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2.
J Neuroimmunol ; 371: 577948, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35964450

RESUMO

The aim of this investigation was to determine if particular immunoglobulin GM (γ marker) alleles and genotypes were associated with Parkinson's disease (PD) and whether they contributed to the interindividual differences in the level of antibodies to herpes simplex virus type 1 (HSV1), which has been implicated in PD pathology. Using a case-control study design, 94 PD patients and 157 controls were characterized for anti-HSV1 IgG antibodies and genotyped for GM alleles expressed on IgG1 (3,17) and IgG2 (23 +, 23-). The homozygosity for the GM 3 and GM 23 alleles was significantly associated with susceptibility to PD (p = 0.004, 0.018, respectively). Also, GM 23 genotypes were significantly associated with anti-HSV1 IgG antibody levels in patients (p = 0.0021), but not in controls. These results suggest that GM genes may act as effect modifiers of the reported HSV1-PD association.


Assuntos
Herpesvirus Humano 1 , Doença de Parkinson , Anticorpos Antivirais , Estudos de Casos e Controles , Humanos , Imunidade Humoral , Imunoglobulina G , Alótipos Gm de Imunoglobulina/genética , Cadeias gama de Imunoglobulina , Doença de Parkinson/genética
3.
Clin Transl Med ; 11(7): e463, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34323424

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA), a degenerative vascular pathology characterized by permanent dilation of the aorta, is considered a chronic inflammatory disease involving innate/adaptive immunity. However, the functional role of antibody-dependent immune response against antigens present in the damaged vessel remains unresolved. We hypothesized that engagement of immunoglobulin G (IgG) Fc receptors (FcγR) by immune complexes (IC) in the aortic wall contributes to AAA development. We therefore evaluated FcγR expression in AAA lesions and analysed whether inhibition of FcγR signaling molecules (γ-chain and Syk kinase) influences AAA formation in mice. METHODS: FcγR gene/protein expression was assessed in human and mouse AAA tissues. Experimental AAA was induced by aortic elastase perfusion in wild-type (WT) mice and γ-chain knockout (γKO) mice (devoid of activating FcγR) in combination with macrophage adoptive transfer or Syk inhibitor treatment. To verify the mechanisms of FcγR in vitro, vascular smooth muscle cells (VSMC) and macrophages were stimulated with IgG IC. RESULTS: FcγR overexpression was detected in adventitia and media layers of human and mouse AAA. Elastase-perfused γKO mice exhibited a decrease in AAA incidence, aortic dilation, elastin degradation, and VSMC loss. This was associated with (1) reduced infiltrating leukocytes and immune deposits in AAA lesions, (2) inflammatory genes and metalloproteinases downregulation, (3) redox balance restoration, and (4) converse phenotype of anti-inflammatory macrophage M2 and contractile VSMC. Adoptive transfer of FcγR-expressing macrophages aggravated aneurysm in γKO mice. In vitro, FcγR deficiency attenuated inflammatory gene expression, oxidative stress, and phenotypic switch triggered by IC. Additionally, Syk inhibition prevented IC-mediated cell responses, reduced inflammation, and mitigated AAA formation. CONCLUSION: Our findings provide insight into the role and mechanisms mediating IgG-FcγR-associated inflammation and aortic wall injury in AAA, which might represent therapeutic targets against AAA disease.


Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Receptores de IgG/metabolismo , Animais , Complexo Antígeno-Anticorpo/efeitos adversos , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/prevenção & controle , Modelos Animais de Doenças , Humanos , Cadeias gama de Imunoglobulina/genética , Cadeias gama de Imunoglobulina/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Estresse Oxidativo , Elastase Pancreática/efeitos adversos , Pirimidinas/uso terapêutico , Receptores de IgG/genética , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo
4.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33573068

