1- Basic Immunology UG Med students - 2023

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1) Complement Synthesis and Receptors

Synthesis of Complement Components

The complement system is a crucial part of the immune response, and its components are primarily
synthesized in the liver.

The liver is the major site of synthesis for complement proteins, which are found in circulating blood
serum.
In addition to the liver, tissue macrophages, monocytes, and fibroblasts can also synthesize
complement proteins.

Complement Binding Receptors

There are four distinct complement receptors that play a role in the immune response by binding to the
surface-bound complement fraction C3 and its cleavage fragments:

1. CR1 (CD35)
2. CR2 (CD21)
3. CR3
4. CR4

CR1 and CR2 are the major receptors for activated fragments of C3, facilitating various immune
functions.
Other important receptors include:
C3a/C4a receptor
C5a receptor

These receptors are essential for the recognition and response to pathogens, enhancing the immune
system's ability to clear infections.

2) Complement System Overview

Overview of the Complement System

The complement system is a crucial component of the immune defense, consisting of about 30 different
soluble and cell-bound proteins found in plasma and on cell surfaces.
 It works in concert with antibodies to enhance the ability to clear pathogens, inactivate viruses, and
mediate tissue damage.
The complement proteins make up about 15% of the serum globulin fraction and circulate in an
inactive form until activated.
The system is heat labile, meaning it can be inactivated at 56°C for 30 minutes.
Activation occurs through a cascade mechanism, where proteins are sequentially activated to amplify
the immune response Page 0.

Functions of the Complement System

The complement system plays several key roles in immune defense, including:

Opsonization

Opsonization is the process by which pathogens are marked for phagocytosis.

C3b and C4b are important opsonins that enhance the phagocytosis of cells, antigen-antibody
complexes, and viruses by up to 1,000 fold Page 26.

Inflammation

Complement proteins such as C3a, C4a, and C5a act as anaphylatoxins, which can cause
degranulation of mast cells and contribute to inflammatory responses.
C5a and the C567 complexes attract neutrophils, activating the inflammatory response Page 26 Page
27.

Cytolysis

The complement system can lead to cytolysis, which is the lysis of cells, including bacteria and
protozoa.
This occurs through the formation of the C56789 complex, which inserts into the cell membrane,
leading to cell lysis.
This mechanism is also involved in the lysis of antibody-coated cells, such as in Rh incompatibility
and hemolytic anemia Page 26.

Clinical Implications of the Complement System

Understanding the complement system is essential for recognizing its clinical implications, particularly in
cases of complement deficiencies.

Deficiencies in complement components can lead to increased susceptibility to infections and

autoimmune diseases.
The complement system's role in opsonization, inflammation, and cytolysis highlights its importance in
both innate and adaptive immunity, making it a critical area of study in immunology Page 27.
3) Biological Functions of Complement

Opsonization

Opsonization (C3b, C4b)

Opsonization is a process that enhances the phagocytosis of cells, antigen-antibody complexes, and
viruses.
The presence of C3b (a potent opsonin) significantly increases the efficiency of phagocytosis by up to
1,000 fold.
This process is crucial for the immune system to effectively clear pathogens from the body.

Anaphylatoxin Production

Anaphylatoxin

C3a, C4a, and C5a are known as anaphylatoxins.

These molecules play a critical role in the immune response by causing the degranulation of mast
cells, which can lead to anaphylaxis.
Anaphylatoxins are important mediators of inflammation and can contribute to allergic reactions.

Cytolysis

Cytolysis

Cytolysis refers to the process by which the complement system leads to the destruction of target
cells.
This occurs through the insertion of the C5b6789 complex into the cell membrane, resulting in the
lysis of bacterial and protozoan cells.
Additionally, cytolysis can also affect antibody-coated cells, such as in cases of Rh-incompatibility
and hemolytic anemia.

