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X-Linked Agammaglobulinemia

  1. Introduction
  2. Cause
  3. Symptoms and Methods of Diagnosis
  4. Treatment
  5. References



X-Linked Agammaglobulinemia (XLA) was the first immunodeficiency disease to be described.  It was first characterized by Ogden C. Bruton in a 1952 case study of an eight year old boy (Bruton, 1952).  Bruton describes the boy as having chronic infections with a variety of pathogens over a four year period, each of which was successfully treated with penicillin or a sulfa drug of some variety.  Since the majority of his infections had been caused by pneumococcus, Bruton attempted to vaccinate him against this pathogen.  When it was discovered that no gamma globulin was produced by the vaccination, the boy was tested to determine whether he could produce antibodies to any antigen.  It was soon proven that the boy could produce virtually no gamma globulin in response to any pathogen.  Bruton therefore named the condition agammaglobulinemia (Bruton, 1952).  The condition was soon observed to only occur in males and was therefore determined to be X-linked.  The disease is now commonly known as Bruton's X-Linked Agammaglobulinemia.

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Historical Background

When Bruton first described agammaglobulinemia in 1952, he suggested that there were two possible causes for the condition; the first being "a congenital dysfunction in the mechanism of gamma globulin production" and the second being "an acquired dysfunction in this mechanism" (Bruton, 1952).  Bruton felt that the disease was acquired since the boy in his case study exhibited no symptoms until after he reached four years of age.  The observation that XLA was X-linked ruled out Bruton's second hypothesis, indicating that the cause of the disease was genetic.  The cause of the condition was further narrowed with the discovery that patients with XLA lack mature B lymphocytes (Geha et al., 1974).  Further research indicated that in addition to the absence of mature B-cells in the periphery, patients with XLA also showed a large decrease in the ratio of pre B-cells to pro B-cells in the bone marrow (Camapana, 1990).  This result indicates that the disease is caused by something arresting the development of B-cells between the pro B-cell and pre B-cell stages.  A major step toward the understanding of the cause of XLA was taken in 1993 with the independent isolation of the gene which, when mutated, causes XLA (Vetrie et al., 1993; Tsukada et al., 1993).  As expected, the gene was located on the X-chromosome.  The gene was found to code for a protein kinase which had not yet been observed (Vetrie et al., 1993).  This new protein kinase was named Bruton's Tyrosine Kinase (Btk) because of its role in XLA.

Current Understanding

Btk is believed to play a role in a kinase signaling cascade that promotes the rearrangement of the light chain in pre B-cells after the pre B-cell receptor is displayed on the B-cell's surface, although the exact role of Btk in this pathway is not yet known (Janeway et al., 1999).  Btk is known to consist of five distinct domains:  Pleckstrin homology (PH), Tec homology (TH), Src homology 3 (SH3), Src homology 2 (SH2), and the catalytic kinase domain (Ki) (Vihinen et al., 1999).  Mutations causing XLA are distributed over all five domains as is shown in Table 1 below.

Table 1:  Distribution of mutations in Btk known to cause XLA.  The table shows that mutations are distributed over all five domains.  Mutations of all types in any of the five domains seem to be able to lead to XLA.  This table is reproduced as printed in Vihinen et al, 1999..  Permission to use this image has been requested, and if denied, the table will be removed from this page.

As is shown in Table 1 above, many different types of mutations in any of the five domains can lead to the XLA phenotype.  These data represent those XLA causing mutations of Btk which were known at the date of publication of Vihinen's paper.  A constantly updated list, known as BTKbase is maintained at  Case studies have shown that mutations in sites that are generally conserved from person to person lead to severe (classical) XLA in which virtually no B-cell development is observed, while mutations in sites which are somewhat more variable lead to a milder form of the disease (Vihinen et al., 1999).  The fact that mutations occurring in any of the five domains can cause XLA suggests that each of Btk's domains plays a vital role in B-cell development.  This hypothesis is supported by many recent studies of the activity of the domains of Btk in vitro.