RESUMO

We aimed to characterize the salivary protein components and identify biomarkers in patients with systemic lupus erythematosus (SLE). A proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry was performed to determine the alterations of salivary proteins between patients with SLE and healthy controls, and the concentrations of the candidate proteins were measured through Western blot analysis and the enzyme-linked immunosorbent assay. The 10 differentially expressed protein spots were immunoglobulin gamma-3 chain C region (IGHG3), immunoglobulin alpha-1 chain C region, protein S100A8, lactoferrin, leukemia-associated protein 7, and 8-oxoguanine DNA glycosylase. The patients with SLE exhibited enhanced salivary IGHG3 (3.9 ± 2.15 pg/mL) and lactoferrin (4.7 ± 1.8 pg/mL) levels compared to patients with rheumatoid arthritis (1.8 ± 1.01 pg/mL and 3.2 ± 1.6 pg/mL, respectively; p < 0.001 for both) or healthy controls (2.2 ± 1.64 pg/mL and 2.2 ± 1.7 pg/mL, respectively; p < 0.001 for both). The salivary IGHG3 levels correlated with the erythrocyte sedimentation rate (r = 0.26, p = 0.01), anti-double-stranded DNA (dsDNA) antibody levels (r = 0.25, p = 0.01), and nephritis (r = 0.28, p = 0.01). The proteomic analysis revealed that the salivary IGHG3 levels were associated with SLE and lupus disease activity, suggesting that salivary IGHG3 may be a promising noninvasive biomarker for SLE.


Assuntos
Imunoglobulina G/análise , Cadeias gama de Imunoglobulina/análise , Lúpus Eritematoso Sistêmico/diagnóstico , Saliva/química , Adulto , Biomarcadores/análise , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
MAbs ; 12(1): 1829334, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33025844

RESUMO

A major asset of many monoclonal antibody (mAb)-based biologics is their persistence in circulation. The MHC class I family Fc receptor, FCGRT, is primarily responsible for this extended pharmacokinetic behavior. Engagement of FCGRT with the crystallizable fragment (Fc) domain protects IgG from catabolic elimination, thereby extending the persistence and bioavailability of IgG and related Fc-based biologics. There is a need for reliable in vivo models to facilitate the preclinical development of novel IgG-based biologics. FcRn-humanized mice have been widely accepted as translationally relevant surrogates for IgG-based biologics evaluations. Although such FCGRT-humanized mice, especially the mouse strain, B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr (abbreviated Tg32), have been substantially validated for modeling humanized IgG-based biologics, there is a recognized caveat - they lack an endogenous source of human IgG that typifies the human competitive condition. Here, we used CRISPR/Cas9-mediated homology-directed repair to equip the hFCGRT Tg32 strain with a human IGHG1 Fc domain. This replacement now results in mice that produce human IgG1 Fc-mouse IgG Fab2 chimeric antibodies at physiologically relevant levels, which can be further heightened by immunization. This endogenous chimeric IgG1 significantly dampens the serum half-life of administered humanized mAbs in an hFCGRT-dependent manner. Thus, such IgG1-Fc humanized mice may provide a more physiologically relevant competitive hFCGRT-humanized mouse model for the preclinical development of human IgG-based biologics.


Assuntos
Anticorpos Monoclonais Humanizados , Antígenos de Histocompatibilidade Classe I , Imunização , Fragmentos Fc das Imunoglobulinas , Cadeias gama de Imunoglobulina , Receptores Fc , Animais , Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Cadeias gama de Imunoglobulina/genética , Cadeias gama de Imunoglobulina/imunologia , Camundongos , Camundongos Transgênicos , Receptores Fc/genética , Receptores Fc/imunologia
6.
Klin Onkol ; 33(4): 282-285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894957

RESUMO

BACKGROUND: Gamma-heavy chain disease is a rare disease, described so far in approximately 150 cases. The aim of this work was laboratory dia-gnostics of immunoglobulin heavy chain disease. MATERIALS AND METHODS: A 60-year-old patient was referred to the University Hospital in Ostrava for suspected marginal zone lymphoma from gastric bio-psy. Staging examinations including bone marrow trepanobio-psy and PET/CT were added; special examinations required serum protein electrophoresis, immunofixation electrophoresis, determination of polyclonal immunoglobulins, free light chains, and immunoglobulin heavy/light chain pairs. Isoelectric focusing in agarose gel followed by affinity immunoblotting and SDS electrophoresis was added due to unclear findings. RESULTS: 0.1 % of plasma cells were found in the bone marrow, of which 87 % were clonal (pathological) plasma cells, followed by the cyt cytotype LAMBDA + CD38 + CD138 + CD45 + CD19 + CD56- CD27 + CD81- CD117-. Monoclonal heavy chains were found in the patients serum. No monoclonal immunoglobulin heavy or light chains were detected in urine. The PET/CT examination showed generalized lymphadenopathy, splenomegaly and inhomogeneous accumulation of fluorodeoxyglucose in axillary and appendicular skeleton, but without the presence of typical osteolytic lesions. CONCLUSION: Monoclonal heavy chains of immunoglobulins are a rare disease. In contrast to the detection of a complete paraprotein molecule, additional methods must be used to confirm them. The finding of monoclonal heavy chain gamma in the serum of the study patient is related to the presence of marginal zone lymphoma, which was proven from a gastric bio-psy. The study was supported by the project of MH CZ - DRO - FNOs /2017 (Biobank in Teaching Hospital Ostrava) The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.


