全文获取类型
收费全文 | 1876篇 |
免费 | 140篇 |
国内免费 | 4篇 |
专业分类
耳鼻咽喉 | 17篇 |
儿科学 | 10篇 |
妇产科学 | 17篇 |
基础医学 | 390篇 |
口腔科学 | 18篇 |
临床医学 | 201篇 |
内科学 | 512篇 |
皮肤病学 | 30篇 |
神经病学 | 216篇 |
特种医学 | 28篇 |
外科学 | 174篇 |
综合类 | 3篇 |
预防医学 | 103篇 |
眼科学 | 25篇 |
药学 | 156篇 |
中国医学 | 2篇 |
肿瘤学 | 118篇 |
出版年
2024年 | 1篇 |
2023年 | 17篇 |
2022年 | 112篇 |
2021年 | 154篇 |
2020年 | 58篇 |
2019年 | 67篇 |
2018年 | 69篇 |
2017年 | 48篇 |
2016年 | 54篇 |
2015年 | 95篇 |
2014年 | 84篇 |
2013年 | 76篇 |
2012年 | 156篇 |
2011年 | 163篇 |
2010年 | 84篇 |
2009年 | 67篇 |
2008年 | 117篇 |
2007年 | 98篇 |
2006年 | 98篇 |
2005年 | 91篇 |
2004年 | 78篇 |
2003年 | 76篇 |
2002年 | 65篇 |
2001年 | 13篇 |
2000年 | 7篇 |
1999年 | 13篇 |
1998年 | 11篇 |
1997年 | 16篇 |
1996年 | 1篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1988年 | 1篇 |
1987年 | 3篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1977年 | 1篇 |
排序方式: 共有2020条查询结果,搜索用时 31 毫秒
61.
Jacques Banchereau Sandra Zurawski LuAnn Thompson-Snipes Jean-Philippe Blanck Sandra Clayton Adiel Munk Yanying Cao Zhiqing Wang Sunaina Khandelwal Jiancheng Hu William H. McCoy IV Karolina A. Palucka Yoram Reiter Daved H. Fremont Gerard Zurawski Marco Colonna Andrey S. Shaw Eynav Klechevsky 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(46):18885-18890
62.
63.
64.
Alexander M. Chernyavskiy Andrey V. Marchenko Vladimir V. Lomivorotov Dmitriy Doronin Sergey A. Alsov Alexey Nesmachnyy 《Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital》2012,39(5):627-629
Nine months after sustaining a transmural anteroseptal myocardial infarction, a 45-year-old man presented with ischemic heart disease, severe mitral valve insufficiency, New York Heart Association functional class IV congestive heart failure, and a left ventricular aneurysm. Coronary angiography revealed 3-vessel disease. Echocardiography showed severe left ventricular impairment, pronounced thrombosis in the left ventricular apex, and low myocardial reserve. To reduce the high risk of performing left ventricular and mitral valve reconstruction concurrently with revascularization, we decided to perform ventricular reconstruction and to implant a Berlin Heart INCOR left ventricular assist device as a bridge to heart transplantation. The patient had an uncomplicated recovery, was discharged from the hospital with symptomatic improvement after 20 days, and was placed on the list for heart transplantation. We describe the patient''s case, the surgical procedure, and the reasoning behind the chosen course of treatment.Key words: Cardiac surgical procedures/methods, cardiac volume/physiology, heart aneurysm/surgery, heart failure/complications, heart-assist devices, prosthesis implantation/methods, reconstructive surgical procedures, treatment outcome, ventricular dysfunction, left/surgeryLeft ventricular (LV) reconstructive surgery is one method of treatment for patients who have ischemic heart disease with LV aneurysm and concomitant congestive heart failure.1–3 However, preoperative deterioration of hemodynamic status is associated with high risk in such patients, who are candidates for heart transplantation. We present the case of a man who underwent LV reconstructive surgery combined with LV bypass with use of the Berlin Heart INCOR® LV assist device (LVAD) (Berlin Heart GmbH; Berlin, Germany). 相似文献
65.
