Immune Response
The immune response is a
complex, highly coordinated physiological mechanism employed by an organism to recognise
and neutralise foreign molecules or antigens such as pathogens (bacteria,
viruses, fungi, parasites), toxins, or altered self-cells (tumours).
Immunity is broadly categorised
into two
- Innate
(Non-Specific) Immunity:
The first line of defence comprising physical barriers (skin, mucous
membranes), chemical factors, phagocytes (macrophages, neutrophils), etc.
It responds immediately upon exposure to an antigen without immunological
memory or specificity.
- Adaptive
(Acquired/Specific) Immunity:
Antigen-specific defence executed by T lymphocytes (cell-mediated
immunity) and B lymphocytes (humoral immunity) are adaptive immunity. Diversity, specificity, self/nonself
recognition, and memory are the hallmarks of an adaptive immune response.
Diversity: The adaptive immune system can
generate a virtually limitless array of distinct lymphocyte receptors (Antibodies
and TCRs) through genetic recombination, enabling the recognition of millions
of unique antigenic structures.
Specificity: Antigen receptors specifically
bind to distinct molecular determinants (epitopes) on foreign antigens,
ensuring that resulting immune response is targeted precisely against the particular
antigen without harming unrelated tissues.
Self/Nonself Recognition: During lymphocyte maturation,
clonal deletion and tolerance mechanisms selectively eliminate or silence
self-reactive immune cells. This allows
the system to destroy foreign antigens while being tolerant of own tissues.
Memory: Encountering an antigen generates
long-lived memory lymphocytes that persist in the body, allowing for a
significantly faster, stronger, and more effective secondary response upon
subsequent exposure to the same antigen.
Immunological memory forms the foundation of primary and secondary
immune responses.
Primary
and secondary immune response
In a primary immune response, naive
B cells are stimulated by an antigen, become activated, and differentiate into
antibody-secreting cells that produce antibodies specific for the antigen. A
secondary immune response is elicited later, when the same antigen stimulates
memory B cells, leading to the production of larger quantities of the same specific
antibodies that were produced during the primary response.
In brief, during the primary immune
response, B and T-cells replicate and produce effector cells and long-lived
memory cells. Memory B and T-cells are antigen-specific and, on encountering
the antigen at a later time, they cause a more rapid and effective immune
response, known as the secondary immune response.
The
primary immune response occurs when an individual encounters a specific
pathogen or foreign antigen for the very first time.
The
primary immune response go through a Lag phase where naive lymphocytes
recognize and process the antigen, a Log phase marked by exponential
antibody production (primarily IgM), a Plateau phase where serum
antibody titers reach their peak, and a Decline phase as the antigen is
cleared and plasma cells undergo Clearance.
Diagram showing a primary and secondary response (Textbook of
Microbiology and Immunology, 2/e, Parija)
1. Lag (Latent) Phase
The
lag phase is the time interval between the initial exposure to a foreign
antigen and the first detectable appearance of specific antibodies in the
serum. Duration ranges between 7 and 14
days (depending on the nature, dose, and route of antigen entry). During this phase there will be no detectable
levels of this specific antibody in serum.
Key
Events:
1. Antigen-presenting
cells (APCs), such as dendritic cells, internalize the antigen, process it, and
display them on MHC class II molecules.
2. APCs
migrate through the lymphatic system to secondary lymphoid organs (lymph nodes
or spleen) to present the antigen to naive TH cells.
3. Naive
B cells with surface membrane-bound antibody specific to the antigen bind the antigen.
4. Activated
5. Naive
B cells undergo initial proliferation and begin differentiating into
short-lived antibody-secreting plasma cells and long-living memory B cells.
2.
Log (Exponential) Phase
This is the period during which
serum antibody levels rise exponentially and reach the maximum titre. This is due to the rapid secretion of
immunoglobulins by plasma cells. This
phase typically lasts several days to 2 weeks following the lag phase.
Key
Events:
1. Plasma
cells actively synthesize and release specific antibodies.
2. The
initial antibodies secreted are predominantly IgM.
3. Later
in the log phase, T-cell-derived cytokines induce B cells to undergo class
switching from IgM to IgG (or IgA/IgE depending on tissue site).
4. Somatic
hypermutation (SHM) begins in the variable regions of immunoglobulin genes
within germinal centres, selecting B cells with higher affinity for the
antigen. Somatic hypermutation (SHM) is
a process that introduces random point mutations into the variable regions of
antibody genes in activated B cells. This mechanism allows the immune system to
rapidly adapt, creating antibodies with higher affinity towards antigen so as
to fight off foreign invaders.
3.
