RESUMO
Disorder of complement response is a significant pathogenic factor causing some autoimmune and inflammation diseases. The Ornithodoros moubata Complement Inhibitor (OmCI), a small 17 kDa natural protein, was initially extracted from soft tick salivary glands. The protein was found binding to complement C5 specifically, inhibiting the activation of the complement pathway, which is a successful therapeutic basis of complement-mediated diseases. However, a short half-life due to rapid renal clearance is a common limitation of small proteins for clinical application. In this study, we extended the half-life of OmCI by modifying it with fatty acid, which was a method used to improve the pharmacokinetics of native peptides and proteins. Five OmCI mutants were initially designed, and single-site cysteine mutation was introduced to each of them. After purification, four OmCI mutants were obtained that showed similar in vitro biological activities. Three mutants of them were subsequently coupled with different fatty acids by nucleophilic substitution. In total, 15 modified derivatives were screened and tested for anticomplement activity in vitro. The results showed that coupling with fatty acid would not significantly affect their complement-inhibitory activity (CH50 and AH50). OmCIT90C-CM02 and OmCIT90C-CM05 were validated as the applicable OmCI bioconjugates for further pharmacokinetic assessments, and both showed improved plasma half-life in mice compared with unmodified OmCI (15.86, 17.96 vs 2.57 h). In summary, our data demonstrated that OmCI conjugated with fatty acid could be developed as the potential long-acting C5 complement inhibitor in the clinic.
Assuntos
Complemento C5 , Ácidos Graxos , Ornithodoros , Animais , Ácidos Graxos/química , Camundongos , Complemento C5/antagonistas & inibidores , Desenho de Fármacos , Meia-Vida , Proteínas Inativadoras do Complemento/farmacologia , Proteínas Inativadoras do Complemento/química , Inativadores do Complemento/farmacologia , Inativadores do Complemento/farmacocinética , Inativadores do Complemento/química , HumanosRESUMO
As the number of patients living with kidney failure grows, the need also grows for kidney transplantation, the gold standard kidney replacement therapy that provides a survival advantage. This may result in an increased rate of transplantation from HLA-mismatched donors that increases the rate of antibody-mediated rejection (AMR), which already is the leading cause of allograft failure. Plasmapheresis, intravenous immunoglobulin therapy, anti-CD20 therapies (i.e., rituximab), bortezomib and splenectomy have been used over the years to treat AMR as well as to prevent AMR in high-risk sensitized kidney transplant recipients. Eculizumab and ravulizumab are monoclonal antibodies targeting the C5 protein of the complement pathway and part of the expanding field of anticomplement therapies, which is not limited to kidney transplant recipients, and also includes complement-mediated microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and ANCA-vasculitis. In this narrative review, we summarize the current knowledge concerning the pathophysiological background and use of anti-C5 strategies (eculizumab and ravulizumab) and C1-esterase inhibitor in AMR, either to prevent AMR in high-risk desensitized patients or to treat AMR as first-line or rescue therapy and also to treat de novo thrombotic microangiopathy in kidney transplant recipients.
Assuntos
Proteínas Inativadoras do Complemento , Transplante de Rim , Rim , Humanos , Transplante Homólogo , Transplante de Rim/efeitos adversos , Aloenxertos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controleRESUMO
Complement constitutes a major part of the innate immune system. The study of complement in human health has historically focused on infection risks associated with complement protein deficiencies; however, recent interest in the field has focused on overactivation of complement as a cause of immune injury and the development of anticomplement therapies to treat human diseases. The kidneys are particularly sensitive to complement injury, and anticomplement therapies for several kidney diseases have been investigated. Overactivation of complement can result from loss-of-function mutations in complement regulators; gain-of-function mutations in key complement proteins such as C3 and factor B; or autoantibody production, infection, or tissue stresses, such as ischemia and reperfusion, that perturb the balance of complement activation and regulation. Here, we provide a high-level review of the status of anticomplement therapies, with an emphasis on the transition from rare diseases to more common kidney diseases.
