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Colonel Bruton's Kinase Defined the
Molecular Basis of X-Linked
Agammaglobulinemia, the First Primary
Immunodeficiency
Wasif N. Khan
J Immunol 2012; 188:2933-2935; ;
doi: 10.4049/jimmunol.1200490
http://www.jimmunol.org/content/188/7/2933
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References
Colonel Bruton’s Kinase Defined the Molecular Basis of
X-Linked Agammaglobulinemia, the First
Primary Immunodeficiency
Wasif N. Khan
T
Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33134
Address correspondence and reprint requests to Dr. Wasif N. Khan, Department of
Microbiology and Immunology, Miller School of Medicine, University of Miami,
1600 NW 10th Avenue, 3347A Rosenstiel Medical Science Building, Miami, FL
33134. E-mail address: [email protected]
Abbreviations used in this article: PH, pleckstrin homology; PID, primary immunodeficiency disease; PLC, phospholipase C; TI, T cell independent; XLA, X-linked
agammaglobulinemia.
Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1200490
the B cell lineage was the source of Igs and that T cells regulated delayed-type hypersensitivity and graft rejection.
Cellular characterization of peripheral blood revealed that
XLA patients have very few or virtually no circulating B cells (3,
7). The peripheral B cell deficiency was found to be due to
a developmental block at the pre-B (CD191cytoplasmic m1)
cell stage in the bone marrow (7–11). However, this defect is
leaky, yielding a few IgM1 immature B cells, which fail to
develop into fully mature B lymphocytes (3, 4). Together,
these studies traced the Ig deficiency to B cell developmental
defects in the bone marrow (pre-B) and in immature B cells in
the periphery. These cellular defects suggested that the protein
encoded by the XLA gene was expressed and critical for B cell
differentiation at multiple stages, from pre-B to plasma cells.
The observation that XLA exclusively affected males indicated that the defective gene was localized to the X chromosome and that the hemizygosity of the X chromosome in males
resulted in expression of the disease phenotype. Because of the
random nature of X-chromosome inactivation in females, Xlinked genes display mosaic expression. The X-linked nature of
the defect was confirmed by X-chromosome inactivation in
XLA patients; only B cells displayed a nonrandom X inactivation (12). Refined gene mapping localized the XLA genetic
defect to the Xq22 region (13–15). Finally, the Bentley group
(16), taking advantage of technical advances in positional
cloning, identified genomic clones spanning the XLA locus
and analyzed the corresponding transcripts for mutations and
disease association. The DXS178 polymorphic DNA marker
was found to be closely linked, and a clone spanning this
marker yielded a transcript that corresponded to a region
altered in all members of an XLA family. The transcript
encoded a novel cytoplasmic tyrosine kinase and was termed
Atk (16). The Witte group, while searching for novel tyrosine
kinases involved in B cell development, identified a cDNA
clone that also mapped close to the DXS178 marker. This
clone encoded a tyrosine kinase and was termed bpk (17).
The findings of the two groups were later reconciled, and the
causative gene for XLA was named Bruton’s agammaglobulinemia tyrosine kinase (BTK ). The seminal research articles
by Vetrie et. al. (16) and Tsukada et. al. (17) describing the
underlying genetic defect in XLA are selected for the Pillars of
Immunology series for this issue of The Journal of Immunology.
Within 1 y of BTK ’s discovery, the Xid locus in the CBA/
N mouse stain was mapped to the Btk gene (18, 19). A naturally occurring mutation (R28C) was found in the pleckstrin homology (PH) domain (see below) of the Btk gene.
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he importance of pathogen-specific humoral immunity was recognized from the early days of immunology. However, that integrity of humoral immunity is
essential to protect against life-threatening infections was established with the discovery of the first primary immunodeficiency disease (PID). In the spring of 1952, Colonel Ogden C.
