B cell development in the bone marrow.

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1 development in the bone. s develop from multipotent haematopoietic stem s in the bone that produce lymphoid progenitors which in turn generate s. s with a unique antibody specificity develop by initial D to J rearrangement of the µ heavy followed by V to DJ joining. The heavy pairs with the surrogate made of λ14.1 and to form the pre-. Failure to assemble a functional pre- prompts rearrangement of the second µ heavy or the dies. A functional pre- capable of signal is tested with a stromal -derived ligand, galectin-1. Pre- signaling failure prevents further development (checkpoint 1). Next, rearrangement of the κ occurs that pairs with the heavy to form the. Autoreactivity is tested with bone -derived antigens (checkpoint 2). An autoreactive prompts rearrangement of the second κ or else the λ s are used. Multipotent haematopoietic stem Lymphoid progenitor Progenitor (Pro-B) Precursor -1 (Pre-B-I) D H to J H Galectin-1 Heavy defective Large V H to DJ H Checkpoint 1 Pre- λ14.1 antigen V L to J L Small -II autoreactive Checkpoint 2 µh Immature κ L or λ L

2 Pre- ligand binding and signal (checkpoint 1). There are two checkpoints in the development of s to test the functionality of the and to prevent the development of autoreactive s. The first checkpoint occurs after the rearrangement of a functional µ heavy which pairs with the surrogate made up of proteins λ14.1 and. This forms the pre- which is expressed on the surface where interaction with the protein ligand, galectin-1, secreted by bone stromal s, occurs. Galectin-1 is captured by -surface integrins (including α4β1, α5β1 or α4β7) and also binds to the λ14.1 protein of the SLC. Binding of galectin-1 to SLC initiates signal via the Igα and Igβ trans proteins that associate with the pre-. Successful intraular signaling events then prompt the to rearrange and express a functional. Failure to transduce the pre- signal results in arrest of further development of the. Marrow stromal Galectin-1 Integrin (α4β1, α5β1 or α4β7) Pre- λ14.1 α β Pre-B-II

3 autoantigen binding and signal (checkpoint 2). κ L or λ L Marrow stromal antigen α β not autoreactive Small -II V L to J L autoreactive Immature If signal of the pre- has been successful, the initiates VJ of the that pairs with the heavy to form the. The second checkpoint in development is a test for potential autoreactivity. s that recognise bone -derived antigens with high affinity trigger an intraular signal that prompts the to rearrange an alternative in order to generate a new. The order of rearrangements is usually the κ genes first followed by λ. Failure to generate a non-autoreactive results in death. Successful s migrate out of the bone to the secondary lymphoid organs where they may potentialy detect foreign antigens.

4 Impaired development in the bone (agammaglobulinaemia). Pre- Multipotent haematopoietic stem Lymphoid progenitor Progenitor (Pro-B) D H to J H Precursor -1 (Pre-B-I) Large λ14.1 V H to DJ H In primary immunodeficiency disease characterised by a lack of circulating antibodies as well as absent or low numbers of mature s there are often defects in the development of s in the bone. A number of abnormalities have been identified in the intraular signaling pathway at the first checkpoint during development involving the pre-. Failure to transduce signals from the pre- following galectin-1 ligand binding prevents the s from further development. This leads to reduced numbers or absent s in the periphery that produce IgM. There is also reduced opportunity for T- dependent activation of s which is a requirement for isotype switching to generate immunoglobulins such as IgG, IgA and IgE.

5 In greater detail, the intraular signaling events following pre- ligand-binding to galectin-1 is shown here with known defective proteins identified in agammaglobuliaemia (indicated in red with an asterisk). The most common mutations (85%) cause Btk protein dysfunction. Btk is encoded by the X-chromosome and is referred to as sex or X-linked agammaglobulinaemia. Pre- signaling recruits to the Igα and Igβ intraular tails which in turn recruits BLNK. Mutations in BLNK are also known to cause agammaglobulinaemia since this protein recruits Btk. Btk activates phospholipase C gamma-2 which is essential for the activation of transcription factors NFAT and NFκΒ required for gene transcription and further development. Less common genetic mutations have been found in the µ heavy, λ14.1 and the Igα or Igβ trans signal domains. Failure to transduce a signal from the pre- results in arrest of further development of s in the bone and the lack of s leads to the symptoms of agammaglobulinaemia. Extraular space λ14.1* Pre- µh* α β Pre- signal (checkpoint 1). Galectin-1 BLNK* Btk* Pre-B LYN Calcium influx cytoplasm nucleus pore NFAT Gene transcription NFκB

6 κ L or λ L signal (checkpoint 2). Autoantigen Extraular space α β LYN Calcium influx cytoplasm nucleus pore NFAT Gene transcription NFκB The second checkpoint in development also involves intraular signaling, but this time the interaction of the with bone -derived antigens is indicative of autoreactivity. An autoreactive prompts the to rearrange an alternative allele, usually in the order of the κ genes first followed by the λ genes. Failure to generate a nonautoreactive will lead to death. Successful s will leave the bone and migrate to secondary lymphoid tissues where foreign antigens can be detected. In agammaglobulinaemia this checkpoint may not be reached due to failure at checkpoint 1, however, some mutations are leaky and permit a reduced level of functionality of the affected proteins. This potentially affects checkpoint 2 where autoreactive s may escape elimination due to insufficient signaling of the when contacting bone self-antigens thus increasing the risk of developing antibody-mediated autoimmune reactions.

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