Complement System: Mechanisms and Functions

• The complement system, inflammation, and acute phase reaction are immunologic defense mechanisms

The Natural or Innate Immune System

• Recognition, mobilization, and destruction are key functions
• Cells involved include phagocytes/monocytes, macrophages, dendritic cells in the interstitial space, and monocytes, neutrophil granulocytes, NK cells in circulation
• Humoral components include antimicrobial enzymes, proteins, and peptides like defensins
• Has limited capabilities, with a fast response time, and no antigen specificity

Recognition and Defense

• Natural immune system detects pathogens, danger signals, and self-deficiencies as the first line of defense
• Requires a sufficient number of constantly present cells
• Provides immediate protection without prior activation

Humoral Factors

• Soluble participants include antimicrobial peptides (directly destroy pathogens), enzyme cascade systems (activated by invaders), and cytokines (influence cell function/communication).

Response Characteristics

• Response capability does not improve with repeated infection, and has no memory
• Identifies a limited number of structures with the same receptors
• Activity and protection cannot be transferred to another individual
• Response time is very short, activating immediately upon detecting danger

Cellular Activity

• Activating signals enhance inflammatory processes at infection site, boosting local cell count.
• Opsonization enhances response
• Macrophages phagocytize and destroy pathogens with receptor cells
• Granulocytes destroy pathogens during the complement process/acute phase
• NK cells (natural killer cells) eliminate tumor/virus-infected cells
• Dendritic cells are crucial for recognition; function as tissue sensors alongside macrophages

System Specificity

• A non-antigen-specific system recognizes molecular patterns of pathogens (PAMP)
• PAMPs are absent in higher organisms but essential for pathogen survival
• Adaptive immune system cells primarily recognize the fine structure of proteins

Structure of the Complement System

• Approximately 30 types of proteins (glycoproteins) can boost the function of antibodies
• Activation occurs via inactive protein converting to active protein through proteolytic cleavage
• It's an enzyme cascade

Activation Pathways

• There are three activation pathways:

  • Alternative Pathway (MAC): continuously active, triggered by foreign surfaces. -Classical Pathway: activated by adaptive immune system, leading to opsonization
  • MB-Lectin pathway: Activated by mannose-binding lectin

• It is essentially an enzyme cascade system in an inactive state within blood plasma/bodily fluids

• Factors activate each other in a chain reaction

• Proenzymes are critical protein molecules in catalytic processes that transform into enzymes when activated

• Inactive proteins become true proteases through three pathways, capable of causing cell damage and fulfilling protective functions

Classical Pathway

• Activation is triggered by antibodies, playing a key role in recognizing pathogens and initiating defense

Functions of the Complement System

• The complement system is involved in opsonization, MAC formation, release of chemical messengers, and anaphylatoxin production
• Opsonization: C3b and C4b components acting as "tags," facilitating engulfment/destruction
• MAC (Membrane Attack Complex): Forms a pore leading to lysis, through C5b, C6, C7, C8, and C9
• Complement components act as chemical messengers, regulating and amplifying immune responses
• Anaphylatoxins(C3a and C5a): act as inflammatory mediators by recruiting immune cells, promoting vasodilation & increasing vascular permeability

Opsonins

• Extracellularly binding protein molecules facilitate pathogen recognition by immune system
• Enhance innate immune cells' ability to recognize and respond to pathogens quickly
• Phagocytes recognize complement components/antibodies bound to pathogens through opsonin receptors
• Opsonins tag antibody-bound antigens, improving their clearance from the body

Membrane Attack Complex (MAC) Action

• The final steps of complement activation result in MAC assembly, a pore-forming protein structure
• The pore inserts into the target cell's or bacterium's membrane, making it permeable
• Disturbance of osmotic balance leads to cell lysis
• Crucial in destroying pathogenic cells

Chemical Messengers & Anaphylatoxins

• Following activation, certain complement components function as chemotactic factors, attracting immune cells.
• Some components (C3a/C5a), trigger local inflammation increasing blood vessel dilation and the permeability of capillary walls
• If uncontrolled, this can lead to excessive inflammation or anaphylaxis

