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Immune System

Distinguish between self and non-self


•A remarkable defense mechanism
•Protection against microbial infection
•Rejection of tumors, transplantation of tissues
and organs

Mistake self for non-self


•Autoimmune diseases
I. The structure of the Immune system:
•Leukocytes
•Lymphoid organs
•Cytokines

II. The types of Immune response:


•Innate Immunity
•Adaptive Immunity
-Cellular immune response
-Humoral immune response

III. Complement
The components of immune system

Leukocytes
Lymphoid organs
Cytokines
Janeway et al. Immunobiology, 5th edn.

Bone marrow

Bone marrow

Give rise to

produce

Blood

Effector cells Tissues Lymph nodes


Cells involved in the immune system:
Leukocytes: derived from hematopoietic stem cells
in the bone marrow.
Myeloid progenitor: (important for innate immunity)
1. Granulocytes: short-lived;produced in large
number during inflammation; important for
first line of defense; including neutrophils(PMN),
eosinophils, basophils.
2. Monocytes (macrophages in tissues): phagocytosis;
presenting antigens
3. Dendritic cells: most potent antigen-presenting cells
4. Master cells: reside near blood vessels; allergic response
Common lymphoid progenitor: (adaptive immunity)
1. Lymphocytes: T cells (helper T cells; cytotoxic T cells)
and B cells (B1; B2); responsible for adaptive immunity
2. Natural killer cells: (large granular lymphocytes);
responsible for killing virus-infected cells and
tumor-bearing cells
The components of immune system

Leukocytes
Lymphoid organs
Cytokines
Tissues involved in the immune system (lymphoid organs):

1. Primary (central): involved in the development and


differentiation of T lymphocytes (Thymus) and
B cells (Bone marrow)
2. Secondary (Peripheral): designed to allow the
accumulation and presentation of antigen to
both naïve and memory lymphocytes
*

* *
*

Central lymphoid organs

Peripheral lymphoid tissues

Janeway et al. Immunobiology, 5th edn.


T and B cells localization

Ag/DC

Janeway et al. Immunobiology, 5th edn.


HEV(high endothelial venule)
Development and Maturation of Lymphocytes

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


The components of immune system

Leukocytes
Lymphoid organs
Cytokines
The Role of Cytokines in Immune Response

• Stimulators of hematopoiesis
-produced by bone marrow stromal cells, leukocytes,
and other cells
(stem cell factor, GM-CSF, IL-3, IL5, IL-7, homeostatic chemokines)

• Mediators and regulators of innate immunity


-produced mainly by mononuclear phagocytes
in response to infectious agents
-most members of this group of cytokines act on
endothelial cells and leukocytes
(IL-1, TNF, IL-6, IL-12, IL-15, IFNs, inflamatory chemokines)

Mediators and regulators of adaptive immunity


-produced mainly by T lymphocytes in response to
specific recognition of foreign antigen
(IL-2, IL-4, IL-5, IFN-γ, lymphotoxin, TGF-β, IL-13, chemokines)
paracrine
Autocrine

IL-2 IL-1

Juxtacrine
TNF-α
IL-6 Endocrine

Gallin and Snyderman, Inflammation:basic and clinical correlates, 3rd. edn


Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Cytokine Signaling by JAKs and STATs

JAK: Janus Kinases

STATs:
Signal Transducers and
Activators of Transcription

SOCS (suppressors of cytokine


signaling) are a family of STAT
pathway inhibitors.

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Signal Transduction by TNF Receptors

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Chemokines
• Family of more than forty small (8-14kD), secreted,
usually inducible proteins

• CXC, CC, C, and CX3C subfamilies by amino-acid


sequence relatedness, not by function

• Signal through seven-transmembrane G protein-


coupled receptors (GPCRs), nineteen identified in
humans

• Can be functionally divided into two classes-


“homeostatic chemokines” and “inflammatory
chemokines”.