Cappato R Smith WM Hood MA Crozier IG Jordaens L Spitzer SG Ardashev AV Boersma L Lupo P Grace AA Bardy GH 《Journal of interventional cardiac electrophysiology》2012,34(3):325-332
The recent introduction of subcutaneous implantable cardioverter defibrillator (S-ICD) has raised attention about the potential of this technology for clinical use in daily clinical practice. We review the methods and results of the four studies conducted in humans for approval of this innovative technology for daily practice. Two studies using a temporary S-ICD system (acute human studies) were conducted to search for an appropriate lead configuration and energy requirements. For this purpose, 4 S-ICD configurations were tested in 78 patients at the time of transvenous (TV)-ICD implantation. The optimal configuration was tested in 49 more patients to comparatively assess the subcutaneous defibrillation threshold (S-DFT) versus the standard TV-ICD. Long-term implants were evaluated in 55 patients using an implanted system (chronic human study). The acute humans studies led to an optimal S-ICD configuration comprising a parasternal electrode and left anterolateral thoracic pulse generator. Both configurations successfully terminated 98% of induced ventricular fibrillation (VF), but significantly higher energy levels were required with S-ICD than with TV-ICD systems (36.6?±?19.8 J vs. 11.1?±?8.5 J). In the chronic study, all 137 VF episodes induced at time of implant were detected with a 98% conversion rate. Two pocket infections and four lead revisions were required during 10?±?1 months of follow-up. During this period, survival was 98%, and 12 spontaneous ventricular tachyarrhythmias were detected and treated by the device. These data show that the S-ICD systems here consistently detected and converted VF induced at time of implant as well as sustained ventricular tachyarrhythmias occurring during follow-up (248). 相似文献
66.
Rawaha Ahmad Andrey Postnov Guy Bormans Jan Versijpt Mathieu Vandenbulcke Koen Van Laere 《European journal of nuclear medicine and molecular imaging》2016,43(12):2219-2227
Purpose
The cannabinoid type 2 receptor (CB2R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB2R is primarily found on microglia. CB2R upregulation has been reported in animal models of Alzheimer’s disease, with a preferential localization near amyloid beta (Aβ) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB2R tracer [11C]NE40 in healthy controls (HC) and in patients with Alzheimer’s disease (AD) to investigate whether higher CB2R availability regionally colocalized to Aβ deposits is present in vivo.Methods
Dynamic 90-min [11C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [11C]PIB scan 40 min after injection. In four HC, a retest scan with [11C]NE40 PET was performed within 9 weeks to investigate test–retest characteristics.Results
[11C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time–activity curves best; both binding potential (BPND) and distribution volume (V T) parameters could be used. Brain uptake was generally low with an average K 1 value of 0.07 ml/min/ml tissue. V T and BPND were in the range of 0.7 – 1.8 and 0.6 – 1.6, respectively. Test values in HC were about 30 % for V T and BPND. AD patients showed overall significantly lower CB2R binding. No relationship was found between regional or global amyloid load and CB2R availability.Conclusion
Kinetic modelling of [11C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [11C]NE40 PET shows lower CB2R availability in vivo in AD patients, with no relationship to Aβ plaques. A possible explanation for these findings is that [11C]NE40 binds to CB2R with lower affinity and/or selectivity than to CB1R.67.
Selective silencing of DNA-specific B lymphocytes delays lupus activity in MRL/lpr mice 总被引:1,自引:0,他引:1
Tchorbanov AI Voynova EN Mihaylova NM Todorov TA Nikolova M Yomtova VM Chiang BL Vassilev TL 《European journal of immunology》2007,37(12):3587-3596
The pathological DNA-specific B lymphocytes in lupus are logical targets for a selected therapeutic intervention. We have hypothesized that it should be possible to suppress selectively the activity of these B cells in lupus mice by administering to them an artificial molecule that cross-links their surface immunoglobulins with the inhibitory FcgammaIIb surface receptors. A hybrid molecule was constructed by coupling the DNA-mimicking DWEYSVWLSN peptide to a monoclonal anti-mouse FcgammaRIIb antibody. This chimeric antibody was added to cultured spleen cells from sick MRL/lpr mice, immunized with diphtheria toxoid, resulting in reduction of the numbers of anti-DNA but not of anti-diphtheria IgG antibody-producing cells. Intravenous infusions with the DNA-peptide antibody chimera to 7-wk-old animals prevented the appearance of IgG anti-DNA antibodies and of albuminuria in the next 2 months. The administration of the DNA-peptide chimeric antibody to 18 wk-old mice with full-blown disease resulted in the maintenance of a flat level of IgG anti-DNA antibodies and in delay of the aggravation of the lupus glomerulonephritis. The use of chimeric antibodies targeting inhibitory B lymphocyte receptors represents a novel approach for the selective suppression of autoreactive disease-associated B cells in autoimmune diseases. 相似文献
68.
