Chapter 5
The Normal Immune Response
- Innate immunity (also called natural, or native, immunity) is mediated by cells and
proteins that are always present (hence the term innate), poised to react against
infectious pathogens first line of defense
- Adaptive immunity is normally silent and responds to the presence of infectious agents
(but also own changed and abnormal cells) by generating potent mechanisms for
neutralizing and eliminating the pathogens
Innate Immunity (non-specific)
- The major components of innate immunity are epithelial barriers that block the entry of
microbes, phagocytic cells (mainly neutrophils and macrophages), dendritic cells (DCs),
natural killer (NK) cells and other innate lymphoid cells, and several plasma proteins,
including the proteins of the complement system
- Phagocytes, dendritic cells and many other cells, such as epithelial cells, express
receptors that sense the presence of infectious agents and substances released from
dead cells
- Pattern recognition receptors are located in all the cellu- lar compartments where
pathogens may be present: plasma membrane receptors detect extracellular patho-
gens, endosomal receptors detect ingested microbes, and cytosolic receptors detect
microbes in the cytoplasm
- The plasma membrane TLRs recognize bacterial products such as lipopolysaccharide
(LPS), and endosomal TLRs recognize viral and bacterial RNA and DNA
- Several of the NLRs (NOD-like receptors) signal via a cytosolic multiprotein complex
called the inflammasome, which activates an enzyme (caspase-1) that cleaves a
precursor form of the cytokine interleukin-1 (IL-1) to generate the biologically active
form
- C-type lectin receptors (CLRs) expressed on the plasma membrane of macrophages and
DCs detect fungal glycans and elicit inflammatory reactions to fungi
- G protein–coupled receptors on neutrophils, macrophages, and most other types of
leukocytes recognize short bacterial peptides containing N-formylmethionyl residues
- Mannose receptors recognize microbial sugars
- The innate immune system provides host defense by the two main reactions:
Inflammation: Cytokines and products of complement activation, as well as other
mediators, are produced during innate immune reactions and trigger the vascular
and cellular components of in ammation
Anti-viral defense: Type I interferons produced in response to viruses act on
infected and uninfected cells and activate enzymes that degrade viral nucleic acids
and inhibit viral replication
Adaptive Immunity (specific)
- The adaptive immune system consists of lymphocytes and their products, including
antibodies
- There are two types of adaptive immunity: humoral immunity, mediated by soluble
proteins called antibodies that are produced by B lymphocytes (also called B cells), and
cell-mediated (or cellular) immunity, mediated by T lymphocytes (also called T cells)
, - Lymphocytes develop from precursors in the generative (primary) lymphoid organs; T
lymphocytes mature in the thymus, whereas B lymphocytes mature in the bone
marrow
- The antigen receptors that are expressed in B cells are called antibodies, while their T-
cell counterparts are called T-cell receptors
- Mature T and B lymphocytes recirculate through peripheral (secondary) lymphoid
organs: the lymph nodes, spleen and mucosal tissues
- Foreign antigens are concentrated in these organs, where they bind to and activate the
clones of lymphocytes that express receptors for those antigens, a process known as
clonal selection
- Thymus-derived T lymphocytes develop into the effector cells of cellular immunity and
“help” B cells to produce antibodies against protein antigens
- T cells sense only peptide fragments of proteins displayed by molecules of the major
histocompatibility complex (MHC) (signal 1) TCRs only recognize antigens presented
by other cells. For T-cell activation a co-stimulatory signal is also necessary
- TCR is a a heterodimer that in most T cells is composed of disulfide-linked α and β
protein chains. Each chain has a variable region that participates in binding a particular
peptide antigen and a constant region that interacts with associated signaling
molecules
- The CD3 proteins and ζ chains do not bind antigens; instead, they are attached to the
TCR and initiate intracel- lular biochemical signals after TCR recognition of antigen
- CD4 and CD8 are expressed on distinct T-cell subsets and act as coreceptors during T-
cell activation
- During antigen recognition, CD4 molecules on T cells bind to invariant portions of class
II MHC molecules on selected antigen-presenting cells (APCs) → extracellular antigen.
