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Arnold JN, Mitchell DA. Tinker, tailor, soldier, cell: the role of C-type lectins in the defense and promotion of disease. Protein Cell 2022; 14:4-16. [PMID: 36726757 PMCID: PMC9871964 DOI: 10.1093/procel/pwac012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 04/25/2022] [Indexed: 02/04/2023] Open
Abstract
C-type lectins (CTLs) represent a large family of soluble and membrane-bound proteins which bind calcium dependently via carbohydrate recognition domains (CRDs) to glycan residues presented on the surface of a variety of pathogens. The deconvolution of a cell's glycan code by CTLs underpins several important physiological processes in mammals such as pathogen neutralization and opsonization, leukocyte trafficking, and the inflammatory response. However, as our knowledge of CTLs has developed it has become apparent that the role of this innate immune family of proteins can be double-edged, where some pathogens have developed approaches to subvert and exploit CTL interactions to promote infection and sustain the pathological state. Equally, CTL interactions with host glycoproteins can contribute to inflammatory diseases such as arthritis and cancer whereby, in certain contexts, they exacerbate inflammation and drive malignant progression. This review discusses the 'dual agent' roles of some of the major mammalian CTLs in both resolving and promoting infection, inflammation and inflammatory disease and highlights opportunities and emerging approaches for their therapeutic modulation.
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Song L, Ge T, Li Z, Sun J, Li G, Sun Y, Fang L, Ma YJ, Garred P. Artesunate: A natural product-based immunomodulator involved in human complement. Biomed Pharmacother 2021; 136:111234. [PMID: 33454596 DOI: 10.1016/j.biopha.2021.111234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/16/2020] [Accepted: 12/31/2020] [Indexed: 01/14/2023] Open
Abstract
Complement is an important innate immune defence machinery. Once dysregulated, it is often linked to pathogenesis of diverse autoimmune diseases. Artesunate (ART) is a well-known anti-malarial compound. Recently, ART has been highlighted by its potential therapeutic effects on certain complement-related autoimmune diseases. However, the underlying mechanisms are hitherto unknown. In the present study, we found that ART mediated complement interception as validated by analysis of complement haemolytic assay. In cell-based setup using dying Jurkat cells, ART-mediated complement interception was also confirmed. Further, we newly established an ELISA system selectively allowing complement activation via the classical pathway, the lectin pathway and the alternative pathway, respectively. ELISA analysis revealed that ART dose-dependently inhibited C4 activation, C3 activation and terminal complement complex assembly via the effector pathways. ART was found to blockade C1q, C3 and C5 with a lesser extent to properdin. The interaction of ART with C1q was determined to be mediated via C1q globular head region. FACS analysis using ART-conjugated mesoporous silica particles revealed that ART specifically bound the key therapeutic targets of C1q, C3 and C5 on microparticles. In conclusion, we for the first time report the anti-complement bioactivities of ART and suggest a potential therapeutic benefit of ART in the complement-related human diseases.
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Affiliation(s)
- Lihong Song
- The Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Ole Maaloesvej 26, 2200, Copenhagen N, Denmark; Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China
| | - Tongqi Ge
- The Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Ole Maaloesvej 26, 2200, Copenhagen N, Denmark; School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China
| | - Zeqin Li
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, 2800, Denmark
| | - Jinfeng Sun
- Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji, China
| | - Gao Li
- Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University College of Pharmacy, Yanji, China
| | - Yi Sun
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, 2800, Denmark
| | - Liang Fang
- Department of Pharmaceutical Science, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China.
| | - Ying Jie Ma
- The Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Ole Maaloesvej 26, 2200, Copenhagen N, Denmark.
