| 1. |
- Bergman, Ingrid-Maria, et al.
(författare)
-
Extensive polymorphism in the porcine Toll-like receptor 10 gene
- 2012
-
Ingår i: International Journal of Immunogenetics. - 1744-3121 .- 1744-313X. ; 39:1, s. 68-76
-
Tidskriftsartikel (refereegranskat)abstract
- The great importance of the Toll-like receptors (TLRs) in innate immunity is well established, but one family member – TLR10 – remains elusive. TLR10 is expressed in various tissues in several species, but its ligand is not known and its function is still poorly understood. The open reading frame of TLR10 was sequenced in 15 wild boars, representing three populations, and in 15 unrelated domestic pigs of Hampshire, Landrace and Large White origin. Amino acid positions corresponding to detected nonsynonymous single nucleotide polymorphisms (SNPs) were analysed in the crystal structures determined for the human TLR1–TLR2–lipopeptide complex and the human TLR10 Toll/Interleukin 1 receptor (TIR) dimer. SNP occurrence in wild boars and domestic pigs was compared, and haplotypes for the TLR10 gene and the TLR6-1-10 gene cluster were reconstructed. Despite the limited number of animals sequenced in the present study (N = 30), a larger number of SNPs were found in TLR10 than recently reported for TLR1, TLR6 and TLR2. Thirty-three SNPs were detected, of which 20 were nonsynonymous. The relative frequency of nonsynonymous (dN) and synonymous (dS) SNPs between wild boars and domestic pigs was higher in TLR10 than recently reported for TLR1, TLR6 and TLR2. However, the polymorphism reported in the present study seems to leave the function of the TLR10 molecule unaffected. Furthermore, no nonsynonymous SNPs were detected in the part of the gene corresponding to the hinge region of the receptor, probably reflecting rigorously acting functional constraint. The total number of SNPs and the number of nonsynonymous SNPs were significantly lower (P < 0.05) in the wild boars than in the domestic pigs, and fewer TLR10 haplotypes were present in the wild boars. The majority of the TLR6-1-10 haplotypes were specific for either wild boars or domestic pigs, probably reflecting differences in microbial environment and population history.
|
|
| 2. |
- Gerogianni, Alexandra, et al.
(författare)
-
Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation
- 2022
-
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- Hemolysis, as a result of disease or exposure to biomaterials, is characterized by excess amounts of cell-free heme intravascularly and consumption of the protective heme-scavenger proteins in plasma. The liberation of heme has been linked to the activation of inflammatory systems, including the complement system, through alternative pathway activation. Here, we investigated the impact of heme on the regulatory function of the complement system. Heme dose-dependently inhibited factor I-mediated degradation of soluble and surface-bound C3b, when incubated in plasma or buffer with complement regulatory proteins. Inhibition occurred with factor H and soluble complement receptor 1 as co-factors, and the mechanism was linked to the direct heme-interaction with factor I. The heme-scavenger protein hemopexin was the main contaminant in purified factor I preparations. This led us to identify that hemopexin formed a complex with factor I in normal human plasma. These complexes were significantly reduced during acute vasoocclusive pain crisis in patients with sickle cell disease, but the complexes were normalized at their baseline outpatient clinic visit. Hemopexin exposed a protective function of factor I activity in vitro, but only when it was present before the addition of heme. In conclusion, we present a mechanistic explanation of how heme promotes uncontrolled complement alternative pathway amplification by interfering with the regulatory capacity of factor I. Reduced levels of hemopexin and hemopexin-factor I complexes during an acute hemolytic crisis is a risk factor for heme-mediated factor I inhibition.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Nilsson, Bo, et al.
(författare)
-
The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies
- 2014
-
Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 61:2, s. 185-190
-
Forskningsöversikt (refereegranskat)abstract
- Cell therapies in which the cells come into direct contact with blood and other body fluids are emerging treatment procedures for patients with various diseases, such as diabetes mellitus, liver insufficiency, and graft-versus-host disease. However, despite recent progress, these procedures are associated with tissue loss caused by thromboinflammatory reactions. These deleterious reactions involve the activation of the complement and coagulation cascades and platelet and leukocyte activation, ultimately resulting in clot formation and damage to the implanted cells. In this concept review, we discuss the basic mechanisms underlying the thrombininflammatory process, with special reference to the engagement of complement and emerging strategies for the therapeutic regulation of these reactions that include the use of selective systemic inhibitors and various procedures to coat the surfaces of the cells. The coating procedures may also be applied to other treatment modalities in which similar mechanisms are involved, including whole organ transplantation, treatment with biomaterials in contact with blood, and extracorporeal procedures. (C) 2014 Published by Elsevier Ltd.
