Table 2.
Previous studies on the effect of BTK deficiency on cytokine productions in response to TLR agonists.
| Cytokine | Effect of BTK deficiency on cytokine production | TLR tested | TLR agonist used | Cell type used | BTK-deficient model | Cytokine detection | Studies | Year |
|---|---|---|---|---|---|---|---|---|
| IFN-α | Decreased | TLR 9 | ODN 2216 | pDC | RN486 | Flow cytometry | Wang et al. (44) | 2014 |
| No effect | TLR 7/8 | CL097/Loxoribine | pDC | XLA patient | ELISA | Marron et al. (45) | 2012 | |
| Gardiquimod | pDC | RN486 | Flow cytometry | Wang et al. (44) | 2014 | |||
| TLR 9 | ODN-2006 | pDC | XLA patient | ELISA | Cunningham-Rundles et al. (46) | 2006 | ||
| IFN-β | Decreased | TLR 3 | Poly I: C | (Mice) BMDM | BTK−/− mice | ELISA | Lee et al. (23) | 2012 |
| TLR 4 | LPS | (Mice) BMDM | BTK−/− mice | ELISA | Lee et al. (23) | 2012 | ||
| TLR 7/8 | R848 | (Mice) BMDC | BTK−/− mice | RT-PCR | Li et al. (47) | 2014 | ||
| TLR 9 | CpG-ODN1668 | (Mice) BMDC | BTK−/− mice | RT-PCR/ELISA | Li et al. (47) | 2014 | ||
| Tumor necrosis factor alpha (TNF-α) | Decreased | TLR 2/6 | PAM3Cys4 | PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 |
| PGN | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | |||
| TLR 3 | Poly I: C | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| (Mice) BMDM | BTK−/− mice | ELISA | Lee et al. (23) | 2012 | ||||
| TLR 4 | LPS | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| Monocyte | XLA patient | ELISA | Horwood et al. (50) | 2003 | ||||
| TLR 7/8 | R848 | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| ssRNA | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | |||
| TLR 9 | ODN-2216 | MoDCs | XLA patient/Ibrutinib | RT-PCR | Lougaris et al. (52) | 2014 | ||
| pDC | RN486 | Flow cytometry | Wang et al. (44) | 2014 | ||||
| Increased | TLR 4 | LPS | B cell depleted PBMC | XLA patient | ELISA | González-Serrano et al. (53) | 2012 | |
| Monocyte/MoDCs | XLA patient | Flow cytometry/ELISA | Marron et al. (45) | 2012 | ||||
| TLR 7/8 | CL097 | Monocyte/MoDCs | XLA patient | Flow cytometry/ELISA | Marron et al. (45) | 2012 | ||
| No effect | TLR 2/6 | PAM3Cys4 | (Mice) BMDM | BTK−/− mice | ELISA | Köprülü et al. (54) | 2013 | |
| Zymosan | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | |||
| TLR 3 | Poly I: C | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| TLR 4 | LPS | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| MoDCs | XLA patient/Ibrutinib | RT-PCR | Lougaris et al. (52) | 2014 | ||||
| Monocyte | XLA patient | Flow cytometry | de Diego et al. (55) | 2006 | ||||
| TLR 5 | Flagellin | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| TLR 7 | Gardiquimod | pDC | RN486 | Flow cytometry | Wang et al. (44) | 2014 | ||
| TLR 9 | ODN-2006 | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| IL-1β | Decreased | TLR 2/6 | PAM3Cys4 | PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 |
| TLR 4 | LPS | PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 | ||
| TLR 7 | Imiquimod | (Mice) BMDM | BTK−/− mice | ECL assay | Byrne et al. (60) | 2013 | ||
| Increased | TLR 4 | LPS | B cell depleted PBMC | XLA patient | ELISA | González-Serrano et al. (53) | 2012 | |
| IL-8 | No effect | TLR 2/6 | PAM3Cys4 | PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 |
| TLR 4 | LPS | PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 | ||
| IL-10 | Decreased | TLR 2/6 | PGN | (Mice) BMDM | BTK−/− mice | ELISA | Schmidt et al. (56) | 2006 |
| TLR 3 | Poly I: C | (Mice) BMDM | BTK−/− mice | ELISA | Schmidt et al. (56) | 2006 | ||
| (Mice) BMDM | BTK−/− mice | ELISA | Lee et al. (23) | 2012 | ||||
| TLR 4 | LPS | (Mice) BMDM | BTK−/− mice | ELISA | Schmidt et al. (56) | 2006 | ||
| TLR 7 | Imiquimod | (Mice) BMDM | BTK−/− mice | ECL assay | Byrne et al. (60) | 2013 | ||
| TLR 9 | E. coli CpG | (Mice) BMDM | BTK−/− mice | ELISA | Schmidt et al. (56) | 2006 | ||
| ODN-1826 | (Mice) B lymphocyte | BTK−/− mice | ELISA | Lee et al. (57) | 2008 | |||
| Increased | TLR 4 | LPS | B cell depleted PBMC | XLA patient | ELISA | González-Serrano et al. (53) | 2012 | |
| MoDCs | XLA patient | ELISA | Gagliardi et al. (58) | 2003 | ||||
| (Mice) BMDM | BTK−/− mice | ELISA | Gabhann et al. (59) | 2012 | ||||
| MoDCs | XLA patient | ELISA | Marron et al. (45) | 2012 | ||||
| TLR 7/8 | CL097 | MoDCs | XLA patient | ELISA | Marron et al. (45) | 2012 | ||
| No effect | TLR 2/6 | PAM3Cys4 | PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 | |
| Zymosan | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | |||
| TLR 3 | Poly I: C | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| TLR 4 | LPS | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 | ||||
