Types of immune response

B cell response (antibody mediated),

T cell response (cell mediated)
Paper II Unit 4.1
 Types of Immune responses
• Whenever foreign particles, including
microorganisms enter the body, they are
recognized as non-self by the immune system,
and a reaction takes place to deal with them.
• This reaction is called an immune response.
• The reaction may take place in different ways,
depending upon the prevalent circumstances.
• According to the mechanism through which the
response is brought about, it can be classified as
a humoral immune response or a cell mediated
immune response.
 The Humoral response
• This is mediated by antibodies through the participation of B
Cells.
• It is therefore also termed as a B cell response.
• In this response, the B cells of the immune system produce
antibodies specific to the antigen.
• The humoral or antibody mediated response also involves
other processes accessory to antibody production.
• They include activation and cytokine production, germinal
centre formation and isotype switching, affinity maturation
and memory cell production.
• Such a response brings about pathogen and toxin
neutralization, complement activation,
promotion of phagocytosis and elimination of the
pathogen.
• The response also involves participation of
cytokines, which are soluble substances secreted
by the cells of the immune system, which bring
about a variety of effects upon other cells.
• T helper cells or TH cells produce a variety of
cytokines and assist in the immune response.
The primary response
• When the body is exposed to an antigen for the first time,
antibody becomes available after some time.
• The first antibody detected in such conditions is always IgM,
whose level later declines.
• The primary response is induced when macrophages, or other
APCs (Antigen presenting cells which are capable of
processing the antibody into fragments) such as B cells,
monocytes, dendritic cells, etc. come into contact with the
antigen.
• Antigens are internalized by endocytosis by these cells,
processed into fragments and presented to competent
lymphocytes to initiate the response.
• Such presentation involves
molecules on the surface of
APCs called the MHC (Major
Histocompatibility Complex,
which facilitates binding of
one cell to another) Class II
molecules.
• The antigenic fragments are
bound to these molecules
on the surface of the
macrophage for presenting
to TH2cells.
• In addition, the macrophage
also produces a cytokine
called IL-1 (Interleukin -1).
• On coming across IL-1 and the antigen bound on the
macrophage, the TH2 cell becomes activated to produce
cytokines.
• It produces IL-2 as well as a membrane receptor for IL-2.
• Attachment of IL-2 to its receptor causes the
autostimulation of TH2 cells to proliferate.
• It also causes secretion of more IL-2 as well as other
cytokines such as IL-4, IL-5, IL-6 and gamma interferon,
required for various aspects of the immune response.
• IL-2 binds with IL-2 receptors on other TH2 cells, stimulating
their proliferation.
• IL-4 stimulates B cells and activates T cells to differentiate
into TH2 cells.
• IL-5 stimulates B cell growth and increases secretion of
immunoglobulins by them.
• IL-6 helps in differentiation of B cells into antibody forming
plasma B cells.
• B cells are activated through cross-linking with the
antigenic epitopes or determinants (part of antigen
that binds to the antibody) with the immunoglobulins
on their surface.
• This takes place with the help of receptors on the B cell
surface, called BCR (B cell receptor).
• The complex formed at the BCR between the antigen
and the immunoglobulin is engulfed by the B cell.
• The antigen is degraded, processed by the B cell and
presented to effector TH2 cells through class II MHC.
• TH2 cells first bind to B cells by cell adhesion molecules
or CAMs, and then by binding the specific peptide on
the class II MHC through TCR (T cell receptors).
• B cells also secrete a substance called CD40L (CD 40
Ligand) which binds to CD40 receptors on the TH2 cell.
• This binding causes the TH2 cells to send a stimulatory
signal to B cells to maintain the antigen specificity.
• There are three gene groups which encode
immunoglobulins, one for the κ chain, one for λchain
(both light chains), and one for the heavy chain.
• The genes have segments for the constant and variable
regions.
• Further, the variable segment contains three
different loci in case of heavy chains, called the V
(variable) locus, D (diversity) locus and the J
(joining) locus.
• The variable segment of the light chain contains
only the V and J loci, but no D locus.
