Today it is generally accepted that B cells require cognate interactions with CD4
IntroductionThe most serious complication in replacement therapy with FVIII products is the development of neutralizing antibodies against FVIII (FVIII inhibitors), which is observed in approximately 25% to 30% of patients with severe hemophilia A. 1 Although several genetic 2 and nongenetic 3 factors that contribute to the risk for patients to develop these antibodies have been identified, why some patients develop antibodies while others do not remains largely unknown.Today it is generally accepted that B cells require cognate interactions with CD4 ϩ T cells to develop high-affinity antibodies against protein antigens. 4,5 In line with this perception, several lines of evidence have supported the involvement of CD4 ϩ T cells in the generation of antibody responses against FVIII in patients with hemophilia A and in murine hemophilia models. 6,7 CD4 ϩ T cells express T-cell receptors that recognize antigen-derived peptides (CD4 ϩ T-cell epitopes) presented by MHC class II molecules, which are expressed on specialized antigen-presenting cells. 8 Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4 ϩ T cells that can bind to the MHC class II-peptide complex. 8,9 The conditions under which CD4 ϩ T cells interact with this complex determine whether the immune system reacts with nonresponsiveness, is activated to develop specific antibodies, or is tolerized to suppress antibody responses. 9,10 Therefore, it is crucial to understand which FVIII peptides are presented by MHC class II complexes under conditions of FVIII replacement therapy and how CD4 ϩ T cells interact with MHC class II-FVIII peptide complexes expressed by antigenpresenting cells. The available information on FVIII peptides presented in the context of specific human MHC class II molecules is limited. Several studies used peripheral blood cells of patients and healthy controls 11 to identify CD4 ϩ T-cell epitopes in the A2 domain, 12 A3 domain, 13 and C2 domain of FVIII. 14 However, these studies lack information on the specific MHC class II molecules associated with the FVIII peptides identified. Jacquemin et al identified T-cell epitopes of FVIII using CD4 ϩ T-cell clones isolated from a mild hemophilia A patient carrying an Arg2150His mutation in the C1 domain of FVIII. 15 All clones recognized FVIII peptides encompassing residue Arg2150. Peptides were presented by HLA-DRB1*0401/HLA-DRB4*01 or HLA-DRDRB1*1501/ HLA-DRB5*0101. One of the peptides identified was a promiscuous epitope that bound to several different HLA-DR proteins. James et al used MHC class II tetramers to analyze FVIII-specific CD4 ϩ T cells obtained from a mild hemophilia A patient carrying an Ala2201Pro mutation in the C2 domain of FVIII. 16 Responses of CD4 ϩ T cells to sequences containing Ala2201 (wild-type), Pro2201 (hemophilic), and other predicted T-cell epitopes were evaluated and resulted in the identification of an HLA-DRB1*0101 restricted T-ce...
Background:The plasminogen system is central in cell migration and is thus involved in many patho/physiological processes. Results: M6P-IGF2R is a regulatory factor in plasminogen-associated complexes and mediates plasminogen internalization. Conclusion: The uptake of plasminogen by M6P-IGF2R might be an important pathway to control plasminogen activation in cells. Significance: M6P-IGF2R restricts plasmin activity and its loss might lead to rampant fibrinolysis.
Rationale:The urokinase plasminogen activator (uPA) system is among the most crucial pericellular proteolytic systems associated with the processes of angiogenesis. We previously identified an important regulator of the uPA system in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R).Objective: Here, we wanted to clarify whether and how did the soluble form of M6P/IGF2R (sM6P/IGF2R) contribute to modulation of the uPA system.
Methods and Results:
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