| | - Peter Garred
- The Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Ole Maaloesvej 26, 2200, Copenhagen N, Denmark
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Nimmerjahn F, Werner A. Sweet Rules: Linking Glycosylation to Antibody Function. EXPERIENTIA SUPPLEMENTUM (2012) 2021; 112:365-393. [PMID: 34687017 DOI: 10.1007/978-3-030-76912-3_12] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Antibodies produced upon infections with pathogenic microorganisms are essential for clearing primary infections and for providing the host with long-lasting immunity. Moreover, antibodies have become the most widely used platform for developing novel therapies against cancer and autoimmunity, requiring an in-depth understanding of how antibodies mediate their activity in vivo and which factors modulate pro- or anti-inflammatory antibody activities. Since the discovery that select residues present in the sugar domain attached to the immunoglobulin G (IgG) fragment crystallizable (Fc) region can modulate both, pro- and anti-inflammatory effector functions, a wealth of studies has focused on understanding how IgG glycosylation is regulated and how this knowledge can be used to optimize therapeutic antibody activity. With the introduction of glycoengineered afucosylated antibodies in cancer therapy and the initiation of clinical testing of highly sialylated anti-inflammatory antibodies the proof-of-concept that understanding antibody glycosylation can lead to clinical innovation has been provided. The focus of this review is to summarize recent insights into how antibody glycosylation is regulated in vivo and how select sugar residues impact IgG function.
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Affiliation(s)
- Falk Nimmerjahn
- Chair of Genetics, Department of Biology, Institute of Genetics, University of Erlangen-Nürnberg, Erlangen, Germany.
- Medical Immunology Campus Erlangen, Erlangen, Germany.
| | - Anja Werner
- Chair of Genetics, Department of Biology, Institute of Genetics, University of Erlangen-Nürnberg, Erlangen, Germany
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Cao X, Shang QH, Chi XL, Zhang W, Xiao HM, Sun MM, Chen G, An Y, Lv CL, Wang L, Nan YM, Chen CY, Tan ZN, Liu XE, Zhuang H. Serum N-glycan markers for diagnosing liver fibrosis induced by hepatitis B virus. World J Gastroenterol 2020; 26:1067-1079. [PMID: 32205997 PMCID: PMC7080998 DOI: 10.3748/wjg.v26.i10.1067] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/10/2020] [Accepted: 01/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is the primary cause of hepatitis with chronic HBV infection, which may develop into liver fibrosis, cirrhosis and hepatocellular carcinoma. Detection of early-stage fibrosis related to HBV infection is of great clinical significance to block the progression of liver lesion. Direct liver biopsy is regarded as the gold standard to detect and assess fibrosis; however, this method is invasive and prone to clinical sampling error. In order to address these issues, we attempted to find more convenient and effective serum markers for detecting HBV-induced early-stage liver fibrosis.
AIM To investigate serum N-glycan profiling related to HBV-induced liver fibrosis and verify multiparameter diagnostic models related to serum N-glycan changes.
METHODS N-glycan profiles from the sera of 432 HBV-infected patients with liver fibrosis were analyzed. Significant changed N-glycan levels (peaks) (P < 0.05) in different fibrosis stages were selected in the modeling group, and multiparameter diagnostic models were established based on changed N-glycan levels by logistic regression analysis. The receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic efficacy of N-glycans models. These models were then compared with the aspartate aminotransferase to platelet ratio index (APRI) , fibrosis index based on the four factors (FIB-4), glutamyltranspeptidase platelet albumin index (S index), GlycoCirrho-test, and GlycoFibro-test. Furthermore, we combined multiparameter diagnostic models with alanine aminotransferase (ALT) and platelet (PLT) tests and compared their diagnostic power. In addition, the diagnostic accuracy of N-glycan models was also verified in the validation group of patients.
RESULTS Multiparameter diagnostic models constructed based on N-glycan peak 1, 3, 4 and 8 could distinguish between different stages of liver fibrosis. The area under ROC curves (AUROCs) of Model A and Model B were 0.890 and 0.752, respectively differentiating fibrosis F0-F1 from F2-F4, and F0-F2 from F3-F4, and surpassing other serum panels. However, AUROC (0.747) in Model C used for the diagnosis of F4 from F0-F3 was lower than AUROC (0.795) in FIB-4. In combination with ALT and PLT, the multiparameter models showed better diagnostic power (AUROC = 0.912, 0.829, 0.885, respectively) when compared with other models. In the validation group, the AUROCs of the three combined models (0.929, 0.858, and 0.867, respectively) were still satisfactory. We also applied the combined models to distinguish adjacent fibrosis stages of 432 patients (F0-F1/F2/F3/F4), and the AUROCs were 0.917, 0.720 and 0.785.