• Random selection of the loci during B cell
development from the germ line cells, first into a
DJ segment (in heavy chains) and then a VDJ
segment, imparts combinational diversity to the
heavy chains.
• Such random selection and rearrangement is possible
due to a dimeric enzyme, produced by the expression
of two genes called RAG-1 and RAG-2 (rearrangement
activation genes).
• The combination of VDJ segment to the C segment
from the constant region imparts the antibody a
specific isotype identity (the class of Ig such as IgA, IgG,
IgM, etc.).
• The DNA of the B cell, thus formed, is also random,
capable of expressing different types of Ig or antibody
molecules through the processes of transcription and
translation.
• Antibody diversity may further increase by overlapping
of DNA segments during rearrangement, filling of gaps
formed by joining of segments by random nucleotides,
and independent pairings between light and heavy
chains.
• The specificity of antibody to the antigen is maintained
through a process called allelic exclusion.
• The diploid B cell has two sets of genes, in the form of
alleles.
• There are alleles for light and heavy chains of the
antibodies.
• Through rearrangement of the B cell genome by the
translocation enzyme , it is ensured that specific alleles
are expressed, while others are excluded, only on one
homologous chromosome, and not on the other, to
form light and heavy chains that are assembled into a
functional antibody.
• The heavy chain gene transcribes mRNA that has a
coding sequence for its transmembrane domain. The Ig
molecules formed by translation of this mRNA get
anchored to the plasma membrane by their C-
terminals.
• On coming across an antigen that binds to its BCR
(surface Ig), the B cell begins to secrete antibodies
similar to the BCR.
• A B cell bound to an antigen and simultaneously
stimulated by IL-4 secreted by a nearby TH2 cell, is
stimulated to grow and divide into identical clones,
each capable of producing identical antibodies.
• Some may show favourable point mutation that
increase antibody affinity with the antigen.
• Most B cells further differentiate into larger plasma B
cells, capable of producing large amounts of
antibodies.
• Proliferation of B cells takes place in the lymph nodes
in groups called the germinal centres. The immature B
cells remain surrounded by TH2 cells, which help them
in maturation and migrate with them into the
circulation.
• Many germinal centres are seen to be formed in about
a week of infection, causing swelling of the lymph
nodes.
• Some B cells do not differentiate into plasma cells.
• Instead, through secondary rearrangements in their
DNA, they place the constant regions of the IgG, IgA or
IgE genes in close proximity with the VDJ region,
instead of the already existing IgM and IgD genes.
• This is termed as class switching, and takes place
with the help of cytokines secreted by the TH2
cells and the antigen.
• The cells so formed are termed as memory B
cells.
• This ensures the formation of a variety of
memory B cells, which are long lived.
• Each cell is capable of producing a new class of
antibodies, called secondary antibodies, which
take part in the secondary response.
The Secondary response
• Also called anamnestic or memory response,
such a response occurs when the body is exposed
to an antigen for the second time.
• Larger amounts of antibodies are secreted in a
very short time of just 1-2 days, due to the
activity of memory cells formed during a primary
response.
• The memory cells when activated by the abtigen,
rapidly differentiate into effector plasma B cells,
which produce high levels of circulating
antibodies.
• The concept of secondary response has been
applied to several ‘booster’ type of
vaccinations given to humans and other
animals.
• Some antigens are called T-independent
antigens. Response to these antigens is
directly by the B cells using IgM.
• No memory cells are formed for such
antigens.
 Cell Mediated Immune Response
• In such a response, various cells of the immune system are
involved in elimination of foreign substances.
• Unlike the humoral response, the cell mediated response
cannot be transferred passively from one organism to
another.
• It is possible to transfer this response only by transfer of
lymphocytes from blood of one organism to another.
• Cell mediated immunity is aimed at killing of intracellular
and extracellular pathogens by cells such as macrophages,
NK cells and cytotoxic T cells.
• The response aids in removal of virus infected cells, defence
against intracellular bacteria, fungi, protozoans and
cancers, and rejection of transplants.
• In this immune response, the T lymphocytes play a
very important role. It is the T lymphocytes that are
activated into effector T Cells.
• Effector T cells are of three different types, each
capable of dealing with a different kind of antigen.
