1- Basic Immunology UG Med students - 2023

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1) Classes and Functions of Immunoglobulins

Overview of Immunoglobulin Classes

Immunoglobulins, also known as antibodies, are crucial components of the immune system. There are five
main classes of immunoglobulins, each with distinct structures and functions:

1. IgG
Structure: Monomer
Serum Percentage: 75-80%
Functions:
Provides the majority of antibody-based immunity against invading pathogens.
Can cross the placenta, providing passive immunity to the fetus.
Involved in opsonization, neutralization, and complement activation.
Increased in chronic infections, liver diseases, and autoimmune conditions like rheumatoid
arthritis.
2. IgA
Structure: Monomer in serum; dimer in secretions (anchored by a J chain and a secretory piece)
Serum Percentage: 13-20%
Functions:
Protects mucosal surfaces (e.g., gastrointestinal and respiratory tracts).
Prevents pathogen attachment to epithelial cells.
Found in secretions such as saliva, tears, and breast milk.
Does not fix complement unless aggregated.
3. IgM
Structure: Pentamer (largest immunoglobulin)
Serum Percentage: 6-10%
Functions:
First antibody produced in response to an infection (primary response).
Fixes complement and is effective in opsonization and agglutination.
Present on the surface of B lymphocytes as a monomer.
Elevated levels in newborns indicate recent infection.
4. IgD
Structure: Monomer
Serum Percentage: <0.5%
 Functions:
Primarily found on the surface of B cells, acting as an antigen receptor.
Role in serum is uncertain; does not fix complement.
5. IgE
Structure: Monomer
Serum Percentage: <0.01%
Functions:
Involved in allergic reactions and responses to parasitic infections.
Binds to mast cells and basophils, triggering histamine release.
Does not fix complement.

Detailed Characteristics of Immunoglobulin Classes

IgG

Molecular Weight: ~150,000

Complement Fixation: Yes (+)
Transplacental Passage: Yes
Opsonization: Highly effective

IgA

Molecular Weight: 175,000 - 385,000

Complement Fixation: No (-)
Mucosal Secretion: Yes (found in secretions)
Half-Life: 6 days

IgM

Molecular Weight: ~950,000

Complement Fixation: Yes (+++)
Opsonization: Yes (+)
Half-Life: 5 days

IgD

Molecular Weight: ~180,000

Complement Fixation: No (-)
Half-Life: 3 days

IgE
 Molecular Weight: ~200,000
Complement Fixation: No (-)
Half-Life: 2.5 days

These characteristics highlight the unique roles each immunoglobulin class plays in the immune response
and their structural differences that contribute to their functions.

For a comparative overview, refer to the table below:

Property IgM IgG IgA IgE IgD

% of Serum Ig 6-10 75-80 13-20 <0.01 <0.5
Structure Pentamer Monomer Dimer Monomer Monomer
Complement Fixation +++ + - - -
Transplacental Passage - + - - -
Allergic Response - - - + -
Mucosal Secretion - - + - -
Opsonization + +++ - - -

This table summarizes the key properties of each immunoglobulin class, aiding in the understanding of their
respective roles in the immune system.

2) Structure of Immunoglobulins

Overview of Immunoglobulin Structure

Immunoglobulins (Igs) are heterogeneous molecules that play a crucial role in the immune response. The
basic structural unit of an immunoglobulin molecule consists of four polypeptide chains: two heavy (H)
chains and two light (L) chains.

Heavy Chain (H Chain):

Molecular Weight: 50-75 kDa
Contains approximately 400 amino acids.
Light Chain (L Chain):
Molecular Weight: 25 kDa
Contains approximately 200 amino acids.

Each heavy and light chain has both a variable (V) region and a constant (C) region, which are essential for
the function of the immunoglobulin. This structure allows for the diversity of antigen recognition and binding,
which is critical for an effective immune response.

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Immunoglobulin Structure and Function

The simplest immunoglobulin molecule has a Y-shaped structure. The key components of this structure
include:

Amino Terminal (N-terminus):

Contains the antigen-binding site, also known as the hypervariable region.
Fab (Fragment of Antigen Binding):
Contains the antigen-binding sites of the antibody.
Each Fab fragment has one antigen-binding site, making it monovalent, while the original molecule
is divalent.
Carboxy Terminal (C-terminus):
Forms the Fc (Fragment Crystallizable) fragment, which is involved in complement binding to cell
surface receptors and activation.
Fc Fragment:
Contains the binding site for C1q of the classical complement pathway, playing a vital role in the
immune response.