PH Domain

In order to become fully active, Btk must bind to the plasma membrane and dimerize, allowing trans-phosphorylation of the SH3 domain of each monomer.  The PH domain of Btk is known to be capable of binding phospholipid head groups in vivo (Baraldi et al., 1999).  XLA causing mutations in the PH domain have been divided into two groups:  those that are large enough to disrupt the folding of the domain and those that alter the domain's affinity for phospholipid head groups (Baraldi et al., 1999).  Clearly, both types of mutations would interfere with the activation of Btk and prohibit it from acting on other kinase molecules in the signaling cascade.

TH and SH3 Domains

As stated above, activation of Btk requires dimerization and trans-phosphorylation of the SH3 domains.  Recent research in vitro has shown that the SH3 domain is capable of binding strongly with the proline- rich TH domain, making both domains unavailable for interaction with other proteins (Patel et al., 1997; Desiderio et al., 1997).  It is likely that this intramolecular binding plays a role in the regulation of the activity of Btk.  It has been shown that mutations in either the TH or SH3 domains can lead to a decrease in the avidity of binding between the two domains (Patel et al., 1997).  This change in avidity could interfere with the ability of Btk to respond to and pass on signals in a kinase cascade and curtail B-cell development.

SH2 and Ki Domains

Important roles of SH2 and kinase domains are known to be binding to phosphorylated tyrosine residues and phosphorylating tyrosine residues, respectively.  Mutations in these domains of Btk could easily interfere with Btk's ability to receive signals by binding to phosphorylated tyrosine residues with its SH2 domain, or to pass signals on by catalyzing the phosphorylation of another molecule with its kinase domain.  The fact that mutations in these domains do interfere with Btk activity are further evidence that Btk is a member of a kinase cascade which is critical to B-cell development (Vihinen, 1999).

Additional Functions

As research into XLA continues, more of Btk's roles are likely to be discovered.  For example, recent work has shown links between mutations in Btk and the activity and location of the nuclear transcription factor TFII-I (Novina et al., 1999).  As more functions are discovered, it will continue to become clear that the complexity of intracellular communication requires each protein to perform multiple roles, leading to many possibilities for mutation.  The same phenotype can often be caused by any one of these mutations, making localization of the cause of disease difficult and making the use of new diagnostic and treatment techniques extremely important.

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Symptoms and Methods of Diagnosis

As described by Bruton, males who are affected by XLA are extremely vulnerable to bacterial infection and are faced with recurrent infections.  These children are often susceptible to infection by a normally harmless pathogen given as a vaccination.  Such cases have been observed with the polio vaccine (Wright et al., 1977).  Diagnosis of XLA is made at an early age by observation of a lack of immunoglobin in the blood stream and the specific mutation which is causing the disease can be determined by genetic analysis.  A current clinical synopsis of the effects of XLA is available through OMIMô (Online Mendelian Inheritance in Man).

Females who are carriers of the disease show no symptoms because all of their mature B-cells exhibit exclusive use of their normal X-chromosome.  This non-random X-inactivation is confined to the carrier's B-cells, indicating that the mutation does not affect cells of other lineages, including T-cells and macrophages (Conley et al., 1986).  Thus, carriers of XLA can easily be identified by the presence of non-random X-inactivation.

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The first successful treatment of XLA was initiated by Bruton in 1952.  He treated his young patient with monthly injections of gamma globulin, with exceptional results.  The boy, who had suffered nineteen cases of sepsis over the past several years, displayed no sepsis during the fourteen months in which he was receiving injections (Bruton, 1952).  This method remained the standard for treatment of XLA until the development of intravenous immunoglobin (IVIG) in 1986 (Lee et al., 1997).  The IVIG method was preferred over intramuscular injections because it allowed for the injection of larger amounts of immunoglobin much less painfully.  A long term study of the effectiveness of IVIG indicated that it was successful in preventing and treating bacterial infections; however, its effectiveness against viral infections was much more limited (Quartier et al., 1999).