CD8 binds to class I MHC molecules intracellular antigen
CD4+ T cells are called helper T cells because they secrete soluble molecules
(cytokines) that help B cells to produce antibodies and also help macrophages to
destroy phagocytosed microbes
CD8+ T cells also can secrete cytokines, but their most important role is to directly
kill virus-infected cells and tumor cells; hence, they are called cytotoxic T lymphocytes
(CTLs)
- CD28: the receptor for molecules called costimulators that are induced on APCs by
microbes, and various adhesion molecules that strengthen the bond between the T
cells and APCs and control the migration of the T cells to different tissues (signal 2)
- γδ T cells (not α and β chains), which do not express CD4 or CD8, recognize nonprotein
molecules
- NKT cells recognize microbial glycolipids and may play a role in defense against some
infections
MHC-molecules
- The normal function of MHC molecules is to display peptides for recognition by CD4+
and CD8+ T lymphocytes MHC-restriction (CD4 binds MHCII and CD8 binds MHCI)
- Class I MHC molecules are encoded by three closely linked loci, designated HLA-A, HLA-
B, and HLA-C. Each of these molecules consists of a polymorphic α chain noncovalently
associated with an invariant β2- microglobulin polypeptide
, - Class II MHC molecules are encoded by genes in the HLA-D region, which contains
three subregions: DP, DQ, and DR. Unlikke class I MHC molecules, which are expressed
on al nucleated cells, expression of class II MHC molecules is restricted to a few cell
types, mainly APC (dendritic cells), macrophages and B cells
- The human MHC, known as the human leukocyte antigen (HLA) complex, consists of a
cluster of genes on chromosome 6
- Each set of maternal and paternal HLA genes is referred to as an HLA haplotype
- The implications of HLA polymorphism for transplantation are obvious; because each
person has HLA alleles that differ to some extent from those of every other unrelated
individual, grafts from unrelated donors will elicit immune responses in the recipient
and be rejected (Only identical twins can accept grafts from one another, without fear
of rejection)
B Lymphocytes
- B (bone marrow–derived) lymphocytes are the cells that produce antibodies, the
mediators of humoral immunity
- B cells recognize antigen by means of membrane-bound antibody of the
immunoglobulin M (IgM) class, expressed on the surface together with signaling
molecules to form the B-cell receptor (BCR) complex
- CD21 (also known as the type 2 complement receptor, or CR2) recognizes a
complement breakdown product that frequently is deposited on microbes and
promotes B-cell responses to microbial antigens
- After stimulation, B cells differentiate into plasma cells, which secrete large amounts of
antibodies. There are fi ve classes, or isotypes, of immunoglobulins: IgG, IgM, IgE (tissue
mast cells), IgD (secreted at very low levels) and IgA (mucosal secretions)
NK cells and Innate Lymphoid Cells
- NK cells are innate immune cells, as they are functional without prior activation and do
not express highly variable and clonally distributed receptors for antigens
Inhibitory receptors recognize self class I MHC molecules, which are expressed on all
healthy cells
Activating receptors recognize molecules that are expressed or upregulated on stressed
or infected cells
- Infections and stress are associated with reduced expression of class I MHC molecules
and increased expression of proteins that engage activating receptors
- NK cells also secrete cytokines such as interferon-γ (IFN-γ), which activates
macrophages to destroy ingested microbes, and thus NK cells provide early defense
against intracellular microbial infections
- Innate lymphoid cells (ILCs) are populations of lymphocytes that lack TCRs but produce
cytokines similar to those that are made by T cells. They are classified into three groups,
which produce IFN-γ, IL-5, or IL-17
Antigen-presenting cells (APCs)
- Antigen-presenting cells are dendritic cells, macrophages and B cells
- Dendritic cells (DCs) are the most important antigen- presenting cells for initiating T-
cell responses against protein antigens
The Normal Immune Response
- Innate immunity (also called natural, or native, immunity) is mediated by cells and
proteins that are always present (hence the term innate), poised to react against
infectious pathogens first line of defense