Andrey Morozov Mark Taratkin Eric Barret Nirmish Singla Evgeniy Bezrukov Denis Chinenov Mikhail Enikeev Juan Gomez Rivas Anastasia Shpikina Dmitry Enikeev 《Andrologia》2020,52(10):e13789
Irreversible electroporation is a treatment option used for focal therapy. In this systematic review, we summarise data on irreversible electroporation outcomes in patients with localised prostate cancer. We performed a literature search in 3 databases and included articles with own data on irreversible electroporation results in patients with localised prostate cancer. Primary outcome was procedure efficacy measured as the absence of cancer in the treatment area on the follow-up biopsy. Secondary outcomes were the absence of prostate cancer recurrence in the treatment area on MRI, out-of-field recurrence, complications and functional outcomes (erectile function and micturition). In-field recurrence rate was 0%–39% and out-field 6.4%–24%. In all studies, PSA level decreased: twice lower than baseline after 4 weeks and by 76% after 2 years. Most of the authors noted sexual and urinary toxicity during the first half year after surgery. However, functional outcomes recovered to baseline after 6 months with mild decrease in sexual function. Complication rates after irreversible electroporation were 0%–1% of Clavien–Dindo III and 5%–20% of Clavien–Dindo I–II. Irreversible electroporation has promise oncological outcomes, rate of post-operative complications and minimal-to-no effects on erectile and urinary function. However, medium and long-term data on cancer-specific and recurrence-free survival are still lacking. 相似文献
69.
Caroline Sobral de Melo Rambo Jose Antônio Silva Jr. Andrey Jorge Serra Ana Paula Ligeiro Rodolfo de Paula Vieira Regiane Albertini Ernesto Cesar Pinto Leal-Junior Paulo de Tarso Camillo de Carvalho 《Lasers in medical science》2014,29(5):1723-1733
The wound-healing process plays an essential role in the protective response to epidermal injury by tissue regeneration. In the elderly, skin functions deteriorate as a consequence of morphological and structural changes. This study aimed to evaluate and compare the effect of low-level laser therapy (LLLT) in cutaneous wound healing in young and aged rats. A total of 60 male rats comprising 30 young (±30 days) and 30 aged (±500 days) was used. The animals were divided into four experimental groups and underwent skin wound and/or treatment with LLLT (660 nm, 30 mW, 1.07 W/cm2, 0.028 cm2, 72 J/cm2, and 2 J). Analyses were conducted to verify the effects of LLLT in the tissue repair process, in the gene expression, and protein expression of TNF-α, IL-1β, and IL-10, obtained in skin wound model. Results showed that there were significant differences between the young control group and the aged control group and their respective treated groups (LLLT young and LLLT aged). We conclude that LLLT has shown to be effective in the treatment of skin wounds in young and aged animals at different stages of the tissue repair process, which suggests that different LLLT dosimetry should be considered in treatment of subjects of different ages. Further clinical trials are needed to confirm these findings in clinical settings. 相似文献
70.