Assuntos
Nefropatias , Doenças Raras , Humanos , Doenças Raras/tratamento farmacológico , Doenças Raras/genética , Proteínas Inativadoras do Complemento , Nefropatias/tratamento farmacológico , Nefropatias/genética , MutaçãoRESUMO
BACKGROUND: Complement-mediated thrombotic microangiopathy (CM-TMA), also called atypical hemolytic uremic syndrome (aHUS), is a difficult-to-diagnose rare disease that carries severe morbidity and mortality. Anti-C5 monoclonal antibodies (aC5-mab) are standard treatments, but large studies and long-term data are scarce. Here, we report our single institution experience to augment the knowledge of CM-TMA treated with aC5-mab therapy. METHODS: We aimed to assess the short and long-term effects of aC5-mab in patients diagnosed with CM-TMA treated outside of a clinical trial. This was a retrospective study. We included all patients diagnosed with CM-TMA and treated with aC5-mab at our institution. There were no exclusion criteria. Endpoints included complete TMA response (CR) defined as normalization of hematological parameters and ≥25% improvement in serum creatinine (Cr) from baseline in patients with renal disease, relapse defined as losing the previously achieved CR, morbidity, adverse events, and survival. RESULTS: We found 28 patients with CM-TMA treated with aC5-mab. The median age was 50 years. Baseline laboratories: platelet counts 93 × 109 /L, hemoglobin 8.6 g/dL, lactate dehydrogenase 1326 U/L, serum Cr 4.7 mg/dL, and estimated glomerular filtration rate 19 mL/min. One individual was on renal replacement therapy (RRT) and 10 initiated RRT within 5 days of the first dose of aC5-mab. Genetic variants associated with CM-TMA included mutations in C3, CFB, CFH, CFHR1/3, CFI, and MCP. The mean duration of hospitalization was 24 days. The median time to initiation of aC5-mab was 10 days. Sixteen subjects received RRT. At the time of hospital discharge, 27 were alive, 14 remained on RRT, and 4 had a CR. At 6 months, 23 patients were alive, 18 continued aC5-mab, 8 remained on RRT, and 9 had a CR. At the last follow-up visit past 6 months, 20 were alive, 14 continued aC5-mab, 5 remained on RRT, 12 had a CR, and 1 was lost to follow-up. CONCLUSIONS: Our study provides real-world experience and insight into the long-term outcomes of CM-TMA treated with aC5-mab. Our findings validate that CM-TMA is an aggressive disease with significant morbidity and mortality, and confirm that aC5-mab is a relatively effective therapy for CM-TMA. Our study adds practical, real-world experience to the literature, but future research remains imperative.
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Proteínas Inativadoras do Complemento , Microangiopatias Trombóticas , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/genética , Proteínas do Sistema ComplementoRESUMO
Centrifugal partition chromatography in the pH-zone-refining mode was successfully applied to the separation of alkaloids from the crude extract of Corydalis decumbens. The experiment was performed with a two-phase solvent system composed of petroleum ether-ethyl acetate-ethanol-water (5:5:3:7, v/v/v/v) where triethylamine (10 mM) was added to the stationary phase and hydrochloric acid (10 mM) to the mobile phase. From 1.6 g of the crude extract, 43 mg protopine, 189 mg (+)-egenine, and 158 mg tetrahydropalmatine were obtained with a purity of 98.2%, 94.6%, and 96.7%, respectively. Tetrahydropalmatine showed an interesting anticomplement effect with CH50 0.11 and AP50 0.25 mg/mL, respectively. In a mechanistic study, tetrahydropalmatine interacted with C1, C3, C4, and C5 components in the complement activation cascade.
