We have developed a model of autoimmunity to investigate autoantibody-mediated cross-presentation of self antigen. RIP-mOVA mice, expressing OVA in pancreatic β cells, develop severe autoimmune diabetes when given OT-I cells (OVA-specific CD8 + T cells) and anti-OVA IgG but not when given T cells alone. Anti-OVA IgG is not directly injurious to the islets but rather enhances cross-presentation of apoptotic islet antigen to the OT-I cells, leading to their differentiation into potent effector cells. Antibody-driven effector T cell activation is dependent on the presence of activating Fc receptors for IgG (FcγRs) and cross-priming DCs. As a consequence, diabetes incidence and severity was reduced in mice lacking activating FcγRs. An intact complement pathway was also required for disease development, as C3 deficiency was also partially protective. C3-deficient animals exhibited augmented T cell priming overall, indicating a proinflammatory role for complement activation after the T cell priming phase. Thus, we show that autoreactive antibody can potently enhance the activation of effector T cells in response to cross-presented self antigen, thereby contributing to T cell-mediated autoimmunity.
The uptake of immune complexes by FcRs on APCs augments humoral and cellular responses to exogenous Ag. In this study, CD11c+ dendritic cells are shown to be responsible in vivo for immune complex-triggered priming of T cells. We examine the consequence of Ab-mediated uptake of self Ag by dendritic cells in the rat insulin promoter-membrane OVA model and identify a role for the inhibitory FcγRIIB in the maintenance of peripheral CD8 T cell tolerance. Effector differentiation of diabetogenic OT-I CD8+ T cells is enhanced in rat insulin promoter-membrane OVA mice lacking FcγRIIB, resulting in a high incidence of diabetes. FcγRIIB-mediated inhibition of CD8 T cell priming results from suppression of both DC activation and cross-presentation through activating FcγRs. Further FcγRIIB on DCs inhibited the induction of OVA-specific Th1 effectors, limiting Th1-type differentiation and memory T cell accumulation. In these MHC II-restricted responses, the presence of FcγRIIB only modestly affected initial CD4 T cell proliferative responses, suggesting that FcγRIIB limited effector cell differentiation primarily by inhibiting DC activation. Thus, FcγRIIB can contribute to peripheral tolerance maintenance by inhibiting DC activation alone or by also limiting processing of exogenously acquired Ag.
Well-characterized mouse models of alloimmune antibody-mediated hemolysis would provide a valuable approach for gaining greater insight into the pathophysiology of hemolytic transfusion reactions. To this end, mouse red blood cells (mRBCs) from human glycophorin A transgenic (hGPA-Tg) donor mice were transfused into non-Tg recipients that had been passively immunized with IgG or IgM hGPA-specific monoclonal antibodies (mAbs). In this novel murine "blood group system," mRBCs from hGPA-Tg IntroductionHemolytic transfusion reactions (HTRs) are dangerous complications of blood transfusions. IgM-mediated HTRs (IgM-HTRs) occur acutely, are usually due to ABO incompatibility, typically cause intravascular hemolysis, and can lead to shock, renal failure, coagulopathy, and death. 1 Although infrequent, IgM-HTRs have a high mortality rate. IgG-mediated HTRs (IgG-HTRs) are more common, but usually less severe, than IgM-HTRs; they can occur acutely or be delayed, typically cause extravascular hemolysis, and occasionally result in renal failure, coagulopathy, and death. 2 Symptomatic immune-mediated red blood cell (RBC) destruction also occurs in autoimmune hemolytic anemia (AIHA), 3 blood group incompatible transplantation, 4 and immune thrombocytopenic purpura (ITP) treated with Rh-immune globulin. 5 Although various different modalities are used to treat HTRs, there is no definitive evidence regarding efficacy. Given the sporadic nature of HTRs, designing human trials to evaluate treatment options is difficult. Therefore, to study the mechanisms underlying HTRs, to evaluate the efficacy of existing treatments, and to develop new treatments, a relevant, inexpensive, and tractable animal model is required. 6 A mouse model would be ideal for this purpose, 7 given the abundance of reagents and relevant knockout (KO) and transgenic (Tg) animals. Although mouse blood group polymorphisms exist, 8 and transfused incompatible mouse RBC (mRBCs) are rapidly cleared, 9,10 no one has exploited these findings to develop a model of HTRs. The availability of a Tg mouse expressing human glycophorin A (hGPA; gene symbol designation, GYPA) on mRBCs 11 offers an approach using a well-described glycoprotein target and well-characterized reagents.We describe initial studies validating mouse models of IgG-and IgM-mediated alloimmune hemolysis. Thus, mRBCs from hGPA-Tg donors were transfused into non-Tg recipients that were passively immunized with IgG or IgM hGPA-specific monoclonal antibodies (mAbs). The clearance of the transfused mRBCs was quantified and the roles of complement and Fc␥ receptors were evaluated. Materials and methods AntibodiesPurified mAbs NaM10-2H12 (IgG3), NaM26-3F4 (IgG1), and NaM10-6G4 (IgG2a), which recognize peptide epitopes on the M and N forms of hGPA, 12 were purchased from EFS (Nantes, France). Hybridomas producing mAb 6A7, an IgG1 specific for a sialic acid-dependent epitope on M-type hGPA, 13-15 10F7, an IgG1 recognizing a nonpolymorphic epitope on hGPA, 13,14 and J11d, a rat IgM recognizing CD24 on mRBCs, 16,17...
Murine leukemia viruses (MuLV) induce leukemia through a multistage process, a critical step being the activation of oncogenes through provirus integration. Transcription elements within the long terminal repeats (LTR) are prime determinants of cell lineage specificity; however, the influence of other factors, including the Env protein that modulates cell tropism through receptor recognition, has not been rigorously addressed. The ability of 10A1-MuLV to use both PiT1 and PiT2 receptors has been implicated in its induction of blast cell leukemia. Here we show that restricting receptor usage of 10A1-MuLV to PiT2 results in loss of blast cell transformation capacity. However, the pathogenicity was unaltered when the env gene is exchanged with Moloney MuLV, which uses the Cat1 receptor. Significantly, the leukemic blasts express erythroid markers and consistently contain proviral integrations in the Fli1 locus, a target of Friend MuLV (F-MuLV) during erythroleukemia induction. Furthermore, an NB-tropic variant of 10A1 was unable to induce blast cell leukemia in C57BL/6 mice, which are also resistant to F-MuLV transformation. We propose that 10A1-and F-MuLV actually induce identical (erythro)blastic leukemia by a mechanism involving Fli1 activation and cooperation with inherent genetic mutations in susceptible mouse strains. Furthermore, we demonstrate that deletion of the Icsbp tumor suppressor gene in C57BL/6 mice is sufficient to confer susceptibility to 10A1-MuLV leukemia induction but with altered specificity. In summary, we validate the significance of the env gene in leukemia specificity and underline the importance of a complex interplay of cooperating oncogenes and/or tumor suppressors in determining the pathogenicity of MuLV variants.
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