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A Review of X-Linked Agammaglobulinemia

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A Review of X-Linked Agammaglobulinemia A Review of X-linked Agammaglobulinemia Maddy Wyburd Word count: 1,836 X-linked Agammaglobulinemia (XLA) be carriers, which results in a 0.5 probability of is a rare primary immunodeficiency dis- male offspring inheriting the condition. The un- order which impairs the bodies ability to derlying genetics is shown by a punnett square fight infections. It is caused by a mutation in Figure 1. It has been found that only 30-50% on the X chromosome, which inhibits the cases of XLA have been inherited, with the rest production of antibodies. Antibodies are being a result of sporadic mutations [3, 4]. essential in fighting bacterial pathogens and therefore patients with XLA are prone to infections. This review outlines how ge- netic mutation can pass through the sex chromosomes and then goes on to explain the role B cells in our immunity. In XLA the production of B cells is interrupted, here we address how this happens, start- ing at the genetic level and working up to the signalling pathways. X-linked The human DNA is divided up into 23 pairs of chromosomes, one from each parent. The first 22 pairs of chromosomes are autosome, containing the same order of genes as its partner. In women the 23rd chromosome is also an autosome, con- taining two equal length X chromosomes. How- Figure 1: A punnett square showing the in- ever, by definition, the last chromosome in men heritance of XLA. The mutated chromosome is is made up of a X and Y chromosome making an shown in red. Here a female carrier and an homologous chromosome pair [1]. The X chromo- healthy male have a 50% change for having male some contains over 800 genes compared to 63 on offspring with XLA whereas it is not possible for the Y [1]. Therefore for 737 genes there is only the female offspring to inherit the condition. Fe- one copy in male offspring, resulting in any mu- male offspring have a 50% of being a carrier, re- tated genes being expressed. As the XLA muta- sulting in a 25% chance of passing the condition tion is found on the X chromosome and does not onto the next generation. have a Y counterpart, it is far more common in males, affecting approximately 1 in 100,000 men [2]. This mutation is recessive allowing women to 1 A Review of X-linked Agammaglobulinemia Maddy Wyburd Figure 2: The development of B cells. B cells start developing in the bone marrow where they begin to form the BCR. The maturity of these cells depend on the BCR structure. At the pre-B cell stage, light chains are being produced but not yet formed. Immature B cells present the final BCR. Authors own B cells a pathogen which allows our immune system to fight it and remember the successful antibody structure. Patients with XLA are therefore un- The damaged DNA sequence found in XLA tran- able to have live vaccines. The role of Btk in scribes Bruton tyrosine kinases (Btk). This en- antibody production is not trivial. To aid our zyme plays a crucial role in the development of B understanding we first need to study B cell de- cells, a type of white blood cell. Also known as velopment and the structure of antibodies. B lymphocytes, these cells make up part of the human adaptive immune system, which creates an immunological memory after responding to a pathogen [1]. Creating a faster and more effective B cell development neutralisation in future attacks. B cells mature in the bone marrow from stem cells. This pro- B cell differentiation starts in the bone marrow cess creates B cell receptors (BCR) on the sur- and is structured around the development and face of the membrane [5, 6]. These cells then specialisation of the BCR also known as the im- migrate through the blood and into the lymph munoglobulin (Ig) receptor, shown in Figure 2. nodes awaiting activation [7]. Foreign pathogens The BCR is a large Y shape protein made up present specific antigens, usually made up of a of four polypeptide chains; two identical heavy small chain of amino acids. B cells are activated chains (H-chain) and two identical light chains by ligation of the BCR with a complementary (L-chain) [1]. The arrangement of these chains antigen [7]. The B cells can then differentiate creates the active site. Each Ig has two antigen into plasma or memory cells. Plasma cells un- binding sites which are formed by the nitrogen dertake clonal expansion and start releasing anti- terminals of the light and heavy proteins, while bodies, which have the same structure as the spe- the C-terminal on the heavy chain forms the Ig cific BCR, to fight the