Assuntos
Alcaloides , Proteínas Inativadoras do Complemento , Corydalis , Corydalis/química , Distribuição Contracorrente/métodos , Alcaloides/farmacologia , Alcaloides/química , Solventes/química , Concentração de Íons de Hidrogênio , Misturas Complexas , Cromatografia Líquida de Alta PressãoRESUMO
BACKGROUND: Owing to the involvement of the overactivated complement system in acute lung injury (ALI) development, anticomplement components may attenuate ALI. Hedyotis diffusa is a traditional Chinese medicine for treating lung heat and its crude polysaccharides (HDP) exhibit significant anticomplement activity in vitro. PURPOSE: To obtain an anticomplement homogeneous polysaccharide from HDP and verify its therapeutic effect and mechanism on ALI. METHODS: Diethylaminoethyl-52 (DEAE-52) cellulose and gel permeation columns were used to isolate a homogeneous polysaccharide HD-PS-3, which was then characterized using nuclear magnetic resonance (NMR) and methylation analysis. In vitro, the anticomplement activities of HD-PS-3 through classical and alternative pathways were determined using a hemolytic test. The therapeutic effects of HDP and HD-PS-3 on ALI were evaluated in lipopolysaccharide (LPS) intratracheal instilled mice. Hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical staining were used to assess histological changes, measure cytokine levels, and evaluate the degree of complement component 3c (C3c) deposition and neutrophil infiltration, respectively. ELISA, western blotting, and immunofluorescence were used to analyze neutrophil extracellular trap (NET) formation. RESULTS: From HDP, 1.5 g of the homogeneous polysaccharide HD-PS-3 was obtained. HD-PS-3 was an acidic heteropolysaccharide with an acetyl group, which was composed of â4,6)-α-Glcp-(1â, â3,4)-α-Glcp-(1â, â4)-α-Glcp-(1â, â4,6)-α-Galp-(1â, â5)-α-Araf-(1â, α-Rhap-(1â, α-Araf-(1â, α-GlcpA-(1â, â4)-ß-Manp-(1â, ß-Manp-(1â and â3)-ß-Manp-(1â. The in vitro results suggest that HD-PS-3 exhibited anticomplement activity with CH50 and AP50 values of 115 ± 12 µg/ml and 307 ± 11 µg/ml, respectively. After confirming the efficacy of HDP (200 mg/kg) in attenuating lung injury, the effect of HD-PS-3 on ALI was also investigated. HD-PS-3 (75 and 150 mg/kg) attenuated LPS-induced ALI as well, evidenced by lung pathology, lung injury scores, protein concentration, leukocyte counts, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) contents in bronchoalveolar lavage fluid (BALF). Mechanistically, HD-PS-3 inhibited complement activation, manifested in reduced pulmonary C3c deposition in lung tissue and complement component 3a (C3a) content in BALF. Neutrophil recruitment was also reduced by HD-PS-3, with significantly reduced pulmonary neutrophil infiltration and lower levels of C-X-C motif chemokine ligand 1 (CXCL1) and myeloperoxidase (MPO) in BALF. In addition, HD-PS-3 reduced the levels of MPO-DNA complex in BALF, decreased citrullinated histone H3 (Cit H3) expression and NET formation (colocalization of MPO, Cit H3, and DNA) in lung tissue. CONCLUSION: An anticomplement homogeneous polysaccharide HD-PS-3 was isolated from H. diffusa. HD-PS-3 exhibited a therapeutic effect against ALI, and the mechanism might be related to its inhibitory effects on complement activation, neutrophil recruitment, and NET formation.
Assuntos
Lesão Pulmonar Aguda , Armadilhas Extracelulares , Hedyotis , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Quimiocinas/metabolismo , Complemento C3a/metabolismo , Complemento C3c/metabolismo , Proteínas Inativadoras do Complemento , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Histonas , Interleucina-6/metabolismo , Ligantes , Lipopolissacarídeos , Camundongos , Peroxidase/metabolismo , Polissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Two novel natural flavonoid substituted polysaccharides (MBAP-1 and MBAP-2) were obtained from Tamarix chinensis Lour. and characterized by HPGPC, methylation, ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MSn), and NMR analysis. The results showed that MBAP-1 was a homogenous heteropolysaccharide with a backbone of 4)-ß-d-Glcp-(1â and â3,4,6)-ß-d-Glcp-(1â. MBAP-2 was also a homogenous polysaccharide which possessed a backbone of â3)-α-d-Glcp-(1â, â4)-ß-d-Glcp-(1â and â3,4)-ß-d-Glcp-2-OMe-(1â. Both the two polysaccharides were substituted by quercetin and exhibited anticomplement activities in vitro. However, MBAP-1 (CH50: 0.075 ± 0.004 mg/mL) was more potent than MBAP-2 (CH50: 0.249 ± 0.006 mg/mL) and its reduced product, MBAP-1R (CH50: 0.207 ± 0.008 mg/mL), indicating that multiple monosaccharides and uronic acids might contribute to the anticomplement activity of the flavonoid substituted polysaccharides of T. chinensis. Furthermore, the antioxidant activity of MBAP-1 was also more potent than that of MBAP-2. In conclusion, these two flavonoid substituted polysaccharides from T. chinensis were found to be potential oxidant and complement inhibitors.