The most recent research in this field has yielded encouraging results on the possibility of the use of transgenes to restore Btk activity.  Studies in mice with the similar X-linked immunodeficiency (XID) have shown that the XID mutation has no dominant negative effect:  the insertion of a Btk transgene was able to restore antiviral TI-2 antibody responses in these mice even though the gene was inserted into a different position than in the wild type mice (Pinschewer et al., 1999).  This research is still far from providing an option for human patients suffering from XLA, but it does provide a glimpse of what will likely become the preferred method of treatment of XLA and similar genetic diseases.

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Baraldi, E., K.D. Carugo, M. Hyvönen, P.L. Surdo, A.M. Riley, B.V. Potter, R. O'Brien, J.E. Ladbury, and M. Saraste. 1999. Structure. 7, 449-460.

Bruton, O.C.  1952Pediatrics. 9, 722-728.

Campana, D., J. Farrant, N. Inamdar, A.D. Webster, G. Janossy.  1990J. Immunol.  145, 1675.

Conley, M.E., P. Brown, A.R. Pickard, R.G. Buckley, D.S. Miller, W.H. Rasking, J.W. Singer, and P.J. Fialkow.  1986. New England Journal of Medicine315, 564-567.

Desiderio, S.  1997Current Opinion in Immunology9, 534-540.

Fuleihan, R., R. Narayanaswamy, and R.,S. Geha. 1995. Advances in Immunology.  60, 37-56.

Geha, R.S., F.S. Rosen, and E. Merler.  1974. J. Clin. Invest.  52, 1726.

Lee, M.L., R.P. Gale, and P.L. Yap.  1997. Annu. Rev. Med.  48, 93-102.

Novina, C.D., S. Kumar, U. Bajpai, V. Cheriyath, K. Zhang, S. Pillai, H.H. Wortis, and A.L. Roy.  1999Molecular and Cellular Biology19, 5014-5024.

OMIMô:  Online Mendelian Inheritance in Man.  2000.  Clinial Synopsis for OMIM ENTRY 300310.  <>  Accessed 2000 Apr 14.

Patel, H.V., S. Tzeng, C. Liao, S. Chen, and J. Cheng. 1997. Proteins:  Structure, Function, and Genetics. 29, 545-552.

Pinschewer, D.D., A.F. Ochsenbein, A.B. Satterthwaite, O.N. Witte, H. Hengartner, and R.M. Zinkernagel.  1999. European Journal of Immunology29, 2981-2987.

Quartier, P., M. Debré, J. DeBlic, R. de Sauverzac, N. Sayegh, N. Jabado, E. Haddad, S. Blanche, J. Casanova, C.I. Smith, F. Le Deist, G. de Saint Basil, and A. Fischer.  1999The Journal of Pediatrics134, 589-596.

Tsukada, S., D.C. Saffran, D.J. Rawlings, O. Parolini, R.C. Allen, I. Klisak, R.S. Sparkes, H. Kubagawa, T. Mohandas, S. Quan, J.W. Belmont, M.D. Cooper, M.E. Conley, and O.N. Witte.  1993. Cell. 72, 279-290.

Vetrie, D., I. Vorechovsky, P. Sideras, J. Holland, A. Davies, F. Flinter, L. Hammarström, C. Kinnon, R. Levinsky, M. Bobrow, C.I. Smith, and D.R. Brently.  1993Nature. 361, 226-233.

Vihinen, M., S. Kwan, H.D. Ochs, I. Resnick, J. Väliaho, M.E. Conley, and C.I. Smith.  1999Human Mutation. 13, 280-285.

Vihinen, M. and C.I. Smith.  2000.  BTKbase: Mutation registry for X-linked agammaglobulinemia.  <>  Accessed 2000 Apr 13.

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