The Membrane Attack Complex Can Lyse a Broad Spectrum of Cells

The membrane-attack complex formed by complement activation can lyse gram-negative bacteria, parasites, viruses, erythrocytes, and nucleated cells. Because the alternative and lectin pathways of activation generally occur without an initial antigen-antibody interaction, these pathways serve as important innate immune defenses against infectious microorganisms. The requirement for an initial antigen-antibody reaction in the classical pathway supplements these nonspecific innate defenses with a more specific defense mechanism. In some instances, the requirement for antibody in the activating event may be supplied by so-called natural antibodies, which are raised against common components of ubiquitous microbes.

The importance of cell-mediated immunity in host defense against viral infections has been emphasized in previous chapters. Nevertheless, antibody and complement do play a role in host defense against viruses and are often crucial in containing viral spread during acute infection and in protecting against reinfection. Most—perhaps

CLINICAL FOCUS

Paroxymal Nocturnal Hemoglobinuria: a Defect in Regulation of Complement Lysis

Common conditions associated with deficiency in the complement components include increased susceptibility to bacterial infections and systemic lupus erythematosus which is related to the inability to clear immune complexes. Deficiency in the proteins that regulate complement activity can cause equally serious disorders. An example is paroxymal nocturnal hemoglo-binuria, or PNH, which manifests as increased fragility of erythrocytes, leading to chronic hemolytic anemia, pancy-topenia (loss of blood cells of all types) and venous thrombosis (formation of blood clots). The name PNH derives from the presence of hemoglobin in the urine, most commonly observed in the first urine passed after a night's sleep. The cause of PNH is a general defect in synthesis of cell-surface proteins, which affects the expression of two regulators of complement, DAF (decay accelerating factor or CD55) and MIRL (membrane inhibitor of reactive lysis or CD59).

DAF and MIRL are cell-surface proteins that function as inhibitors of com plement-mediated cell lysis, but act at different stages of the process. DAF inhibits cell lysis by causing dissociation and inactivation of the C3 convertases of the classical, lectin, and alternative pathways (see Figure 13-9b). MIRL acts later in the pathway by binding to the C5b678 complex, which inhibits C9 binding and prevents formation of the pores that destroy the cell under attack. Both proteins are expressed on erythrocytes as well as a number of other hematopoetic cell types. Deficiency in these proteins leads to highly increased sensitivity of host cells to the lytic effects of the host's complement activity. PNH, the clinical consequence of deficiency in DAF and MIRL, is a chronic disease with a mean survival time between 10 and 15 years. The most common causes of mortality in PNH are venous thrombosis affecting hepatic veins and progressive bone-marrow failure.

An obvious question about this rare but serious disease concerns the fact that two different proteins are involved in its pathogenesis. The simultaneous occurrence of a genetic defect in each of them would be rarer than the 1 in 100,000 incidence of PNH. The answer is that neither protein itself is defective in PNH; the defect lies in a posttransla-tional modification of the peptide anchor that binds them to the cell membrane. While most proteins that are expressed on the surface of cells have hydrophobic sequences that traverse the lipid bilayer in the cell membrane, some proteins are bound by glycol ipid anchors (glycosyl phosphatidylinositol, or GPI) attached to amino acid residues in the protein. Without the ability to form GPI anchors, proteins that attach in this manner will be absent from the cell surface, including both DAF and MIRL.

The defect identified in PNH lies early in the enzymatic path to formation of a GPI anchor and resides in the pig-a gene (phosphatidylinositol glycan complementation class A gene). Transfection of cells from PNH patients with an intact pig-a gene restored the cells' resistance to host complement lysis. Examination of pig-a sequences in PNH patients reveals a number of different defects in this X-linked gene, indicating somatic rather than genetic origin of the defect. This description of PNH underscores the fact that the complement system is a powerful defender of the host but also a dangerous one. Complex systems of regulation are necessary to protect host cells from the activated complement complexes generated to lyse intruders.

all—enveloped viruses are susceptible to complement-mediated lysis. The viral envelope is largely derived from the plasma membrane of infected host cells and is therefore susceptible to pore formation by the membrane-attack complex. Among the pathogenic viruses susceptible to lysis by complement-mediated lysis are herpesviruses, orthomyxoviruses, paramyxoviruses, and retroviruses.