|
|
| 6. |
- Nilsson, Per H., 1980-
(författare)
-
Interactions between platelets and complement with implications for the regulation at surfaces
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Disturbances of host integrity have the potential to evoke activation of innate immunologic and hemostatic protection mechanisms in blood. Irrespective of whether the activating stimulus is typically immunogenic or thrombotic, it will generally affect both the complement system and platelets to a certain degree. The theme of this thesis is complement and platelet activity, which is intersected in all five included papers. The initial aim was to study the responses and mechanisms of the complement cascade in relation to platelet activation. The secondary aim was to use an applied approach to regulate platelets and complement on model biomaterial and cell surfaces. Complement activation was found in the fluid phase in response to platelet activation in whole blood. The mechanism was traced to platelet release of stored chondroitin sulfate-A (CS-A) and classical pathway activation via C1q. C3 was detected at the platelet surface, though its binding was independent of complement activation. The inhibitors factor H and C4-binding protein (C4BP) were detected on activated platelets, and their binding was partly dependent on surface-exposed CS-A. Collectively, these results showed that platelet activation induces inflammatory complement activation in the fluid phase. CS-A was shown to be a central molecule in the complement-modulatory functions of platelets by its interaction with C1q, C4BP, and factor H.Platelet activation and surface adherence were successfully attenuated by conjugating an ADP-degrading apyrase on a model biomaterial. Only minor complement regulation was seen, and was therefore targeted specifically on surfaces and cells by co-immobilizing a factor H-binding peptide together with the apyrase. This combined approach led to a synchronized inhibition of both platelet and complement activation at the interface of biomaterials/xenogeneic cells and blood.In conclusion, here presents a novel crosstalk-mechanism for activation of complement when triggering platelets, which highlights the importance of regulating both complement and platelets to lower inflammatory events. In addition, a strategy to enhance the biocompatibility of biomaterials and cells by simultaneously targeting ADP-dependent platelet activation and the alternative complement C3-convertase is proposed.
|
|
| 7. |
- Suzuki, Haruna, et al.
(författare)
-
Impact of spontaneous liposome modification with phospholipid polymer-lipid conjugates on protein interactions
- 2022
-
Ingår i: Science and Technology of Advanced Materials. - : Taylor & Francis Group. - 1468-6996 .- 1878-5514. ; 23:1, s. 845-857
-
Tidskriftsartikel (refereegranskat)abstract
- Liposome surface coating has been studied to avoid the immunological responses caused by the complement system, and alternative materials to poly(ethylene glycol) (PEG) have been explored recently since the production of anti-PEG IgM antibodies has been found in humans. We previously reported a liposome coating with poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC))-conjugated lipids (PMPC-lipids) and demonstrated its protective effect on blood protein interactions. Here, we attempted to modify the liposome surface by exogenously adding PMPC-lipids, which were spontaneously incorporated into the outer membrane via hydrophobic interactions. The polymerization degree of the PMPC segment was regulated from 10 to 100. The incorporated ratio of PMPC-lipid increased with a decrease in the degree of PMPC polymerization. Due to surface modification with PMPC-lipids, increase in the length of the PMPC-chain increased the size of the liposomes. The modified liposomes were kept stable for 14 d in terms of their size, polydispersity, and surface properties, where approximately 70% of PMPC-lipids were incorporated into the liposome surface. We demonstrated that liposome surface modification with PMPC-lipids can inhibit protein adsorption when exposed to serum, regardless of the degree of polymerization of PMPC. In addition, the PMPC-lipid modified surface was not recognized by the anti-PEG IgM antibody, whereas PEG-lipid was recognized by the antibody. Thus, we successfully fabricated an inert liposome surface via spontaneous modification with PMPC-lipids, where only the outer bilayer surface was modified. This technique can be available for full loading of water-soluble active pharmaceutical ingredient inside the modified liposome.
|
|
| 8. |
- Teramura, Yuji, et al.