Florina Olaru Wentian Luo Hani Suleiman Patricia L. St. John Linna Ge Adam R. Mezo Andrey S. Shaw Dale R. Abrahamson Jeffrey H. Miner Dorin-Bogdan Borza 《Journal of the American Society of Nephrology : JASN》2014,25(5):918-925
The neonatal Fc receptor (FcRn) is a major regulator of IgG and albumin homeostasis systemically and in the kidneys. We investigated the role of FcRn in the development of immune complex–mediated glomerular disease in mice. C57Bl/6 mice immunized with the noncollagenous domain of the α3 chain of type IV collagen (α3NC1) developed albuminuria associated with granular capillary loop deposition of exogenous antigen, mouse IgG, C3 and C5b-9, and podocyte injury. High-resolution imaging showed abundant IgG deposition in the expanded glomerular basement membrane, especially in regions corresponding to subepithelial electron dense deposits. FcRn-null and -humanized mice immunized with α3NC1 developed no albuminuria and had lower levels of serum IgG anti-α3NC1 antibodies and reduced glomerular deposition of IgG, antigen, and complement. Our results show that FcRn promotes the formation of subepithelial immune complexes and subsequent glomerular pathology leading to proteinuria, potentially by maintaining higher serum levels of pathogenic IgG antibodies. Therefore, reducing pathogenic IgG levels by pharmacologic inhibition of FcRn may provide a novel approach for the treatment of immune complex–mediated glomerular diseases. As proof of concept, we showed that a peptide inhibiting the interaction between human FcRn and human IgG accelerated the degradation of human IgG anti-α3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG.The MHC class I–like neonatal Fc receptor (FcRn), a heterodimer comprising a heavy chain and β2-microglobulin light chain, is the major regulator of IgG and albumin homeostasis.1 Perinatally, FcRn mediates the transfer of IgG from mother to offspring, across the placenta in primates and trans-intestinally in suckling rodents. Throughout life, FcRn protects IgG and albumin from catabolism, explaining the unusually long t1/2 and high serum levels of these proteins. IgG and albumin taken up by cells by pinocytosis bind strongly to FcRn at pH 6.0–6.5 in endosomes. FcRn-bound ligands are then recycled to the plasma membrane, where they dissociate at pH 7.4, whereas IgG and albumin not bound to FcRn are targeted to lysosomes for degradation. FcRn is thought to promote some autoimmune diseases because it protects pathogenic IgG from degradation. For instance, Fcrn−/− mice are resistant to passive transfer of arthritis by K/BxN sera and autoimmune skin pathology induced by antibodies targeting autoantigens at the dermal–epidermal junction, although this protection can be overcome by excess autoantibodies.2–4In kidneys, FcRn is expressed in podocytes and proximal tubular epithelial cells.5 Overall, renal FcRn reclaims albumin but facilitates elimination of IgG.6 Tubular FcRn mediates IgG transcytosis.7 Podocytes use FcRn to clear IgG from the glomerular basement membrane (GBM).8 IgG accumulates in the glomeruli of aged Fcrn−/− mice due to impaired clearance of IgG from the GBM, and saturating this clearance mechanism by excess ligand potentiates the pathogenicity of nephrotoxic sera in wild-type mice. Podocyte FcRn has been postulated to be involved in the clearance of immune complexes (ICs) present in pathologic conditions such as membranous nephropathy.5 Expression of FcRn in human podocytes is increased in various immune-mediated glomerular diseases.9 Given its role in IgG and albumin handling in the kidneys and systemically, FcRn can be expected to influence the development of immune-mediated kidney diseases at multiple levels. This conjecture awaits experimental verification.To determine the role of FcRn in IgG-mediated glomerular disease, we asked how FcRn deficiency alters the course of disease in mice immunized with the NC1 domain of α3 type IV collagen (α3NC1). We chose this antigen because of its reported ability to induce disease in C57Bl/6 (B6) mice,10 corroborated in pilot studies (Supplemental Figure 1). Fcrn−/− mice are hypoalbuminemic due to impaired albumin recycling,11 and also exhibit reduced urinary albumin excretion.12 As a control for this potential confounder, we used FCRN-humanized mice, which have normal serum albumin because human FcRn recycles mouse albumin but not mouse IgG.13All mice immunized with α3NC1 developed circulating mouse IgG anti-α3NC1 antibodies, which reached the maximum titer about 6 weeks later and gradually declined thereafter. At all times, the