4) Lectin Pathway Function

Overview of the Lectin Pathway

The lectin pathway (LP) is a crucial component of the complement system that operates independently of
antibodies. It is initiated when mannose-binding lectin (MBL) binds to specific carbohydrate structures,
particularly mannose residues, on the surface of pathogens.
 Lectin: A protein that binds to microbial carbohydrates or mannose residues on pathogen surfaces.
Mannose-binding lectin (MBL): An acute phase protein produced by the liver during inflammatory
responses. It binds to mannose residues found on glycoproteins or carbohydrates on the surface of
microbes, such as lipopolysaccharides (LPS).

This pathway is structurally similar to the classical pathway, utilizing MBL instead of C1q to initiate
complement activation.

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Activation of the Lectin Pathway

The lectin pathway is activated through the following steps:

1. Binding of MBL: MBL binds to mannose residues on the pathogen surface.

2. Activation of MASPs: This binding activates MBL-associated serine proteases (MASP-1 and MASP-
2), which are similar to C1r and C1s in the classical pathway.
3. Cleavage of Complement Proteins: MASP-2 cleaves C4 into C4a and C4b, and C2 into C2a and C2b.
The C4b and C2a then combine to form the C3 convertase (C4b2a), which is essential for further
complement activation.
4. Formation of C5 Convertase: The pathway continues through the action of C4 and C2 to produce the
C5 convertase, marking the end of the lectin pathway.

This pathway is particularly important in innate immunity, especially in defending against mycobacterial
infections.
Page 23

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5) Complement Activation Pathways

Overview of Complement System Activation Pathways

Complement activation occurs through three distinct pathways:

1. Classical pathway (specific immune system)

2. Alternative pathway (non-specific immune system)
3. Lectin pathway

Each pathway differs in how it is activated but ultimately leads to the production of a key enzyme called C3
convertase.

The components of these pathways are sequentially activated by specific stimuli, resulting in the formation
of an active lytic unit. Despite their differences, all pathways converge to achieve a similar end result: the
lysis of target cells.

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6) Regulation of Complement System

Overview of Complement Regulation

The complement system is a crucial part of the immune response, but its activation must be tightly
regulated to prevent damage to host tissues.

Bacterial capsules can prevent complement activation.

Surface lipid-carbohydrates can inhibit the formation of the membrane attack complex (MAC).
Due to its non-specific nature, multiple regulatory mechanisms are in place to minimize "collateral
damage" to host cells.
The genes responsible for the production of complement components are located on human
chromosome 6, near the HLA locus.
Some complement components possess enzymatic activity, while others act as enhancers or
inhibitors.
At least 12 proteins are known to be involved in the regulation of the complement system.

This regulation is essential for maintaining a balance between effective immune response and preventing
autoimmunity or tissue damage. Page 28

Key Regulatory Proteins

Several key proteins play significant roles in regulating the complement system, particularly in the classical
and alternative pathways. Here are some of the main regulatory proteins and their functions:

C1 Inhibitor (C1INH)

Function: Regulates the classical pathway by inactivating the C1 esterase inhibitor.

C3 Endopeptidase

Function: Acts as a C3b inhibitor.

B1H

Function: Competes with cell surface receptors to regulate complement activity.

Serum Carboxypeptidase

Function: Involved in the regulation of complement components.

Factor H

Function: Regulates the alternative pathway by binding to C3b and removing Bb from the alternative
pathway C3 convertase.

Factor I

Function: Inactivates C3b, further regulating the complement cascade.

Membrane Attack Complex (MAC) Inhibitor

Function: Prevents the formation of the MAC, which can damage host cells.

Decay-Accelerating Factor (DAF)

Function: A glycoprotein located on the surfaces of human cells that helps to regulate complement
activation.

These regulatory proteins are vital for ensuring that the complement system functions effectively without
causing harm to the body's own cells. Page 29

7) Classical Pathway Mechanisms

Phases of the Classical Pathway

The classical pathway of complement activation consists of three main phases:

1. Initiation / Recognition Phase

This phase involves the binding of the C1 complex to antibodies (IgM or IgG) that are bound to antigens.
The classical pathway is initiated when C1 proteins bind to the Fc region of antibodies in an antigen-
antibody complex.

