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Radiation toxicity: complement system activation.
1. Dmitri Popov. PhD, Radiobiology.
MD (Russia)
Advanced Medical Technology and Systems Inc.
Canada.
intervaccine@gmail.com
Radiation toxicity: Complement system
activation, Membrane Attack Complex.
2. Radiation Toxicity: Complement
Cascade Activation, MAC formation
Activation of the complement system is,
however, also involved in the pathogenesis of the
systemic Acute Radiation Syndromes.
3. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
Complement system is composed of more than
25 different proteins produced by hepatocytes,
macrophages and intestinal epithelial cells.
Fibroblasts and intestinal epithelial cells make C1,
while the liver makes C3, C6, and C9.
Complement proteins are present in the
circulation as inactive molecules.
4. Radiation Toxicity: Complement
Cascade Activation, MAC formation
Complement is part of the innate immune system.
Its major function is recognition and elimination of
pathogens via direct killing and/or stimulation of
phagocytosis.
Activation of the complement system , however,
also involved in the pathogenesis of the systemic
autoimmune diseases.
Activation of the complement system also
involved in the pathogenesis of the Acute
Radiation Syndromes, Membrane Attack Complex
formation and cell necrosis after irradiation.
5. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
Activation of the complement system involves participation of
a large number of plasma proteins including C1q, C1r, C1s, C2
through C9, factor B, factor D, and properdin. There are three
pathways of complement activation, i.e. the classical, alternative
and lectin pathway. All three pathways are activated in a
sequential manner, with activation of one component leading to
activation of the next.
Min Chen a,b, Mohamed R. Daha c, Cees G.M. Kallenberg a,*
a Department of Rheumatology and Clinical Immunology,
University Medical Center Groningen, University of Groningen,
The Netherlands
b Renal Division, Peking University First Hospital, Beijing
100034, China
c Department of Nephrology, Leiden University Medical Center,
The Netherlands.
6. Membrane Attack Complex.
The membrane attack complex (MAC) is
typically formed on the surface
of pathogenic bacterial cells as a result of the
activation of the host's alternative pathway and
the classical pathway of the complement system,
and it is one of the effector proteins of
the immune system. The membrane-attack
complex (MAC) forms transmembrane channels.
These channels disrupt the phospholipid bilayer
of target cells, leading to cell lysis and death
7. Membrane Attack Complex.
A number of proteins participate in the assembly
of the MAC. Freshly activated C5b binds to C6 to
form a C5b-6 complex, then to C7 forming the
C5b-6-7 complex. The C5b-6-7 complex binds to
C8, which is composed of three chains (alpha,
beta, and gamma), thus forming the C5b-6-7-8
complex. C5b-6-7-8 subsequently binds to
C9 and acts as a catalyst in the polymerization of
C9.
Active MAC has a subunit composition of C5b-
C6-C7-C8-C9.
9. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
An essential aspect of innate immunity is
recognition of molecular patterns on the surface
of pathogens or altered self through the lectin and
classical pathways, two of the three well-
established activation pathways of the
complement system.
Altered self – after irradiation.
10. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
The ability of pattern-recognition molecules to
bind foreign markers such as pathogen-
associated molecular patterns is central to the
innate immune defense. One such defense
mechanism is complement, which is capable of
recognizing molecular patterns associated with
microbes and apoptotic or necrotic cells
11. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
Recognition causes activation of proteolytic enzyme
cascades, resulting in cleavage of the complement
proteins C3, C4, and C5. Fragments of these proteins
have important effector functions through binding to
host cell receptors and pathogen surfaces.
Rune T. Kidmosea,1, Nick S. Laursena,1, József
Dobób , Troels R. Kjaerc , Sofia Sirotkinaa , Laure
Yatimea , Lars Sottrup-Jensena , Steffen Thielc ,
Péter Gálb , and Gregers R. Andersena,2
Departments of a Molecular Biology and Genetics and
c Biomedicine, Aarhus University, DK-8000 Aarhus,
Denmark; and b Institute of Enzymology, Research
Centre for Natural Sciences, Hungarian Academy of
Sciences, H-1113, Budapest, Hungary
12. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
Complement is traditionally thought of as a pro-
inflammatory effector mechanism of antitumor immunity.
However, complement is also important for effective
clearance of apoptotic cells, which can be an anti-
inflammatory and tolerogenic process. We show that
localized fractionated radiation therapy (RT) of
subcutaneous murine lymphoma results in tumor cell
apoptosis and local complement activation. Cotreatment of
mice with tumor-targeted complement inhibition markedly
improved therapeutic outcome of RT, an effect linked to
early increases in apoptotic cell numbers and increased
inflammation.
Complement-dependent modulation of antitumor
immunity following radiation therapy.
Elvington M1, Scheiber M1, Yang X1, Lyons K2, Jacqmin
D2, Wadsworth C1, Marshall D2, Vanek K2, Tomlinson S3.
13. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
In cells irradiation by heavy ions has been hypothesized to produce
microlesions, regions of local damage. In cell membranes this damage
is thought to manifest itself in the form of holes. The primary evidence
for microlesions comes from morphological studies of cell membranes,
but this evidence is still controversial, especially since holes also have
been observed in membranes of normal, nonirradiated, cells. However,
it is possible that damage not associated with histologically discernable
disruptions may still occur. In order to resolve this issue, we developed
a system for detecting microlesions based on liposomes filled with
fluorescent dye. We hypothesized that if microlesions form in these
liposomes as the result of irradiation.
Detection of microlesions induced by heavy ions using liposomes filled
with fluorescent dye
Original Research Article
Pages 1373-1377
J.P. Koniarek, J.L. Thomas, M. Vazquez
14. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
Damage of cell membranes after irradiation
possible occur after membrane attack complex
action.
Proteins of the complement membrane attack
complex (MAC) and the protein perforin (PF)
share a common MACPF domain that is
responsible for membrane insertion and pore
formation (Cajnko et al. 2014)
15. Radiation Toxicity: Complement
Cascade Activation, MAC formation.
Appropriate complement inhibition with
monoclonal antibodies playing a promising
strategy to enhance a mainstay of treatment for
Acute Radiation Syndromes.