CONCLUSION Multiparameter models based on serum N-glycans are effective supplementary markers to distinguish between adjacent fibrosis stages of patients caused by HBV, especially in combination with ALT and PLT.
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Affiliation(s)
- Xi Cao
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Qing-Hua Shang
- Department of Liver Disease, No. 88 Hospital of Chinese People’s Liberation Army, Tai'an 271000, Shandong Province, China
| | - Xiao-Ling Chi
- Department of Hepatology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Wei Zhang
- Department of Liver Disease, No. 88 Hospital of Chinese People’s Liberation Army, Tai'an 271000, Shandong Province, China
| | - Huan-Ming Xiao
- Department of Hepatology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Mi-Mi Sun
- Department of Liver Disease, No. 88 Hospital of Chinese People’s Liberation Army, Tai'an 271000, Shandong Province, China
| | - Gang Chen
- Department of Liver Disease, No. 88 Hospital of Chinese People’s Liberation Army, Tai'an 271000, Shandong Province, China
| | - Yong An
- Department of Liver Disease, No. 88 Hospital of Chinese People’s Liberation Army, Tai'an 271000, Shandong Province, China
| | - Chun-Lei Lv
- Department of Liver Disease, No. 88 Hospital of Chinese People’s Liberation Army, Tai'an 271000, Shandong Province, China
| | - Lin Wang
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
| | - Cui-Ying Chen
- Department of Molecular Biomedical Research, Xian si-da Biotechnology Company Limited, Nanjing 210000, Jiangsu Province, China
| | - Zong-Nan Tan
- Department of Molecular Biomedical Research, Xian si-da Biotechnology Company Limited, Nanjing 210000, Jiangsu Province, China
| | - Xue-En Liu
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Hui Zhuang
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
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Goulet DR, Atkins WM. Considerations for the Design of Antibody-Based Therapeutics. J Pharm Sci 2020; 109:74-103. [PMID: 31173761 PMCID: PMC6891151 DOI: 10.1016/j.xphs.2019.05.031] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/02/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023]
Abstract
Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.
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Affiliation(s)
- Dennis R Goulet
- Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195.
| | - William M Atkins
- Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195
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6
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Kronimus Y, Dodel R, Galuska SP, Neumann S. IgG Fc N-glycosylation: Alterations in neurologic diseases and potential therapeutic target? J Autoimmun 2019; 96:14-23. [DOI: 10.1016/j.jaut.2018.10.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 12/30/2022]
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Arend P. ABO phenotype-protected reproduction based on human specific α1,2 L-fucosylation as explained by the Bombay type formation. Immunobiology 2018; 223:684-693. [PMID: 30075871 DOI: 10.1016/j.imbio.2018.07.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 07/10/2018] [Indexed: 12/19/2022]
Abstract
The metabolic relationship between the formation of the ABO(H) blood group phenotype and human fertility is evident in the case of the (Oh) or Bombay blood type, which Charles Darwin would have interpreted as resulting from reduced male fertility in consanguinities, based on the history of his own family, the Darwin/Wedgwood Dynasty. The classic Bombay type occurs with the extremely rare, human-specific genotype (h/h; se/se), which (due to point mutations) does not encode fucosyltransferases 1(FUT1) and 2 (FUT2). These enzymes are the basis for ABO(H) phenotype formation on the cell surfaces and fucosylation of plasma proteins, involving neonatal immunoglobulin M (IgM). In the normal human blood group O(H), which is not protected by clonal selection with regard to environmental A/B immunization, the plasma contains a mixture of non-immune and adaptive anti-A/B reactive isoagglutinins, which in the O(h) Bombay type show extremely elevated levels, associated with decreased levels of fucosylation-dependent functional plasma proteins, suchs as the van Willebrand factor (vWF) and clotting factor VIII. In fact, while the involvement of adaptive immunoglobulins remains unknown, poor fucosylation may explain the polyreactivity in the Bombay type plasma, which exhibits pronounced complement-binding cross-reactive anti-A/Tn and anti-B IgM levels, with additional anti-H reactivity, acting over a wide range of temperatures, with an amplitude at 37 °C. This aggressive anti-glycan-reactive IgM molecule suggests the induction of ADCC (antibody-dependent) and/or complement-mediated cytotoxicity via overexpressed glycosidic bond sites against the embryogenic stem cell-to-germ cell transformation, which is characterized by fleeting appearances of A-like, developmental trans-species GalNAcα1-O-Ser/Thr-R glycan, also referred to as the Tn (T "nouvelle") antigen.