Assuntos
Flavonoides , Tamaricaceae , Proteínas Inativadoras do Complemento , Flavonoides/farmacologia , Peso Molecular , Polissacarídeos/química , Polissacarídeos/farmacologiaRESUMO
The complement system plays crucial roles in homeostasis and host defense against microbes. Deficiency of early complement cascade components has been associated with increased susceptibility to systemic lupus erythematosus (SLE), whereas excessive complement consumption is a hallmark of this disease. Although enhanced classical pathway activation by immune complexes was initially thought to be the main contributor to lupus nephritis (LN) pathogenesis, an increasing body of evidence has suggested the alternative and the lectin pathways are also involved. Therapeutic agents targeting complement activation have been used in LN patients and clinical trials are ongoing. We review the mechanisms by which complement system dysregulation contributes to renal injury in SLE and summarize the latest evidence on the use of anticomplement agents to manage this condition.
Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Proteínas Inativadoras do Complemento/uso terapêutico , Proteínas do Sistema Complemento , Humanos , Rim/patologia , Lúpus Eritematoso Sistêmico/complicaçõesRESUMO
Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents myriad questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anticomplement therapy trials either planned or under way, the National Kidney Foundation facilitated an all-virtual scientific workshop entitled "Improving Clinical Trials for Anti-Complement Therapies in Complement-Mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anticomplement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, participant risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.
Assuntos
Proteínas Inativadoras do Complemento , Nefropatias , Proteínas Inativadoras do Complemento/uso terapêutico , Proteínas do Sistema Complemento , Humanos , RimRESUMO
COVID-19 is characterized by virus-induced injury leading to multi-organ failure, together with inflammatory reaction, endothelial cell (EC) injury, and prothrombotic coagulopathy with thrombotic events. Complement system (C) via its cross-talk with the contact and coagulation systems contributes significantly to the severity and pathological consequences due to SARS-CoV-2 infection. These immunopathological mechanisms overlap in COVID-19 and pre-eclampsia (PE). Thus, mothers contracting SARS-CoV-2 infection during pregnancy are more vulnerable to developing PE. SARS-CoV-2 infection of ECs, via its receptor ACE2 and co-receptor TMPRSS2, can provoke endothelial dysfunction and disruption of vascular integrity, causing hyperinflammation and hypercoagulability. This is aggravated by bradykinin increase due to inhibition of ACE2 activity by the virus. C is important for the progression of normal pregnancy, and its dysregulation can impact in the form of PE-like syndrome as a consequence of SARS-CoV-2 infection. Thus, there is also an overlap between treatment regimens of COVID-19 and PE. C inhibitors, especially those targeting C3 or MASP-2, are exciting options for treating COVID-19 and consequent PE. In this review, we examine the role of C, contact and coagulation systems as well as endothelial hyperactivation with respect to SARS-CoV-2 infection during pregnancy and likely development of PE.
