The Complement System: Role in Immunity

This article will discuss the role of the complement system in the body’s defense mechanisms, including its site of origin and mechanism of action.

Table of Contents

1. Complement activation results in
2. Site of synthesis
   1. Nomenclature of complement
   2. Main types of complements
3. The complement system gets activated by three biochemical pathways-
4. Functions of the Complement System:
5. Mechanisms of Lysis
   1. Regulation of the Complement System
6. Applied
   1. Diagnosis

Introduction

The complement system is crucial in the body’s defense against invading pathogens and tumor cells. Its components enhance the antibacterial activities of antibodies.

The complement system, or the complement cascade, consists of over 50 small inactive protein precursors in blood, body fluids, and tissues. They contribute about 10% of the globulin of plasma protein. The inactive form is known as zymogen. When stimulated by appropriate stimulus, proteases in the system cleave specific zymogen to release active enzymes.

Complement activation results in

1. Opsonization-to speed up phagocytosis.

2. Formation of ‘membrane attack complex (MAC) to cytolyse or cell killing and

3. Produce inflammation to attract phagocytic cells and other immunocompetent cells to the invasion site.

Site of synthesis

Hepatocytes synthesize complement molecules.

Monocytes, macrophages, platelets, and epithelial tissues of the gastrointestinal tract and urogenital tract also contribute in small amounts.

The complement system is a system of plasma enzymes. The liver synthesizes enzymes of the complement system. It comprises over 50 enzymes circulating in the blood and is responsible for cell killing by humoral and cellular immunity.

The precursors are zymogens, inactive enzymes in the blood, body fluids, and tissues. When stimulated, they become active enzymes at sites of infection locally and trigger events that exert effects when stimulated by an antigen-antibody complex or other pathways.

When in active form, they work in a sequence of cascade reactions to remove pathogens, kill pathogens, initiate and promote inflammation, and activate other immunological cells.

In a complement cascade system, an active complement enzyme formed by cleavage of its zymogen precursor then cleaves its substrate, another complement zymogen, to its active enzyme to form. This, in turn, cleaves and activates the next zymogen of the complement pathway. In this way, activating a small number of complement proteins at the start of the path, amplified by each successive enzymatic reaction, rapidly generates a significant complement response.

There are many regulatory mechanisms to prevent uncontrolled complement activation.

Nomenclature of complement

All components of the classical complements are designated by the letter C followed by a number, for example, C1. The number was allotted in the order of their discovery.

The products of the cleavage reaction of a complement are designated ‘b’ for large fragments and ‘a’ for small fragments.

Main types of complements

There are nine named complement enzymes in the complement system, and their names are C1, C2, C3, C4, C5, C6, C7, C8, and C9. Complement C1 has three subunits C1q, C1r, and C1s. The C1 complex has one molecule of C1q, two molecules of C1r, and two molecules of C1s.

Activating one complement of this system triggers cascade reactions that activate other system complements.

The complement system gets activated by three biochemical pathways-

The three pathways generate protease C3 convertase. The formation of C3 convertase is an early event of complement activation, and the formation of C5 convertase and onwards is a late event.

1. Classical Pathway-Antibody- antigen complex binds with C1 and activates C1. Activated C1 triggers a sequence of reactions that activates C3. As the classical pathway requires the antigen-antibody complex for activation, it is involved in specific immune responses. Activation occurs when C1q binds to the Fc portion of pentamer IgM or six units of IgG monomer. C1q can bind directly to the pathogen surface.

These bindings cause conformational changes in the C1q molecules, which lead to the activation of C1r, which cleaves C1s.The C1r,s split C4 and C2 to form

C4——–C1r,C1s———–àC4a and C4b.

C2———C1r,C1s———-à C2a and C2b.

C4b and C2b form C3 convertase, which cleaves C3 into C3a and C3b.

C3b joins with C4b and C2b to make a (C4b, C2bC3b complex), which promotes the formation of C5 convertase. C4b and C3b can bind to the Fc portion of immunoglobulins.

2. Lectin Pathway:

The lectin pathway activates the complement system without the presence of an antibody. It occurs by antigen and C3 hydrolysis. Mannose-binding lectin (MBL)binds with mannose residues on the surface of the bacterial wall and stimulates the MBL-associated serine proteases MASP-1 and MASP-2, which split.

C4 to C4a and C4b and C2 into C2a and C2b.

C4b and C2b join to form the classical C3 convertase. MBL fixation on viral surfaces enhances the neutralization of viruses—complement system.

3. Properdin or Alternative pathway–

Alternative pathways do not depend on the antigen-antibody complex; they are essential to innate immunity.