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Affiliation(s)
- Peter Arend
- Philipps University Marburg, Department of Medicine, D-355, Marburg, Lahn, Germany; Gastroenterology Research Laboratory, University of Iowa, College of Medicine, Iowa City, IA, USA; Research Laboratories, Chemie Grünenthal GmbH, D-52062 Aachen, Germany.
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8
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Lis-Kuberka J, Orczyk-Pawiłowicz M, Królak-Olejnik B, Berghausen-Mazur M, Barańska K, Kątnik-Prastowska I. Lectin-based analysis of human milk immunoglobulin G fucosylated variants in relation to milk maturation and perinatal risk factors. J Appl Biomed 2018. [DOI: 10.1016/j.jab.2018.02.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
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9
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Roles of N-glycans in the polymerization-dependent aggregation of mutant Ig-μ chains in the early secretory pathway. Sci Rep 2017; 7:41815. [PMID: 28157181 PMCID: PMC5291101 DOI: 10.1038/srep41815] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 12/28/2016] [Indexed: 02/07/2023] Open
Abstract
The polymeric structure of secretory IgM allows efficient antigen binding and complement fixation. The available structural models place the N-glycans bound to asparagines 402 and 563 of Ig-μ chains within a densely packed core of native IgM. These glycans are found in the high mannose state also in secreted IgM, suggesting that polymerization hinders them to Golgi processing enzymes. Their absence alters polymerization. Here we investigate their role following the fate of aggregation-prone mutant μ chains lacking the Cμ1 domain (μ∆). Our data reveal that μ∆ lacking 563 glycans (μ∆5) form larger intracellular aggregates than μ∆ and are not secreted. Like μ∆, they sequester ERGIC-53, a lectin previously shown to promote polymerization. In contrast, μ∆ lacking 402 glycans (μ∆4) remain detergent soluble and accumulate in the ER, as does a double mutant devoid of both (μ∆4–5). These results suggest that the two C-terminal Ig-μ glycans shape the polymerization-dependent aggregation by engaging lectins and acting as spacers in the alignment of individual IgM subunits in native polymers.
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10
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Ricklin D, Reis ES, Lambris JD. Complement in disease: a defence system turning offensive. Nat Rev Nephrol 2016; 12:383-401. [PMID: 27211870 DOI: 10.1038/nrneph.2016.70] [Citation(s) in RCA: 405] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris - such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways - can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.