Assuntos
Doença das Cadeias Pesadas/diagnóstico , Cadeias gama de Imunoglobulina/sangue , Doença das Cadeias Pesadas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
10.
Sci Rep ; 10(1): 318, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941975

RESUMO

Protein glycosylation is known to be involved in biological progresses such as cell recognition, growth, differentiation, and apoptosis. Fucosylation of glycoproteins plays an important role for structural stability and function of N-linked glycoproteins. Although many of biological and clinical studies of protein fucosylation by fucosyltransferases has been reported, structural classification of fucosylated N-glycoproteins such as core or outer isoforms remains a challenge. Here, we report for the first time the classification of N-glycopeptides as core- and outer-fucosylated types using tandem mass spectrometry (MS/MS) and machine learning algorithms such as the deep neural network (DNN) and support vector machine (SVM). Training and test sets of more than 800 MS/MS spectra of N-glycopeptides from the immunoglobulin gamma and alpha 1-acid-glycoprotein standards were selected for classification of the fucosylation types using supervised learning models. The best-performing model had an accuracy of more than 99% against manual characterization and area under the curve values greater than 0.99, which were calculated by probability scores from target and decoy datasets. Finally, this model was applied to classify fucosylated N-glycoproteins from human plasma. A total of 82N-glycopeptides, with 54 core-, 24 outer-, and 4 dual-fucosylation types derived from 54 glycoproteins, were commonly classified as the same type in both the DNN and SVM. Specifically, outer fucosylation was dominant in tri- and tetra-antennary N-glycopeptides, while core fucosylation was dominant in the mono-, bi-antennary and hybrid types of N-glycoproteins in human plasma. Thus, the machine learning methods can be combined with MS/MS to distinguish between different isoforms of fucosylated N-glycopeptides.


Assuntos
Fucose/análise , Cadeias gama de Imunoglobulina/metabolismo , Aprendizado de Máquina , Espectrometria de Massas em Tandem/métodos , Sequência de Aminoácidos , Sequência de Carboidratos , Cromatografia Líquida de Alta Pressão , Glicopeptídeos/análise , Glicopeptídeos/química , Glicopeptídeos/metabolismo , Glicosilação , Humanos
12.
Transplantation ; 104(4): 715-723, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31764762

RESUMO

BACKGROUND: Humanized immune system immunodeficient mice have been extremely useful for the in vivo analyses of immune responses in a variety of models, including organ transplantation and graft versus host disease (GVHD) but they have limitations. Rat models are interesting complementary alternatives presenting advantages over mice, such as their size and their active complement compartment. Immunodeficient rats have been generated but human immune responses have not yet been described. METHODS: We generated immunodeficient Rat Rag-/- Gamma chain-/- human signal regulatory protein alpha-positive (RRGS) rats combining Rag1 and Il2rg deficiency with the expression of human signal regulatory protein alpha, a negative regulator of macrophage phagocytosis allowing repression of rat macrophages by human CD47-positive cells. We then immune humanized RRGS animals with human peripheral blood mononuclear cells (hPBMCs) to set up a human acute GVHD model. Treatment of GVHD was done with a new porcine antihuman lymphocyte serum active through complement-dependent cytotoxicity. We also established a tumor xenograft rejection model in these hPBMCs immune system RRGS animals by subcutaneous implantation of a human tumor cell line. RESULTS: RRGS animals receiving hPBMCs showed robust and reproducible reconstitution, mainly by T and B cells. A dose-dependent acute GVHD process was observed with progressive weight loss, tissue damage, and death censoring. Antihuman lymphocyte serum (L1S1) antibody completely prevented acute GVHD. In the human tumor xenograft model, detectable tumors were rejected upon hPBMCs injection. CONCLUSIONS: hPBMC can be implanted in RRGS animals and elicit acute GVHD or rejection of human tumor cells and these are useful models to test new immunotherapies.