The complement system is generally quite effective in lysing gram-negative bacteria (Figure 13-11). However, some gram-negative bacteria and most gram-positive bacteria have mechanisms for evading complement-mediated damage (Table 13-5). For example, a few gram-negative bacteria can develop resistance to complement-mediated lysis that correlates with the virulence of the organism. In Escherichia coli and Salmonella, resistance to complement is associated with the smooth bacterial phenotype, which is characterized by the presence of long polysaccharide side chains in the cell-wall lipopolysaccharide (LPS) component. It has been proposed that the increased LPS in the wall of resistant strains may prevent insertion of the MAC into the bacterial membrane, so that the complex is released from the bacterial cell rather than forming a pore. Strains of Neisseria

Summary of biological effects mediated by complement products

Effect

Complement product mediating*

Cell lysis

Inflammatory response

Degranulation of mast cells and basophils* Degranulation of eosinophils

Extravasation and chemotaxis of leukocytes at inflammatory site Aggregation of platelets

Inhibition of monocyte/macrophage migration and induction of their spreading Release of neutrophils from bone marrow Release of hydrolytic enzymes from neutrophils Increased expression of complement receptors type 1 and 3 (CR1 and CR3) on neutrophils

Opsonization of particulate antigens, increasing their phagocytosis

Viral neutralization

Solubilization and clearance of immune complexes

C5b-9, the membrane-attack complex (MAC)

C3a,C4a, and C5a (anaphylatoxins)

C3a, C5a

C3a, C5a, C5b67

C3a, C5a

C3c C5a C5a

*Boldfaced component is most important in mediating indicated effect.

TDegranulation leads to release of histamine and other mediators that induce contraction of smooth muscle and increased permeability of vessels.

gonorrheae resistant to complement-mediated killing have been associated with disseminated gonococcal infections in humans. Some evidence suggests that the membrane proteins of resistant Neisseria strains undergo noncovalent interactions with the MAC that prevent its insertion into the outer membrane of the bacterial cells. These examples of resistant gram-negative bacteria are the exception; most gram-negative bacteria are susceptible to complement-mediated lysis.

Gram-positive bacteria are generally resistant to complement-mediated lysis because the thick peptidoglycan layer in their cell wall prevents insertion of the MAC into the inner membrane. Although complement activation can occur on the cell membrane of encapsulated bacteria such as Streptococcus pneumoniae, the capsule prevents interaction between C3b deposited on the membrane and the CR1 on phagocytic cells. Some bacteria possess an elastase that inactivates C3a and C5a, preventing these split products from inducing an

Complement-binding receptors

Receptor

Major ligands

Activity

Cellular distribution

CR1 (CD35)

CR2 (CD21)

C3a/C4a receptor C5a receptor

C3b, C4b

C3d, C3dg, iC3b iC3b

C3a, C4a C5a

Blocks formation of C3 convertase; binds immune complexes to cells

Part of B-cell coreceptor; binds Epstein-Barr virus

Bind cell-adhesion molecules on neutrophils, facilitating their extravasation; bind immune complexes, enhancing their phagocytosis

Induces degranulation of mast cells and basophils

Induces degranulation of mast cells and basophils

Erythrocytes, neutrophils, monocytes, macrophages, eosinophils, follicular dendritic cells, B cells, some T cells

B cells, follicular dendritic cells, some T cells

Monocytes, macrophages, neutrophils, natural killer cells, some T cells

Mast cells, basophils, granulocytes

Mast cells, basophils, granulocytes, monocytes, macrophages, platelets, endothelial cells

*Cleavage of C3dg by serum proteases generates C3d and C3g.

Erythrocyte Membrane Blebbing
FIGURE 13-11

Scanning electron micrographs of E. colishowing (a) intact cells and (b, c) cells killed by complement-mediated lysis.

Note membrane blebbing on lysed cells. [From R. D. Schreiber et al., 1979, J. Exp. Med. 149:870.]

inflammatory response. In addition to these mechanisms of evasion, various bacteria, viruses, fungi, and protozoans contain proteins that can interrupt the complement cascade on their surfaces, thus mimicking the effects of the normal complement regulatory proteins C4bBP, CR1, and DAF.

Lysis of nucleated cells requires formation of multiple membrane attack complexes, whereas a single MAC can lyse a red blood cell. Many nucleated cells, including the majority of cancer cells, can endocytose the MAC. If the complex is removed soon enough, the cell can repair any membrane

TABLE 13-51 Microbial evasion of complement-mediated damage

Microbial component

Mechanism of evasion

Examples

GRAM-NEGATIVE BACTERIA

Long polysaccharide chains in cell-wall LPS

Side chains prevent insertion of MAC into bacterial membrane

Resistant strains of E. coli and Salmonella

Outer membrane protein

MAC interacts with membrane protein and fails to insert into bacterial membrane

Resistant strains of Neisseria gonorrhoeae

Elastase

Anaphylatoxins C3a and C5a are inactivated by microbial elastase

Pseudomonas aeruginosa

GRAM-POSITIVE BACTERIA

Peptidoglycan layer of cell wall

Insertion of MAC into bacterial membrane is prevented by thick layer of peptidoglycan

Streptococcus

Bacterial capsule

Capsule provides physical barrier between C3b deposited on bacterial membrane and CR1 on phagocytic cells

Streptococcus pneumoniae

OTHER MICROBES

Proteins that mimic complement regulatory proteins

Protein present in various bacteria, viruses, fungi, and protozoans inhibit the complement cascade

Vaccinia virus, herpes simplex, Epstein-Barr virus, Trypanosoma cruzi, Candida albicans

KEY: CR1 = type 1 complement receptor; LPS = lipopolysaccharide; MAC = membrane-attack complex (C5b-9).