| MoDCs | XLA patient/Ibrutinib | RT-PCR | Lougaris et al. (52) | 2014 | ||||
| Monocyte | XLA patient | ELISA | Marron et al. (45) | 2012 | ||||
| TLR 5 | Flagellin | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| TLR 7/8 | CL097 | Monocyte | XLA patient | ELISA | Marron et al. (45) | 2012 | ||
| ssRNA | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | |||
| TLR 9 | ODN-2216 | MoDCs | XLA patient/Ibrutinib | RT-PCR | Lougaris et al. (52) | 2014 | ||
| IL-6 | Decreased | TLR 3 | Poly I: C | (Mice) BMDM | BTK−/− mice | ELISA | Lee et al. (23) | 2012 |
| TLR 8 | ssRNA | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| TLR 9 | ODN-2216 | MoDCs | XLA patient/Ibrutinib | RT-PCR | Lougaris et al. (52) | 2014 | ||
| pDC | RN486 | Flow cytometry | Wang et al. (44) | 2014 | ||||
| CpG-ODNs | PBMC | XLA patient/LFM-A13 | ELISA | Doyle et al. (24) | 2007 | |||
| Increased | TLR 4 | LPS | B cell depleted PBMC | XLA patient | ELISA | González-Serrano et al. (53) | 2012 | |
| MoDCs | XLA patient | RT-PCR | Lougaris et al. (52) | 2014 | ||||
| (Mice) BMDM | BTK−/− mice | ELISA | Schmidt et al. (56) | 2006 | ||||
| Monocyte/MoDCs | XLA patient | Flow cytometry/ELISA | Marron et al. (45) | 2012 | ||||
| TLR 7/8 | CL097 | Monocyte/MoDCs | XLA patient | Flow cytometry/ELISA | Marron et al. (45) | 2012 | ||
| TLR 9 | ODN-1826 | (Mice) B lymphocyte | BTK−/− mice | ELISA | Lee et al. (57) | 2008 | ||
| No effect | TLR 2/6 | PAM3Cys4 | PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 | |
| (Mice) BMDM | BTK−/− mice | ELISA | Köprülü et al. (54) | 2013 | ||||
| Zymosan | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | |||
| PGN | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | |||
| TLR 3 | Poly I: C | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||||
| TLR 4 | LPS | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| PBMC | XLA patient | ELISA | Horwood et al. (48) | 2006 | ||||
| MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||||
| MoDCs | Ibrutinib | RT-PCR | Lougaris et al. (52) | 2014 | ||||
| Monocyte | XLA patient | Flow cytometry | de Diego et al. (55) | 2006 | ||||
| TLR 5 | Flagellin | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| TLR 7/8 | R848 | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| Gardiquimod | pDC | RN486 | Flow cytometry | Wang et al. (44) | 2014 | |||
| TLR 9 | ODN-2006 | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| IL-12 | Decreased | TLR 3 | Poly I:C | (Mice) BMDM | BTK−/− mice | ELISA | Lee et al. (23) | 2012 |
| TLR 4 | LPS | (Mice) BMDM | BTK−/− mice | ELISA | Gabhann et al. (59) | 2012 | ||
| TLR 7 | Imiquimod | (Mice) BMDM | BTK−/− mice | ECL assay | Byrne et al. (60) | 2013 | ||
| TLR 9 | ODN-2216 | MoDCs | XLA patient/Ibrutinib | RT-PCR | Lougaris et al. (52) | 2014 | ||
| Increased | TLR 9 | ODN-1826 | (Mice) B lymphocyte | BTK−/− mice | ELISA | Lee et al. (57) | 2008 | |
| No effect | TLR 2/6 | Zymosan | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | |
| PGN | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | |||
| TLR 3 | Poly I:C | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||||
| TLR 4 | LPS | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||||
| MoDCs | XLA patient | ELISA | Gagliardi et al. (58) | 2003 | ||||
| MoDCs | XLA patient/Ibrutinib | RT-PCR | Lougaris et al. (52) | 2014 | ||||
| TLR 5 | Flagellin | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | ||
| TLR 7/8 | R848 | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| ssRNA | MoDCs | XLA patient/LFM-A13 | Flow cytometry | Sochorová et al. (51) | 2007 | |||
| TLR 9 | ODN-2006 | MoDCs | XLA patient | ELISA | Taneichi et al. (49) | 2008 | ||
| IL-18 | Decreased | TLR 4 | LPS | (Mice) BMDM | BTK−/− mice | ELISA | Gabhann et al. (59) | 2012 |
| CXCL-1 | Decreased | TLR 7 | Imiquimod | (Mice) BMDM | BTK−/− mice | ECL assay | Byrne et al. (60) | 2013 |
PGN, Zymosan and PAM3Cys4 are TLR 2/6 agonist. Poly I:C is TLR 3 agonist. LPS is TLR4 agonist. Flagellin is TLR5 agonist. CL097 and R848 are TLR 7/8 agonist. Gardiquimod and Loxoribine are TLR 7 agoinst. ssRNA is TLR8 agonist. E. coli CpG, CpG-ODNs, ODN-2006, CpG-ODN1668, ODN-1826, and ODN-2216 are TLR9 agonist. LFM-A13, RN486, and Ibrutinib are BTK inhibitors.
TLR, toll-like receptor; IFN, interferon; IL, interleukin; CXCL, chemokine (C-X-C motif) ligand; ECL assay, electrochemiluminescence assay; pDC, plasmacytoid dendritic cells; BMDM, bone marrow-derived macrophages; BMDC, bone marrow-derived conventional dendritic cells; MoDCs, monocyte-derived dendritic cells; PBMC, peripheral blood mononuclear cells; XLA, X-linked agammaglobulinemia; BTK, Bruton’s tyrosine kinase.