Molecular cell biology of complement membrane attack

Morgan, B. Paul; Boyd, Courtney M.; Bubeck, Doryen

doi:10.1016/j.semcdb.2017.06.009

Cited by 69 publications

(52 citation statements)

References 77 publications

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“…In order to improve both quantitative and qualitative assessments of the erythroid component in PNH we have introduced CD71 (transferrin receptor) as a marker of immature RBCs (iRBC) and examined the utility of assessing the clone size within this fraction and whether a clearer delineation of Type II and Type III cells can be made. iRBCs are unaffected by complement‐mediated lysis (Morgan et al, ; Sadallah et al, ) or by transfusions of mature RBCs (Thomson‐Luque et al, ).…”

Section: Discussionmentioning

confidence: 99%

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CD71 improves delineation of PNH type III, PNH type II, and normal immature RBCS in patients with paroxysmal nocturnal hemoglobinuria

Sutherland

Richards

Ortíz

et al. 2019

Cytometry Part B Clinical

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Background The diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) relies on flow cytometric demonstration of loss of glycosyl‐phosphatidyl inositol (GPI)‐anchored proteins from red blood cells (RBC) and white blood cells (WBC). High‐sensitivity multiparameter assays have been developed to detect loss of GPI‐linked structures on PNH neutrophils and monocytes. High‐sensitivity assays to detect PNH phenotypes in RBCs have also been developed that rely on the loss of GPI‐linked CD59 on CD235a‐gated mature RBCs. The latter is used to delineate PNH Type III (total loss of CD59) and PNH Type II RBCs (partial loss of CD59) from normal (Type I) RBCs. However, it is often very difficult to delineate these subsets, especially in patients with large PNH clones who continue to receive RBC transfusions, even while on eculizumab therapy. Methods We have added allophycocyanin (APC)‐conjugated CD71 to the existing CD235aFITC/CD59PE RBC assay allowing simultaneous delineation and quantification of PNH Type III and Type II immature RBCs (iRBCs). Results We analyzed 24 medium to large‐clone PNH samples (>10% PNH WBC clone size) for PNH Neutrophil, PNH Monocyte, Type III and Type II PNH iRBCs, and where possible, Type III and Type II PNH RBCs. The ability to delineate PNH Type III, Type II, and Type I iRBCs was more objective compared to that in mature RBCs. Additionally, total PNH iRBC clone sizes were very similar to PNH WBC clone sizes. Conclusions Addition of CD71 significantly improves the ability to analyze PNH clone sizes in the RBC lineage, regardless of patient hemolytic and/or transfusion status.

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Section: Discussionmentioning

confidence: 99%

“…Since immature PNH RBCs are not hemolyzed by activated complement (Morgan, Boyd, & Bubeck, 2017;Sadallah, Hanno, & Schifferli, 2010) and are not significantly diluted by transfusions of mature RBCs, other authors have proposed to assess immature RBC (nucleated RBCs and/or reticulocytes). A variety of flow cytometry assays have been developed to achieve this.…”

mentioning

confidence: 99%

CD71 improves delineation of PNH type III, PNH type II, and normal immature RBCS in patients with paroxysmal nocturnal hemoglobinuria

Sutherland

Richards

Ortíz

et al. 2019

Cytometry Part B Clinical

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“…[ 31 ] All the complement pathways activate a cascade of events such as the membrane attack complex (MAC), anaphylatoxins (C3a, C4a, and C5a), and opsonins (C3b, C4b, and C1q). [ 32 ] These mediators have the following functions: i) MAC forms a transmembrane channel in the phospholipid bilayer that lead to the lyses and thereby death of targeted cells; [ 33 ] ii) anaphylatoxins generate a local inflammatory response through the degranulation of endothelial cells, mast cells and phagocytes; iii) opsonins increase the phagocytosis rate of xenobiotics. [ 34 ]…”

Section: Complement System Activationmentioning

confidence: 99%

Immunogenicity of Polyethylene Glycol Based Nanomedicines: Mechanisms, Clinical Implications and Systematic Approach

d’Avanzo

Celia

Barone

et al. 2020

Advanced Therapeutics

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PEGylation technique is currently considered the gold standard approach to provide a long and safe circulation of drugs. Although this is the accepted dogma, various clinical reports and animal studies show the occurrence of immunogenic responses against polyethylene glycol (PEG) after systemic injection. These side effects, associated with complement activation and/or anti‐PEG antibody production, result in hypersensitivity reactions and lack of therapeutic efficacy of the drug during clinical protocols. Furthermore, different healthy patients show the presence of anti‐PEG antibodies in their blood stream, even though they have not received PEGylated drugs. The aim of this review is to discuss the main mechanisms based on PEG immunogenicity and its clinical implications and report the most promising approaches to reduce these unexpected side effects.

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“…[16][17][18] However, the exact molecular mechanism by which MAC pores kill Gram-negative bacteria remains largely unknown. These studies have revealed the overall dimensions of the MAC and provided structural insights into how the MAC ruptures single-membrane particles, such as liposomes and erythrocytes.…”

Section: Introductionmentioning

confidence: 99%

“…These studies have revealed the overall dimensions of the MAC and provided structural insights into how the MAC ruptures single-membrane particles, such as liposomes and erythrocytes. [16][17][18] However, the exact molecular mechanism by which MAC pores kill Gram-negative bacteria remains largely unknown. The cell envelope of Gram-negative bacteria consists of an outer membrane (OM) that contains a large amount of lipopolysaccharides (LPS), an inner membrane (IM), and a peptidoglycan (PG) layer in between.…”

Section: Introductionmentioning

confidence: 99%

How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram‐Negative Bacteria

2019

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The human immune system can directly lyse invading micro-organisms and aberrant host cells by generating pores in the cell envelope, called membrane attack complexes (MACs). Recent studies using single-particle cryoelectron microscopy have revealed that the MAC is an asymmetric, flexible pore and have provided a structural basis on how the MAC ruptures single lipid membranes. Despite these insights, it remains unclear how the MAC ruptures the composite cell envelope of Gram-negative bacteria. Recent functional studies on Gram-negative bacteria elucidate that local assembly of MAC pores by surface-bound C5 convertase enzymes is essential to stably insert these pores into the bacterial outer membrane (OM). These convertase-generated MAC pores can subsequently efficiently damage the bacterial inner membrane (IM), which is essential for bacterial killing. This review summarizes these recent insights of MAC assembly and discusses how MAC pores kill Gramnegative bacteria. Furthermore, this review elaborates on how MAC-dependent OM damage could lead to IM destabilization, which is currently not well understood. A better understanding on how MAC pores kill bacteria could facilitate the future development of novel strategies to treat infections with Gram-negative bacteria.

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Molecular cell biology of complement membrane attack

Cited by 69 publications

References 77 publications

CD71 improves delineation of PNH type III, PNH type II, and normal immature RBCS in patients with paroxysmal nocturnal hemoglobinuria

CD71 improves delineation of PNH type III, PNH type II, and normal immature RBCS in patients with paroxysmal nocturnal hemoglobinuria

Immunogenicity of Polyethylene Glycol Based Nanomedicines: Mechanisms, Clinical Implications and Systematic Approach

How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram‐Negative Bacteria

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