Assuntos
Antígenos de Diferenciação/imunologia , Proteínas de Homeodomínio/imunologia , Hospedeiro Imunocomprometido , Cadeias gama de Imunoglobulina/imunologia , Síndromes de Imunodeficiência/imunologia , Leucócitos Mononucleares/transplante , Receptores Imunológicos/imunologia , Animais , Antígenos de Diferenciação/genética , Soro Antilinfocitário/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Cadeias gama de Imunoglobulina/genética , Síndromes de Imunodeficiência/genética , Leucócitos Mononucleares/imunologia , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores Imunológicos/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Clin Exp Hematop ; 59(4): 196-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31866621

RESUMO

Gamma heavy chain disease (γ-HCD) is a rare B-cell neoplasm that produces a truncated immunoglobulin γ-heavy chain lacking the light chain. The clinical features of γ-HCD are heterogeneous, resembling different types of B-cell lymphomas. Although rheumatoid arthritis (RA) is one of the common underlying diseases of γ-HCD, the therapeutic modality for RA has changed greatly in recent years; therefore, γ-HCD as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) should be taken into consideration. Here, we report such a γ-HCD case. A 69-year-old female was admitted because of fever, multiple lymph node swelling in the abdominal cavity, and peritoneal effusion. She had been treated using methotrexate for RA for 14 years, and using infliximab and adalimumab for Crohn's disease for one year. The serum concentration of IgG was 3,525 mg/dL, which was revealed to be monoclonal IgG lacking the light chain by rocket immunoselection assay. CD19+/CD20-/smκ-/smλ- large abnormal lymphocytes were observed in the peritoneal fluid, which were demonstrated to be clonal B-cells by PCR examination. Discontinuation of methotrexate did not improve her condition and she died of pneumonia. Many abnormal lymphocytes positive for IgG and EBER but negative for the light chain were found on immunohistological examination of necropsy specimens from the spleen and bone marrow.


Assuntos
Artrite Reumatoide , Neoplasias Hematológicas , Cadeias gama de Imunoglobulina/metabolismo , Síndromes de Imunodeficiência , Linfoma de Células B , Metotrexato/efeitos adversos , Proteínas de Neoplasias/metabolismo , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Evolução Fatal , Feminino , Neoplasias Hematológicas/induzido quimicamente , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Síndromes de Imunodeficiência/induzido quimicamente , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Linfoma de Células B/induzido quimicamente , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Metotrexato/administração & dosagem , Pessoa de Meia-Idade
14.
PLoS One ; 14(8): e0221034, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430311

RESUMO

Several laboratories have created rat basophil leukemia (RBL) cell lines stably transfected with the human high affinity IgE receptor (FcεRIH). More recently, humanized RBL cell lines saw the introduction of reporter genes such as luciferase (RS-ATL8) and DsRed (RBL NFAT-DsRed). These reporters are more sensitive than their parental non-reporter humanized RBL cell lines. However, no studies so far have addressed the levels of FcεRIH surface expression on humanized RBL cell lines. This is a critical parameter, as it determines the ability of these cells to be efficiently sensitized with human IgE, hence it should affect the sensitivity of the cell assay-a critical parameter for any diagnostic application. Our purpose was to assess and compare the levels of expression of the transfected FcεRIH chain in humanized RBL cell lines. We compared surface levels of FcεRIαH by flow cytometry, using a fluorescently labelled monoclonal antibody (CRA-1/AER-37) and determined receptor numbers using calibration microspheres. FcεRIαH copy numbers were assessed by qPCR, and the sequence verified. Transfection with FcεRIγH cDNA was assessed for its ability to increase FcεRIαH expression in the NFAT-DsRed reporter. While both SX-38 and RS-ATL8 expressed about 500.000 receptors/cell, RBL 703-21 and NFAT-DsRed had approximately 10- to 30-fold lower FcεRIαH expression, respectively. This was neither related to FcεRIH gene copy numbers, nor to differences in steady state mRNA levels, as determined by qPCR and RT-qPCR, respectively. Instead, FcεRIαH surface expression appeared to correlate with the co-expression of FcεRIγH. Stable transfection of NFAT-DsRed cells with pBJ1 neo-huFcεRI gamma, which constitutively expresses FcεRIγH, increased FcεRIαH chain expression levels. Levels of FcεRIαH surface expression vary greatly between humanized RBL reporter cell lines. This difference will affect the sensitivity of the reporter system when used for diagnostic purposes.