- Adaptive immunity is normally silent and responds to the presence of infectious agents
(but also own changed and abnormal cells) by generating potent mechanisms for
neutralizing and eliminating the pathogens
Innate Immunity (non-specific)
- The major components of innate immunity are epithelial barriers that block the entry of
microbes, phagocytic cells (mainly neutrophils and macrophages), dendritic cells (DCs),
natural killer (NK) cells and other innate lymphoid cells, and several plasma proteins,
including the proteins of the complement system
- Phagocytes, dendritic cells and many other cells, such as epithelial cells, express
receptors that sense the presence of infectious agents and substances released from
dead cells
- Pattern recognition receptors are located in all the cellu- lar compartments where
pathogens may be present: plasma membrane receptors detect extracellular patho-
gens, endosomal receptors detect ingested microbes, and cytosolic receptors detect
microbes in the cytoplasm
- The plasma membrane TLRs recognize bacterial products such as lipopolysaccharide
(LPS), and endosomal TLRs recognize viral and bacterial RNA and DNA
- Several of the NLRs (NOD-like receptors) signal via a cytosolic multiprotein complex
called the inflammasome, which activates an enzyme (caspase-1) that cleaves a
precursor form of the cytokine interleukin-1 (IL-1) to generate the biologically active
form
- C-type lectin receptors (CLRs) expressed on the plasma membrane of macrophages and
DCs detect fungal glycans and elicit inflammatory reactions to fungi
- G protein–coupled receptors on neutrophils, macrophages, and most other types of
leukocytes recognize short bacterial peptides containing N-formylmethionyl residues
- Mannose receptors recognize microbial sugars
- The innate immune system provides host defense by the two main reactions:
Inflammation: Cytokines and products of complement activation, as well as other
mediators, are produced during innate immune reactions and trigger the vascular
and cellular components of in ammation
Anti-viral defense: Type I interferons produced in response to viruses act on
infected and uninfected cells and activate enzymes that degrade viral nucleic acids
and inhibit viral replication
Adaptive Immunity (specific)
- The adaptive immune system consists of lymphocytes and their products, including
antibodies
- There are two types of adaptive immunity: humoral immunity, mediated by soluble
proteins called antibodies that are produced by B lymphocytes (also called B cells), and
cell-mediated (or cellular) immunity, mediated by T lymphocytes (also called T cells)
, - Lymphocytes develop from precursors in the generative (primary) lymphoid organs; T
lymphocytes mature in the thymus, whereas B lymphocytes mature in the bone
marrow
- The antigen receptors that are expressed in B cells are called antibodies, while their T-
cell counterparts are called T-cell receptors
- Mature T and B lymphocytes recirculate through peripheral (secondary) lymphoid
organs: the lymph nodes, spleen and mucosal tissues
- Foreign antigens are concentrated in these organs, where they bind to and activate the
clones of lymphocytes that express receptors for those antigens, a process known as
clonal selection
- Thymus-derived T lymphocytes develop into the effector cells of cellular immunity and
“help” B cells to produce antibodies against protein antigens
- T cells sense only peptide fragments of proteins displayed by molecules of the major
histocompatibility complex (MHC) (signal 1) TCRs only recognize antigens presented
by other cells. For T-cell activation a co-stimulatory signal is also necessary
- TCR is a a heterodimer that in most T cells is composed of disulfide-linked α and β
protein chains. Each chain has a variable region that participates in binding a particular
peptide antigen and a constant region that interacts with associated signaling
molecules
- The CD3 proteins and ζ chains do not bind antigens; instead, they are attached to the
TCR and initiate intracel- lular biochemical signals after TCR recognition of antigen
- CD4 and CD8 are expressed on distinct T-cell subsets and act as coreceptors during T-
cell activation
- During antigen recognition, CD4 molecules on T cells bind to invariant portions of class
II MHC molecules on selected antigen-presenting cells (APCs) → extracellular antigen.