Bruton (1) reported an 8-y-old boy with extreme susceptibility to infections. He had suffered from $19 episodes of
clinical pneumococcal sepsis within the past 4 y. Electrophoretic analysis revealed a lack of gammaglobulins (IgG) in
the patient’s serum. Remarkably, furnishing IgG controlled
the life-threatening infections. This was the first description
of a PID and its IgG replacement therapy (1). Janeway and
colleagues’ observations with an additional five males corroborated Bruton’s findings (2). Based on the X-linked pattern
of inheritance, the disease later became known as X-linked
agammaglobulinemia (XLA), and IgG replacement remains
an effective treatment for XLA today. XLA, a prototype forB cell developmental defects and Ab deficiency, is the most
frequent PID and is responsible for disease in 85% of earlyonset Ab-deficient patients (3).
The XLA defect is primarily characterized by a failure to
clear infections, particularly those involving encapsulated
bacteria. This defect is accompanied by a severe reduction in
the basal serum Igs, as well as a failure to produce Ag-induced
Ab responses against infectious agents or immunizations (3, 4).
Thus, XLA is a selective Ab defect that leaves cellular immunity relatively intact. This phenotype suggested that the immune system is composed of specialized compartments for
humoral and cellular immune responses. These insights were
highly significant, because, at this time, the basis for cellular
and humoral immunity was not known. The selective Ab
defect in XLA contributed to the concept of specialized lymphocyte lineages and the discovery by Cooper et al. (5, 6) that
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activation of PLC-g2 provided a missing link between BCR
and the generation of lipid second messengers. Consistently,
BTK-deficient B cells are impaired in activating the protein
kinase C- and Ca21-regulated transcription factors NF-kB
and NFAT (31–35).
Recent studies demonstrate an involvement of BTK function in many signaling pathways in addition to that downstream of the BCR. These include pathways induced by
stimulation of cytokine receptors, G protein-coupled receptors, receptors of the TNFR family, and most TLRs (31,
36–38). Recent studies also suggest that TLR and BAFF
receptors play an important role in regulating TI Ab responses. It remains to be explored whether defective BTK
signaling in the TLR and BAFF receptor pathways contributes
to the defective TI immune responses in XLA and Xid. A role
for BTK in these signaling pathways is also relevant for immune tolerance and autoimmunity. Recently, a novel function of BTK in the full activation of TLR signaling was
described in which it forms a complex with nonconventional
endosomal MHC class II, CD40, and MyD88 (39). This type
of signaling in B cells can enhance B cell survival and activation and can play a role in TLR7/9-dependent development
of autoimmunity. The physiological significance of these
newly discovered BTK signaling mechanisms in B cell development, survival, and immune responses both in health and
autoimmune disease remains to be explored.
The identification of BTK has allowed detection of female
carriers of the defective XLA allele and corroboration of
clinical diagnosis of XLA patients with specific mutations in
the BTK gene. The discovery of BTK also has implications for
prenatal screening for the PIDs. Given that XLA is the most
common monogenetic immunodeficiency in humans, the potential for gene replacement and correction therapy needs
to be explored. Indeed, Btk gene replacement has been successful in mouse models; thus, human XLA gene therapy
remains a potential goal (40, 41). A successful human XLA
gene therapy may require precise genetic manipulations, such
as targeting the endogenous BTK locus in stem cells. The
origins of the clinical usefulness and potential for BTK gene
therapy lie in the discovery of XLA and the underlying defect
in the gene encoding Colonel Bruton’s kinase.
Acknowledgments
I thank Drs. Max D. Cooper and Emily S. Clark for helpful discussions
and critical reading of the manuscript.
Disclosures
The author has no financial conflicts of interest.
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Soon thereafter, gene-targeted mice with a Btk-null mutation
unequivocally demonstrated that Xid is caused by a defect in
the Btk gene (20–22).The Xid mouse strain has been a model
for B cell and Ab immunodeficiency in mice since 1975 (23).
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triphosphate and diacylglycerol, mobilizing intracellular Ca21
and activating protein kinase C and RasGRP (24, 31). BTK
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