• CD8 Cytotoxic T lymphocytes (CTL) kill pathogen
infected cells displaying peptide epitopes with class I
MHC.
• CD4 TH1 Cells activate macrophages with persistent
pathogens whose peptide fragments are displayed with
class II MHC, and also activate B cells to produce
opsonising antibodies.
• NK (Natural Killer) cells show cytotoxic activity against
virus infected or virus transformed cells.
• T cells are present in the circulating blood and lymph, and
in the lymphoid tissues.
• The TCR (T Cell Reptors) on their surfaces can recognize
specific antigens associated with class I MHC displayed by
altered self cellsin case of CTL and by macrophages and
other APCs with class II MHC in case of TH1 and TH2 cells.
• During a primary response, the antigen is presented to
precursor CTLs.
• All nucleated cells essentially have class I MHC on their
surfaces.
• Any cell also displaying antigen fragments is thus the target
of such a CTL.
• TH cells that encounter antigens produce a
variety of lymphokines (Cytokines secreted by
lymphocytes).
• These stimulate B cells and CTLs to proliferate
and mature.
• TH1 cells produce IL-2, γ-IFN (gamma
interferon) and cytotoxins.
• γ-IFN activates macrophages and NK cells to
express their full cytolytic potential.
Role of Cytotoxic T Lymphocytes
• CTLs form a major defence against viruses,
intracellular bacteria and cancers by bringing
about destruction of infected cells.
• CTLs, derived from T8 lymphocytes, can kill
infected cells as long as they display antigen
fragments on their surfaces in association with
class I MHC.
• They kill the cells by releasing their toxic contents
directly on to the cell membranes of the infected
cells, leading to their lysis.
• In addition, CTLs release IFN-γ, TNF-α (Tumor
Necrosis Factor) and TNF - β. IFN-γ, in addition to
inhibition of viral replication, acts with TNF-α and
TNF - β and causes activation of macrophages to
act as APCs and to directly kill some cells.
• CTLs may release substances called perforins that
polymerizes in presence of calcium into channels
through the membranes of target cells.
• The cell contents leak out causing cell lysis.
• The cells may release enzymes such as granzymes that
enter the infected cells through the perforin channels
and activate other enzymes called caspases.
• These break down nucleoproteins, structural
Cytoskeletal proteins and DNA of the target cell.
• In addition, CTLs may bind with the target cells that
express receptors called Fas or CD 98 through a Fas
ligand on their surface.
• When this happens, the cell is activated to undergo
apostosis (programmed death through a series of
genetic and biochemical changes).
Role of Macrophages
• Macrophages process and present antigens to TH1 cells.
• TCRs and CD4 molecules on TH1 cells interact with class II
MHC – peptide epitope complex on the surface of the
macrophage.
• Co stimulatory molecules called CD40L on T cell surface
bind with receptors termed as CD40 on macrophage
surfaces.
• TH1 cells also release IFN-γ which binds with IFN-γ receptors
on macrophage surfaces.
• This activates the macrophages to increase the number of
lysosomes and to secrete more microbicidal substances.
• In case of infection of cells by Tuberculosis
bacilli, it is not always possible for
macrophages to eliminate the bacilli.
• More and more macrophages collect at the
site of infection, causing release of
fibrinogens, which in turn cause granulation
and fibrosis.
• This result in formation of structures called
granulomas or nodules.
Role of NK cells
• These are found in blood and lymphoid tissues,
especially spleen.
• They do not exhibit typical B cell or T cell
markers, and have CD56, CD16 or both, on their
surfaces.
• They are not MHC restricted, and are able to kill
cells showing altered antigens on their surfaces.
• NK cells are present even in absence of antigen,
and are therefore called natural killer cells.
• They can, in addition, be activated by T cells,
through IL-2 and IFN-γ.
• Some NK cells have receptors called CD16 which
recognize the Fc portion of IgG. This is termed as
ADCC (Antibody Dependent Cell mediated
Cytotoxicity).
• This is an important form of defence against
larger pathogens such as protozoa and helminths.
• NK cells also have receptors for the C3
component of the compliment system and
recognize target cells coated with C3.