CD8 binds to class I MHC molecules intracellular antigen
CD4+ T cells are called helper T cells because they secrete soluble molecules
(cytokines) that help B cells to produce antibodies and also help macrophages to
destroy phagocytosed microbes
CD8+ T cells also can secrete cytokines, but their most important role is to directly
kill virus-infected cells and tumor cells; hence, they are called cytotoxic T lymphocytes
(CTLs)
- CD28: the receptor for molecules called costimulators that are induced on APCs by
microbes, and various adhesion molecules that strengthen the bond between the T
cells and APCs and control the migration of the T cells to different tissues (signal 2)
- γδ T cells (not α and β chains), which do not express CD4 or CD8, recognize nonprotein
molecules
- NKT cells recognize microbial glycolipids and may play a role in defense against some
infections
MHC-molecules
- The normal function of MHC molecules is to display peptides for recognition by CD4+
and CD8+ T lymphocytes MHC-restriction (CD4 binds MHCII and CD8 binds MHCI)
- Class I MHC molecules are encoded by three closely linked loci, designated HLA-A, HLA-
B, and HLA-C. Each of these molecules consists of a polymorphic α chain noncovalently
associated with an invariant β2- microglobulin polypeptide
, - Class II MHC molecules are encoded by genes in the HLA-D region, which contains
three subregions: DP, DQ, and DR. Unlikke class I MHC molecules, which are expressed
on al nucleated cells, expression of class II MHC molecules is restricted to a few cell
types, mainly APC (dendritic cells), macrophages and B cells
- The human MHC, known as the human leukocyte antigen (HLA) complex, consists of a
cluster of genes on chromosome 6
- Each set of maternal and paternal HLA genes is referred to as an HLA haplotype
- The implications of HLA polymorphism for transplantation are obvious; because each
person has HLA alleles that differ to some extent from those of every other unrelated
individual, grafts from unrelated donors will elicit immune responses in the recipient
and be rejected (Only identical twins can accept grafts from one another, without fear
of rejection)
B Lymphocytes
- B (bone marrow–derived) lymphocytes are the cells that produce antibodies, the
mediators of humoral immunity
- B cells recognize antigen by means of membrane-bound antibody of the
immunoglobulin M (IgM) class, expressed on the surface together with signaling
molecules to form the B-cell receptor (BCR) complex
- CD21 (also known as the type 2 complement receptor, or CR2) recognizes a
complement breakdown product that frequently is deposited on microbes and
promotes B-cell responses to microbial antigens
- After stimulation, B cells differentiate into plasma cells, which secrete large amounts of
antibodies. There are fi ve classes, or isotypes, of immunoglobulins: IgG, IgM, IgE (tissue
mast cells), IgD (secreted at very low levels) and IgA (mucosal secretions)
NK cells and Innate Lymphoid Cells
- NK cells are innate immune cells, as they are functional without prior activation and do
not express highly variable and clonally distributed receptors for antigens
Inhibitory receptors recognize self class I MHC molecules, which are expressed on all
healthy cells
Activating receptors recognize molecules that are expressed or upregulated on stressed
or infected cells
- Infections and stress are associated with reduced expression of class I MHC molecules
and increased expression of proteins that engage activating receptors
- NK cells also secrete cytokines such as interferon-γ (IFN-γ), which activates
macrophages to destroy ingested microbes, and thus NK cells provide early defense
against intracellular microbial infections
- Innate lymphoid cells (ILCs) are populations of lymphocytes that lack TCRs but produce
cytokines similar to those that are made by T cells. They are classified into three groups,
which produce IFN-γ, IL-5, or IL-17
Antigen-presenting cells (APCs)
- Antigen-presenting cells are dendritic cells, macrophages and B cells
- Dendritic cells (DCs) are the most important antigen- presenting cells for initiating T-
cell responses against protein antigens