2. Amplification / Enzymatic Activation Phase

In this phase, the activated C1s cleaves C4 into C4a and C4b, and C2 into C2a and C2b.
C4b binds covalently to the microbial surface, and C2a binds to C4b, forming the C4b2a complex,
which is known as C3 convertase.

3. Membrane Attack Phase / Lytic Unit

This phase involves the formation of the membrane attack complex (MAC) from C5 to C9, leading to
cell lysis.

These phases highlight the differences and similarities between the classical and alternative pathways of
complement activation, with the classical pathway being antibody-dependent Page 4.

Mechanism of the Classical Pathway

The classical pathway is primarily activated by immunologic means, relying on antibodies to initiate the
response.

C1 Complex: The C1 complex consists of C1q, C1r, and C1s. When C1q binds to the ends of antibodies in
an antigen-antibody complex, it activates C1r and C1s, leading to the cleavage of C4 and C2.
 C3 Convertase Formation: The C4b2a complex acts as the C3 convertase, cleaving C3 into C3a and
C3b in the presence of Mg++. C3b can then bind to the membrane, forming the C4b2a3b complex,
which functions as the C5 convertase, cleaving C5 into C5a and C5b Page 3.

Formation of C3 and C5 Convertases

C3 Convertase

The C3 convertase is formed from the C4b2a complex, where C2a is the enzymatic component. This
complex cleaves C3 into C3a and C3b.

C5 Convertase

The C5 convertase is formed when C3b binds to the C4b2a complex, resulting in the C4b2a3b
complex. This complex cleaves C5 into C5a and C5b, initiating the formation of the membrane attack
complex Page 8.

Role of C3 and C5 Cleavage Products in Inflammation

The cleavage products of C3 and C5 play significant roles in the inflammatory response:

C3a: This fragment increases the inflammatory response by binding to mast cells, causing them to
release histamine, which contributes to vasodilation and increased vascular permeability.
C5a: Known as the most powerful chemotactic factor for leukocytes, C5a disperses away from the
bacteria and binds to mast cells, further enhancing inflammation and attracting immune cells to the
site of infection Page 4.

8) Alternative Pathway Activation

Overview of the Alternative Pathway

The Alternative Pathway (AP) is a crucial part of the non-specific immune defense system. Unlike the
classical pathway, it does not require antibodies to initiate the activation process.

Speed: The AP is generally slower than the classical pathway.

Triggers: The pathway can be initiated by various substances, including:
Bacterial cell wall components (e.g., LPS, polysaccharides, teichoic acid)
Fungal/yeast cell wall components (e.g., zymosan)
Viral envelopes
Cobra venom factor
Parasite surface components (e.g., S. mansoni)
Immune complexes
This pathway is essential for the immune response, especially when specific antibodies are not available
early in an infection. Page 14

Components of the Alternative Pathway

The alternative pathway involves several key serum proteins:

Factor B
Factor D: A serine protease that resembles C1s in the classical pathway.
Properdin (P): A protein that stabilizes the C3bBb complex.
Initiating Factor (IF)

Other components include C3, C5, C6, C7, C8, and C9. These factors interact with each other and with C3b
to form the C3bBb complex, also known as the C3 convertase, which plays a critical role in the amplification
loop of the pathway. Page 15

Activation Process of the Alternative Pathway

The activation of the alternative pathway begins with the spontaneous conversion of C3 into an active
protease.

1. Spontaneous Activation: C3 is susceptible to spontaneous hydrolysis by water, leading to the

formation of C3b.
2. Formation of C3 Convertase:
Factor B binds to cell-bound C3b, forming the complex C3bB.
Factor D then cleaves Factor B into Bb and Ba, resulting in the formation of C3bBb.
Properdin stabilizes the C3bBb complex, creating a functional C3 convertase capable of cleaving
additional C3 into C3a and C3b.

This process is crucial for opsonization and the activation of inflammatory responses. Page 16

Formation of C5 Convertase

Following the activation of the alternative pathway, some of the C3b generated binds to the C3bBb complex
to form C3bBb3b, which acts as the C5 convertase.