Assuntos
COVID-19/imunologia , Proteínas do Sistema Complemento/imunologia , Pré-Eclâmpsia/imunologia , Complicações Infecciosas na Gravidez/imunologia , COVID-19/fisiopatologia , Proteínas Inativadoras do Complemento/uso terapêutico , Endotélio/imunologia , Feminino , Humanos , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/prevenção & controle , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/fisiopatologia , SARS-CoV-2 , Trombose/imunologia , Tratamento Farmacológico da COVID-19RESUMO
To assess the relative contribution of opsonisation by antibodies, classical and alternative complement pathways to pneumococcal phagocytosis, we analyzed killing of pneumococci by human blood leukocytes collected from vaccine-naïve and PCV13-vaccinated subjects. With serotype 4 pneumococci as model, two different physiologic opsonophagocytosis assays based on either hirudin-anticoagulated whole blood or on washed cells from EDTA-anticoagulated blood reconstituted with active serum, were compared. Pneumococcal killing was measured in the presence of inhibitors targeting the complement components C3, C5, MASP-2, factor B or factor D. The two assay formats yielded highly consistent and comparable results. They highlighted the importance of alternative complement pathway activation for efficient opsonophagocytic killing in blood of vaccine-naïve subjects. In contrast, alternative complement pathway inhibition did not affect pneumococcal killing in PCV13-vaccinated individuals. Independent of amplification by the alternative pathway, even low capsule-specific antibody concentrations were sufficient to efficiently trigger classical pathway mediated opsonophagocytosis. In heat-inactivated or C3-inhibited serum, high concentrations of capsule-specific antibodies were required to trigger complement-independent opsonophagocytosis. Our findings suggest that treatment with alternative complement pathway inhibitors will increase susceptibility for invasive pneumococcal infection in non-immune subjects, but it will not impede pneumococcal clearance in vaccinated individuals.
Assuntos
Via Alternativa do Complemento , Proteínas do Sistema Complemento/imunologia , Opsonização , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Streptococcus pneumoniae/imunologia , Vacinação , Adulto , Idoso , Proteínas Inativadoras do Complemento/imunologia , Proteínas Inativadoras do Complemento/metabolismo , Proteínas do Sistema Complemento/metabolismo , Feminino , Interações Hospedeiro-Patógeno , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infecções Pneumocócicas/sangue , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/patogenicidadeRESUMO
The Sez6 family consists of Sez6, Sez6L, and Sez6L2. Its members are expressed throughout the brain and have been shown to influence synapse numbers and dendritic morphology. They are also linked to various neurological and psychiatric disorders. All Sez6 family members contain 2-3 CUB domains and 5 complement control protein (CCP) domains, suggesting that they may be involved in complement regulation. We show that Sez6 family members inhibit C3b/iC3b opsonization by the classical and alternative pathways with varying degrees of efficacy. For the classical pathway, Sez6 is a strong inhibitor, Sez6L2 is a moderate inhibitor, and Sez6L is a weak inhibitor. For the alternative pathway, the complement inhibitory activity of Sez6, Sez6L, and Sez6L2 all equaled or exceeded the activity of the known complement regulator MCP. Using Sez6L2 as the representative family member, we show that it specifically accelerates the dissociation of C3 convertases. Sez6L2 also functions as a cofactor for Factor I to facilitate the cleavage of C3b; however, Sez6L2 has no cofactor activity toward C4b. In summary, the Sez6 family are novel complement regulators that inhibit C3 convertases and promote C3b degradation.