Assuntos
Dosagem de Genes , Genes de Cadeia Pesada de Imunoglobulina/genética , Cadeias gama de Imunoglobulina/genética , Leucemia Basofílica Aguda/genética , Receptores de IgE/genética , Animais , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Genes Reporter/genética , Cadeias gama de Imunoglobulina/metabolismo , Leucemia Basofílica Aguda/patologia , Ratos , Receptores de IgE/metabolismo , Transfecção
15.
Front Immunol ; 10: 1161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214166

RESUMO

Even though immunoglobulins are critical for immune responses and human survival, the diversity of the immunoglobulin heavy chain gene (IGH) is poorly known and mostly characterized only by serological methods. Moreover, this genomic region is not well-covered in genomic databases and genome-wide association studies due to particularities that impose technical difficulties for its analysis. Therefore, the IGH gene has never been systematically sequenced across populations. Here, we deliver an unprecedented and comprehensive characterization of the diversity of the IGHG1, IGHG2, and IGHG3 gene segments, which encode the constant region of the most abundant circulating immunoglobulins: IgG1, IgG2, and IgG3, respectively. We used Sanger sequencing to analyze 357 individuals from seven different Brazilian populations, including five Amerindian, one Japanese-descendant and one Euro-descendant population samples. We discovered 28 novel IGHG alleles and provided evidence that some of them may have been originated by gene conversion between common alleles of different gene segments. The rate of synonymous substitutions was significantly higher than the rate of the non-synonymous substitutions for IGHG1 and IGHG2 (p = 0.01 and 0.03, respectively), consistent with purifying selection. Fay and Wu's test showed significant negative values for most populations (p < 0.001), which indicates that positive selection in an adjacent position may be shaping IGHG variation by hitchhiking of variants in the vicinity, possibly the regions that encode the Ig variable regions. This study shows that the variation in the IGH gene is largely underestimated. Therefore, exploring its nucleotide diversity in populations may provide valuable information for comprehension of its evolution, its impact on diseases and vaccine research.


Assuntos
Alelos , Conversão Gênica , Genes de Cadeia Pesada de Imunoglobulina , Variação Genética , Genética Populacional , Cadeias gama de Imunoglobulina/genética , Seleção Genética , Brasil/epidemiologia , Frequência do Gene , Geografia , Haplótipos , Humanos , Alótipos Gm de Imunoglobulina/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
18.
Mol Vis ; 24: 759-766, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581282

RESUMO

Purpose: To identify retinal protein changes that mediate beneficial effects of intravitreal bevacizumab in experimental branch retinal vein occlusion (BRVO). Methods: In six Danish Landrace pigs, BRVO was induced with argon laser in both eyes. After BRVO was induced, the right eye of each animal was given an intravitreal injection of bevacizumab while the left eye was treated with saline water. The retinas were collected 15 days after BRVO, and differentially expressed proteins were analyzed with tandem mass tags-based mass spectrometry. Validation of statistically significantly changed proteins was performed with immunohistochemistry and western blotting. Results: Fluorescein angiography showed no recanalization of the occluded vessels. A total of 4,013 proteins were successfully identified and quantified. Nine proteins were statistically significantly changed following bevacizumab intervention. In experimental BRVO, bevacizumab treatment resulted in upregulation of transthyretin (TTR) and pantothenate kinase 3. Bevacizumab downregulated protocadherin 7, protein FAM192A, and ATP synthase protein 8. Immunohistochemistry revealed that TTR was highly abundant in the choroid following bevacizumab intervention. Conclusions: Bevacizumab intervention in experimental BRVO resulted in an increased level of TTR. This is the second study in which we showed an increased retinal level of TTR following anti-vascular endothelial growth factor (VEGF) intervention in experimental BRVO. We hypothesize that there is an interaction between TTR and VEGF and that bevacizumab may exert a beneficial effect on the retina by upregulating TTR.