levels of mouse IgG anti-α3NC1 antibodies in sera from Fcrn−/− mice and FCRN-humanized mice were approximately 50%–70% lower than those in wild-type mouse sera (Figure 1A). The results were similar for mouse IgG1, IgG2b, and IgG2c anti-α3NC1 antibodies (Supplemental Figure 2). Wild-type B6 mice immunized with α3NC1 started developing progressive albuminuria 8–10 weeks later (Figure 1B). By week 14, the urinary albumin creatinine ratio increased approximately 100-fold, and hypoalbuminemia developed (Figure 1C). Urinary albumin excretion in Fcrn−/− mice and FCRN-humanized mice immunized with α3NC1 was not significantly higher than in adjuvant-immunized control mice. No mice developed renal failure (Supplemental Figure 3).Open in a separate windowFigure 1.FcRn ablation reduces serum levels of mouse IgG anti-α3NC1 antibodies and prevents the development of albuminuria in α3NC1-immunized mice. (A) The left panel shows circulating mIgG anti-α3NC1 antibodies from C57Bl6 wild-type mice (○), Fcrn−/− mice (□), FCRN-humanized (hFCRN) mice (◇), and the control CFA group (△), which are assayed by indirect ELISA in plates coated with α3NC1 (100 ng/well). Mouse sera are diluted 1:5000. The right panel shows the significance of circulating mIgG anti-α3NC1 antibody differences among groups at week 12, as assessed by one-way ANOVA followed by Bonferroni post tests for pairwise comparisons. (B) The left panel shows that the urinary albumin creatinine ratio (mean±SEM) time course is monitored in C57Bl6 wild-type mice (○), Fcrn−/− mice (□), and hFCRN mice (◇) immunized with α3NC1 (n=5–8 mice in each group, from two separate experiments). Mice in the control group (△) are immunized with adjuvant alone (n=9). The right panel shows the urinary albumin creatinine ratio (mean±SEM) at 14 weeks, when mice are euthanized. The significance of differences among groups is assessed by one-way ANOVA followed by Bonferroni post tests for pairwise comparisons. (C) The left panel shows SDS-PAGE analysis of serum (0.5 µl/lane) and urine samples (2 µl/lane) from CFA-immunized control mice (a) and α3NC1-immunized wild-type mice (b), Fcrn−/− mice (c), and hFCRN mice (d) collected at week 14. The right panel presents a densitometric analysis of the relative levels of albumin in mouse serum samples showing that α3NC1-immunized wild-type mice developed hypoalbuminemia. *P<0.05 by two-tailed t test versus CFA-immunized wild-type mice; **P<0.01; ***P<0.001. ns, not significant; WT, wild type.At 14 weeks after α3NC1 immunization, kidneys examined by light microscopy showed mild glomerular pathology, with few crescents and relatively little inflammation (Figure 2A), similar to α3NC1-immunized DBA/1 mice with comparable albuminuria.14,15 Electron microscopy showed extensive subepithelial IC deposits surrounded by an expanded GBM and effacement of podocyte foot processes in α3NC1-immunized B6 mice, whereas Fcrn−/− mice had fewer subepithelial deposits (Figure 2B, Supplemental Figure 4). Immunofluorescence staining showed granular capillary loop deposition of mouse IgG, exogenous antigen, C3, and C5b-9, more intense in wild-type mice than in Fcrn−/− mice and FCRN-humanized mice (Figure 2, Ca–Cp, Supplemental Figure 5). A loss of nephrin staining, indicative of podocyte injury, occurred in α3NC1-immunized B6 mice but not in Fcrn−/− mice or FCRN-humanized mice (Figure 2, Cq–Ct).Open in a separate windowFigure 2.FcRn deficiency reduces formation of pathogenic subepithelial ICs. (A) Light microscopic evaluation of kidneys from adjuvant-immunized control mice (a) and α3NC1-immunized wild-type mice (b) and Fcrn−/− mice (c) revealed few pathogenic changes and the absence of glomerular inflammation (periodic acid–Schiff staining). (B) Transmission electron microscopy shows normal GBM (arrow) and podocyte foot processes in control mice (a), extensive subepithelial electron dense deposits (arrowhead), thickened GBM, and podocyte foot process effacement in α3NC1-immunized wild-type mice (b), and fewer IC deposits in the Fcrn−/− mice (c). (C) Immunofluorescence analysis of kidneys from adjuvant-immunized control mice (a, e, i, m, and q) and α3NC1-immunized wild-type mice (b, f, j, n, and r), FcRn−/− mice (c, g, k, o, and s), and hFCRN mice (d, h, l, p, and t) evaluate the deposition of mouse IgG (a–d), exogenous α3NC1 antigen stained by mAb RH34 (e–h), mouse C3c (i–l), C5b-9 (m–p), and nephrin staining (q–t) at 14 weeks. Wild-type mice exhibit linear-granular GBM deposition of mouse IgG and granular GBM deposition of exogenous antigen, C3, and C5b-9, which are attenuated in