pathogens. Memory cells tail [1]. are responsible for immunological memory and protect against a secondary infection [7]. Live The chains themselves are made up around 110 vaccines exploit memory cell production, by in- amino acids and can be separated into a variable jecting the body with a controllable amount of (V) and constant (C) region [1]. The variable re- Page 2 A Review of X-linked Agammaglobulinemia Maddy Wyburd Figure 3: Bar chart courtesy of Dingjan et al.. This chart shows the concentration of L chains in pre-B cells when Btk formation is active, Btk+, and when Btk is not active Btk−. It is clear to see that Btk− individuals have significantly less λ L chain than Btk+ gion is found at the N- terminal and therefore is coding for L-chains are ordered and combined responsible for antigen binding. In turn there are with the H-chain to form an Ig molecule [1, 9, five classes of H-chains, α; γ; , µ and δ and two 10]. This checkpoints brings on the third phase classes of L-chains, λ and κ. The arrangement where the new immature B cell present the anti- of these classes allows for 5x1013 unique antigen body on its cell surface which is thought to bind binding sites [1, 9]. Each class is encoded at sep- to ligands, triggering clonal expansion [11]. The arate loci on separate chromosomes [1]. In for- antibody presenting cells then migrate into the mation of the Ig in the bone marrow, a complete lymph nodes where they become activated by an coding sequence for each of the chains and regions antigen [12]. is needed which is assembled by site-specific ge- netic recombination. For H-chains, this requires the correct classes of genes for both V and C re- gions to be rearranged. Once the correct V gene Defects in XLA segment is next to the correct C region it can be co-transcribed resulting in a RNA script. This The gene re-arrangement in pro-B cells and pre-B goes on to produce an mRNA molecule which cells requires complicated downstream signalling codes for the polypeptide chain [1]. pathways. Genetic defects, like in XLA, affect these pathways which has accelerated our study The rearrangement of the L-chain and H-chain of them. The mutation in XLA effects Btk forma- defines the developmental stages of the B-cell and tion. Btk is a non-receptor tyrosine kinase made form the conditions for the biological checkpoints up of 659 amino acids [13, 14]. A kinase protein [9]. In cell cycles checkpoints described the con- is a type of enzyme which catalyses the transfer ditions which must be met before entering the of phosphate groups. Btk plays a crucial part next stage. In the first stage, pro-B cells begin in the signalling pathways in B cells, including to rearrange the H-chain segments and start tran- the maturation of pre-B cells into mature B cells scription, shown in Figure 2 [10]. The creation [4]. XLA patients have significantly less mature of the heavy polypeptide opens entry to the next B cells and therefore antibodies than healthy pa- phase, pre-B cell stage. Here the gene segments tients. The exact pathway of Btk which inhibits Page 3 A Review of X-linked Agammaglobulinemia Maddy Wyburd Figure 4: Adapted from Singh et al.. Signalling pathway of Btk in the B cells. Btk mediated signalling events are regulated by phosphates which are recruited from the cell membrane. The cascade ends in the nucleus, shown by the dotted orange line. Here the genes describing L chain can be rearranged. antibody production was at first difficult to iden- the plasma membrane [8]. This activates Btk tify as the enzyme is involved in so many pro- which can then go on to phosphorylate phos- cesses. However, various experiment have been pholipase C (PLC). The active PLC enzyme carried out in mice to try and detect a mech- then binds and breaks down phosphatidylinos- anism which correlates a decrease of Btk with a itol 4,5-bisphosphate (PIP2) into inositol 1,4,5- lack of antibodies. They found that Btk deficient trisphosphate (IP3) and diacylglycerol (DAG) mouse showed a significant decrease in λ L-chain [5]. IP3 and DAG are secondary messengers proteins [8, 15], shown in Figure 3. A lack of which starts a signalling cascade into the nucleus. the L-chain stops the development at the pre-B Here the genes which define the L-chain are or- cell checkpoint. It now commonly accepted that dered and transcribed. Patients without Btk can- Btk signalling is actively involved in L-chain re- not signal to the nucleus to rearrange the λ L- arrangement and assembly [11]. chain segments resulting in an incomplete BCR and therefore can not pass through the check- The exact signalling pathway between Btk and point.
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