Assuntos
Convertases de Complemento C3-C5/metabolismo , Complemento C3b/imunologia , Fibrinogênio/metabolismo , Proteínas de Membrana/metabolismo , Complemento C3b/metabolismo , Proteínas Inativadoras do Complemento/genética , Proteínas Inativadoras do Complemento/metabolismo , Via Alternativa do Complemento/efeitos dos fármacos , Via Clássica do Complemento/efeitos dos fármacos , Expressão Gênica , Humanos , Imuno-Histoquímica , Proteínas de Membrana/genética , Proteínas de Membrana/farmacologia , Proteólise , Proteínas Recombinantes de FusãoRESUMO
The Lymphocyte antigen-6 (Ly-6) superfamily has been considered to play an important role in the innate immunity of mammals. The functions of Ly-6 proteins are diverse since their low sequence homology. Currently, the function of Ly-6D, a member of Ly-6 family proteins, is completely unknown in teleost. In the present study, we identified and characterized a Ly-6D homologue (named PoLy-6D) from the teleost fish Paralichthys olivaceus and examined its immune function. PoLy-6D possesses a hydrophobic signal peptide, a LU domain including a conserved "LXCXXC" motif in N-terminus and a "CCXXXXCN" motif in C-terminus. Under normal physiological condition, PoLy-6D expression distributes in all the examined tissues, the highest three tissues are successively spleen, head kidney, and blood. When infected by extracellular and intracellular bacterial pathogens and viral pathogen, PoLy-6D expression was induced and the patterns vary with different types of microbial pathogens infection and different immune tissues. In vitro experiment showed recombinant PoLy-6D (rPoLy-6D) inhibited the lysis of rabbit red blood cells by serum and selectively improved bacterial survival in serum. After serum were treated by antibody of rPoLy-6D, bacteriostatic effect of serum was obviously enhanced. These results indicate the importance of PoLy-6D as a complement regulator. rPoLy-6D possessed the binding activity to multiple bacteria but did not exhibit antimicrobial activities. The interaction between rPoLy-6D and bacteria suggests that PoLy-6D is involved in host clearance of pathogens probably by serving as a receptor for pathogens. Overexpression of PoLy-6D in vivo promoted the host defense against invading E. piscicida. These findings add new insights into the regulation mechanism of the complement system in teleost and emphasize the importance of Ly-6D products for the control of pathogen infection.
Assuntos
Antígenos Ly/imunologia , Ativação do Complemento/imunologia , Proteínas Inativadoras do Complemento/metabolismo , Proteínas do Sistema Complemento/imunologia , Linguado/imunologia , Sequência de Aminoácidos , Animais , Antígenos Ly/genética , Sequência de Bases , Edwardsiella/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Imunidade Inata/imunologia , Fatores Imunológicos/imunologia , Domínios Proteicos , Alinhamento de Sequência , Análise de Sequência de DNA , Vírus/imunologiaRESUMO
Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here, we show that Susd4, a gene coding for a complement-related transmembrane protein, is expressed by many neuronal populations starting at the time of synapse formation. Constitutive loss-of-function of Susd4 in the mouse impairs motor coordination adaptation and learning, prevents long-term depression at cerebellar synapses, and leads to misregulation of activity-dependent AMPA receptor subunit GluA2 degradation. We identified several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, as SUSD4 binding partners. Our findings shed light on the potential role of SUSD4 mutations in neurodevelopmental diseases.
Assuntos
Proteínas Inativadoras do Complemento/genética , Aprendizagem , Proteínas de Membrana/genética , Atividade Motora/genética , Plasticidade Neuronal/genética , Animais , Proteínas Inativadoras do Complemento/metabolismo , Masculino , Proteínas de Membrana/metabolismo , CamundongosRESUMO
Intracerebral hemorrhage (ICH) is a significant cause of death and disability and current treatment is limited to supportive measures to reduce brain edema and secondary hematoma expansion. Current evidence suggests that the complement cascade is activated early after hemorrhage and contributes to brain edema/injury in multiple ways. The aim of this review is to summarize the most recent literature about the role of the complement cascade after ICH. Primary literature demonstrating complement mediated brain edema and neurologic injury through the membrane attack complex (MAC) as well as C3a and C5a are reviewed. Further, attenuation of brain edema and improved functional outcomes are demonstrated after inhibition of specific components of the complement cascade. Conversely, complement also plays a significant role in neurologic recovery after ICH and in other neurologic disorders. We conclude that the role of complement after ICH is complex. Understanding the role of complement after ICH is essential and may elucidate possible interventions to reduce brain edema and injury.