Fcrn−/− mice and hFCRN mice and essentially absent in control mice. Compared with control mice, α3NC1-immunized wild-type mice but not Fcrn−/− or hFCRN mice exhibit a loss of nephrin staining, indicative of podocyte injury. WT, wild type; EM, electron microscopy, PAS, periodic acid–Schiff. Original magnification, ×400 in A; ×2850 in B; ×200 in C.Because B6 mice immunized with bovine GBM NC1 hexamers have normal kidney function and histology despite linear GBM deposition of IgG autoantibodies binding to mouse α345(IV) collagen (Supplemental Figure 1), the question arises as to what causes proteinuria in α3NC1-immunized mice. Because the clinical presentation, morphology, and effector mechanisms depend on where ICs are localized in the capillary wall, we compared IgG distribution in α3NC1-immunized mice and mice injected with anti-α3NC1 antibodies modeling anti-GBM autoantibodies. The distribution and relative abundance of mouse IgG, as imaged by immunoperoxidase immunoelectron microscopy and stochastic optical reconstruction microscopy (STORM), a method for super-resolution fluorescence microscopy, were concordant. In α3NC1-immunized mice, IgG deposition was abundant in the areas of expanded GBM and especially in regions corresponding to the subepithelial dense deposits seen by routine electron microscopy. By contrast, in mice injected with α3NC1-specific anti-GBM mAb, the IgG was confined to an ultrastructurally normal GBM that lacked subepithelial deposits (Figure 3).Open in a separate windowFigure 3.Localization of IgG by high-resolution imaging. The localization of mouse IgG in glomerular capillary walls of wild-type mice immunized with α3NC1 (A, C–E), or intravenously injected with anti-mouse α3NC1 IgG mAb 8D1 (B, F–H) is determined by immunoperoxidase electron microscopy (A and B) and STORM imaging (C–H). In A, the GBM is irregularly thickened, and abundant electron dense peroxidase reaction product is present in discontinuous, subepithelial patterns beneath broadly effaced podocyte foot processes (arrows). In B, the peroxidase reaction product is diffusely present throughout the GBM (arrowhead), but less abundant compared with A. Electron dense deposits are absent, and podocyte foot process architecture appears normal. (C–E) By STORM imaging, anti-agrin (blue) identifies both normal and thickened areas of the GBM, both of which contain dense accumulations of mouse IgG throughout (red). The electron microscopy correlation in E shows GBM staining with respect to the podocytes and endothelial cells. (F–H) IgG mAb 8D1 (red) is present in the GBM, which shows no evidence of thickening. CL, capillary lumen; EM, electron microscopy En, endothelium;Po, podocyte.Subepithelial ICs, a hallmark of human membranous nephropathy (MN), form when IgG antibodies bind to podocyte antigens, such as phospholipase A2 receptor (PLA2R) and neutral endopeptidase (NEP), or to planted antigens, such as cationic BSA.16–18 Subsequent expansion of the GBM, complement activation, and podocyte injury by C5b-9 cause proteinuria. Although it is unexpected, formation of subepithelial ICs in α3NC1-immunized mice may be explained by exogenous α3NC1 deposited in glomeruli acting as a planted antigen.19 Alternatively, anti-α3NC1 antibodies in complex with α3NC1 antigen may act as surrogate antipodocyte antibodies, because α3NC1-containing ICs bind to podocytes.20 After four immunizations with α3NC1 monomers, B6 mice and DBA/1 mice eventually develop crescentic GN by 26 and 10 weeks, respectively.10,14 The combination of subepithelial ICs and crescentic anti-GBM antibody GN was most recently described in a series of eight patients with circulating anti-α3NC1 autoantibodies but undetectable anti-PLA2R autoantibodies.21In contrast to wild-type B6 mice, congenic Fcrn−/− mice and FCRN-humanized mice did not develop albuminuria after α3NC1 immunization. Their resistance to proteinuria was associated with lower serum titers of anti-α3NC1 IgG antibodies and reduced glomerular deposition of IgG, antigen, C3, and C5b-9. Because C5b-9 is an essential mediator of podocyte damage and proteinuria by subepithelial ICs,22,23 reduced complement activation potentially explains the attenuated glomerular pathology in FcRn-deficient mice. The resistance of FCRN-humanized mice indicates that FcRn promotes IC-mediated glomerular disease due to its interaction with IgG rather than albumin. We propose that FcRn promotes the development of subepithelial ICs and subsequent glomerular injury primarily by maintaining higher serum levels of pathogenic IgG (Supplemental Figure 