Clearance of immune complexes by the mononuclear phagocyte system is important for maintaining normal host defenses against bacterial and viral assault (1), but also contributes to the pathogenesis of a variety of immune-mediated diseases . For example, removal from the circulation of IgG-coated erythrocytes and platelets by the MPS is the sine qua non of immune-mediated cytopenias (2, 3). On the other hand, abnormally decreased removal by the MPS of smaller, soluble immune complexes may play a role in the pathogenesis of immune complex-mediated tissue damage found in such autoimmune diseases as SLE (4).Although the physicochemical nature and the size of immune complexes can influence rates of clearance and sites of deposition (reviewed in 5), interactions between immune complexes and the MPS in vivo are poorly understood . The inability to directly measure binding or internalization of immune complexes by cells in the liver and spleen has made the analysis of the molecular basis of immune complex clearance very difficult . Receptors for the Fc portion of IgG (FcyR) and for complement (CR) undoubtedly play a role in the removal of immune complexes, but the relative importance of these receptors is not known.There are three types of FcyRs on human leukocytes . A 72 kD receptor with high affinity for monomeric IgG is found on monocytes (6) and some resident macrophages (7). Two receptors exist with low affinity for monomeric IgG, one with broad electrophoretic mobility (51-73 kD) on neutrophils (8), natural killer cells (9), and macrophages (8); the other recently described (40 kD) on platelets (10), monocytes (10), and several tumor cell lines (11). All three bind immunoglobulin that is aggregated or complexed to antigen . The 51-73 kD receptor is recognized by mAb 3G8, which blocks ligand binding and has been very useful in the partial biochemical characterization of this receptor (8).In vitro analysis of the role played by FcyRs in individuals with abnormally prolonged clearance of opsonized red cells (model particulate immune complexes) generally has been limited to studies of high-affinity FcyRs on monocytes.
To examine potential mechanisms by which hematopoiesis may be regulated by endothelial cells within the bone marrow (BM) microenvironment, we have devised a technique for the in vitro study of the interaction of human BM microvascular endothelial cells (BMEC) with hematopoietic cells. Microvessels isolated by collagenase digestion of spicules obtained from filtered BM aspirate were plated on gelatin-coated plastic dishes, and colonies of endothelial cells grown from microvessel explants were further purified by Ulex europaeus lectin affinity separation. BMEC monolayers isolated by this technique grew in typical cobblestone fashion, stained positively with antibody to factor VIII/von Willebrand factor, and incorporated acetylated LDL. Immunohistochemical studies showed that BM microvessels and BMEC monolayers express CD34, PECAM, and thrombospondin. Incubation of resting BMEC with BM mononuclear hematopoietic cells resulted in the selective adhesion of relatively large numbers of CD34+ progenitor cells and megakaryocytes. The binding of purified BM-derived CD34+ progenitor cells to BMEC was dependent on divalent cations and was partially blocked by antibodies to CD34. IL-1 beta treatment of BMEC monolayers resulted in an increase of CD34+ progenitor cell adhesion by mechanisms independent of CD34 or divalent cations. BMEC exhibit specific affinity for CD34+ progenitor cells and megakaryocytes, suggesting that the BM microvasculature may play a role in regulating the trafficking, proliferation, and differentiation of lineage specific hematopoietic elements, and possibly of pluripotent stem cells within the CD34+ population.
Eighty-three patients with circulating anticoagulants were studied at The New York Hospital. The lupus-type anticoagulant, an inhibitor of the prothrombin activator complex, was demonstrated in 58 patients. The inhibitor was identified using the blood and tissue thromboplastin inhibition tests. Inhibition by the lupus anticoagulant was augmented in 67% of these patients by a cofactor present in normal plasma. The lupus inhibitor was detected primarily because of an unsuspected abnormal coagulation test. One-half of the patients with the lupus-type anticoagulant did not have systemic lupus erythematosus.
Human marrow cells were processed sequentially by density centrifugation and by velocity sedimentation in serum-free Percoll gradients in order to purify megakaryocytes and to determine if these cells are the source of the growth factor derived from platelets. Cell homogenates were made from the resulting fractions and tested for growth-promoting activity(ies) in 3T3 cells and in well characterized human marrow fibroblasts. Growth was evaluated by 3H-TdR incorporation and changes in DNA cell content, as measured by flow microfluorometry. The highest mitogenic activity was derived from homogenates of low density (less than 1.050 g/cu cm), rapidly sedimenting cells. This fraction contained the highest percentage of megakaryocytes. The assessment of growth-promoting activity(ies) derived from various megakaryocyte-enriched marrow cell homogenates containing different proportions of megakaryocytes demonstrated a positive correlation between the number of megakaryocytes and their stimulatory capacity as determined by 3H-TdR uptake. The growth-promoting activities elicited from homogenates of platelets and marrow fractions enriched for megakaryocytes were similar. The dose--response curves for both were parallel, and they were both temperature resistant and trypsin sensitive. These findings implicate megakaryocytes as a source of the growth factor derived from platelets and suggest that megakaryocytes may play a role in the pathogenesis of the marrow fibrosis observed in myeloproliferative disorders by stimulating fibroblast proliferation and collagen secretion.
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