Assuntos
Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Hemorragia Cerebral/metabolismo , Ativação do Complemento/fisiologia , Proteínas do Sistema Complemento/metabolismo , Animais , Ácido Aurintricarboxílico/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/patologia , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/patologia , Ativação do Complemento/efeitos dos fármacos , Proteínas Inativadoras do Complemento/administração & dosagem , Proteínas do Sistema Complemento/agonistas , HumanosRESUMO
Little is known about the role of complement (C') in infections with highly prevalent circulating human coronaviruses such as OC43, a group of viruses of major public health concern. Treatment of OC43-infected human lung cells with human serum resulted in C3 deposition on their surfaces and generation of C5a, indicating robust C' activation. Real-time cell viability assays showed that in vitro C'-mediated lysis of OC43 infected cells requires C3, C5 and C6 but not C7, and was substantially delayed as compared to rapid C'-mediated killing of parainfluenza virus type 5 (PIV5)-infected cells. In cells co-infected with OC43 and PIV5, C'-mediated lysis was delayed, similar to OC43 infected cells alone, suggesting that OC43 infection induced dominant inhibitory signals. When OC43-infected cells were treated with human serum, their cell surfaces contained both Vitronectin (VN) and Clusterin (CLU), two host cell C' inhibitors that can alter membrane attack complex (MAC) formation and C'-mediated killing. VN and CLU were not bound to OC43-infected cells after treatment with antibody-depleted serum. Reconstitution experiments with purified IgG and VN showed that human antibodies are both necessary and sufficient for VN recruitment to OC43-infected lung cells-novel findings with implications for CoV pathogenesis.
Assuntos
Anticorpos/metabolismo , Clusterina/metabolismo , Proteínas Inativadoras do Complemento/metabolismo , Coronavirus Humano OC43/imunologia , Pulmão/virologia , Vitronectina/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Sobrevivência Celular/imunologia , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Proteínas do Sistema Complemento/metabolismo , Coronavirus Humano OC43/patogenicidade , Humanos , Pulmão/metabolismo , Vírus da Parainfluenza 5/imunologiaRESUMO
A new monoterpene glycoside named as pedivertoside D (1), together with 13 known compounds (2-14, resp.) were isolated from the whole plant of Pedicularis verticillata L. The new compound was identified as (2E,6E,5R)-5,8-dihydrooxy-2,6-dimethyl-3,7-octadienyl-ß-D-glucopyranoside by spectroscopic methods including 2 D-NMR techniques. The known compounds were determined spectroscopically and compared with previously reported spectral data. Compounds 6 and 9 exhibited anticomplementary effects against the classical pathway (CP) with CH50 values of 0.07 mM and 0.23 mM, respectively, which are plausible candidates for developing potent anti-complementary agents from this plant.
Assuntos
Glicosídeos/farmacologia , Monoterpenos/farmacologia , Pedicularis/química , Animais , Ativação do Complemento/efeitos dos fármacos , Proteínas Inativadoras do Complemento/farmacologia , Avaliação Pré-Clínica de Medicamentos , Eritrócitos/efeitos dos fármacos , Glicosídeos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Monoterpenos/química , OvinosRESUMO
The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I-III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies.
Assuntos
Inativadores do Complemento/administração & dosagem , Proteínas do Sistema Complemento/imunologia , Sistemas de Liberação de Medicamentos/tendências , Imunoterapia/tendências , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/terapia , Animais , Proteínas Inativadoras do Complemento/administração & dosagem , Proteínas Inativadoras do Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/imunologia , Imunoterapia/métodos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sinapses/efeitos dos fármacos , Sinapses/imunologiaAssuntos
Betacoronavirus , Proteínas Inativadoras do Complemento/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , COVID-19 , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Resultado do TratamentoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation driven mainly by high levels of interferon gamma. The clinical presentation of HLH can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have a simultaneous presentation of complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger). Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal replacement therapy, severe hypertension, serositis, and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement-mediated TMA. Patients with HLH and without TMA required ventilator support mainly due to CNS symptoms, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA. Ten patients received eculizumab for complement-mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab in addition to the interferon gamma blocker emapalumab had complete resolution of their TMA and survived. Our observations suggest co-activation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like refractory HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as an early institution of a brief course of complement blocking therapy in addition to HLH-targeted therapy may improve clinical outcomes in these patients.