6). However, we cannot formally exclude a possible pathogenic role of podocyte FcRn, whose stimulation by ICs may induce maladaptive signaling.9 Future studies in mice with podocyte-specific ablation of FcRn would address this possibility.Our findings identify FcRn as a potential target for therapeutic intervention in IC-mediated glomerular diseases, typically treated with nonspecific immunosuppressants that are toxic and sometimes ineffective. More specific therapies include ablation of B cells by rituximab. In patients with idiopathic MN who respond to rituximab therapy, serum levels of anti-PLA2R IgG autoantibodies decline over a period of many months, and their disappearance is followed by resolution of proteinuria.24 The slow decline in proteinuria is problematic for patients already suffering from complications of nephrotic syndrome, who would benefit from ancillary therapies that reduce pathogenic IgG antibodies more rapidly. This may be achieved by inhibiting FcRn.One implementation of this concept is therapy with high-dose intravenous Ig (HD-IVIG). HD-IVIG accelerates the degradation of IgG by saturating FcRn,25 one of the mechanisms that explain the beneficial effects of HD-IVIG therapy in some autoimmune diseases.3 In pregnant women with circulating anti-NEP alloantibodies mediating antenatal MN, treatment with HD-IVIG reduces the titers of IgG alloantibodies by approximately 30% within 2–3 weeks.26 However, HD-IVIG is inefficient, because large amounts of IgG (1–2 g/kg) cause relatively modest reductions in pathogenic IgG titers. Specific FcRn inhibitors recapitulate this activity of HD-IVIG more effectively at lower doses. By reducing pathogenic IgG levels, function-blocking anti-FcRn mAbs ameliorate experimental myasthenia gravis in rats,27 and engineered IgG “Abdegs” that bind with high affinity to FcRn ameliorate arthritis transferred by K/BxN serum.28To assess the translational potential of our findings, we asked whether pharmacologic blockade of human FcRn can reproduce the effects of genetic FcRn deficiency. To this end, FCRN-humanized and Fcrn−/− mice were passively immunized with human IgG containing anti-α3NC1 (Goodpasture) autoantibodies. To inhibit human FcRn, we used a lysine analog of SYN1436 (Figure 4A),29 a peptide that binds with subnanomolar affinity to human FcRn, thus preventing IgG binding.30
In vivo, SYN1436 reduces IgG levels in cynomolgus monkeys by 80%.30 Serum anti-α3NC1 autoantibodies in FCRN-humanized mice treated with anti-FcRn peptide, but not with control peptide, sharply decreased to the same levels as in Fcrn−/− mice (Figure 4B), and were no longer detected after 4 days. In mice, human IgG elicits murine anti-human IgG antibodies, forming ICs that can deposit in glomeruli, as shown in active serum sickness models. Glomerular deposition of ICs containing human IgG was abolished in mice treated with anti-FcRn peptide, but not with control peptide (Figure 4C). Linear GBM deposition of human anti-GBM IgG was not observed, because the epitopes recognized by Goodpasture autoantibodies are completely inaccessible in the mouse GBM.31 These results provide proof of concept that therapies targeting human FcRn effectively lower serum levels of pathogenic human IgG autoantibodies, which could be beneficial in patients with IgG-mediated kidney diseases. Because FcRn also mediates the trans-placental transfer of IgG from mother to the fetus, FcRn inhibition may be particularly attractive for preventing antenatal MN caused by maternal anti-NEP alloantibodies.Open in a separate windowFigure 4.Pharmacologic blockade of human FcRn accelerates the catabolism of human IgG autoantibodies in FCRN-humanized mice. (A) Structure of a peptide that binds with high affinity to human FcRn, competitively inhibiting its interaction with human IgG (top). The control peptide (bottom) containing D-amino acids does not bind to human FcRn. Pen, Sar, and NMeLeu denote penicillamine, sarcosine, and N-methyl-leucine, respectively. (B) Serum level of human IgG anti-α3NC1 antibodies in FCRN-humanized mice treated with anti-FcRn peptide (▪) or control peptide (●) and in Fcrn−/− (▲) mice sera (n=3 in each group) is analyzed by indirect ELISA in plates coated with α3NC1 (100 ng/well). Mouse sera are diluted 1:500. (C) Kidney deposition of human IgG (a and b) and mouse IgG (c and d) in FCRN-humanized mice treated with control peptide (a and c) or anti-FcRn peptide (b and d) is evaluated by direct immunofluorescence staining. Treatment with anti-FcRn peptide prevents the glomerular deposition of ICs containing human IgG. 相似文献