A18, 19, 20 Inflammation; Classical pathways of Complement System; Lectin Pathway of Complement System

Question 1

Inflammation

Answer 1

• Part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants.
• A protective attempt by the organism to remove the injurious stimuli and to initiate the healing process.
• Not a synonym for infection, even in cases where inflammation is caused by infection. Although infection is caused by a microorganism, inflammation is one of the responses of the organism to the pathogen.
• However, inflammation is a stereotyped response, and therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen.
• Inflammation can be classified as either acute or chronic.

Question 2

Acute inflammation

Answer 2

is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues.
▪ A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue.
• Acute inflammation: IL-8, IL-16, G-CSF

Question 3

Chronic inflammation

Answer 3

o Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
• Chronic inflammation: IL-2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14, 15, IFN

Question 4

Complement System

Answer 4

• Helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. • It is part of the innate immune system that is not adaptable . However, it can be recruited and brought into action by the adaptive immune system.
• The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins).
• When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages.
• The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex.
• > 25 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. They account for about 5% of the globulin fraction of blood serum.
• Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway

Question 5

Basic functions of the complement

Answer 5

o Opsonization - enhancing phagocytosis of antigens o Chemotaxis - attracting macrophages and neutrophils
o Lysis – rupturing membranes of foreign cells, clumping of antigen-bearing agents

Question 6

Classical Pathway

Answer 6

1. The classical pathway is triggered by activation of the C1-complex (composed of 1 molecule of C1q, 2 molecules of C1r and 2 molecules of C1s, thus forming C1qr2 s2), which occurs when C1q binds to IgM or IgG complexed with antigens (a single IgM can initiate the pathway, while multiple IgGs are needed), or when C1q binds directly to the surface of the pathogen.
2. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two C1r molecules. They then cleave C1s. The C1r2 s2 component now splits C4 and then C2, producing C4a, C4b, C2a, and C2b.
3. C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b; C3b later joins with C4b2b (the C3 convertase) to make C5 convertase (C4b2b3b complex).
4. The inhibition of C1r and C1s is controlled by C1-inhibitor.

Question 7

Lectin Pathway:

Answer 7

• Homologous to the classical pathway, but with the opsonin, mannose-binding lectin (MBL), and ficolin, instead of C1q.
• Antibody independent
• Activated by binding of MBL to mannose residues on the pathogen surface, which activates the MBL associated serine proteases, MASP-1, and MASP-2 (very similar to C1r and C1s), which can then split C4 into C4a and C4b and C2 into C2a and C2b.
• C4b and C2b then bind together to form the classical C3-convertase, as in the classical pathway.

Question 8

Alternative Pathway:

Answer 8

• Antibody independent – instead it is activated by the spontaneous hydrolysis of C3 (due to breakdown of internal thioester bond) to C3a and C3b.
• Binding surfaces: bacteria, yeast, fungi, tumor cells, virus infected cells, etc
• The instable thioester bond in C3 is activated, binds C3b to hydroxyl or amino group of surfaces, the Ag binds through C5 and C3b receptors of phagocytic cells