Components Types of the Complement System

• Plasma Proteins: C (C1 - C9 + subunits), produced as zymogen forms in the liver, activated by proteolytic cleavage via a pathogen
• C3 is activated by all three pathways.
• Recognition molecules: PRMs (Pattern Recognition Molecules)
• Activating molecules cause the reaction
• Regulatory Factors: Factor B, D, H, I, P & Proteins decay accelerating factor (DAF); CR1, protein-S (vitronectin); C1 inhibitor (C1-INH, serpin); C4 binding protein (C4-BP), C5 (starting step of MAC)
• Membrane proteins prevent damage to self-cells
• Mannose-binding lectin (MBL); MBL-associated proteases MASP-1 and MASP-2 are also important elements

Complement System Recognition

• PRMs recognize microorganisms and pathogen-associated molecular patterns (PAMPs)

Proteases

• Upon activation, proteases will cleave another component down into:
  • a) smaller subunit to enter the microenvironment
  • b) larger subunit that binds to the pathogen to facilitate phagocytosis or lysis
• C2 protein is the exception, reversing the subunit sizes C3 serves as a glycoprotein and is considered most important protein of the complement system & liver is main synthesis site
• Transformations into mature two-chain of a-/ẞ-chains are through a single disulphide bond

Activation Of The Complement System

• All 3 pathways cleave the C3 component, activating C5 for lytic complex (MAC) formation
  • Antibody dependent: Classical Pathway: Activated by adaptive immune system - opsonization & Creation of opsonized surfaces
  • Antibody independent : Alternative Pathway (MAC): Continuous activation by foreign cell surface structures & BM-Lectin Pathway: Mannose-binding lectin

Alternative Pathway:

• C3 spontaneous activation IF bind to anything
• C3i then binds to Factor B, enabling Factor D to cleave Factor B into two subunits

Activation Loop:

• Occurs if activating membrane (bacterial or foreign) is present
• The C3iBb complex binds and cleaves C3, forming a convertase, producing C3b that re-binds Factor B and turns it into C3 convertase

Control In Activation

• DAF, Decay-Accelerating Factor, prevents C3b binding, blocking C3b-B interaction

Stabilization and Activation

• Stabilizes the complex, allowing it to bind and cleave, thus acting as a C5 convertase

Lectin Pathway

• MBL searches for and binds to mannose side chains in the bloodstream
• MASP-1 and MASP-2 then bind from the blood, and MASP-1 cleaves MASP-2
• Activated MASP-2 cleaves C4 and C2
• C4 larger subunits binds to bacterial surface AND C2 larger subunit binds alongside C4b, forming C4bC2a, a C3 convertase

Classical Pathway:

• It's activated by antibodies and antigens, leading to phagocyte recruitment and inflammatory mediators
• Antibodies (IgG or IgM) produced by the body bind to surface of bacterium in presence of Ca++
• Then r activates s and C4 binds (creating bacterial surface)
• Active complex cleaves C2 and a binds alongside C4b, forming C4bC2a (C3 convertase that binds is then cleaved & forms C4bC2aC3b complex that acts as C5 convertase that starts Complex formation.

Main Components and Effector Effects

Key pathways and components:

• Classical: antigen-antibody with C1q, C1r, C1s
• MB-Lectin: mannose and MBL, MASP-1, MASP-2
• Alternative: B & D factors and pathogen surfaces for BD

Common Outcomes:

• C3 convertase activating C3a/C5a with inflammatory and phagocyte
• C3b that binds to phagocytes
• Terminal components causing Membran-Attack with C5b C6, C7, C8, C9

Late-Phase Activation - MAC

• The pathways work to form the Lytic pathway
• The C5 convertase earlier only cleaves C5 and binds C5, producing subunits
  • They binds to C6, C7 which anchors the surface, and then binds to C8 forms a poor THEN C9 binds to expand that core and form a full complex
  • Also assists in the elimination of virus-infected cells via the alternative pathway

Inhibition of The Complement System

• In regulatory is always in check with molecules by various proteins in the serum and on cell surfaces, preventing against microbial recognition
• Inhibitory Molecules Inhibitory Molecules - e.g., FHR (Factor H-Related proteins)./ Complement Regulatory Proteins (in serum, on cell surfaces) - e.g., Factor H (FH), C1 inhibitor.