Assuntos
Inibidores da Angiogênese/farmacologia , Bevacizumab/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Pré-Albumina/genética , Retina/efeitos dos fármacos , Oclusão da Veia Retiniana/tratamento farmacológico , Animais , Caderinas/antagonistas & inibidores , Caderinas/genética , Caderinas/metabolismo , Corioide/irrigação sanguínea , Corioide/diagnóstico por imagem , Corioide/efeitos dos fármacos , Corioide/metabolismo , Angiofluoresceinografia , Perfilação da Expressão Gênica , Humanos , Cadeias gama de Imunoglobulina/genética , Cadeias gama de Imunoglobulina/metabolismo , Cadeias kappa de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/metabolismo , Injeções Intravítreas , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , ATPases Mitocondriais Próton-Translocadoras/genética , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pré-Albumina/agonistas , Pré-Albumina/metabolismo , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Oclusão da Veia Retiniana/diagnóstico por imagem , Oclusão da Veia Retiniana/genética , Oclusão da Veia Retiniana/patologia , Suínos
19.
Front Immunol ; 9: 2202, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319646

RESUMO

Nano-antibodies possess great potential in many applications. However, they are naturally derived from heavy chain-only antibodies (HcAbs), which lack light chains and the CH1 domain, and are only found in camelids and sharks. In this study, we investigated whether the precise genetic removal of the CH1 exon of the γ1 gene enabled the production of a functional heavy chain-only IgG1 in mice. IgG1 heavy chain dimers lacking associated light chains were detected in the sera of the genetically modified mice. However, the genetic modification led to decreased expression of IgG1 but increased expression of other IgG subclasses. The genetically modified mice showed a weaker immune response to specific antigens compared with wild type mice. Using a phage-display approach, antigen-specific, single domain VH antibodies could be screened from the mice but exhibited much weaker antigen binding affinity than the conventional monoclonal antibodies. Although the strategy was only partially successful, this study confirms the feasibility of producing desirable nano-bodies with appropriate genetic modifications in mice.


Assuntos
Anticorpos Monoclonais/imunologia , Cadeias gama de Imunoglobulina/imunologia , Engenharia de Proteínas , Anticorpos de Domínio Único/imunologia , Animais , Anticorpos Monoclonais/genética , Éxons/genética , Éxons/imunologia , Estudos de Viabilidade , Regiões Constantes de Imunoglobulina/genética , Regiões Constantes de Imunoglobulina/imunologia , Cadeias gama de Imunoglobulina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Biblioteca de Peptídeos , Domínios Proteicos/genética , Domínios Proteicos/imunologia , Anticorpos de Domínio Único/genética
20.
J Dermatol ; 45(10): 1211-1215, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30035313

RESUMO

Heavy-chain deposition disease (HCDD) is characterized by tissue deposits of a truncated monoclonal immunoglobulin heavy-chain (HC) on basement membranes. Diagnosis is usually made on kidney biopsy, showing nodular glomerulosclerosis with HC deposits which can be missed, resulting in delay in diagnosis. We report four γ1-HCDD patients presenting with cutis laxa, hypocomplementemia and hypoalbuminemia. In two patients, unsuspected HCDD was revealed by cutis laxa and diagnosis was made on skin biopsy. In all patients, serum albumin and complement represented surrogate markers for disease monitoring. In γ-HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious tools for an early diagnosis, which is crucial to avoid progression of irreversible renal and elastic tissue damage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cútis Laxa/etiologia , Doença das Cadeias Pesadas/diagnóstico , Hipoalbuminemia/diagnóstico , Insuficiência Renal/etiologia , Adulto , Idoso , Biópsia , Proteínas do Sistema Complemento/análise , Feminino , Doença das Cadeias Pesadas/sangue , Doença das Cadeias Pesadas/complicações , Doença das Cadeias Pesadas/tratamento farmacológico , Humanos , Hipoalbuminemia/sangue , Cadeias gama de Imunoglobulina , Rim/patologia , Masculino , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal/diagnóstico , Insuficiência Renal/terapia , Pele/patologia , Resultado do Tratamento
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