• Chemotactic for leukocytes


Homeostatic Chemokines
•Are involved in maintaining physiological traffic and
positioning of lymphocytes.
•Are produced in discrete microenviroments within
lymphoid or nonlymphoid tissues, such as the skin and
mucosa.

Inflammatory Chemokines
•Are expressed in inflamed tissues by resident and
infiltrated cells upon stimulation by proinflammatory
cytokines or during contact with pathogenic agents.
•Are specialized for the recruitment of effector cells,
including monocytes, granulocytes and effector T cells.
Recruitment of Leukocytes to Inflammatory Sites by Chemokines

Cell 76:301,1994
The components of immune system

Leukocytes
Lymphoid organs
Cytokines
Routes of Antigen Entry

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Types of Immunity

Two general systems of immunity to infectious agents


• Innate immunity (non-specific)
• Adaptive immunity (specific)
-Cellular immunity
-Humoral immunity

The essential difference between the two systems is the means


by which they recognize microorganisms.
Innate : specific for structures that are common to
groups of related microbes and may not
distinguish fine differences
Adaptive: specificity for distinct molecules
Innate immunity (Natural; Naïve; Non-specific)

Innate immune systems use proteins encoded in the


germ line to identify microbial pathogens. These
proteins, include cell surface receptors
(Pattern Recognition Receptors; PRR) and soluble
proteins. These proteins recognize structures
that are characteristic of microbial pathogens and are
not present on mammalian cells. PRR are mainly expressed
in phagocytic cells.

Ex. Cell surface receptors:


Mannose receptor; TLR(Toll-like receptor)
Soluble proteins:
Complement
Different innate immune responses may be specific for structures
that are shared by particular classes of microbes

Nucleic acids-double-stranded RNA


Unmethylated CpG DNA
Bacteria proteins
Pathogen-Associated
Complex lipid and carbohydrates
Molecular Patterns
LPS in gram-negative bacteria
(PAMPs)
teichoic acids in gram-positive bacteria
mannose-rich oligosaccharides

PAMPs are recognized by host PRR (Pattern Recognition


Receptor).
Phagocytosis and intracellular destruction of microbes

Phagocytic cells
PAMP PRR

TLR3

TLR4

TLR9

GPCR

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


TIR domain: Toll/IL-1 receptor

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


The Toll of innate immunity on microbial pathogens
(Toll-like Receptors; TLR)

PAMP

Plasma membrane
PRR

Endosomal membrane

SCIENCE 303:1481, 2004


The Signaling Pathway Triggered by TLRs

International Immunol. 17: 1, 2005


Adaptive Immunity (Specific; Acquired)

• The defining characteristics of adaptive immunity are


exquisite specificity for distinct molecules and an ability to
“remember” and respond more vigorously to repeated
exposures to the same microbe.

• The components of adaptive immunity are lymphocytes,


peripheral lymphoid organ and cytokines .

• Two types of adaptive immune responses:


Humoral immunity
Cell-mediated immunuity
Two important links between innate immunity and adaptive immunity:

1. The innate immune response to microbes stimulates adaptive immune


responses and influences the nature of adaptive responses.
2. Adaptive immune responses use many of the effector mechanisms of
innate immunity to eliminate microbes, and they often function by
enhancing the anti-microbial activities of the defense mechanisms of
innate immunity.
Innate immunity dictates and influence the conduct of the adaptive immunity
Innate immunity dictates and influence the conduct of the adaptive immunity

International Immunol. 17: 1, 2005


Adaptive immunity

Humoral immunity
•mediated by antibodies that are produced by B cells
•the principal defense mechanism against extracellular
microbes and their toxin

Cell-mediated immunity
•mediated by T lymphocytes
•Defense against intracellular microbes
Types of Adaptive Immunity
Humoral Cell-mediated
immunity immunity

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Clonal Selection

Clonal selection theory (1957)-Burnet proposed that genetic


mechanisms exist for producing antibodies of widely
different specificities, but that antibody-producing cells
are clonally committed during differentiation to produce
a single homogenous antibody of unique specificity-a
monoclonal antibody.