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Immunoglobulin Fragments and Their Functions

Immunoglobulins can be cleaved into fragments that have distinct functions:

Fab Fragments:
There are two Fab fragments per immunoglobulin molecule.
These fragments are responsible for antigen binding.
 Fc Fragment:
There is one Fc fragment per immunoglobulin molecule.
This fragment has effector functions, such as complement activation and binding to receptors on
immune cells.

The protease papain can cleave immunoglobulins near the hinge region, resulting in two Fab fragments and
one Fc fragment. The Fab fragments possess the antigen-binding sites, while the Fc fragment lacks the
ability to bind antigen but determines the biological properties of the immunoglobulin, such as complement
fixation and placental transfer.

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Structural Variations Among Immunoglobulin Classes

Different classes of immunoglobulins (IgG, IgA, IgM, IgD, and IgE) have unique structural features that
determine their specific functions in the immune response:

IgG:
Monomeric structure with a single Y-shaped unit.
IgA:
Exists as a monomer in serum and as a dimer (secretory IgA) in secretions, linked by a J chain and
a secretory component.
IgM:
Pentameric structure consisting of five monomer units connected by a J chain, with an extra
domain (CH4).
These structural variations allow each immunoglobulin class to perform specific roles in the immune
response, such as neutralization of pathogens, opsonization, and activation of the complement system.

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3) Antibody Mechanisms in Host Defense

Activation of Complement

Activation of Complement

Antibodies play a crucial role in the activation of the complement system, which enhances the immune
response.

Mechanism: When antibodies bind to the surface antigens of pathogens, they activate the
complement cascade.
Effects: This activation leads to:
Lysis of cells: The complement proteins form a membrane attack complex that can directly kill
pathogens.
Release of biologically active molecules: These molecules enhance inflammation and recruit
immune cells to the site of infection.

This process not only helps in directly killing pathogens but also makes them more susceptible to
phagocytosis by immune cells, thereby increasing the efficiency of the immune response.

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Neutralization of Pathogens

Neutralization of Pathogens

Antibodies can neutralize pathogens and toxins, preventing them from causing harm to the host.

Mechanism: Antibodies bind to pathogens (such as bacteria and viruses) or toxins, blocking their
ability to interact with host cells.
Steric Hindrance: This binding creates a physical barrier that prevents pathogens from adhering to
mucosal surfaces or entering cells, thereby reducing their infectivity.
Outcome: Neutralization is a critical function of antibodies, particularly in protecting mucosal surfaces
from infections.

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Opsonization

Opsonization

Opsonization is the process by which antibodies enhance the phagocytosis of pathogens.

Mechanism: Antibodies, particularly IgG and IgM, coat the surface of pathogens. This coating makes it
easier for phagocytes (like macrophages and neutrophils) to recognize and engulf the pathogens.
Phagocyte Interaction: Antibodies have specific sites that bind to both the antigen on the pathogen
and receptors on phagocytes, facilitating the ingestion of the opsonized microorganisms.
Outcome: Opsonization significantly increases the efficiency of phagocytosis, allowing the immune
system to clear infections more effectively.
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Agglutination and Precipitation

Agglutination and Precipitation

Antibodies can also cause agglutination and precipitation of pathogens, which aids in their clearance from
the body.

Agglutination: When antibodies bind to multiple antigens on the surface of pathogens, they can cause
them to clump together. This reduces the number of infectious units and makes them easier for
phagocytes to engulf.
Precipitation: Similar to agglutination, antibodies can bind to soluble antigens, forming larger
complexes that can be more readily cleared by the immune system.
Outcome: Both processes enhance phagocytosis and reduce the number of pathogens that need to be
dealt with by the immune system.

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Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

ADCC is a mechanism through which antibodies mediate the destruction of target cells by immune cells.

Mechanism: Antibodies bind to antigens on the surface of target cells (such as infected or cancerous
cells). This binding marks the target cells for destruction.
Role of Immune Cells: Natural killer (NK) cells and other immune cells recognize the bound antibodies
and initiate a cytotoxic response, leading to the destruction of the target cell.
Outcome: ADCC is an important mechanism for eliminating cells that are infected with viruses or
transformed by cancer.

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4) B Cell Antibody Production

B Cell Development and Antibody Production

B cells develop from stem cells in the bone marrow of adults (or liver of fetuses).

After maturation, B cells migrate to lymphoid organs (lymph node or spleen).

Clonal selection: When a B cell encounters an antigen (Ag) it recognizes, it is stimulated and divides into
many clones called plasma cells, which actively secrete antibodies.

Each B cell produces antibodies that will recognize only one antigenic determinant.

