College of Veterinary Sciences & Animal Husbandry

Selesih, Aizawl, Mizoram Pin-796 014

Complement system and its

Name: Nisantu Sutradhar

Submitted to
Department of Veterinary Microbiology
Complement System and its Role in Providing Immunity
 The complement system is a vital part of both the innate and adaptive immune systems,
acting as a crucial defence mechanism against microbes and playing various regulatory roles. It is an
essential innate defence subsystem consisting of a complex mixture of enzymes, regulatory proteins,
and receptors that works rapidly to detect and kill invaders before other defences have a chance to
respond.
Here is a breakdown of the complement system:
• Components and Nature: The system is composed of numerous serum and cell surface proteins.
These proteins are either labelled numerically (C1-C9) or designated as "factors" (FB, FD, FP, FI).
They collectively account for 5% to 10% of the proteins in blood serum, highlighting the system's
critical importance. Complement proteins are synthesized in multiple sites, including the liver (C3,
C6, C8, FB), macrophages (C2, C3, C4, C5, FB, FD, FP, FI), and mast cells (C1q). Neutrophil
granules may also store large quantities of C6 and C7. Complement proteins are normally inactive but
become activated under specific conditions.
• Activation Pathways: Complement activation occurs through three major pathways:
◦ The Alternative Pathway: This is an evolutionary ancient innate pathway. It is triggered when
microbial cell walls meet complement proteins in the blood. There is a continuous low-level
spontaneous breakdown of C3 in plasma ("C3 tick-over"). If C3b, a breakdown product, deposits on
microbial surfaces (which typically lack complement-regulating sialic acid), it initiates the pathway.
This involves binding of Factor B (FB) and its cleavage by Factor D (FD) (an example of substrate
modulation, forming the alternative C3 convertase (C3bBb). Properdin (FP) can bind to and stabilize
the C3bBb complex. This pathway establishes a positive feedback loop, generating increasing
amounts of surface-bound C3b. It accounts for 80% to 90% of all complement activation.
◦ The Lectin Pathway: Also, an innate pathway. It is triggered by the binding of soluble pattern-
recognition molecules, such as Mannose-Binding Lectin (MBL) and ficolins (defense collagens21), to
microbial carbohydrates like mannose or N-acetylglucosamine18.... This binding activates associated
proteases (e.g., MASP-2), which cleave C4 into C4a and C4b. C4b then binds to the microbial
surface, and C2 binds to C4b. MASP-2 also cleaves C2, forming the classical C3 convertase (C4b2b,
equivalent to C4b2a in the classical pathway). Apart from initiation, the rest of the steps are the same
as the classical pathway.
◦ The Classical Pathway: This pathway is typically activated as a mechanism of adaptive immunity
It is initiated by the binding of the C1 complex to antibody molecules (IgM or certain IgG subclasses
like IgG3 and IgG1) that have bound antigen, usually on microbial surfaces. C1 is a complex of C1q,
C1r, and C1s. Clq binds to the Fc regions of antibodies (IgM is more efficient than IgG due to its
multimeric structure). This activates C1r and C1s proteases. Activated C1s cleaves C4 and C2,
forming the classical C3 convertase (C4b2a). While primarily antibody-dependent, C1q can also bind
directly to certain microbes or host components (like apoptotic cells or amyloid), but these activations
are usually controlled by inhibitors.
• Late Steps and MAC Formation: All C3 convertases (C3bBb or C4b2a/C4b2b) lead to proteolytic
cleavage of C3 into C3a and C3b18. C3b then participates in forming the C5 convertase. The C5
convertase cleaves C5 into C5a and C5b. C5b initiates the assembly of the terminal complement
components (C6, C7, C8, and multiple C9 molecules) on the cell surface. This forms the Membrane
Attack Complex (MAC), also called the terminal complement complex (TCC). The MAC inserts
into the microbial membrane, forming a pore that causes osmotic lysis. MAC-mediated lysis is
particularly important for defence against Neisseria species. TCCs appear as ring-shaped structures by
electron microscopy.