(författare)
-
Potential of Cell Surface Engineering with Biocompatible Polymers for Biomedical Applications
- 2020
-
Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 36:41, s. 12088-12106
-
Tidskriftsartikel (refereegranskat)abstract
- The regulation of the cellular surface with biomaterials can contribute to the progress of biomedical applications. In particular, the cell surface is exposed to immunological surveillance and reactions in transplantation therapy, and modulation of cell surface properties might improve transplantation outcomes. The transplantation of therapeutic cells, tissue, and organs is an effective and fundamental treatment and has contributed to saving lives and improving quality of life. Because of shortages, donor cells, tissues, and organs are carefully transplanted with the goal of retaining activity and viability. However, some issues remain to be resolved in terms of reducing side effects, improving graft survival, managing innate and adaptive immune responses, and improving transplant storage and procedures. Given that the transplantation process involves multiple steps and is technically complicated, an engineering approach together with medical approaches to resolving these issues could enhance success. In particular, cell surface engineering with biocompatible polymers looks promising for improving transplantation therapy and has potential for other biomedical applications. Here we review the significance of polymer-based surface modification of cells and organs for biomedical applications, focusing on the following three topics: Cell protection: cellular protection through local immune regulation using cell surface modification with biocompatible polymers. This protection could extend to preventing attack by the host immune system, freeing recipients from taking immunosuppressive drugs, and avoiding a second transplantation. Cell attachment: cell manipulation, which is an important technique for delivery of therapeutic cells and their alignment for recellularization of decellularized tissues and organs in regenerative therapy. Cell fusion: fusion of different cells, which can lead to the formation of new functional cells that could be useful for generating, e.g., immunologically competent or metabolically active cells.
|
|
| 9. |
- Toda, Shota, et al.
(författare)
-
Optimization of Islet Microencapsulation with Thin Polymer Membranes for Long-Term Stability
- 2019
-
Ingår i: Micromachines. - : MDPI. - 2072-666X. ; 10:11, s. 1-10
-
Tidskriftsartikel (refereegranskat)abstract
- Microencapsulation of islets can protect against immune reactions from the host immune system after transplantation. However, sufficient numbers of islets cannot be transplanted due to the increase of the size and total volume. Therefore, thin and stable polymer membranes are required for the microencapsulation. Here, we undertook the cell microencapsulation using poly(ethylene glycol)-conjugated phospholipid (PEG-lipid) and layer-by-layer membrane of multiple-arm PEG. In order to examine the membrane stability, we used different molecular weights of 4-arm PEG (10k, 20k and 40k)-Mal to examine the influence on the polymer membrane stability. We found that the polymer membrane made of 4-arm PEG(40k)-Mal showed the highest stability on the cell surface. Also, the polymer membrane did not disturb the insulin secretion from beta cells.
|
|
| 10. |
- Vogt, Leonie M., et al.
(författare)
-
Apolipoprotein E Triggers Complement Activation in Joint Synovial Fluid of Rheumatoid Arthritis Patients by Binding C1q
- 2020
-
Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 204:10, s. 2779-2790
-
Tidskriftsartikel (refereegranskat)abstract
- We identified apolipoprotein E (ApoE) as one of the proteins that are found in complex with complement component C4d in pooled synovial fluid of rheumatoid arthritis (RA) patients. Immobilized human ApoE activated both the classical and the alternative complement pathways. In contrast, ApoE in solution demonstrated an isoform-dependent inhibition of hemolysis and complement deposition at the level of sC5b-9. Using electron microscopy imaging, we confirmed that ApoE interacts differently with C1q depending on its context; surface-bound ApoE predominantly bound C1q globular heads, whereas ApoE in a solution favored the hinge/stalk region of C1q. As a model for the lipidated state of ApoE in lipoprotein particles, we incorporated ApoE into phosphatidylcholine/phosphatidylethanolamine liposomes and found that the presence of ApoE on liposomes increased deposition of C1q and C4b from serum when analyzed using flow cytometry. In addition, posttranslational modifications associated with RA, such as citrullination and oxidation, reduced C4b deposition, whereas carbamylation enhanced C4b deposition on immobilized ApoE. Posttranslational modification of ApoE did not alter Clq interaction but affected binding of complement inhibitors factor H and C4b -binding protein. This suggests that changed ability of C4b to deposit on modified ApoE may play an important role. Our data show that posttranslational modifications of ApoE alter its interactions with complement. Moreover, ApoE may play different roles in the body depending on its solubility, and in diseased states such as RA, deposited ApoE may induce local complement activation rather than exert its typical role of inhibition.
|
|