The alternative pathway is always active at a low level. This is due to spontaneous C3 hydrolysis forming C3 convertase due to the breakdown of the internal thioesters bond.

C3b is formed, which is unstable in aqueous media. Factor H and I rapidly inactivate the C3 convertase.

Pathogens do not have complement regulatory proteins on their surfaces, but they do on the host cells. The alternative pathway distinguishes self from non-self due to the presence of complement regulatory proteins.

When a complement is activated on a host cell surface, the activation is limited by endogenous complement regulator proteins, which include CD35, CD46, CD55, and CD59. Host cells do not have cell surface C3b receptors, but foreign cells, pathogens, and abnormal cells may have many C3b receptors.

Polysaccharides on invading microbes’ bacterial cell walls, tumor cells interact with Properdin and initiate the complement system. Spontaneous hydrolysis of C3 forms active C3 that activates the complement cascade. and C5.

When active, the complement system causes invading microorganisms and tumor cells to lysis.

Each pathway generates a protease called C3 convertase. The reactions causing the formation of C3 convertase are early events of complement activation, which consists of triggered-enzyme cascades in which inactive complement zymogens are successively cleaved to yield two fragments, the larger of which is an active serine protease. The active protease remains at the pathogen surface and ensures that the next complement zymogen in the pathway is cleaved and activated at the pathogen surface.

The small peptide fragment is released from the reaction site and acts as a soluble mediator.

In the early events of complement activation, C3 convertase is formed that will bind to the pathogen surface. The formation of C3 convertase activity is pivotal in complement activation. Here, they cleave C3 to generate large amounts of C3b and C3a. The C3b molecule is the primary effector molecule of the complement system. C3a is a peptide mediator of inflammation.

The C3b molecules act as opsonins and react with phagocytes that have receptors for C3b. They also bind to the C3 convertase to form a C5 convertase that produces the C5a and C5b.

The C5a is an essential small peptide mediator of inflammation.

The C5b initiates the late events of complement activation. These comprise a sequence of polymerization reactions in which the terminal complement components interact to form a membrane-attack complex (MAC).The mac consists of C5b,C6,C7,C8,and polymeric C9.

Functions of the Complement System:

1. Opsonization

Complements, especially C3b, coat the surface of pathogens, enabling efficient and prompt phagocytosis by phagocytic cells.

Opsonization is a process of coating the surface of pathogens with complement enzymes.

1. Cell lysis:

Complements C5b, C6, C7, C8, and C9 form a membrane attack complex (MAC) that penetrates the cell membrane and leads to cell death.

1. Inflammation

Active C3 (C3a)and C5(C5a) cause histamine release from granulocytes, mast cells, and platelets. Histamine is a potent vasodilator. Blood vessels dilate under the influence of histamine, increasing capillary permeability, so leucocytes and other cells come to the antigen-antibody complex site, causing inflammation.

4. Enhancement of antibody-dependent cell-mediated cytotoxicity

The complement system enhances antibody-dependent cell-mediated (ADCC) so that immune cells, for example, natural killer cells, destroy target cells.

Mechanisms of Lysis

1. The active complement from C5 to C9 causes perforation in the cell membrane of invading microorganisms and tumor cells. Ions enter the cell and cause its death.

2. Active C3 (C3a) and C5(C5a) release histamine from granulocytes, mast cells, and platelets. Histamine is a potent vasodilator. Blood vessels dilate under the influence of histamine, increasing capillary permeability, so leucocytes and other cells come to the antigen-antibody complex site.

3. Active C3of the system performs two functions-

It causes opsonization and phagocytosis of bacteria.

It activates other complement enzymes.

4. Active C5, C6, and C7 attracts WBCs to antigen-antibody reaction site.

Regulation of the Complement System

Complement control proteins in the blood and host cell membrane regulate the complement system and protect cells from it. Some inhibiting factors, such as C1 inhibitors and Factor H( FH), also exist.

Some genes produce complement control proteins; if one has defects, the synthesis becomes defective, causing several diseases.

Mutation in the genes of complement regulation causes diseases.

Applied

Excessive complement activity was responsible for severe COVID-19 symptoms.

In HIV infection, the complement system causes more damage to the body.

Although the complement system protects the body, it may cause damage beyond repair in stress and severe infections.

The complement system is essential in the pathogenesis of diseases like asthma and lupus erythematosus.

Deficiencies in the complement system increase susceptibility to infections.

Uncontrolled function and inappropriate activation of the complement system can cause autoimmune diseases, chronic inflammation, and tissue damage.

Diagnosis

1. Total complement activity test to measure complement activity.

2. Complement fixation test.