The C5 convertase is capable of cleaving C5 into C5a and C5b.

This step is essential for the downstream effects of the complement system, including the formation of
the membrane attack complex (MAC) and further amplification of the immune response. Page 18
Illustrations of the Alternative Pathway

To better understand the alternative pathway, refer to the following illustrations:

1. Diagram of the Alternative Pathway:

2. Flowchart of the Alternative Pathway:

These illustrations depict the sequence of reactions involved in the activation of the alternative pathway,
highlighting the roles of various components and the formation of C3 and C5 convertases. Page 19 Page 20

9) Complement Deficiencies

Overview of Complement Deficiencies

Complement deficiencies are rare but can have significant clinical implications. Understanding these
deficiencies is crucial for recognizing their impact on the immune response.

Types of Complement Deficiencies

1. C2 Deficiency: This deficiency is associated with immune complex disorders.

2. Deficiency of Early Components of the Classical Pathway (C1, C4, C2): These deficiencies are linked
to autoimmune diseases, particularly Systemic Lupus Erythematosus (SLE).
3. Inherited or Acquired Deficiency of C5-C8: This deficiency enhances susceptibility to Neisseria
bacteremia, making individuals more prone to infections caused by this bacterium.
4. C3 Deficiency: Leads to severe recurrent pyogenic respiratory tract and sinus infections, significantly
impacting the individual's ability to fight off infections.
5. C1 Esterase Inhibitor (C1INH) Deficiency: Results in angio-neurotic edema, which is characterized by
severe non-pitting swelling.
6. Mannose-Binding Lectin (MBL) Deficiency: This deficiency is linked with frequent pyogenic
infections, including pneumococcal infections in infants.
These deficiencies highlight the critical role of the complement system in immune defense and the potential
consequences when components are lacking.

Clinical Implications of Complement Deficiencies

The clinical implications of complement deficiencies can vary widely depending on which component is
deficient and the pathways affected.

Immune Complex Disorders

Deficiencies in early components of the classical pathway (C1, C4, C2) can lead to the formation of
immune complexes that are not adequately cleared, resulting in autoimmune diseases such as SLE.

Increased Susceptibility to Infections

C5-C8 Deficiencies: Individuals with these deficiencies are particularly vulnerable to infections from
Neisseria species, which can lead to severe and life-threatening conditions.
C3 Deficiency: This deficiency significantly increases the risk of recurrent infections, particularly from
pyogenic bacteria, due to the essential role of C3 in opsonization and pathogen clearance.

Angio-neurotic Edema

The deficiency of C1INH can lead to episodes of angio-neurotic edema, which can be life-threatening if
it affects the airway.

Pediatric Considerations

MBL deficiency is particularly concerning in infants, as it is associated with increased rates of severe
infections, including those caused by pneumococcus.

Understanding these clinical implications is vital for healthcare providers to manage and treat patients with
complement deficiencies effectively.

Pathways and Deficiencies

The complement system consists of several pathways that can be affected by deficiencies, leading to
various clinical outcomes.

Complement Pathways Overview

 Classical Pathway: Involves C1, C2, and C4. Deficiencies in these components can lead to immune-
complex diseases.
Alternative Pathway: Involves Factor D and Factor P. Deficiencies here can lead to infections with
pyogenic bacteria and Neisseria species, but not immune-complex disease.
C3 Convertase: Both pathways converge at this point, and a deficiency in C3 can lead to infections
with pyogenic bacteria and Neisseria species, as well as sometimes immune-complex disease.
Membrane-Attack Components (C5, C6, C7, C8, C9): Deficiencies in these components primarily
lead to infections with Neisseria species only.

Understanding the pathways and their associated deficiencies is crucial for recognizing the potential clinical
implications and guiding appropriate treatment strategies.

