Spectrum and Management of Complement Immunodeficiencies (Excluding Hereditary Angioedema) Across Europe

Turley, A.J.; Gathmann, Benjamin; Bangs, Catherine; Bradbury, Mark; Seneviratne, Suranjith L.; González-Granado, Luis Ignacio; Hackett, Scott; Kütükçüler, Necil; Alachkar, Hana; Hambleton, Sophie; Ritterbusch, Henrike; Králíčková, Pavlína; Maródi, László; Seidel, Markus G.; Dueckers, G; Roesler, Joachim; Huissoon, Aarnoud; Baxendale, Helen; Litzman, Jiří; Arkwright, Peter D.

doi:10.1007/s10875-015-0137-5

Cited by 42 publications

(34 citation statements)

References 42 publications

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“…It results from activation of the complement cascade (present in blood and most bodily fluids; Kang et al , ; Ricklin et al , ), when newly formed C5b6 complexes bind C7, C8, and multiple C9 molecules to build hetero‐oligomeric MAC pores into target cell membranes. The MAC has an essential role in human immune protection against Gram‐negative bacteria; this is evident from recurrent infections in patients lacking MAC activity due to genetic deficiencies (Ram et al , ; Turley et al , ) or due to treatment with complement‐inhibitory drugs (Konar & Granoff, ; McNamara et al , ; Ricklin et al , ). Since MAC‐dependent cell lysis can be specifically triggered via antibodies, this killing mechanism is also exploited for therapeutic development of antibodies that target cancer cells or drug‐resistant bacterial infections (Szijártó et al , ; de Jong et al , ).…”

Section: Introductionmentioning

confidence: 99%

Bacterial killing by complement requires membrane attack complex formation via surface‐bound C5 convertases

et al. 2019

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The immune system kills bacteria by the formation of lytic membrane attack complexes (MACs), triggered when complement enzymes cleave C5. At present, it is not understood how the MAC perturbs the composite cell envelope of Gram‐negative bacteria. Here, we show that the role of C5 convertase enzymes in MAC assembly extends beyond the cleavage of C5 into the MAC precursor C5b. Although purified MAC complexes generated from preassembled C5b6 perforate artificial lipid membranes and mammalian cells, these components lack bactericidal activity. In order to permeabilize both the bacterial outer and inner membrane and thus kill a bacterium, MACs need to be assembled locally by the C5 convertase enzymes. Our data indicate that C5b6 rapidly loses the capacity to form bactericidal pores; therefore, bacterial killing requires both in situ conversion of C5 and immediate insertion of C5b67 into the membrane. Using flow cytometry and atomic force microscopy, we show that local assembly of C5b6 at the bacterial surface is required for the efficient insertion of MAC pores into bacterial membranes. These studies provide basic molecular insights into MAC assembly and bacterial killing by the immune system.

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Section: Introductionmentioning

confidence: 99%

Bacterial killing by complement requires membrane attack complex formation via surface‐bound C5 convertases

et al. 2019

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“…The chimera Cpl-711 was the most efficient lysin, reducing the colonization by S. pneumoniae not only of nasopharyngeal cells but also of lung cells. This is of great relevance in terms of public health, as the clearance of the pneumococcal carrier state might be beneficial for certain groups at risk of suffering recurrent IPD episodes (31,(34)(35)(36)(37). The results of the present study demonstrate that the local administration of enzybiotics successfully kills the bacteria attached to nasopharyngeal and lung epithelial cells, being effective in the reduction of colonization of cell tissues and mucous sites, which might be very important from a prophylactic perspective.…”

Section: Discussionmentioning

confidence: 58%

Chemotherapy with Phage Lysins Reduces Pneumococcal Colonization of the Respiratory Tract

Corsini

Díez-Martínez

Aguinagalde

et al. 2018

Antimicrob Agents Chemother

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Bacteriophage-borne lytic enzymes, also named lysins or enzybiotics, are efficient agents for the killing of bacterial pathogens. The colonization of the respiratory tract by is a prerequisite for the establishment of the infection process. Hence, we have evaluated the antibacterial activities of three different lysins against pneumococcal colonization using human nasopharyngeal and lung epithelial cells as well as a mouse model of nasopharyngeal colonization. The lysins tested were the wild-type Cpl-1, the engineered Cpl-7S, and the chimera Cpl-711. Moreover, we included amoxicillin as a comparator antibiotic. Human epithelial cells were infected with three different multidrug-resistant clinical isolates of followed by a single dose of the corresponding lysin. The antimicrobial activities of these lysins were also evaluated using a mouse nasopharyngeal carriage model. The exposure of the infected epithelial cells to Cpl-7S did not result in the killing of any of the pneumococcal strains investigated. However, the treatment with Cpl-1 or Cpl-711 increased the killing of organisms adhered to both types of human epithelial cells, with Cpl-711 being more effective than Cpl-1, at subinhibitory concentrations. In addition, a treatment with amoxicillin had no effect on reducing the carrier state, whereas mice treated by the intranasal route with Cpl-711 showed significantly reduced nasopharyngeal colonization, with no detection of bacterial load in 20 to 40% of the mice. This study indicates that Cpl-1 and Cpl-711 lysins might be promising antimicrobial candidates for therapy against pneumococcal colonization.

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“…This complex forms a channel that allows the free diffusion of substance, disrupting the cellular osmotic balance and leading to death of the invading organism [7]. Inherited complement deficiencies are rare [2], corresponding to 4.9% of all primary immunodeficiencies [8]. The most common one is C1 deficiency, occurring in 0.01% of the population [9].…”

Section: Discussionmentioning

confidence: 99%

Necrotizing Fasciitis in the Puerperium of a Woman with Complement Deficiency: Case Report and Review Literature

Vettorazzi¹,

Valério²,

Faulhaber³

et al. 2018

OJOG

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Complement deficiencies are uncommon types of primary immunodeficiency. Necrotizing fasciitis is a rare complication in pregnancy characterized by soft tissue invasion and necrosis of the subcutaneous and other adjacent tissues, leading to high mortality rates. We report a case of a 29-year-old pregnant woman with functional deficiency of the C4 complement component and short uterine cervix. Admitted at the hospital with preterm labor, she received multiple doses of immunoglobulin. After 8 weeks, she had a premature membrane rupture, and due to pelvic presentation she had a cesarean. The patient presented multiple obstetric complications, such as operative wound infection, endometritis, sepsis, necrotizing fasciitis and pelvic septic thrombophlebitis. She underwent multiple antimicrobial schemes, a hysterectomy and 4 extensive debridements of the abdominal wall because of significant necrosis. She stayed at the hospital for 101 days (32 of those in ICU in immediate postpartum). 41 days after cesarean, patient was discharged in good conditions. Our case emphasizes individual handling and high multiple doses of immunoglobulin for favorable outcome of the case.

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Spectrum and Management of Complement Immunodeficiencies (Excluding Hereditary Angioedema) Across Europe

Cited by 42 publications

References 42 publications

Bacterial killing by complement requires membrane attack complex formation via surface‐bound C5 convertases

Bacterial killing by complement requires membrane attack complex formation via surface‐bound C5 convertases

Chemotherapy with Phage Lysins Reduces Pneumococcal Colonization of the Respiratory Tract

Necrotizing Fasciitis in the Puerperium of a Woman with Complement Deficiency: Case Report and Review Literature

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