Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity

Laura Israel, and J.L Casanova et al.,

Cell. 2017 Feb 23;168(5):789-800

Speaker: Jia-Bao Chen (陳家寶)                          Time: 14:00~15:00, June. 21, 2017

Commentator: Lu, Cheng-Chan (呂政展 老師)   Place: Room 601

Abstract:

Staphylococcus aureus is a common cause of human diseases, including cutaneous infections, invasive hematogenous infections, and children necrotizing staphylococcal pneumonitis. Severe staphylococcal disease may result from various single-gene inborn errors of immunity.^1. In previous study, autosomal recessive MyD88 and interleukin-1 receptor-associated kinase 4 (IRAK-4) deficient patients are susceptible to invasive bacterial infections, particularly those caused by S.aureus.² In this study, the author  investigated a 9-year-old patient with pneumonia and sepsis PVL producing S. aureu but neither MyD88 deficiency nor IRAK-4 deficiency. Therefore, the authors investigated the other TLR pathway proteins mutation furthermore. First, Genome-wide SNP genotyping by whole-exome sequencing was used to find possible mutations in this patient associated with immunodeficiency, and then confirmed  that this patient carried a homozygous mutation at R121W residue in TIRAP, which encodes a TIR-domain-containing adaptor of TLR2 and TLR4. Next, the authors found no detectable impact of the R121W mutation on the mRNA and protein level of TIRAP in patient cells. Then, in vitro biochemical studies showed that TIRAP-R121W mutation led to the decreased association between TLR2 and MyD88 and the decreased IL-6 cytokine induction. However, the induction of IL-6 via the TLR2/6 pathway in response to LTA was normal in healthy individuals homozygous for TIRAP-R121W. Based on these results, the authors hypothesized that the sera of healthy individuals carrying TIRAP-R121W may contain anti-LTA antibodies, and these antibodies and CD36 may help IL-6 induction. Further analyses demonstrated that adding anti-LTA antibodies  to patient PBMCs carrying TIRAP-R121W rescued IL-6 induction upon LTA stimulation. Finally, in vivo study using a mouse model showed that anti-LTA antibodies rescued Tirap-/- mice to induce IL-6 production. In conclusion, these results suggest that the TIRAP-independent mechanism via anti-LTA Abs can rescue the impact of TIRAP deficiency on the TLR2/6 pathway. In these study, we could learn a concept that somatic diversity of adaptive immune responses can compensate or even rescue inborn errors of innate immunity.

References：

1.     Aziz Bousfiha et al., The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol. 2015; 35(8): 727–738.2015 Oct 7

2.     Jean-Laurent Casanova ., Severe infectious diseases of childhood as monogenic inborn errors of immunity. PNAS;112(51) 2015 Dec 22