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Presence in peripheral blood of healthy individuals of autoreactive T cells to a membrane antigen present on bone marrow-derived cells
CURRENT LITERATURE RHCe gene, and the partner chromosome has the hybrid RHD-RHCe-RHD gene and a regular RHCe gene. The DC w individual has one chromosome with a deleted RHD gene aligned with a hybrid RHCWe-RHD gene and a partner chromosome with a hybrid R H D - R H C e gene and a deleted RHCE gene. The phenotypic homozygosity versus genotypic heterozygosity shown in this study shows unexpected genetic diversity in the Rh blood group system.
Presence in peripheral blood of healthy individuals of autoreactive T cells to a membrane antigen present on bone marrow-derived cells. Filion MC, Proulx C, Bradley A J, Devine DV, Sekaly R-P, Decary F, Chartrand R Blood 88:2144-2150, 1996 The immune system is endowed with the capability of responding to foreign antigens without responding to self antigens. In some individuals, however, a sustained response to self antigens occurs and the individual develops an autoimmune syndrome. Because T helper cells are the orchestrators of the immune system, it is at the level of the T helper cell where specificity for foreign antigens and tolerance to self-antigens is regulated. One hypothesis as to how self tolerance is maintained, is that T helper cells with specificity to self antigens do not exist in the circulation of normal individuals, because of deletion of these autoreactive T cells during thymie maturation. However, several reports have shown that normal individuals in fact do have low numbers of circulating autoreactive T helper cells to such antigens as myelin basic protein (the antigen implicated in multiple sclerosis), type II collagen (the antigen implicated in rheumatoid arthritis), and others. It has also been reported that healthy individuals may have peripheral blood T cells reacting to the Rhesus self-antigen present on red blood cells. The above autoreactive T cells however are directed against sequestered antigens that would not be expected to enter the thymic environment. Thus it is possible that autoreactive T cells exist to sequestered antigens but not to non-sequestered antigens. This manuscript describes the presence of autoreactive T helper cells to the non-sequestered platelet and megakaryocyte glycoprotein (GP) IIb-IIIa antigen (integrin ~irol33), which is present in the circulation, the bone man'ow, as well as on early thymic epithelial cells. Using proliferation and cytol~ne assays for measuring T helper cell activation, these authors have shown that healthy individuals possess e43 q-cell receptor positive GP IIb-IIIa antoreactive T helper cells. The authors show that these T cells only proliferate in the presence of the GP IIb-IIIa antigen that has been endocytosed, processed, and presented in association with HLA-DR class II molecules in the presence of exogenous interleukin (IL)-2. The absolute requirement for IL-2 indicates that these T cells ate characteristic of anergic cells which may explain their presence in the absence of a corresponding anti-GP IIb-IIIa antibody. In summary, these data suggest that autoreactive T cells to the GP IIb-IIIa antigen are present in most, if not all, individuals and are tolerized in the periphery to prevent autoimmune reaction against GP IIb-IIIa.
Antigen Topography is Critical for Interactions of IgG2 Anti-red-cell Antibodies with Fc3' Receptors. Kumpel BM, Van De Winkel JGJ, Wostordaal NAC, et aL Br J Haematol 94:175-183, 1996 It is evident that the structure of an antigen affects the isotype of IgG antibody produced in response to immunization. This is
147 particularly evident with anti-red cell antibodies. IgG antibodies to the Rh D polypeptide antigen are normally of the IgG1 and IgG3 isotypes, whereas those made in response to the carbohydrate blood group A antigen are predominantly IgG2. These authors have attempted to define the functional implications of the isotype restriction of anti-A and anti-D antibodies in Fc3'R interaction. Fc receptors that interact with the constant region of the IgG heavy chain (3' chain) are divided into 3 classes, the Fc3'RI which binds monomeric IgG (and is expressed in monocytes, macrophages and activated neutrophils), the Fc3'RII which binds complexed or cell-bound IgG and displays heterogeneity (expressed in monocytes, macrophages, neutrophils, B lymphocytes, natural killer (NK) cells and platelets), and the Fc3'RIII which preferentially binds complexed IgG (expressed in monocytes, macrophages and NK cells). All three Fc3'R's bind human IgG1 and IgG3. In contrast, only the Fc3'RII binds human IgG2. Because IgG2 does not efficiently activate complement, the Fc3'RI[ would be expected to mediate IgG2-sensitized red cell clearance. The authors have used cell lines transfected with the Fc3'RII to assess and compare IgG subclass binding. The antibodies tested included expected IgG's produced in response to Rh D (IgG1 