Factor H (FH) and C1

• Factor H is an important regulatory protein of the alternative pathway, inhibiting C3 and C5
• C1 inhibitor, when present in high concentrations acts as inhibits C1r and C1s

Antibody / Antigens

• Activation leads to phagocyte recruitment and the appearance of inflammatory peptide.

• Diseases Caused if inadequate function occurs Classical Pathway/ Hereditary angioedema (C2b overproduction.)/

• The predisposition to systemic lupus erythematosus (SLE) (opsonized immune

• Also Susceptibility to bacterial infections

• Increased bacteria from pyogenic and lack of lytic complex with Gram- outer cell

Inflammatory Process

• The function is to remove and restore harmful effects from infections, chemical/radioactive effects, foreign substances, tumor/reactions
• Exogenous bacteria/virus tissue death
• Can cause tissue damage

Acute Inflammation

• It's an immediate immune response & natural to a harmful element resulting a leukocyte
• nature = area of affected tissue/ changes= permeability of vessel walls

Symptoms include:

• Swelling (oedema)
• Skin redness (blush)
• Feeling of warmth
• Pain
• Loss of function

Innate immunity response and localized infection

• To control infections and response.
• Increase diameter of blood vessels -Hyperemia slower blood flow
• Permeability allows WBC-leukocytes for blood coagulation and bloodstream
• Cytokines trigger cell release

Cellular Changes:

• Macrophages for destruction of pathogens with Cytokines

• Dendritic Transport of antigens

• Epithelial activate neutrophil granulocytes with granulocytes and recruiting monocytes

• CytokineProduction

• Liver makes Proteins for acute production Bone Marrow Increases production of white blood cells

• Blood Vessel Cells Separate cells, to reach for site that can allow

Activation Steps

• Macrophages and dendritic cells are triggered near potential pathogen Dendritic = transport to the lymph nodes as the adaptive cells
• Macrophage functions perform to destruction if Minor/Large + production of the bloodstream

Acute Inflammation

• Members of the Monocyte-Macrophage System:, are:
  • Bone Marrow Precursors (monoblast, promonocyte)
  • Mature monocyte, free cells and immobilized ones

Monoblast fraction from the bone marrow precursors

• Promonocytes, phagocytosis with cells

• Monocytes, leave the marrow within 24 houts and transform for lungs and brain functions

• Dendriic are bridge cells and extensions to the innate system where they can produce antiviral cells

• Macrophages respond to pathogens with phagocytosis

Cytotoxins

• Hormone-like that cells at concentrations
• Can act (autocrine/para/endocrine manners)
• Ability of depend to the ability if the receptors can simultaneously cause multiple receptors
• Lymphocytes made by Lymphokines/ Monokines with interleukins
• Over 30 interleukins, facilitate communication

Effects of Cytotoxins:

• Interleukins can vasodilate, proliferate T celle and act as growth factors:
• Cytokines attract inflammatory signals in blood streams

Inflammatory Cytotoxins:

• TNF, Interleukins, Chemokine influence inflammation
• Monocyte activation that have systemic effects
• Cytokines produce Acute Phase Proteins

Acute Phase Reaction

• This reaction occurs from traumas & Infections causing the Activation of cells - the amounts of these responses depend on Macrophages
• Pyrogenic & Cell damaging effects occur w liver function

Acute Phase Proteins:

• Cause complent activation, scavenging
• Alter blood and elevate laboratory results for sedimentation

C-Reactive influence what cell of infection can cause in the systems to enhance:

Bacterial + Activate component cell - Mannose-binding Lectin - Detect surface Increased indicator of various diseases infections

Outcomes of Acute:

Resolution/ secondary infections and fibrosis: Types are pus clear (pale yellow fluid) with fibrin

Fluid accumulation: Extracellular bacteria proliferate in the intercellular space and on epithelial surfaces.

These pathogens can Firstly, they can initiate an inflammatory process Secondly, they can produce toxic substances, toxins

• The former are known as endotoxins, and the latter as exotoxins*
• The endotoxin LPS (lipopolysaccharide) in the cell wall of Gram-negative bacteria stimulates cytokine production in macrophages, leading to inflammation.

Explore the complement system's role in eliminating virus-infected cells and regulating immune responses. Learn about complement regulatory proteins, activation mechanisms, and the functions of components like Factor H and anaphylatoxins. Understand how the complement system contributes to chemotaxis and inflammation.