bacteria but are generally not susceptible to viral infections (1, 4). XLA patients are vulnerable to severe enterovirus infections, notably chronic meningoencephalitis from Echo virus and vaccine-associated paralytic poliomyelitis (VAPP) from live-attenuated oral poliovirus vaccine (OPV) (5–9). Antibodies deficiency has been suggested to be responsible for the increase in susceptibility (10), but enterovirus infections in XLA patients with adequate immunoglobulin replacement have been reported (11, 12), indicating that antibody deficiency alone cannot fully explain the susceptibility toward severe enterovirus infections. To date the exact mechanism behind this unique susceptibility is unknown. X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by Bruton’s tyrosine kinase (BTK) mutation. Patients are susceptible to severe enterovirus infections. BTK is involved in toll-like receptors pathway, which initiates antiviral responses including interferon (IFN) productions
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