10) Infection Recognition by Immune System

Recognition of Infection by the Immune System

Infection is first recognized by the immune system through the detection of bacterial components. This
recognition is mediated by a second line of defense that utilizes diverse recognition elements, specifically
four key families of cellular receptors:

1. Toll-like receptors (TLRs) - These are transmembrane receptors that play a crucial role in recognizing
pathogens.
2. C-type lectin receptors (CLRs) - Another class of transmembrane receptors involved in pathogen
recognition.
3. RigI-like receptors (RLRs) - These are cytoplasmic RNA helicases that detect viral RNA.
 4. NOD-like receptors (NLRs) - These are cytoplasmic sensors that recognize intracellular pathogens.

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Overview of Toll-Like Receptors (TLRs)

Toll-Like Receptors (TLRs) are a class of proteins expressed in sentinel cells such as macrophages,
dendritic cells, and epithelial cells. They recognize structurally conserved molecules derived from both
pathogenic and non-pathogenic microbes.

There are at least 13 TLR members in mammals, with TLR1 to TLR11 found in humans.
TLRs are a type of pattern recognition receptor (PRR) that recognize molecules broadly shared by
pathogens, known as pathogen-associated molecular patterns (PAMPs).

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PAMPs and PRRs Interactions

The innate immune system recognizes various determinants through the interaction of PAMPs and PRRs.
Here are some key interactions:

PAMP PRR Biological consequence of interaction

Microbial cell wall
Complement Opsonization; Complement activation
components
Mannose-containing Mannose-binding
Opsonization; Complement activation
carbohydrates protein
Polyanions Scavenger receptors Phagocytosis
Lipoproteins of Gram+ TLR-2 (Toll-like Macrophage activation; Secretion of
bacteria receptor 2) inflammatory cytokines

This table illustrates how different PAMPs are recognized by specific PRRs, leading to various biological
responses.

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Mechanisms of Immune Response Activation

Following the recognition of bacterial components, several mechanisms are activated:

1. Activation of the alternative pathway of complement

2. Production of proinflammatory cytokines
3. Induction of lymphocyte-mediated response
Phagocytic cells, such as neutrophils and resident macrophages, recognize groups of pathogens through
TLRs. For example:

Bacterial LPS is recognized by TLR4.

Viral nucleic acids are recognized by TLR3, 7, and 8.

Most bacteria are effectively killed by phagocytes, while only a few Gram-negative bacteria are killed by
complement.

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11) Innate vs. Adaptive Immunity

Overview of Innate and Adaptive Immunity

The immune system is divided into two main types of immunity: innate immunity and adaptive immunity.

Innate Immunity (also known as nonspecific resistance) is the body's first line of defense against
pathogens. It includes:

Physical barriers: such as intact skin and mucous membranes.

Chemical barriers: such as antimicrobial substances.
Cellular defenses: including phagocytic white blood cells and natural killer (NK) cells.
Inflammatory responses and fever that help to eliminate pathogens quickly.

Adaptive Immunity (also known as specific resistance) is the body's third line of defense. It is characterized
by:

Specificity: Tailored responses to individual pathogens, often described as a "key-in-lock" mechanism

where only specific antigens (epitopes) can trigger a response.
Memory: The ability to remember past encounters with pathogens, leading to a faster and more potent
response upon re-exposure.
Specialization: Involves B cells and T cells, which mediate humoral and cellular immunity, respectively.

This distinction is crucial for understanding how the immune system functions to protect the body against
infections.

Response Timelines of Innate and Adaptive Immunity

The response timelines for innate and adaptive immunity differ significantly:

Innate Immunity:

Response Time: Active within hours (0, 6, 12) after infection.

Components: Includes epithelial barriers, phagocytes, and NK cells that respond immediately to
pathogens.
Adaptive Immunity:

Response Time: Takes days (1, 3, 5) to become fully active after infection.
Components: Involves B lymphocytes producing antibodies and T lymphocytes developing into
effector T cells.

The diagram below illustrates the timeline and components of both immune responses:

Understanding these timelines helps in recognizing how quickly the body can respond to infections and the
importance of both types of immunity in overall health and disease management.