The clonal selection theory of Burnet led to development of


the monoclonal antibody technique by Kohler and Milstein.
(1984 Nobel prize for their discovery of
“the principle for production of monoclonal antibody”)
The Clonal Selection Hypothesis
Question: How million of different antigen receptors could
be generated from a small number of genes?

The human genome only contains about ~30,000 genes,


it seemed unreasonable that they could allow the
production of may be a billion different antibodies.

Susumu Tonegawa solved this mystery.

Germ line encoded vs somatic rearrangement


Germline Organization of Human Immuoglobulin Loci

V = 45
D = 23
J=6

VxDxJ=6210

6210 x 175 =1 x 106

V = 35
J=5
VxJ=175

V = 30
J=4
V x J =120

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Evidence for somatic rearrangeement of immunoglobulin genes coding for variable and constant regions

1. Digest DNA from early embryo or from MOPC 321 plasmacytoma with BamH I
2. Fractionate resulting DNA fragments by gel electrophoresis
3. Hybridize gel-extracted DNA with 125I-labeled,
whole κ-mRNA of MOPC 321 or its 3’-end half fragment

The Vκ and Cκ genes, which are


some distance away from each 2.4x106
other in the embryo cells, are B-cell DNA
joined to form a contiguous Germline DNA
polynucleotide stretch during
differentiation of lymphocytes.
(V-C gene joining)
6x106

3.9x106

Hozumi and Tonegawa Proc. Natl. Acad. Sci. 73: 3628, 1976
Somatic rearrangement

κ Light chain
BamH I BamH I BamH I

Germline DNA
3.9x106

6x106

Somatic recombination
V-J joining

B-cell DNA
3’-half probe 2.4x106
Whole probe
Diversity of antigen receptor genes

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


The generation of diversity immunoglobulins:
Susumu Tonegawa, 1987 Nobel prize in
Physiology/Medicie for his discovery of the
genetic principle for generation of antibody
diversity

1. Random rearrangement of different V (variable ) gene


segments, different J (joining) gene segments,
different D (diversity) segments.
2. Joining variability
3. Random combination of H and L chains
4. Somatic mutation of immunoglobulin V genes.
Ig Heavy and Light Chain Gene Recombination and Expression

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Antigen recognition

Effector function

V: variable
C: constant
H: heavy chain
L: light chain
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Cell-mediated Immunity
Routes of Antigen Entry

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Role of Dendritic Cells in Antigen Capture and Presentation

Immature dendritic cells

Mature dendritic cells

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


How do T cells recognize the processed antigen
presented by APC (antigen presenting cells;
dendritic cells, macrophages, B cells)?

Molecules involved:
T cells : TCR, accessory molecules (CD4, CD8, CD28)
Antigen presenting cells: major histocompatibility
complex (MHC), accessory molecules (B7, CTLA-4)

T cells only recognize processed antigens (peptides)


presented in the context of MHC on the membrane of antigen
presenting cells. (8-10 amino acids for class I MHC, and 13-20
amino acids for class II MHC).
T-cell Receptor complex

ITAMs
Immunoreceptor
tyrosine-based
activation motifs

Janeway et al. Immunobiology, 5th edn.


When T cells recognize antigens presented by APC (the
T cell receptor (TCR)-peptide-MHC complex), signals
are delivered to the lymphocytes by proteins associated
with the antigen receptors.

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Two classes of MHC (Major Histocompatibility Complex) molecule:

MHC class I and MHC class II


MHC class I molecule: presents peptides to CD8 T cells;
binds peptides from proteins degraded
in the cytosol.
· MHC class II molecule: presents peptides to CD4 T cells;
binds peptides from proteins that are degraded
in acidified intracelular vesicles.

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Janeway et al. Immunobiology, 5th edn.
Class I MHC:
α−helix

β-pleated sheet

Computer graphic representation


Class II MHC:

Janeway et al. Immunobiology, 5th edn.


Don Craig Wiley (1944-2001)
Science 265:498, 1994
Cell 70:1035, 1992
MHC class I MHC class II

constrained extended conformation


8-10 amino acids 13-20 amino acids

Janeway et al. Immunobiology, 5th edn.