and IgG3) and blood group A (IgG2) immunization, in comparison with somewhat rare IgG2 antiRhD,.and tgG1 + IgG3 anti-A antibody. As exPected, antigen positi;~e red cells sensitized with the IgG1 and IgG3 anti-Rh D and the IgG2 anti-A all formed rosettes w i t h the Fc3'RII transfectants. When the IgG2 anti-D sensitized red Cells were used, these cells did not interact with the Fc-/RII positive cell line. IgG2 anti-D sensitized red cells also could not be lysed in an ADCC assay. In contrast, IgGl and IgG3 anti-A sensitized red cells formed rosettes and were lysed by the appropriate Fc3'R expressing cell. The inability of IgG2 anti-D sensitized cells to interact with an Fc3'RII was not caused by suboptimal sensitization because cells sensitized up to 100,000 molecules per cell were not bound or lysed by Fc3'RII positive cells. The anthors speculate that differences in antigen topography between the RhD antigen and the A blood group antigen are responsible for the differences observed. The RhD antigen is an integral transmembrane protein containing 12 putative transmembrane spanning segments and the extracelhilar domains do not protrude far from the plasma membrane. The blood group A antigen, on the other hand, is expressed on the band 4.5 glycoprotein at a site that is relatively far from the surface of the plasma membrane. It is speculated that the IgG2 antibody, which has a short rigid hinge region, may not be sufficiently flexible to allow efficient interaction with the Fc3'RII receptor. Thus, in an Rh D positive individual with IgG2 anti-D antibody, one could possibly expect to find sensitized red cells that would not lyse because of the inefficiency of IgG2 to activate complement as well as its inability to bind to an Fc3'R.
Randomized Trial of Prophylactic Early Fresh-Frozen Plasma or Gelatin or Glucose in Preterm Babies: Outcome at 2 Years. Northern Neonatal Nursing Initiative Trial Group. Lancet 348:229-232, 1996. Babies born more than 8 Weeks before term are at high risk of hemorrhagic and ischemic brain injury and the early prophylactic use of fresh-frozen plasma (FFP) has been proposed as an approach to reduce the risk of intraventricular hemorrhage. It remains unclear, however, whether the reduction in periventric-
Presence in peripheral blood of healthy individuals of autoreactive T cells to a membrane antigen present on bone marrow-derived cells. Filion MC, Proulx C, Bradley A J, Devine DV, Sekaly R-P, Decary F, Chartrand R Blood 88:2144-2150, 1996 The immune system is endowed with the capability of responding to foreign antigens without responding to self antigens. In some individuals, however, a sustained response to self antigens occurs and the individual develops an autoimmune syndrome. Because T helper cells are the orchestrators of the immune system, it is at the level of the T helper cell where specificity for foreign antigens and tolerance to self-antigens is regulated. One hypothesis as to how self tolerance is maintained, is that T helper cells with specificity to self antigens do not exist in the circulation of normal individuals, because of deletion of these autoreactive T cells during thymie maturation. However, several reports have shown that normal individuals in fact do have low numbers of circulating autoreactive T helper cells to such antigens as myelin basic protein (the antigen implicated in multiple sclerosis), type II collagen (the antigen implicated in rheumatoid arthritis), and others. It has also been reported that healthy individuals may have peripheral blood T cells reacting to the Rhesus self-antigen present on red blood cells. The above autoreactive T cells however are directed against sequestered antigens that would not be expected to enter the thymic environment. Thus it is possible that autoreactive T cells exist to sequestered antigens but not to non-sequestered antigens. This manuscript describes the presence of autoreactive T helper cells to the non-sequestered platelet and megakaryocyte glycoprotein (GP) IIb-IIIa antigen (integrin ~irol33), which is present in the circulation, the bone man'ow, as well as on early thymic epithelial cells. Using proliferation and cytol~ne assays for measuring T helper cell activation, these authors have shown that healthy individuals possess e43 q-cell receptor positive GP IIb-IIIa antoreactive T helper cells. The authors show that these T cells only proliferate in the presence of the GP IIb-IIIa antigen that has been endocytosed, processed, and presented in association with HLA-DR class II molecules in the presence of exogenous interleukin (IL)-2. The absolute requirement for IL-2 indicates that these T cells ate characteristic of anergic cells which may explain their presence in the absence of a corresponding anti-GP IIb-IIIa antibody. In summary, these data suggest that autoreactive T cells to the GP IIb-IIIa antigen are present in most, if not all, individuals and are tolerized in the periphery to prevent autoimmune reaction against GP IIb-IIIa.