Plateau (Steady-State) Phase
This phase represents the peak of
the primary response, where the rate of new antibody production by plasma cells
balances the rate of antibody degradation and clearance. This lasts several
days to a few weeks, depending on the persistence of the antigen and the
host's immune status.
Key
Events:
1. Antibody-secreting
plasma cells function at peak efficiency, maintaining steady serum
concentrations of immunoglobulins.
2. Isotype
Switch Completion - antibody profile transitions from IgM to IgG class switch reaches
completion in germinal centers.
3. Peak
concentrations of antibodies bind actively to foreign antigens, forming
antigen-antibody (immune) complexes that facilitate neutralization, complement
activation, and phagocytosis by macrophages and neutrophils.
4. B
cells and T cells that survived germinal center selection fully differentiate
into resting memory B cells and memory T cells, which exit secondary lymphoid
tissues and circulate through blood and lymph.
4.
Decline (Contraction) Phase
The
phase marks the resolution of the primary response following the successful
elimination of the invading pathogen or antigen, and the duration spans several
weeks to months. Serum antibody levels gradually
decrease to a low baseline level. There
will be undetectable levels of IgM, and low levels of protective IgG persist
for long-term immunity.
Key
Events:
1. As
macrophages and neutrophils clear the antigen-antibody complexes, the antigenic
stimulus required to sustain lymphocyte activation goes down.
2. Short-lived
plasma cells in secondary lymphoid organs undergo programmed cell death (apoptosis).
3. Circulating
IgM and IgG molecules undergo natural metabolic degradation, leading to a
steady drop in serum antibody titre.
4. Up
to 90% to 95% of activated effector T and B cells are eliminated via apoptosis.
5. A
small population of plasma cells migrates to bone marrow, while memory
cells remain in circulation and secondary lymphoid organs to provide
long-term surveillance.
The Secondary (Anamnestic) Immune
Response
The secondary immune response is also
called the anamnestic response. It is
the highly accelerated immune reaction that occurs upon re-exposure to a
previously encountered antigen. The
secondary immune response is triggered when pre-existing Memory B cells
and Memory T cells encounter their specific antigen upon re-exposure. Upon re-exposure, the secondary immune
response enters a brief lag phase lasting only 1 to 3 days as long-lived
memory B and T cells immediately recognize the antigen. This is followed by a
rapid log phase where high-affinity IgG antibodies are secreted in
massive quantities, reaching a peak that is 100 to 1,000 times higher than the
primary response. Serum antibody levels then remain elevated during a prolonged
plateau and gradual decline phase, providing long-lasting protection.
Key Features of Secondary Response
- Memory
B cells, upon antigen recognition, rapidly proliferate and differentiate
into plasma cells, generating large quantities of antibodies to clear the
pathogen before clinical symptoms develop.
- A
subpopulation of activated memory B cells re-enter germinal centers and
undergo additional rounds of somatic hypermutation and class-switching,
continually improving antibody affinity over time.
- Memory
B cells express high levels of MHC Class II and co-stimulatory molecules, and
serve as efficient antigen-presenting cells (APCs) that reactivate
effector and memory T cells.
- Memory
cells persist for decades without requiring exposure to antigen or survival
signals and predominantly secrete high-affinity IgG.
Clinical Relevance
- Vaccination
& Booster Shots: Primary vaccines establish the pool of memory cells;
booster doses exploit the secondary response to elevate antibody titers,
increase affinity, and generate long-lived plasma cells in the bone
marrow.
- Diagnostic
Serology:
- High
IgM with low/absent IgG = Primary/Acute Infection.
- High
IgG with low/absent IgM = Secondary Exposure, Past Infection, or
Re-vaccination.
- Original
Antigenic Sin: The immune system's tendency to utilize memory cells
established during a primary response against a mutated variant of a
pathogen, sometimes reducing immunological efficiency (e.g., Influenza,
SARS-CoV-2 strains). Original
Antigenic Sin is also known as immunological imprinting or Hoskins'
phenomenon. This is a phenomenon
where the immune system relies on memory B cells established during its first
exposure to a pathogen (or vaccine) when encountering a slightly altered
variant of that same pathogen later in life. Instead of eliciting a fresh, primary
immune response against the newly mutated pathogen, the body remembers the
old response, which may be less effective against the modified strain. This
results in the body making old antibodies instead of fighting the new
strain.
References
Textbook of Microbiology and
Immunology, 2/e, Parija
Kuby Immunology - Textbook by Jenni
Punt and Judith A. Owen
Ananthanarayan and Paniker's
Textbook of Microbiology
Immunology: A Short Course by Eli
Benjamini
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