Hematopoiesis takes place in the intersinusoidal spaces of the medullary cavity in association with several types of hematopoietic and non-hematopoietic cells that together form the hematopoietic micro environment (see Fig. 1). These populations include mesenchymal stromal cells, adipocytes, osteoblasts, sympathetic nervous system fibers, and endothelial cells.

Fig2. THE HEMATOPOIETIC MICROENVIRONMENT. (A) Cross-section of bone showing elements of the medullary circulation and the marrow sinusoids. Stromal cells that support developing blood cells are located in the intersinusoidal spaces. (B) Pro-B cells are tightly adherent to IL-7 producing stromal cells via their expression of adhesion molecules such as focal adhesion kinase and vascular cell adhesion molecule-1. Following the successful expression of Ig μ heavy chain and assembly of the pre-B-cell receptor (pre-BCR), pre-B cells must ultimately attenuate IL-7 receptor signaling in order to recombine Ig light chain genes and mature into BCR expressing B lymphocytes. A current model proposes that they are less adherent to stromal cells compared to pro-B cells and as a result migrate away from IL-7 rich areas. This results in attenuated IL-7 receptor signaling while pre-BCR signaling in these cells induces cell cycle exit, RAG expression, and light chain gene recombination. (A, From Dorshkind K. Regulation of hematopoiesis by bone marrow stromal cells and their products. Annu Rev Immunol. 1990;8:111. Reprinted by permission from the Annual Review of Immunology. B, Based on concepts reviewed and depicted in reference 14.)

Several cell surface determinants, some of which have been introduced above, mediate adhesion between developing B lineage cells and stromal cells. Both murine and human pre-B cells express the VLA-4 integrin that interacts with a stromal cell ligand identified as vascular cell adhesion molecule-1 (VCAM-1). Pro- and pre-B cells also express varying amounts of FAK involved in stromal cell binding via mediation of integrin signaling. FAK is an intracellular kinase typically linked to surface integrins. The hematopoietic microenvironment is also a source of cytokines that regulate B lymphopoiesis and include CXCL12 (SDF1), Flt3 ligand, Stem Cell Factor, IL-7, Wnt family members, TGF-β family members, and thymic stromal lymphopoietin (TSLP).

A full discussion of the cytokines that regulate B-cell development is beyond the scope of this chapter, but the focus can be narrowed when only those with obligate effects on B-cell development are considered. The critical B lymphopoietic cytokine in mice is IL-7, which binds to the IL-7R. IL-7 signaling potentiates the recombination of a VH region gene segment to an already rearranged DJH complex and, as discussed above, is critical for pro-B-cell proliferation which expands the size of clones expressing a particular Ig heavy chain.

The IL-7R is formed by the IL-7R α chain and the common cytokine γ chain. The Janus kinases (JAK) JAK3 and JAK1 are associated with the γc and IL-7 Rα, respectively and are critical for IL-7R mediated signaling. When IL-7 binds to the IL-7R, these JAK kinases are phosphorylated, and this in turn recruits signal transducer and activator of transcription 5 A (STAT5A) and STAT5B. The STAT molecules can then translocate to the nucleus where they act as transcriptional activators. The requirement for IL-7 in murine B-cell development is demonstrated by studies showing a block in B-cell development at approximately the pro-B-cell stage in IL-7 and IL-7R knock-out mice.

The precise role of IL-7 during human B-cell development is unclear. Human CD34+CD19+ pro-B cells proliferate in response to IL-7, but human B-lymphopoiesis may not be dependent on IL-7, because B cells are present in patients whose B-lineage cells express a mutated IL-7Rα chain. In addition, B cells are present in patients with X-linked severe combined immunodeficiency; these individuals have mutations in the gene encoding the cytokine common γ chain, which is part of the receptor for IL-7.

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مواضيع ذات صلة

Secondary Lymphoid Tissue

The Pro-B- and Pre-B-Cell Checkpoints

Immunoglobulin Gene Rearrangement : Heavy Chain Gene Rearrangement

Transcriptional Regulation of B-Cell Development

Stages of B-Cell development

Genetic Engineering of Natural Killer Cells

The role of Natural Killer Cells in Human Disease

Natural Killer Cells and Hematopoietic Cell Transplantation

Natural Killer Cell Receptor: C-Type Lectin Receptors

Killer-Cell Immunoglobulin-Like Receptors

CD56bright Natural Killer Cells

CD56dim Natural Killer Cells