Antigen Topography is Critical for Interactions of IgG2 Anti-red-cell Antibodies with Fc3' Receptors. Kumpel BM, Van De Winkel JGJ, Wostordaal NAC, et aL Br J Haematol 94:175-183, 1996 It is evident that the structure of an antigen affects the isotype of IgG antibody produced in response to immunization. This is
147 particularly evident with anti-red cell antibodies. IgG antibodies to the Rh D polypeptide antigen are normally of the IgG1 and IgG3 isotypes, whereas those made in response to the carbohydrate blood group A antigen are predominantly IgG2. These authors have attempted to define the functional implications of the isotype restriction of anti-A and anti-D antibodies in Fc3'R interaction. Fc receptors that interact with the constant region of the IgG heavy chain (3' chain) are divided into 3 classes, the Fc3'RI which binds monomeric IgG (and is expressed in monocytes, macrophages and activated neutrophils), the Fc3'RII which binds complexed or cell-bound IgG and displays heterogeneity (expressed in monocytes, macrophages, neutrophils, B lymphocytes, natural killer (NK) cells and platelets), and the Fc3'RIII which preferentially binds complexed IgG (expressed in monocytes, macrophages and NK cells). All three Fc3'R's bind human IgG1 and IgG3. In contrast, only the Fc3'RII binds human IgG2. Because IgG2 does not efficiently activate complement, the Fc3'RI[ would be expected to mediate IgG2-sensitized red cell clearance. The authors have used cell lines transfected with the Fc3'RII to assess and compare IgG subclass binding. The antibodies tested included expected IgG's produced in response to Rh D (IgG1 and IgG3) and blood group A (IgG2) immunization, in comparison with somewhat rare IgG2 antiRhD,.and tgG1 + IgG3 anti-A antibody. As exPected, antigen positi;~e red cells sensitized with the IgG1 and IgG3 anti-Rh D and the IgG2 anti-A all formed rosettes w i t h the Fc3'RII transfectants. When the IgG2 anti-D sensitized red Cells were used, these cells did not interact with the Fc-/RII positive cell line. IgG2 anti-D sensitized red cells also could not be lysed in an ADCC assay. In contrast, IgGl and IgG3 anti-A sensitized red cells formed rosettes and were lysed by the appropriate Fc3'R expressing cell. The inability of IgG2 anti-D sensitized cells to interact with an Fc3'RII was not caused by suboptimal sensitization because cells sensitized up to 100,000 molecules per cell were not bound or lysed by Fc3'RII positive cells. The anthors speculate that differences in antigen topography between the RhD antigen and the A blood group antigen are responsible for the differences observed. The RhD antigen is an integral transmembrane protein containing 12 putative transmembrane spanning segments and the extracelhilar domains do not protrude far from the plasma membrane. The blood group A antigen, on the other hand, is expressed on the band 4.5 glycoprotein at a site that is relatively far from the surface of the plasma membrane. It is speculated that the IgG2 antibody, which has a short rigid hinge region, may not be sufficiently flexible to allow efficient interaction with the Fc3'RII receptor. Thus, in an Rh D positive individual with IgG2 anti-D antibody, one could possibly expect to find sensitized red cells that would not lyse because of the inefficiency of IgG2 to activate complement as well as its inability to bind to an Fc3'R.
Randomized Trial of Prophylactic Early Fresh-Frozen Plasma or Gelatin or Glucose in Preterm Babies: Outcome at 2 Years. Northern Neonatal Nursing Initiative Trial Group. Lancet 348:229-232, 1996. Babies born more than 8 Weeks before term are at high risk of hemorrhagic and ischemic brain injury and the early prophylactic use of fresh-frozen plasma (FFP) has been proposed as an approach to reduce the risk of intraventricular hemorrhage. It remains unclear, however, whether the reduction in periventric-