Key Differences Between Innate and Adaptive Immunity

Here are the key differences between innate and adaptive immunity:

Feature Innate Immunity Adaptive Immunity

Specificity Nonspecific Highly specific
Response Time Rapid (hours) Slower (days)
Memory No memory Has memory
Physical barriers, phagocytes, NK
Components B cells, T cells, antibodies
cells
Mechanism of Tailored responses to specific
General defense mechanisms
Action pathogens

These differences highlight the complementary roles of both immune systems in protecting the body from
infections and diseases.

12) Specific/Adaptive Immunity Components

Components of Specific/Adaptive Immunity

Specific/adaptive immunity is a crucial part of the immune system that provides a targeted response to
pathogens. The main components of specific/adaptive immunity include:

1. Lymphocytes: These are white blood cells (leucocytes) that are generated in the bone marrow through
the process of hematopoiesis. Lymphocytes play a vital role in recognizing and responding to specific
antigens.
2. Antigen-Presenting Cells (APCs): These cells are essential for the activation of lymphocytes. APCs
possess class II Major Histocompatibility Complex (MHC) molecules on their plasma membrane. These
MHC molecules bind to antigen-derived peptides and present them to lymphocytes, which are then
activated to mount an immune response. This interaction is critical for the initiation of the adaptive
immune response.

For further details, refer to Page 41.

Understanding Antigens and Immunogens

Antigens

Immunogen: A substance that induces a specific immune response.

Antigen (Ag): Known as an antibody generator, an antigen is a substance that induces an immune
response and reacts with the products of that response. Antigens stimulate an immune response and
bind with effectors such as antibodies or immune cells.
Antigens are typically foreign or non-self substances that possess immunogenicity and specificity.
Key Point: All immunogens are antigens, but not all antigens are immunogens. This distinction is
important in understanding how the immune system recognizes and responds to different substances.

For more information, see Page 42.

Epitopes and Paratopes

Epitopes and Paratopes

Epitope: This is a small part of an antigen that interacts with an antibody or T-cell receptor (TCR).
Epitopes are typically composed of 10-12 amino acids and are also referred to as antigen determinants.
Paratope: The site in the variable (V) domain of an antibody or T-cell receptor that binds to an epitope
on an antigen.

Examples of Antigens

Microbial Antigens: These include components such as capsules, cell walls, toxins, viral capsids, and
flagella.
 Non-Microbial Antigens: Examples include pollen, egg white, red blood cell surface molecules, serum
proteins, and surface molecules from transplanted tissues.

Understanding these concepts is essential for grasping how the immune system identifies and responds to
various pathogens and foreign substances.

For additional details, refer to Page 43.

13) Immunogenicity Factors

Chemical Nature of Immunogens

A. Proteins

The majority of immunogens are proteins, which can be pure proteins, glycoproteins, or lipoproteins.
Generally, proteins are very good immunogens due to their higher molecular weights.

B. Polysaccharides

Pure polysaccharides (PS) and lipopolysaccharides (LPS) are also good immunogens.

C. Nucleic Acids

Nucleic acids are usually poorly immunogenic.

However, they may become immunogenic when they are single-stranded or when complexed with
proteins.

D. Lipids

In general, lipids are non-immunogenic, although they may act as haptens.

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Factors Influencing Immunogenicity

I. Contribution of the Immunogen

1. Foreignness

The immune system discriminates between self and non-self, meaning that only foreign molecules are
immunogenic.

2. Size

There is no absolute size above which a substance will be immunogenic, but generally:
The larger the molecule, the more immunogenic it is likely to be.
Good immunogens: > 100,000 Daltons
 Poor immunogens: < 5,000 - 10,000 Daltons

II. Other Factors Influencing Immunogenicity

3. Chemical Composition

The more complex a substance is chemically, the more immunogenic it will be.
Homopolymers are less immunogenic than heteropolymers.

4. Physical Form

Particulate antigens are generally more immunogenic than soluble ones.

Denatured antigens are more immunogenic than their native forms.

5. Degradability

Antigens that are easily phagocytosed are generally more immunogenic.

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