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Affiliation(s)
- Daniel Ricklin
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar Chance, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA
| | - Edimara S Reis
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar Chance, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA
| | - John D Lambris
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar Chance, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA
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11
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Orczyk-Pawiłowicz M, Augustyniak D, Hirnle L, Kątnik-Prastowska I. Lectin-based analysis of fucose and sialic acid expressions on human amniotic IgA during normal pregnancy. Glycoconj J 2012; 30:599-608. [PMID: 23250795 PMCID: PMC3717160 DOI: 10.1007/s10719-012-9460-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 11/06/2012] [Accepted: 12/02/2012] [Indexed: 01/14/2023]
Abstract
The sugar moiety of IgA is known to provide a link between the innate and adaptive immune systems. Terminally located glycotopes on IgA are potential ligands engaged in the interactions which may modulate the biological activities of IgA. In the present work the expressions of Maackia amurensis (MAA), Sambucus nigra (SNA), Lens culinaris (LCA), Tetragonolobus purpureus (LTA), and Ulex europaeus (UEA) reactive glycotopes on maternal plasma and amniotic IgA were evaluated in relation to the progression of a normal human pregnancy, from the 2nd trimester, throughout the 3rd trimester, perinatal period, post-date pregnancy and delivery, by lectin-IgA-ELISA, using specific biotinylated lectins. The amniotic and maternal plasma IgA concentrations and a degree of SNA and LCA reactivity of maternal plasma IgA were almost unaltered during the normal pregnancy. The amniotic IgA from the 2nd trimester was decorated by MAA-, SNA-reactive and LCA-, LTA-, and UEA-reactive glycotopes. At the turn of the 2nd and 3rd trimesters the expression of MAA-, SNA-, LTA-, and UEA-reactive glycotopes, except for LCA-reactive, increased and remained almost at unaltered levels throughout the perinatal period and delivery. However, in the post-date pregnancy the expression of LCA-, LTA-, and UEA-reactive and SNA-reactive glycotopes were significantly higher. The unique fucosylated and sialylated glycovariants of amniotic IgA associated with the progression of the normal pregnancy may illustrate a general importance of carbohydrate-lectin receptor interactions in the control and modulation of biological events to ensuring homeostasis during pregnancy, protection and well-being of fetus.
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Affiliation(s)
- Magdalena Orczyk-Pawiłowicz
- Department of Chemistry and Immunochemistry, Wrocław Medical University, Bujwida 44a, 50-345, Wrocław, Poland.
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12
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Alley WR, Vasseur JA, Goetz JA, Svoboda M, Mann BF, Matei DE, Menning N, Hussein A, Mechref Y, Novotny MV. N-linked glycan structures and their expressions change in the blood sera of ovarian cancer patients. J Proteome Res 2012; 11:2282-2300. [PMID: 22304416 PMCID: PMC3321095 DOI: 10.1021/pr201070k] [Citation(s) in RCA: 158] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Glycosylated proteins play important roles in a broad spectrum of biochemical and biological processes, and prior reports have suggested that changes in protein glycosylation occur during cancer initiation and progression. Ovarian cancer (OC) is a fatal malignancy, most commonly diagnosed after the development of metastases. Therefore, early detection of OC is key to improving survival. To this end, specific changes of the serum glycome have been proposed as possible biomarkers for different types of cancers. In this study, we extend this concept to OC. To characterize differences in total N-glycan levels, serum samples provided by 20 healthy control women were compared to those acquired from patients diagnosed with late-stage recurrent OC who were enrolled in an experimental treatment trial prior to receiving therapy (N=19) and one month later, prior to the second treatment cycle (N=11). Additionally, analyses of the N-glycans associated with IgG and characterization of the relative abundance levels of core vs outer-arm fucosylation were also performed. The N-linked glycomic profiles revealed increased abundances of tri- and tetra-branched structures with varying degrees of sialylation and fucosylation and an apparent decrease in the levels of "bisecting" glycans in OC samples compared to controls. Increased levels of a-galactosylation structures were observed on N-linked glycans derived from IgG, which were independent of the presence of fucose residues. Elevated levels of outer-arm fucosylation were also identified in the OC samples. These results allowed the control samples to be distinguished from the baseline ovarian cancer patients prior to receiving the experimental treatment. In some cases, the pre-treatment samples could be distinguished from the post-experimental treatment samples, as many of those patients showed a further progression of the disease.