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Clonal Selection of B Cells

Clonal selection of B cells is caused by antigenic stimulation.

In this process, a variety of B cells, each with unique antigen receptors on their surfaces, are stimulated by
an antigen. This triggers cell proliferation, leading to the formation of two types of cell clones:

1. Plasma cells: These larger, oval-shaped cells secrete antibodies into circulation.
2. Memory cells: These smaller, round cells are retained for future immune responses.

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Apoptosis in Antibody Production

Apoptosis is the process of programmed cell death, often referred to as "falling away."
The human body produces approximately 100 million lymphocytes every day. If an equivalent number does
not die, it can lead to conditions such as leukemia.

B cells that do not encounter stimulating antigens will self-destruct and send signals to phagocytes to
dispose of their remains.

Additionally, many virus-infected cells will undergo apoptosis to help prevent the spread of the infection.

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5) Primary vs. Secondary Immune Responses

Primary Immune Response

The primary immune response occurs when an antigen (Ag) is encountered for the first time. Key
characteristics include:

Lag Phase: There is a longer lag period (7-10 days) before antibodies are detectable in serum,
depending on the nature, dose, and route of administration of the antigen.
B Cell Activation: A small clone of B and plasma cells specific for the antigen forms, leading to the
production of antibodies.
Antibody Production: The first antibodies to appear are predominantly IgM, followed by IgG. IgM levels
decline earlier than IgG levels.
Duration: Serum antibody concentration rises for several weeks before declining to low levels.

This information is detailed in Page 35.

Secondary Immune Response

The secondary immune response, also known as the anamnestic response, occurs upon a second
encounter with the same or closely-related antigen, typically months or years later. Key characteristics
include:

Rapid Response: The response is much faster, occurring within 3-5 days due to the persistence of
memory cells.
Higher Antibody Levels: The amount of IgM produced is similar to that of the first contact, but there is
a significantly larger amount of IgG produced, which persists for a longer duration compared to the
primary response.
Long-lasting Immunity: Anamnesis can persist for years in humans, providing long-term immunity
against the specific antigen.

This information is detailed in Page 36.

Comparison of Primary and Secondary Responses

The following table summarizes the differences between primary and secondary antibody responses:

Characteristic Primary Response Secondary Response

Response Speed Slow & Small Rapid & Large
Antibody Affinity Low High
Ig Isotype Predominantly IgM Predominantly IgG
Antigen Dose Large Low

This comparison is based on information from Page 39.

Dynamics of Antibody Response

The dynamics of antibody response can be illustrated through graphs showing the changes in IgM and IgG
titers over time following antigen exposure:

After initial exposure, IgM levels rise, peaking around day 7, then decline.
IgG levels rise later, peaking around day 14, and then also decline.
Upon a second exposure, both IgM and IgG levels rise again, with IgG peaking higher and later than IgM.

This dynamic response is further illustrated in Page 38.

Role of Memory Cells

Memory cells play a crucial role in the immune response and long-term immunity:

They are the second cell type produced by the division of B cells and have a prolonged lifespan of over
20 years.
Memory cells enable the immune system to respond much faster upon re-exposure to the same
intruder, often eliminating the invader before symptoms appear.
This rapid response is what provides the body with immunity against previously encountered antigens.

This information is detailed in Page 40.

6) Immunoglobulin Class Switching

Overview of Immunoglobulin Class Switching

Immunoglobulin class switching, also known as isotype switching, is a biological mechanism that allows a B
cell to change the class of antibody (Ab) it produces from one isotype to another. This process is crucial for
the adaptive immune response, particularly during subsequent exposures to an antigen (Ag).

Key Features of Class Switching

Initial Production: B cells initially produce IgM antibodies in response to an antigen.

Subsequent Exposure: Upon re-exposure to the same antigen, the immune response shifts to produce
IgG antibodies.
Active Immune Response: Class switching occurs only during an active immune response, allowing for
a more effective and tailored immune reaction.
Ag Specificity: The process retains the same antigen specificity, meaning that the antibodies produced
after switching will still target the same pathogen.

Mechanism of Class Switching

The mechanism of immunoglobulin class switching involves several key steps:

DNA Rearrangement

Class switching involves further DNA rearrangements that modify the constant region of the heavy
chains of the antibody.
The variable regions of the heavy chain and the light chain remain unchanged, ensuring that the
antibody retains its specificity for the antigen.

Role of Cytokines
 Class switching is influenced by cytokines released by helper T cells during an immune response to T-
dependent antigens.
These cytokines stimulate mature B cells to undergo the switching process, allowing them to produce
different classes of antibodies such as IgG, IgE, or IgA throughout an individual's lifetime.