How do T cell recognize foreign antigens?

• T cells recognize antigenic peptide in the context of MHC.

• T cells from any one individual recognize antigenic peptide


only when these peptides are bond to and displayed
by the MHC molecules of that individual.

MHC Restriction
(MHC-restricted antigen recognition)
MHC restriction
T cells from any one individual recognize foreign peptide antigens only when these
peptides are bound to and displayed by the MHC molecules of that individual.

TCR is specific for MHCa/peptide x

Naïve T clles

Janeway et al. Immunobiology, 5th edn.


Virus-x MHC Restriction
2. T cells in the mouse are activated by virus infected
1. Mouse of the cells and start to attack them
strain “a” is
inoculated
with virus “x”

MHC-a 3. T killer cells are isolated and mixed with different


Virus-infected cells in tissue culture

Isolated lymphocytes

Virus-infected target cells

Wrong combination: Wrong combination: Correct combination


right virus antigen (x) right MHC (a) of virus antigen (x)
wrong MHC molecule (b) wrong virus (y) and MHC (a) leads
lysis of virus-infected
Drs. Peter Doherty and Rolf Zinkernagel (1996 Nobel Laureate) cells.
Differentiation of naïve T cells into subsets of effector cells:

A naïve T cell recognizes its specific peptide:MHC ligand on the surface


of professional antigen-presentating cells (dendritic cells, macrophages)
and becomes activated. A naïve T cell requires two signals (TCR, CD28)
for activation, and differentiates its progeny into armed effector T cells
(Th1, Th2, Tc). Effector cells have only a limited life span and most of the
antigen specific cells generated by clone expansion undergo
programmed cell death (PCD), and some become memory cells,
which respond to antigen more rapid and effective on a second
encounter with pathogen.
Two Signals Are Required for T Cell Activation

What is the second signal?


costimulatory factor
B7 CD28/B7

TCR-peptide-MHC
complex

CD28

Janeway et al. Immunobiology, 5th edn.


Co-stimulatory Molecules Are Required for T Cell Activation

Janeway et al. Immunobiology, 5th edn.


TCR signaling through tyrosine phosphorylation

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Interaction of CTLA-4 and B7 molecules down-regulates the
proliferative phase of the response:

Once T cells are activated, they express an additional receptor


called CTLA-4 (CD152). CTLA-4 binds same molecules as CD28,
however, with more avidly than CD28, and delivers an inhibitory signal
to the activated T cells. Thus binding of CTLA-4 to B7 molecules is essential
for limiting the proliferative response of activated T cells to antigen and B7,
effectively shutting down the proliferative phase of the response.
Avtivated signal Inhibitory signal

Cross-linking of CD28 delivers the co-stimulatory signal during activation CTLA-4 binds B7 more avidity than does CD28 and
of naïve T cells and induces the expression of CTLA-4 delivers inhibitory signals to activated T cells

Janeway et al. Immunobiology, 5th edn.


Differentiation of naïve CD4+ T cells into effector Th1 and Th2 cells:

Properties of Th1, Th2 and TFH subsets of effector T cells


1. Th1 and Th2 populations are distinguished most clearly by
the cytokines they produce; IFN-γ is the signature cytokine
of Th1 cells, and IL-4 and IL-5 are the defining cytokines of Th2.

2. The Th1 differentiation pathway is the response to microbes


that infect or activated macrophages and to those that
activate NK cells.

3. Th2 differentiation occurs in response to helminths and


allergens, which cause chronic T cell stimulation, often
without a significant innate immune response or macrophage
activation.

4. IFN-γ promotes further Th1 differentiation and inhibits the


proliferation of Th2 cells. Conversely,IL-4 promotes Th2
differentiation,and inhibits activation of Th1 cells.

TFH (Follicular B Helper T cells) : provide help to germinal-center B cells.


