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DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation.

Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, Rauter I, Benson H, Schneider L, Baxi S, Recher M, Notarangelo LD, Wakim R, Dbaibo G, Dasouki M, Al-Herz W, Barlan I, Baris S, Kutukculer N, Ochs HD, Plebani A, Kanariou M, Lefranc G, Reisli I, Fitzgerald KA, Golenbock D, Manis J, Keles S, Ceja R, Chatila TA, Geha RS - Nat. Immunol. (2012)

Bottom Line: DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells.After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation.Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27(+) memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

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Impaired antibody responses, failure to maintain serologic memory and decreased memory B cells in DOCK8 deficient patients(a) Serial antibody titers after re-immunization with TT in two DOCK8 deficient patients aged 8 (Pt. 4) and 15 years (Pt. 7). The dotted line represents the lower limit of the protective antibody titer. (b) Percentage of CD3+ (T) cells and CD19+ (B) cells in PBMCs from DOCK8 deficient patients (Pt) and controls (C (c) Representative flow cytometry analysis of CD19 and CD27 expression by PBMCs from DOCK8 deficient patients and controls. (d) Percentage of CD27+ memory B cells and CD27− naïve B cells in the CD19+ B cell population of DOCK8 deficient patients and controls. Each symbol (b,d) represents an individual subject; small horizontal lines indicate the mean. *P<0.05 and **P<0.001 (Student’s t-test).
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Figure 1: Impaired antibody responses, failure to maintain serologic memory and decreased memory B cells in DOCK8 deficient patients(a) Serial antibody titers after re-immunization with TT in two DOCK8 deficient patients aged 8 (Pt. 4) and 15 years (Pt. 7). The dotted line represents the lower limit of the protective antibody titer. (b) Percentage of CD3+ (T) cells and CD19+ (B) cells in PBMCs from DOCK8 deficient patients (Pt) and controls (C (c) Representative flow cytometry analysis of CD19 and CD27 expression by PBMCs from DOCK8 deficient patients and controls. (d) Percentage of CD27+ memory B cells and CD27− naïve B cells in the CD19+ B cell population of DOCK8 deficient patients and controls. Each symbol (b,d) represents an individual subject; small horizontal lines indicate the mean. *P<0.05 and **P<0.001 (Student’s t-test).

Mentions: Ten patients aged 3.5–15 years with homozygous mutations in DOCK8 were studied (Supplementary Table 1). None had detectable DOCK8 protein in lysates of peripheral blood mononuclear cells (PBMCs) or Epstein-Barr virus (EBV) transformed B cells (data not shown). All had typical clinical characteristics of DOCK8 deficiency (Supplementary Table 2). Five patients, from whom serum was available prior to initiation of immunoglobulin replacement therapy, showed defective IgG antibody response to tetanus toxoid (TT), hepatitis B vaccine (Hep. B), TT-conjugated Haemophilus influenzae type B vaccine (HiB) and conjugated pneumococcal polyvalent vaccine (PV) (Table 1). The IgM TT antibody response was significantly decreased in these patients (Supplementary Fig. 1). Two of these patients, aged 8 and 15 years mounted a brisk early antibody response 8 weeks after a booster dose of TT, which fell below the protective level twelve and fifteen months later (Fig. 1a). This response is in contrast to >99% of normal children, in whom protective antibody titers persist five years after TT booster vaccination 25, 26.


DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation.

Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, Rauter I, Benson H, Schneider L, Baxi S, Recher M, Notarangelo LD, Wakim R, Dbaibo G, Dasouki M, Al-Herz W, Barlan I, Baris S, Kutukculer N, Ochs HD, Plebani A, Kanariou M, Lefranc G, Reisli I, Fitzgerald KA, Golenbock D, Manis J, Keles S, Ceja R, Chatila TA, Geha RS - Nat. Immunol. (2012)

Impaired antibody responses, failure to maintain serologic memory and decreased memory B cells in DOCK8 deficient patients(a) Serial antibody titers after re-immunization with TT in two DOCK8 deficient patients aged 8 (Pt. 4) and 15 years (Pt. 7). The dotted line represents the lower limit of the protective antibody titer. (b) Percentage of CD3+ (T) cells and CD19+ (B) cells in PBMCs from DOCK8 deficient patients (Pt) and controls (C (c) Representative flow cytometry analysis of CD19 and CD27 expression by PBMCs from DOCK8 deficient patients and controls. (d) Percentage of CD27+ memory B cells and CD27− naïve B cells in the CD19+ B cell population of DOCK8 deficient patients and controls. Each symbol (b,d) represents an individual subject; small horizontal lines indicate the mean. *P<0.05 and **P<0.001 (Student’s t-test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3362684&req=5

Figure 1: Impaired antibody responses, failure to maintain serologic memory and decreased memory B cells in DOCK8 deficient patients(a) Serial antibody titers after re-immunization with TT in two DOCK8 deficient patients aged 8 (Pt. 4) and 15 years (Pt. 7). The dotted line represents the lower limit of the protective antibody titer. (b) Percentage of CD3+ (T) cells and CD19+ (B) cells in PBMCs from DOCK8 deficient patients (Pt) and controls (C (c) Representative flow cytometry analysis of CD19 and CD27 expression by PBMCs from DOCK8 deficient patients and controls. (d) Percentage of CD27+ memory B cells and CD27− naïve B cells in the CD19+ B cell population of DOCK8 deficient patients and controls. Each symbol (b,d) represents an individual subject; small horizontal lines indicate the mean. *P<0.05 and **P<0.001 (Student’s t-test).
Mentions: Ten patients aged 3.5–15 years with homozygous mutations in DOCK8 were studied (Supplementary Table 1). None had detectable DOCK8 protein in lysates of peripheral blood mononuclear cells (PBMCs) or Epstein-Barr virus (EBV) transformed B cells (data not shown). All had typical clinical characteristics of DOCK8 deficiency (Supplementary Table 2). Five patients, from whom serum was available prior to initiation of immunoglobulin replacement therapy, showed defective IgG antibody response to tetanus toxoid (TT), hepatitis B vaccine (Hep. B), TT-conjugated Haemophilus influenzae type B vaccine (HiB) and conjugated pneumococcal polyvalent vaccine (PV) (Table 1). The IgM TT antibody response was significantly decreased in these patients (Supplementary Fig. 1). Two of these patients, aged 8 and 15 years mounted a brisk early antibody response 8 weeks after a booster dose of TT, which fell below the protective level twelve and fifteen months later (Fig. 1a). This response is in contrast to >99% of normal children, in whom protective antibody titers persist five years after TT booster vaccination 25, 26.

Bottom Line: DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells.After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation.Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27(+) memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

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