KEY: CR1 = type 1 complement receptor; LPS = lipopolysaccharide; MAC = membrane-attack complex (C5b-9).

damage and restore its osmotic stability. An unfortunate consequence of this effect is that complement-mediated lysis by antibodies specific for tumor-cell antigens, which offers a potential weapon against cancer, may be rendered ineffective by endocytosis of the MAC (see Chapter 22).

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Responses

  • gerry whited
    Why do bacteria lyse red blood cells?
    8 years ago
  • janne
    Why RBC need a single MAC to lyse while nucleated cells need a multiple MAC to lyse?
    8 years ago
  • Tarquinio
    Are gram positive bacteria lysed by complement?
    8 years ago
  • Irvin Bledsoe
    How does complement lyse bacterial cell walls?
    8 years ago
  • Agenore
    Do gram negative bacteria lyse red blood cells?
    7 years ago
  • willow paterson
    Why cant mac lyse gram positive bacteria?
    7 years ago
  • berilac
    Why is Membrane Attack Complex more effective against gram negative bacteria than gram postive?
    7 years ago
  • primrose bolger
    What doess activation of complement achieve in addition to lysing susceptible bacteria?
    7 years ago
  • clara
    What does lysozyme do in conjuction with membrane attack complex?
    7 years ago
  • DEAN
    How does membrane attack complex destroy encapsulated microbes?
    7 years ago
  • Tesmi
    What cells are associated with the membrane attack complex?
    7 years ago
  • ami
    What type of bacteria is the Membrane Attack Complex (MAC) least effective of?
    7 years ago
  • idris kifle
    Why are enveloped viruses susceptible to complementedmediated lysis?
    7 years ago
  • charlie
    Can membrane attack complex lyse gram negative bacteria?
    5 years ago
  • klaus
    Why is formation of membrane attack complexes more effective against gram negative?
    5 years ago
  • birikti
    Why lysis of nucleated cell require multiple MAC wherase single mac can lyse RBC?
    4 years ago
  • neftalem kinfe
    Can membrane attack complex estroy gram positive?
    4 years ago
  • liya
    What components in blood can lyse pathogens using membrane attack complex system?
    4 years ago
  • winta yemane
    Why RBC required a single MAC for lysis?
    3 years ago
  • vanessa
    How membrane attack complex lead to lyse Gram positive bacteria?
    3 years ago
  • juliane
    Why nucleated cells require mutiple MAC to lyse?
    3 years ago
  • asmeret
    Why membranes attack complex is only effective on gram negetive not gram positive?
    3 years ago
  • maryam
    Why gram positive bacteria is resistant to complement lysis?
    3 years ago
  • andrea
    Is gram positive or negative susceptible to MAC?
    3 years ago
  • ROBIN
    Which group of bacteria are more susceptible to membrane attack complex?
    2 years ago
  • Rosa
    What kind of bacteria are susceptible to MAC?
    2 years ago
  • GOYTIOM
    How the membrane attack complex can lyse a broad spectrum of cells?
    2 years ago
  • malva
    How does the membrane attack complex (mac) kill gramnegative bacteria?
    2 years ago
  • folcard
    Which is least sensitive to complement mediated lysis between leukocytes and gram positive bacteria?
    2 years ago
  • mari
    Why streptococcus ,pseudomonas are resistent to MAC lysis?
    2 years ago
  • jari groop
    What type of bacteria are not susceptible to MAC?
    2 years ago
  • gloria bristol
    Which bacteria are susptible to lysis by membrane attack complex?
    1 year ago
  • PETTERI
    Which group of organism is more susceptible to MAC and why?
    1 year ago
  • Phillipp Thalberg
    What bacterial microbes does the mac complex target?
    12 months ago
  • steffen durr
    How gram negative bacteria attack bacteria cells?
    9 months ago
  • DODINAS
    Why gram positive bacteria are resistant to compelment lysis?
    8 months ago
  • adalgiso
    How are pathogens killed bt the mac complex?
    7 months ago
  • eila
    What type if cells does MAC lyse?
    4 months ago

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