Generation of post-germinal centre myeloma plasma B cell.

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1 Generation of post-germinal centre myeloma. DNA DAMAGE CXCR4 Homing to Lytic lesion activation CD38 CD138 CD56 Phenotypic markers Naive Secondary lymphoid organ Multiple myeloma is a malignancy of s caused by alterations to genetic material following activation in the germinal centres of secondary lymphoid organs. Genetic defects include primary translocations of immunoglobulin heavy/light chain genes to other chromosomes near oncogenes/cell-cycle proteins and secondary changes including duplication/loss of chromosomes and/or mutations in cell growth/tumour suppressor genes. s also express CXCR4 receptors for, a chemokine that regulates homing to the where disease develops.

2 DNA damage following activation of s in the germinal centre. Germinal centre help Th2 CD4+ T cell IL-4 IL-10 DNA DAMAGE Follicular dendritic cell T cell zone Migration to s are primed by receptor recognition of antigens presented by follicular dendritic cells in the germinal centres of secondary lymphoid organs. CD4+ helper T cell interaction activates s to differentiate into cells and also induces isotype switching and affinity maturation. During this process abnormal DNA recombination events translocate heavy and light immunoglobulin genes to other chromosomes and generate a malignant phenotype. Secondary genetic alterations involving duplication/deletion of chromosomes or mutations in other genes can follow. The myeloma s continue to produce immunoglobulins resulting in a gammopathy and ultimately home to the where disease develops.

3 Adhesion of myeloma s to stromal cells. stromal cell Homing to IL-6 TNF-α IL-1β OPN IGF-1 BAFF APRIL VCAM-1 or fibronectin VLA-4 ICAM-1 LFA-1 or MUC-1 TGF-β TNF-α Gammopathy CXCR4 Monoclonal antibody The myeloma s express CXCR4 receptors that bind, a chemokine that regulates homing to the. s also express cellular adhesion molecules, such as VLA-4, LFA-1 and MUC-1, that interact with ligands expressed on stromal cells. Stimulation of adhesion molecules on stromal cells generates intracellular signals that promote the secretion of soluble cellular factors that help to maintain the myeloma s in an anti-apoptotic and drug-resistant state. Soluble cellular factors that stimulate the stromal cells are are also secreted by the myeloma s.

4 destruction mediated by unbalanced formation/resorption. resorption formation Osteoclast Osteoblast In multiple myeloma, disease is characterised by the presence of lytic lesions and raised blood calcium levels as a result of an imbalance between formation (mediated by osteoblasts) and resorption (mediated by osteoclasts). s home to and via interaction with stromal cells introduce changes in the microenvironment. Various soluble factors secreted by cells in the collectively reduce formation and promote resorption.

5 stromal cells Increased resorption by osteoclast activation. Osteoblast OPG OPG OPG Hypercalcaemia s RANKL TNF-α LT MIP-1α CD138 resorption IL-6 Lytic lesion Mineral RANKL RANK Osteoclast resorption destruction is mediated by the resorption activity of multinucleated osteoclasts. RANKL is a required activation signal for osteoclasts. RANKL is secreted along with other growth factors by myeloma s. In addition, an inhibitor of osteoclast activation, osteoprotegerin (OPG), which is secreted by osteoblasts and stem cells, is degraded by CD138 receptors expressed on myeloma s. stromal cells also have reduced production of OPG. OPG acts as a decoy molecule that competes with RANKL for binding to RANK receptors expressed by osteoclasts. Activated osteoclasts secrete IL-6 that promotes the survival of myeloma s.

6 stromal cells Reduced formation by osteoblast inhibition. Activin A s Dkk-1 IL-3 TGF-β formation Mineral Osteoblast formation destruction is exacerbated by the inhibition of osteoblast activity needed for formation. s secrete soluble factors that inhibit osteoblast activity. In addition, stromal cells secrete activin A which also inhibits osteoblast function.

7 Induced angiogenesis in. stromal cells bfgf Angiogenesis s IL-6 IGF-1 To improve oxygen and nutrient supply to the myeloma s, the formation of new blood vessel is promoted by soluble factors secreted by both stromal cells and myeloma s. In addition, blood vessel endothelial cells also secrete growth factors that promote the survival of the myeloma s.

8 List of abbreviations for soluble factors IL-6 IL-1β OPN OPG IGF-1 IL-8 BAFF APRIL TNF-α Dkk-1 IL-3 TGF-β RANKL LT MIP-1α bfgf VLA-4 VCAM-1 MUC-1 LFA-1 ICAM-1 Interleukin-6 Interleukin 1-beta Osteopontin Osteoprotegerin Vascular endothelial growth factor Insulin-like growth factor-1 Interleukin-8 Stromal cell derived factor 1-alpha activating factor A proliferation-inducing ligand Hepatocyte growth factor Tumour necrosis factor-alpha Dickkopf homologue-1 Interleukin-3 Transforming growth factor-beta Receptor activator of nuclear factor kappa B ligand Lymphotoxin mnacrophage inflammatory protein 1-alpha Basic fibroblast growth factor Very kate activation antigen-4 Vascular cell adhesion molecule-1 Mucin-1 Lymphocyte function-associated antigen-1 Intercellular adhesion molecule-1 BACK

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