RESUMO
Thromboembolism complicates disorders caused by immunoglobulin G (IgG)-containing immune complexes (ICs), but the underlying mechanisms are incompletely understood. Prior evidence indicates that induction of tissue factor (TF) on monocytes, a pivotal step in the initiation, localization, and propagation of coagulation by ICs, is mediated through Fcγ receptor IIa (FcγRIIa); however, the involvement of other receptors has not been investigated in detail. The neonatal Fc receptor (FcRn) that mediates IgG and albumin recycling also participates in cellular responses to IgG-containing ICs. Here we asked whether FcRn is also involved in the induction of TF-dependent factor Xa (FXa) activity by IgG-containing ICs by THP-1 monocytic cells and human monocytes. Induction of FXa activity by ICs containing IgG antibodies to platelet factor 4 (PF4) involved in heparin-induced thrombocytopenia (HIT), ß-2-glycoprotein-1 implicated in antiphospholipid syndrome, or red blood cells coated with anti-(α)-Rh(D) antibodies that mediate hemolysis in vivo was inhibited by a humanized monoclonal antibody (mAb) that blocks IgG binding to human FcRn. IgG-containing ICs that bind to FcγR and FcRn induced FXa activity, whereas IgG-containing ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an α-FcRn mAb prevented fibrin deposition after microvascular injury in a murine model of HIT in which human FcγRIIa was expressed as a transgene. These data implicate FcRn in TF-dependent FXa activity induced by soluble and cell-associated IgG-containing ICs. Antibodies to FcRn, now in clinical trials in warm autoimmune hemolytic anemia to lower IgG antibodies and IgG containing ICs may also reduce the risk of venous thromboembolism.
Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Heparina/toxicidade , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoglobulina G/metabolismo , Receptores Fc/metabolismo , Trombocitopenia/imunologia , Tromboplastina/metabolismo , Animais , Anticoagulantes/toxicidade , Complexo Antígeno-Anticorpo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Masculino , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Fator Plaquetário 4/genética , Fator Plaquetário 4/metabolismo , Receptores Fc/genética , Receptores Fc/imunologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Trombocitopenia/patologiaRESUMO
The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.
Assuntos
Albuminas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Receptores Fc/metabolismo , Acetaminofen/efeitos adversos , Acetaminofen/metabolismo , Animais , Bile/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cães , Feminino , Hepatócitos/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Homeostase , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores Fc/genética , Albumina Sérica Humana/genética , Albumina Sérica Humana/metabolismo , Transcitose/genéticaRESUMO
Increased baseline expression and lack of induction of interferon-stimulated genes (ISG) are strong negative predictors of therapeutic response to PegIFN/RBV in patients co-infected with HIV and hepatitis C virus (HCV). This study specifically addressed whether ISG-15 expression influences therapeutic responses in 20 HIV/HCV genotype-1 subjects undergoing HCV treatment. Non-responders had significantly higher baseline expression and selective induction of ISG-15 after IFN-α treatment relative to participants with sustained virological response. High baseline levels of ISG-15 were also associated with less induction of ISG with treatment. These results support a role for ISG-15 as a prognostic indicator and resistance factor to IFN-α.
Assuntos
Antivirais/uso terapêutico , Citocinas/genética , Expressão Gênica/efeitos dos fármacos , Infecções por HIV/genética , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ubiquitinas/genética , Adulto , Coinfecção , Citocinas/imunologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1 , Hepatite C Crônica/genética , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/metabolismo , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Ubiquitinas/imunologiaRESUMO
We investigated whether interferon-inducible genes (IFIGs) with known anti-human immunodeficiency virus (HIV) activity in vitro were associated with in vivo virological response in HIV infection. Nine untreated HIV-1-infected volunteers were treated for 12 weeks with peginterferon alfa-2a. A subset of IFIGs (23 of 47) increased compared with baseline through 6 weeks beyond therapy, and 10 of the 23 IFIGs significantly inversely correlated (r = -0.7; P < .05) with virological response. The strength of peginterferon alfa-2a-induced IFIG response significantly correlated with declines in HIV load during treatment (r(2) = 0.87, p = .003). This study links HIV virological response to a specific IFIG subset, a potential prognostic indicator in peginterferon alfa-2a-treated patients with HIV infection.
Assuntos
Antivirais/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/genética , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Humanos , Leucócitos Mononucleares/metabolismo , RNA Viral/genética , RNA Viral/isolamento & purificação , Proteínas Recombinantes/administração & dosagem , Carga ViralRESUMO
During preclinical development of neuroprotective antiaddiction therapeutic monoclonal antibodies (mAbs) against phencyclidine (PCP) and (+)-methamphetamine, we discovered novel, gestation stage-specific changes in mAb disposition spanning the entire reproductive cycle of female rats. Each pharmacological change was independent of mAb dose and antigen target but was precisely coincident with transitions between the gestational trimesters, parturition, and lactation periods of the female reproductive cycle. Whereas anti-PCP mAb6B5 terminal elimination half-life (t(1/2λz)) in nonpregnant females was 6.6 ± 1.6 days, the mAb6B5 t(1/2λz) significantly changed to 3.7 ± 0.4 days, then 1.4 ± 0.1 days, then 3.0 ± 0.4 days in the second trimester, third trimester, and postpartum periods, respectively (p < 0.05 for each change). Initially, these evolving changes in mAb6B5 clearance (3.3-fold), distribution volume (1.8-fold), and elimination half-life (4.7-fold) affected our ability to sustain sufficient mAb6B5 levels to sequester PCP in the bloodstream. However, understanding the mechanisms underlying each transition allowed development of an adaptive mAb-dosing paradigm, which substantially reduced PCP levels in dam brains and fetuses throughout pregnancy. These mAb functional studies also revealed that antidrug mAbs readily cross the placenta before syncytiotrophoblast barrier maturation, demonstrating the dynamic nature of mAb pharmacokinetics in pregnancy and the importance of maintaining maternal mAb levels. These studies provide the first preclinical pregnancy model in any species for chronic mAb dosing and could have important implications for the use of antibody therapies involving blood organ barriers (such as addiction) or other chronic diseases in women of childbearing age (e.g., irritable bowel diseases, multiple sclerosis, breast cancer, rheumatoid arthritis).
