Bruton's tyrosine kinase defect in dendritic cells from X-linked agammaglobulinaemia patients does not influence their differentiation, maturation and antigen-presenting cell function

Bruton's tyrosine kinase (Btk), a Tec-family tyrosine kinase, is essential for B-cell function. We present crystallographic and biochemical analyses of Btk, which together reveal molecular details of its autoinhibition and activation. Autoinhibited Btk adopts a compact conformation like that of inactive c-Src and c-Abl. A lipid-binding PH-TH module, unique to Tec kinases, acts in conjunction with the SH2 and SH3 domains to stabilize the inactive conformation. In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk. This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains. Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk.

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Bruton's tyrosine kinase regulates TLR9 but not TLR7 signaling in human plasmacytoid dendritic cells

European Journal of Immunology ◽

10.1002/eji.201344030 ◽

2014 ◽

Vol 44 (4) ◽

pp. 1130-1136 ◽

Cited By ~ 21

Author(s):

Jingming Wang ◽

Kai-Yeung Lau ◽

Jimmy Jung ◽

Palanikumar Ravindran ◽

Franck J. Barrat

Keyword(s):

Dendritic Cells ◽

Tyrosine Kinase ◽

Plasmacytoid Dendritic Cells ◽

Bruton’S Tyrosine Kinase ◽

Bruton's Tyrosine Kinase

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Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages.

Journal of Experimental Medicine ◽

10.1084/jem.177.2.397 ◽

1993 ◽

Vol 177 (2) ◽

pp. 397-407 ◽

Cited By ~ 371

Author(s):

P G Holt ◽

J Oliver ◽

N Bilyk ◽

C McMenamin ◽

P G McMenamin ◽

...

Keyword(s):

Dendritic Cells ◽

Alveolar Macrophages ◽

Cell Function ◽

Normal Lung ◽

Antigen Presenting Cell ◽

Epithelial Surface ◽

Intratracheal Administration ◽

Antigen Presenting

Class II major histocompatibility complex (Ia)-bearing dendritic cells (DC) from airway epithelium and lung parenchyma express low-moderate antigen presenting cell (APC) activity when freshly isolated. However, this function is markedly upregulated during overnight culture in a manner analogous to epidermal Langerhans cells. The in vitro "maturation" process is inhibited by coculture with pulmonary alveolar macrophages (PAM) across a semipermeable membrane, and the degree of inhibition achieved can be markedly increased by the presence of tumor necrosis factor alpha. In addition, PAM-mediated suppression of DC function is abrogated via inhibition of the nitric oxide synthetase pathway. Functional maturation of the DC is accompanied by increased expression of surface Ia, which is also inhibited in the presence of PAM. Prior elimination of PAM from DC donors via intratracheal administration of the cytotoxic drug dichloromethylene diphosphonate in liposomes, 24-72 h before lung DC preparation, achieves a comparable upregulation of APC activity, suggesting that (consistent with the in vitro data) the resident PAM population actively suppresses the APC function of lung DC in situ. In support of the feasibility of such a regulatory mechanism, electron microscopic examination of normal lung fixed by intravascular perfusion in the inflated state (which optimally preserves PAM in situ), revealed that the majority are preferentially localized in recesses at the alveolar septal junctions. In this position, the PAM are in intimate association with the alveolar epithelial surface, and are effectively separated by as little as 0.2 microns from underlying interstitial spaces which contain the peripheral lung DC population. A similar juxtaposition of airway intraepithelial DC is demonstrated with underlying submucosal tissue macrophages, where the separation between the two cell populations is effectively the width of the basal lamina.

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Antigen-presenting cell function of dendritic cells and macrophages in proliferative T cell responses to soluble and particulate antigens

European Journal of Immunology ◽

10.1002/eji.1830160405 ◽

1986 ◽

Vol 16 (4) ◽

pp. 345-350 ◽

Cited By ~ 56

Author(s):

Martien L. Kapsenberg ◽

Marcel B. M. Teunissen ◽

Frank E. M. Stiekema ◽

Hiskias G. Keizer

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cell Function ◽

T Cell Responses ◽

Antigen Presenting Cell ◽

Cell Responses ◽

Antigen Presenting

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Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease

Acta Neuropathologica ◽

10.1007/s00401-020-02204-z ◽

2020 ◽

Vol 140 (4) ◽

pp. 535-548 ◽

Cited By ~ 1

Author(s):

Sebastian Torke ◽

Roxanne Pretzsch ◽

Darius Häusler ◽

Philipp Haselmayer ◽

Roland Grenningloh ◽

...

Keyword(s):

B Cells ◽

Tyrosine Kinase ◽

B Cell ◽

Demyelinating Disease ◽

Cell Receptor ◽

Bruton’S Tyrosine Kinase ◽

Bruton's Tyrosine Kinase ◽

Functionally Impaired ◽

Anti Cd20 ◽

Antigen Presenting

Abstract Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton’s tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties.

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