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Affiliation(s)
- William R. Alley
- Department of Chemistry, Indiana University, Bloomington, IN
- National Center for Glycomics and Glycoproteomics, Indiana University, Bloomington, IN
| | - Jacqueline A. Vasseur
- Department of Chemistry, Indiana University, Bloomington, IN
- National Center for Glycomics and Glycoproteomics, Indiana University, Bloomington, IN
| | - John A. Goetz
- Department of Chemistry, Indiana University, Bloomington, IN
- National Center for Glycomics and Glycoproteomics, Indiana University, Bloomington, IN
| | - Martin Svoboda
- Department of Chemistry, Indiana University, Bloomington, IN
- National Center for Glycomics and Glycoproteomics, Indiana University, Bloomington, IN
| | - Benjamin F. Mann
- Department of Chemistry, Indiana University, Bloomington, IN
- National Center for Glycomics and Glycoproteomics, Indiana University, Bloomington, IN
| | | | - Nancy Menning
- Indiana University School of Medicine, Indianapolis, IN
| | - Ahmed Hussein
- Department of Chemistry, Indiana University, Bloomington, IN
- National Center for Glycomics and Glycoproteomics, Indiana University, Bloomington, IN
| | - Yehia Mechref
- Department of Chemistry, Indiana University, Bloomington, IN
- National Center for Glycomics and Glycoproteomics, Indiana University, Bloomington, IN
| | - Milos V. Novotny
- Department of Chemistry, Indiana University, Bloomington, IN
- Indiana University School of Medicine, Indianapolis, IN
- National Center for Glycomics and Glycoproteomics, Indiana University, Bloomington, IN
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13
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Fang M, Zhao YP, Zhou FG, Lu LG, Qi P, Wang H, Zhou K, Sun SH, Chen CY, Gao CF. N-glycan based models improve diagnostic efficacies in hepatitis B virus-related hepatocellular carcinoma. Int J Cancer 2010; 127:148-59. [PMID: 19904744 DOI: 10.1002/ijc.25030] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The early diagnosis of hepatocellular carcinoma (HCC) is of great clinical desirable due to lack of specific and sensitive markers. Alterations in the sugar chains of glycoprotein synthesized by the liver contribute to the molecular basis of abnormalities in carcinogenesis. This study aims to construct and assess the diagnostic value of N-glycan based diagnostic model in HCC identification and follow-up. A total of 393 subjects including HBV-related HCC, liver fibrosis and healthy controls were recruited. Follow-up was carried out before and after surgical treatment in HCC. N-glycome of serum glycoprotein was profiled by DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). Multiparameters diagnostic models were constructed based on N-glycan markers. The result found that 2 N-glycan structure abundances (NG1A2F, Peak 4; NA3Fb, Peak 9) were useful as N-glycan markers. The diagnostic efficacy of the log ratio [log(p9/4)] was similar to that of AFP in differentiating HCC from fibrosis. The accuracy and sensitivity of the diagnostic model combining AFP and N-glycan markers (Cscore B) were increased 7-10% compared with that of AFP. Log(p9/4) was more efficient in monitoring the progression of HCC with regarding to vascular invasion at improved specificity (16%) and accuracy (8%) compared with that of AFP. The N-glycan markers were found to be changed significantly after surgical resection in HCC follow-up. We conclude that the branching alpha (1,3)-fucosylated triantennary glycan and a biantennary glycan are promising as N-glycan markers. The diagnostic models based on the N-glycan markers and AFP improve the efficacy in HCC diagnosis and progression monitoring.
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Affiliation(s)
- Meng Fang
- Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China
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Trouw LA, Haisma EM, Levarht EWN, van der Woude D, Ioan-Facsinay A, Daha MR, Huizinga TWJ, Toes RE. Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways. ACTA ACUST UNITED AC 2009; 60:1923-31. [PMID: 19565507 DOI: 10.1002/art.24622] [Citation(s) in RCA: 197] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE It has been suggested that anti-citrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used. METHODS We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement. RESULTS Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place. CONCLUSION Our findings indicate that anti-CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement-mediated damage in RA.
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Affiliation(s)
- L A Trouw
- Leiden University Medical Center, Leiden, The Netherlands.
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