Switch Regions

The process involves specific DNA sequences known as switch regions, which facilitate the
recombination of the heavy chain genes necessary for class switching.

Significance of Class Switching in Immune Response

Immunoglobulin class switching plays a vital role in enhancing the effectiveness of the immune response:

Enhanced Immune Function

IgG Production: The switch to IgG production is significant because IgG antibodies are more effective
in opsonization, neutralization, and activating complement pathways compared to IgM.
Diverse Antibody Functions: Different classes of antibodies have distinct functions and properties,
allowing the immune system to tailor its response to various pathogens and conditions.

Long-term Immunity

Class switching contributes to the development of long-term immunity by enabling the production of
high-affinity antibodies that can persist and respond more effectively upon re-exposure to the same
antigen.
This adaptability is crucial for the body's ability to remember and respond to previously encountered
pathogens.

7) Types of Immunity

Types of Active Immunity

Active Immunity

Active immunity can be classified into two main types:

Natural Active Acquired Immunity

This type of immunity develops as a result of previous exposure to a live pathogen through natural
infection.
It is induced by the individual's own immune cells in response to the infection, leading to the production
of antibodies against the foreign antigens.

Artificially Active Acquired Immunity

This immunity is acquired artificially through immunization, such as the use of toxoids or vaccines.
 Vaccines stimulate a primary immune response against the antigen without causing the symptoms of
the disease.

This classification highlights how the immune system can be activated either through natural exposure or
through medical intervention, both leading to the development of immunity.

Advantages of Active Immunity

Advantages

Greater Response: Active immunity typically results in a more robust immune response compared to
passive immunity.
Long-lasting Effectiveness: The immunity developed through active means is generally long-lasting,
providing prolonged protection against the pathogen.
Sustained Relief: Once established, active immunity can provide relief from infections for an extended
period.

Disadvantages of Active Immunity

Disadvantages

Slow Onset: The development of resistance through active immunity can be slow, as it requires time for
the immune system to recognize the pathogen and produce antibodies.
Need for Repeated Exposure: Active immunity often requires repeated and prolonged contact with
the antigen to maintain immunity, which may not always be feasible or safe.
Side Effects: While vaccines may have rare and mild side effects, these can still be a concern for some
individuals.

8) Genetic Diversity of Immunoglobulins

Immunoglobulin Gene Families

Immunoglobulins are encoded by specific gene families located on different chromosomes:

Heavy (H) chain gene family: Located on Chromosome 14.

Kappa (K) light chain gene family: Located on Chromosome 2.
Lambda (A) light chain gene family: Located on Chromosome 22.

The light chain genes are encoded by three genes:

V (variable gene)
J (joining gene)
 C (constant gene)

The combination of V and J genes codes for the variable region (VL), while the C gene codes for the
constant region (CL).

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Heavy Chain Genes

Heavy chain genes are encoded by four genes:

Variable region: Coded by three genes:

V H (variable)
J H (joining)
D H (diversity)

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Immunoglobulin Diversity: Isotypes, Allotypes, and Idiotypes

Immunoglobulin diversity is characterized by three main types of determinants:

Isotypes

Isotype: Refers to one of the five major kinds of heavy chains in immunoglobulins.
The differences among isotypes are found in the constant region.
Isotypes are antigenic features of a class of Ig heavy or light chain.
Different isotypes can share common variable regions.
Isotypes are variants present in all members of a species, meaning all normal humans share certain
isotypes because they all produce heavy or light chains.

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Allotypes

Allotype: Refers to the allelic variation seen at loci specifying the light and heavy chains of
immunoglobulins.
Allotypes are caused by intraspecies genetic differences, similar to the ABO blood group system.

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Idiotypes

Idiotype: Refers to the unique antigen determinants of the hypervariable region of an antibody.
Idiotypes are caused by structural heterogeneity in the antibody variable regions.
Each B-cell produces one type of antibody, meaning one B-cell makes one idiotype.
The set of antigenic determinants (idiotopes) characterizes each unique antibody or T-cell receptor.
Idiotopes are generated by the unique amino acid sequence specific for each antigen.
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Summary of Determinants

Isotypic determinants: Variants present in all members of a species.

Allotypic determinants: Variants caused by genetic differences within a species.
Idiotypic determinants: Unique to each antibody, determined by the specific antigen it binds to.

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This overview of the genetic basis of immunoglobulin diversity highlights the roles of isotypes, allotypes, and
idiotypes, which are crucial for understanding how antibodies function and vary among individuals.