(Nat. Immunol 5: 853)
Effector Functions of Th1 and Th2 cells

Th1 cells
Th2 cells

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


1. · Differentiation of naïve CD8+T cells into Cytotoxic T cells that
2. are able to kill target cells by perforin (a pore-forming protein)
3. and granzymes (granule enzyme), and induce apoptosis
4. (Fas/Fas ligand) in target cells.
CTL-mediated Lysis of Target Cells

Perforing and
granzymes

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Humoral Immunity
Humoral Immune response-
The humoral immune response is characterized by the production
of antibodies.

Cells involved-
B cells (B1; B2; Marginal zone B cells)-recognition of antigens by BCR
Helper T cells- direct contact with B cells and provide secondary signal
(Thymus –dependent antigens; TD Ag); secretion of cytokines
(TD Ag and Thymus-independent antigens; TI Ag)
Phagocytic cells (macrophages and neutrophils)-effector functions
Major molecules involved-
Antibodies (IgM, IgG, IgA, IgE): recognition of antigen;
activation of complement cascade; activation of phagocytic cells
Cytokines: B cell growth/differentiation factors IL-4, IL-5, IL-6, CD40L,etc.
Complement and complement receptor (CR): opsonization (C3b);
chemotaxis (C5a); membrane-attack complex (C5-9); activation of
phagocytic cells; removal of immune complex
Fc receptors: activation of phagocytic cells, natural killer cells

Activation of B cells by TD antigen (B2 cell-follicular B cells)


T-B cooperation: require two signals, B cell antigen receptor (BCR)
and CD40L/CD40
B Cell Activation Requires Signals from BCR and CD40/CD40L
in Response to Thymus-dependent Antigen (TD Ag)

Two signals are required for B-cell activation in response to TD Ag.


Janeway et al. Immunobiology, 5th edn.
Antigen recognition

Effector function

Janeway et al. Immunobiology, 5th edn.


Signal transduction by the BCR comples

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


B Cell Selection in Germinal Centers

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Janeway et al. Immunobiology, 5th edn.
Kinetics of primary and secondary humoral immune responses

IgM > IgG

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Human Antibody Isotype

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Neutralization of Microbes and Toxins by Antibodies

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Antigen recognition

Effector function

V: variable
C: constant
H: heavy chain
L: light chain
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Fc receptors (effector function)

-Fc receptors on phagocytes are activated by antibodies bound


to the surface of pathogens.
-Fc receptors on phagocytes allow them to ingest and destroy
opsonized extracellular pathogens.
-Fc receptors activate natural killer cells to destroy antibody-
coated targets (ADCC: antibody-dependent cell-mediated
cytotoxicity)
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Effector Functions of Antibodies

ADCC

Ag-Ab
complex

Complement activation
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Regulation of B cell Activation by Ig Fc Receptors

Fab

FcγRIIB

ITIM

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Complement
The Complement System

The complement system consists of several plasma proteins that are


activated by microbes and promote destruction of the microbes through a
action of enzyme cascade.

There are three ways that complement can recognize the microbes:
• The classical pathway: recognize antibody-bounded microbe
• The alternative pathway: direct recognize certain microbial surface structures
• The lectin pathway: triggered by a plasma protein called mannose-binding
lectin, which recognize terminal mannose residues on microbial
glycoproteins and glycolipids.
Pathways of Complement Activation

C5b6789
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Physiological Regulation of the Complement Cascade
Activation of Complement Pathways

•Complement activation proceeds via a series of proteolytic


cleavage reactions.

•Effector functions of complement:


1. Opsonins (C3b): promote pathogens uptaken and
removed by phagocytes
2. Chemotactic activity (C5a): recruit leukocytes to the
inflammatory sites
3. Membrane-attack complex (MAC): damage pathogens
Functions of Complement

C5b6789

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Effector Functions of Antibody

ADCC

C5b6789

C5b

C5a

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Coligation of BCR and CD19/CD21 with complement-tagged antigen
enhances B cell signaling processes

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Overview of Immune Response in vivo

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.


Phases of Adaptive Immune Responses

Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.