Assuntos
Anticorpos Monoclonais/farmacocinética , Metanfetamina/imunologia , Fenciclidina/imunologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Feminino , Feto/metabolismo , Troca Materno-Fetal , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) γ-receptors (FcγRs). Of these, the highly prevalent FcγRIIa (CD32a) histidine (H)-131 variant (CD32aH) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32aR) variant, CD32aH more avidly bound human (h) IgG1 IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32aH. Conversely, FcRn induced responses to IgG IC independently of classical FcγR, but optimal responses required FcRn and FcγR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn's direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32aH variant, providing a novel mechanism for its disease association.
Assuntos
Autoimunidade/imunologia , Antígenos de Histocompatibilidade Classe I/fisiologia , Imunoglobulina G/imunologia , Receptores Fc/fisiologia , Imunidade Adaptativa/imunologia , Animais , Artrite Reumatoide/imunologia , Suscetibilidade a Doenças , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Fc/imunologia , Receptores de IgG/imunologiaRESUMO
Antibodies are essential components of an adaptive immune response. Immunoglobulin G (IgG) is the most common type of antibody found in circulation and extracellular fluids. Although IgG alone can directly protect the body from infection through the activities of its antigen binding region, the majority of IgG immune functions are mediated via proteins and receptors expressed by specialized cell subsets that bind to the fragment crystallizable (Fc) region of IgG. Fc gamma (γ) receptors (FcγR) belong to a broad family of proteins that presently include classical membrane-bound surface receptors as well as atypical intracellular receptors and cytoplasmic glycoproteins. Among the atypical FcγRs, the neonatal Fc receptor (FcRn) has increasingly gained notoriety given its intimate influence on IgG biology and its ability to also bind to albumin. FcRn functions as a recycling or transcytosis receptor that is responsible for maintaining IgG and albumin in the circulation, and bidirectionally transporting these two ligands across polarized cellular barriers. More recently, it has been appreciated that FcRn acts as an immune receptor by interacting with and facilitating antigen presentation of peptides derived from IgG immune complexes (IC). Here we review FcRn biology and focus on newer advances including how emerging FcRn-targeted therapies may affect the immune responses to IgG and IgG IC.
Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoglobulina G/metabolismo , Placenta/imunologia , Receptores Fc/metabolismo , Animais , Complexo Antígeno-Anticorpo/imunologia , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Tolerância Imunológica , Imunidade , Imunoglobulina G/imunologia , Gravidez , Conformação Proteica , Transporte Proteico , Receptores Fc/imunologiaRESUMO
Lymphomas arising in the adrenal are rare, and to our knowledge, 2 cases of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (DLBCL) in an adrenal pseudocyst have been reported. We report an incidental EBV-positive DLBCL arising in an adrenal pseudocyst in a 58-year-old man with a 7-year history of lymphoplasmacytic lymphoma (LPL). The DLBCL was present in the fibrinous exudate, while the LPL resided in the cyst wall. The patient underwent de-roofing of the same cyst 3 years previously; review of histology revealed foci of LPL in the cyst wall, but not of DLBCL. There have been reports of similar microscopic EBV-positive DLBCLs within enclosed cystic spaces. However, all these cases were incidental extranodal primary DLBCLs. Since residual LPL was present alongside DLBCL, with similar light chain restriction, we propose that this may represent transformation, rather than a de novo primary EBV-driven lymphoma.
Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Primárias Múltiplas/patologia , Macroglobulinemia de Waldenstrom/patologia , Infecções por Vírus Epstein-Barr/complicações , Humanos , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-IdadeRESUMO
Lymphangiomas are neoplastic lesions derived from lymphatic endothelium. They are largely encountered in the head and neck region. We describe a case of an adrenal lymphangioma, an extremely uncommon cystic lesion of the adrenal and discuss the differential diagnosis, clinical, imaging, histopathologic and immunophenotypic features of this lesion.
Assuntos
Dor Abdominal/diagnóstico , Intoxicação por Chumbo/etiologia , Preparações de Plantas/efeitos adversos , Adulto , Terapia por Quelação , Diagnóstico Diferencial , Feminino , Humanos , Chumbo/análise , Intoxicação por Chumbo/diagnóstico , Intoxicação por Chumbo/terapia , Mercúrio/análise , Preparações de Plantas/análiseRESUMO
Brown recluse spider bites may cause severe local and systemic morbidity, but data regarding morbidity in children are limited. This study reviewed inpatient medical records (n = 26; 10 years) with a discharge diagnosis of "spider bite" from a tertiary pediatric hospital. The majority (85%) of children had an inflammatory response accompanying necrosis, usually with signs of secondary cellulitis (77%). Hemolytic anemia (50%), rhabdomyolysis (27%), and acute renal failure (12%) were the most prevalent systemic effects. Hemolytic anemia was bimodal in distribution relative to the time-of-onset of the bite (early, 2.2 ± 0.4; late, 6.9 ± 1.5 days postbite, respectively; P = .004). Although no fatalities occurred in the population, 65% of children had major morbidity, including wound complications requiring surgical care and acute orbital compartment syndrome. The findings emphasize the importance of anticipatory patient/family education for outpatients and careful monitoring for systemic morbidity in inpatients. Timely and appropriate supportive care should yield favorable outcomes in most cases.