SIK2008 GENERAL IMMUNOLOGY

AKADEMI PENGAJIAN ISLAM

UNIVERSITI MALAYA

SEMESTER 2 2023/2024

TUTORIAL:

COMPLEMENT SYSTEM & CLASSICAL PATHWAY

INSTRUCTOR:
DR. SITI PATONAH BINTI MOHAMAD

No. Name Matric No.

1. FATIMAH NABIHAH BINTI MOHAMAD KHALID U2000050/2

2. ATIKAH IZZATI BINTI ZAMRI U2000023/2

3. NUHA BINTI BURHANUDDIN U2000058/2

4. AZRA AFIQAH BINTI MOHD HAIR U2000035/2

5. AMIRAH NAJWA ‘IZZATI BINTI ABD. RASHID U2000031/2

6. ASFA BINTI AZAMHARI U2000064/2

7. FATIMAH FAQIHAH BINTI KHAZRI U2000038/2

8. NUR ALYA MUNIRAH BINTI KAMALUDIN U2000059/2

9. SARAH ELLYSYA BINTI SAZALI U2000020/2

10. SYAHIRAH AIMUNI BINTI ABDUL AZIZ U2000076/2

 The complement system, a key component of the innate immune system, was first
recognized by Belgian scientist Jules Bordet in the 1890s. Bordet proposed that blood contained
two distinct protective elements: a heat-stable component (antibodies) and a heat-labile
component (complement). The term “complement” reflects its role in complementing the
heat-stable immune response. In mammals, the complement system consists of several
circulating proteins. These proteins, known as zymogens, remain inactive until they undergo a
biochemical change. When one protein is activated, it triggers a cascade by cleaving and
activating the next protein in the sequence. This coordinated process is aptly named the
complement cascade.

Next is the nomenclature of the complement system. There are nine main complement
proteins which are named with a C followers by a number; ex: C1, C2, C3. When the complement
protein is cleaved, the cleavage products are given a lowercase alphabet after the number; ex;
C3a, C3b and many of these cleavage fragments complex together to form enzymes or other
functional proteins. Complement proteins have numerous roles. They act as a signal for
phagocytic cells like macrophages and B cells, allowing them to better consume pathogens or
serve as markers to indicate target. This process is known as opsonization. Certain complement
proteins can join to produce attack complexes, which open pores in microbial cell membranes.
These structures destroy pathogens by causing their contents to leak. When innate mechanisms
fail to eliminate an infection, the adaptive immune response is alerted and activated.

The complement system is a multi-component system that consists of a group of more than
30 proteins and it only exists in 2 forms: Soluble and Cell-bound. This system was produced
mostly by hepatocytes, monocytes, adipocytes, skin fibroblasts and some epithelial cells. It is a
mechanism of non-specific immunity and specific immunity. Since the complement system can
be found in lower-order organisms, there are three pathways that may be used to activate the
complement system: the Classical, Lectin, and Alternative pathways. Every one of these
pathways will lead to the C3 cleavage, which will subsequently cause the complement system's
effector activities to be triggered.

C1q can bind to some bacterial surfaces, antibodies bound to pathogens or to an acute phase
C-reactive protein that also can bind to bacterial surfaces. The complement system, while
essential for immune defense, can also pose a risk to the body’s own tissues. Therefore, precise
regulatory mechanisms are necessary to control and limit its activation. Various mechanisms
and proteins play a crucial role in inhibiting specific steps within the complement cascade.
Firstly, the enzymes involved are all zymogens which means they need to be activated to be
functional; The enzymatic activity is then restricted to the pathogen’s surface to prevent the
active enzymes from circulating throughout the body. Next, the proteins C3b and C4b contain a
reactive group that becomes inactive unless they promptly bind to a pathogen’s surface. This
mechanism prevents the proteins from tagging the host’s cells. There are also proteins that
regulate the complement activation like C1 inhibitor, decay-accelerating factor, factor H (FH),
vitronectin and protectin. Hence, the complementary system is produced by various cells and
exists in soluble and cell-bound forms, with activation occurring through 3 pathways (the
classical pathway, the lectin pathway and the alternative pathway) which the activation will
leads to a cascade of events that enhance immune reponses and eliminate pathogens.

The classical pathway is the first pathway discovered. It is activated via antigen-antibody
complexes, also known as Ag-Ab binding. It is an antibody dependent activation which binds
with C1, a protein complex. There are 3 distinct subunits that make up C1 which are C1q, C1r
and C1s. The C1q subunit consists of an umbrella-like array of 6 chains, each with a globular
head connected by collagen-like arms to a central stalk. C1r and C1s are categorized as enzymes
called proteases that help to cleave proteins. These enzymes are inactive during normal
conditions.

When this antibody-antigen complex binds with C1, C1s will be activated. C1s will then
cleavage into C4 and C2. Thus, C4 and C2 will form C4b2b which is also called as C3
convertase.C3 convertase will cleave circulating C3 into C3a and C3b. C3a is released into the
circulation to recruit neutrophils and other phagocytes to the site of infection. C3b can bind to
surface of pathogen, coating it in a process called opsonization. It can also bind to existing C3
convertase creating a C5 convertase. Once C5 is formed, it can cleaves C5 into C5a and C5b.
Similar to C3a, C5a released into the circulation to recruit phagocytes. Meanwhile, C5b
nucleates the membrane attack complex, causing the pathogen to lyse.

Then the C5b will bind to the C6 and C7 to form a C5b/C6/C7 complex and acts as a receptor
for C8 and C9 . Next, C8 will bind with the C5b/C6/C7 complex and followed by the
polymerization of up to sixteen C9 molecules together to form the cylindrical Membrane Attack
Complex (MAC) that is important as it generates a channel or pore in the membrane thus the
pathogen can be killed by the swelling and bursting of the cells which named of cell lysis or cell
death.

The classical pathway of the complement system is a vital part of our immune system's
defense against invaders like bacteria and viruses. It marks these invaders for destruction
through opsonization, helps trigger inflammation to fight off threats, and directly attacks
invaders by causing their cells to burst. However, when the immune system becomes confused,
it can mistakenly attack the body's cells, leading to autoimmune diseases. Overall, the classical
pathway is a crucial defense mechanism, protecting our body from harm and maintaining our health.