• Functions and Biological Consequences: The complement system has multiple crucial functions:
◦ Opsonization and Phagocytosis: C3b and iC3b (an inactive fragment of C3b) act as potent opsonin
by coating microbes. Phagocytes (neutrophils, macrophages) have complement receptors (CR1, CR3,
CR4) that bind these fragments, promoting or enhancing phagocytosis. Phagocytosis is particularly
efficient when microbes are coated with both C3b and IgG.
◦ Stimulation of Inflammation: The small fragments C3a, C4a, and C5a are anaphylatoxins. They
bind to receptors on mast cells and neutrophils, inducing degranulation (releasing inflammatory
mediators like histamine). C5a is a powerful chemoattractant for leukocytes, recruiting neutrophils,
eosinophils, macrophages, and basophils to infection sites. It increases vascular permeability and
triggers the neutrophil respiratory burst. C5a can also enhance production of pro-inflammatory
cytokines (TNF-α, IL-1β, IL-6).
◦ Immune Regulation: Complement components provide critical second signals for B cell
activation. C3d bound to antigens binds to the CR2 (CD21)/CD19 complex on B cells, significantly
enhancing B cell receptor (BCR) signalling. Complement is essential for effective antibody responses;
deficiencies severely impair them. CR2 also traps immune complexes on follicular dendritic cells in
germinal centres, important for B cell selection and memory. Complement fragments like C3b and
C5a influence T cell activation. C3 is cleaved within CD4+ T cells upon activation, and C3a drives
cytokine production via its receptor.
◦ Immune Complex Clearance: Complement proteins bind to immune complexes, promoting their
solubilization and clearance. CR1 on erythrocytes binds C3b/C4b-coated immune complexes and
transports them to the liver and spleen for removal by phagocytes.
◦ Removal of Apoptotic Cells: Complement helps remove apoptotic cells by opsonization with
C3b/C4b, facilitated by the loss of complement inhibitors on these dying cells.
Blood Coagulation: The system enhances blood coagulation.
• Regulation: The complement system is tightly regulated to prevent unwanted activation on healthy
host cells and control the duration of the response. Regulatory mechanisms include:
◦ Inhibition of C1 by C1 inhibitor (C1 INH).
◦ Inhibition of C3 and C5 convertase assembly or acceleration of their decay by membrane proteins on
host cells (MCP/CD46, CR1/CD35, DAF/CD55) and plasma proteins (Factor H, C4BP). Sialic acid
on mammalian cells Favors Factor H bindin.
◦ Proteolytic degradation of C3b and C4b by Factor I (FI) with cofactors.
◦ Inhibition of MAC formation by CD59 (Protectin) on host membranes and plasma S protein
(Vitronectin).
• Genetics and Deficiencies: Genes encoding complement proteins are scattered throughout the
genome, with important clusters in the MHC Class III region (C2, C4, FB) and the RCA cluster
(regulators). Genetic variations (polymorphism) exist. Deficiencies in complement components
increase susceptibility to infections. C3 deficiency is severe, leading to recurrent sepsis and impaired
antibody responses. Factor H or Factor I deficiencies cause uncontrolled C3 activation and depletion.
Deficiencies of MAC components (C5-C9) primarily increase susceptibility to Neisseria infections.
Complement deficiencies or receptor deficiencies (CR1) are also linked to autoimmune diseases,
likely due to impaired immune complex clearance.

Role in Disease: Beyond host defence, the complement system is involved in the pathogenesis of
various conditions. Immune complexes can deposit in tissues and activate complement, causing
inflammation and tissue damage. This is seen in immune complex diseases like glomerulonephritis.
Autoantibodies binding to host cells can also activate complement, causing cell lysis or phagocytosis.
Uncontrolled complement activation due to regulatory protein deficiencies or persistent stimuli can
also lead to pathology. Complement is also involved in hyperacute graft rejection.

References:
• Ian Tizard Veterinary Immunology - 11th Edition.
• Immunology - Edition 9 - Edited by David Male.
• Kuby Immunology 8 th edition.
• Cellular and Molecular Immunology – Abdul K. Abbas 10th Edition.