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Bruton's X-linked agammaglobulinemia
Bruton's X-linked agammaglobulinemia (XLA) is a genetic disease which is manifested by a serious immunodeficiency. It is the first known immunodeficiency with confirmed heredity. It was diagnosed in 1952 for the first time by doctor Ogden Bruton. (vu, 2014) XLA is caused by an abnormal product of a gene coding for Bruton's tyrosine kinase (BTK). BTK belongs to the Tec family of non-receptor protein kinases notable for a pleckstrin homology domain (link to wikipedia?). BTK is expressed in a great amount in B-lymphocyte precursors.
BTK
Function
Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase present in B lymphocytes, where it plays a key role in cell development, differentiation and signaling. For its proper function, one Zn2+ cofactor is needed. BTK acts as a platform to bring together various signaling proteins and is implicated in cytokine receptor signaling pathways. It is critical for the proper function of immune cells of both innate and adaptive immunity, as a component of the Toll-like receptors (TLR) pathway.
BTK also acts as a transcription regulator. Firstly, it is a part of the signaling pathway linking TLR8 and TLR9 (which causes BTK activation) to the NF-kappa-B complex. Inducing activity of this complex by its phosphorylation leads to significant changes of gene expression, since NF-kappa-B is involved in regulating the expression of hundreds of genes.
On top of that, BTK also phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. This regulator then translocates to the nucleus and binds regulatory enhancer elements to modulate gene expression. There is also a negative feedback mechanism to fine-tune BCR signaling. Activated PRKCB down-modulates BTK function via direct phosphorylation of BTK at Ser180, resulting in translocation of BTK back to the cytoplasmic fraction (UniProtKB, 2019).
There are many molecules identified as BTK activity inhibitors, for example PIN1, SH3BP5, and IBTK. Some of them are specific (LFM-13A), others cause a dramatic down-regulation of the kinase activity (CAV1). BTKs activity is also blocked by Dasatinib, a cancer drug acting as a non-specific tyrosine kinase inhibitor (UniProtKB, 2019). ((!!structure picture!!ibrutinib)
It has been shown, that alternative splicing results in multiple transcript variants encoding different isoforms (RefSeqGene, 2019).
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Disease
Etiology and pathogenesis
Bruton’s agammaglobulinemia is caused by an abnormal product of a gene coding for Bruton’s tyrosine kinase (BTK). BTK belongs to the Tec family of non-receptor protein kinases notable for a pleckstrin homology domain (link to wikipedia?). BTK is expressed in a great amount in B-lymphocyte precursors.
Under normal circumstances, during B-lymphocyte development IgH (BCR heavy chain) gene segments rearrange then the rearrangement takes place for the light chain. Disease causing BTK mutation aborts this process after rearrangement of IgH, light chains are not synthesized, immunoglobulins cannot be assembled which leads to apoptosis of B-cell precursors. The cause is most likely a malfunction of a signal path which transfers information from B-lymphocyte precursor receptors and in which BTK kinase is involved. (Taneja, 2019)
The critical part on the long arm of X chromosome linked to this disease is Xq21.3-q22. It contains 19 exons 37,5 kb long (Zheng, 2014). The final protein is composed of 659 amino acids and of 5 domains: TH, SH3, SH2, PH and a kinase domain. Over 1 000 mutations causing XLA were identified in this gene (Lee, 2016). In 40% of cases the defective allele is inherited, in 60% a spontaneous mutation arises. So it is an X-linked recessive hereditary disease. Due to that the disease usually occurs only in males, and females are healthy carriers. Prevalence in USA is 1 in 379,000 births in total and 1 in 190,000 births of male. (Taneja, 2019)
[To study this disease are used Xid mice models. It is lab mice with mutated BTK and express spontaneous mutation of CpG place of PH3 domain. Despite the mutation these mice are able to have about half amount of mature B-lymphocytes in blood. (Mohamed, 2009)]
[BTK is the only one in the Tec family which is connected to some kind of disease.]
BTK is mostly produced by precursors and immature cells, in mature lymphocytes the intracellular amount is decreased. In plasmatic cells it is not produced. Mutation in BTK causes a malfunction of other types of cells than B-lymphocytes, e.g. thrombocytes, macrophages and osteoclasts nevertheless in a smaller scale. After the activation of BCR, BTK is moved from the cytoplasm to the cell membrane where it is phosphorylated by Src family kinase. In cooperation with the adaptor B-cell linker protein (BLNK) it phosphorylates Cγ2 phospholipase which triggers another signal cascade. BTK interacts with TLR4, TLR6, TLR8, TLR9 and key proteins in signal paths of TLR like myeloid differentiation protein 88 (MyD88), MyD88 adapter-like protein (mal) , and interleukin-1 receptor (IL-1R)-associated kinase-1 (IRAK-1). BTK is important even for the congenital immunity. (Mohamed, 2009)
Clinical picture
Defective BTK has a consequence that a patient’s body cannot produce mature B-lymphocytes so it does not produce antibodies at all or at least in minimal scale. So it is not able to effectively defend against the infections.
The disease manifests itself after 6th month of age, at the time mother’s antibodies leave the child’s body. Typical are serious infections of breath paths and skin caused by commensal bacteria (S. Pneumoniae, H. Influenzae type B, S. Pyogenes, Pseudomonas) also usual are repetitive inflammation of the middle ear. The proneness to the enteroviruses (poliovirus, echovirus, coxsackievirus) is increased which is manifested in increased occurrence of meningitis and hepatitis. Approximately in 20% of patients arthritis is developed during the life most likely due to joint infections. (Taneja, 2019)
Diagnostics and therapy
One of the criteria for diagnostics of XLA is less than 2% of CD19 B-cells in peripheral blood excluding other causes of hypoagammaglobulinemia, and at the same time, having one of these symptoms: repetitive bacterial infection, non-responsiveness to vaccines (Segundo, 2018) or low level of serum antibodies. (Lim et al., 2013).
One of the most important parts of treatment of diagnosed patients is the prevention of bacterial infection contagion (increased hygiene, antibacterial lotions, …). It is recommended to cure any bacterial infection which patient gets by antibiotics to prevent serious or even deadly effects of these diseases. Then are these patients treated by intravenously given immunoglobulins. This treatment seems to be effective, the frequency of bacterial diseases is significantly decreased within the group of treated patients. Nonetheless the treatment is not able to fully compensate the function of antibodies as in a healthy individual (Taneja, 2019). In case of an infection, the level of serum antibodies does not elevate, and intravenously dosing immunoglobulin (IVIG) does not have the physiological proportions of the types of antibodies, IgG (95%) dominates and IgM and IgA are lacking. (Jolles, 2005)
Another possible treatment of XLA is bone marrow transplantation. It fully heals the patient but there is a high chance for complications. The transplantation comes with the risk of graft-versus-host disease (GVHD). (Howard, 2003)
Structural highlights
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References
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
