Introduction to the immune system

Kusworini Handono
Dept of Clinical Pathology, Faculty of Medicine,
Brawijaya University

Terminology
Immunity is defined as resistance to disease
specifically infectious disease
Immune system : collection of cells, tissue and
molecules that mediate resistance to infections
Immune response : reaction of these cells and
molecules to infectious microbes
Immunology is the study of the immune system
and its responses to invading pathogens

The Importance of the Immune System

Role of the immune system

Implications

Defense against infections

Deficient immunity results in increased

susceptibility to infections
Vaccination boosts immune defenses
and protects against infections

The immune system recognizes and

responds to tissue grafts and newly
introduced proteins

Immune responses are important

barriers to transplantation and gene
therapy

Defense against tumors

Potential for immunotherapy of cancer

Antibodies are highly specific reagents

for detecting any class of molecules

Immunologic approaches for laboratory

testing are widely used in clinical
medicine and research

General properties of immune

response

Physiologic function of the immune system

Defence against infectious microbes
The defence is mediated through early reactions of
innate immunity and the latter responses of adaptive
immunity
There two types of adaptive immune responses, called
humoral immunity and cell mediated immunity, that are
mediated by different component of the immune system
and function to eliminate different types of microbe

Innate and adaptive immunity

Cells and tissue of the immune system

Anatomy and functions of lymphoid tissues

Generative ( primary ) lymphoid organs :
- bone marrow, where all the circulating blood cells
(including lymphocytes) arises and the site of B cells
maturation
- thymus, where T cells mature and reach a state of
functional competence
Peripheral ( secondary ) lymphoid organs, where
lymphocyte responses to foreign antigens are initiated
and develop : lymph nodes, the spleen, the mucosal
and cutaneous immune systems

Hematopoiesis in the Bone Marrow

Maturation of lymphocyte

Thymus

Lymph nodes, spleen and the lymphatic system

Lymph nodes are the organs in which adaptive immune
responses to lymph-borne antigens are initiated
Different classes of lymphocytes are sequstered to
distinct regions of lymph nodes
The anatomic segregation of different classes of
lymphocytes in distinct areas of the node is dependent
on cytokines
Antigens are transported to lymph nodes mainly in
lymphatic vessels
The spleen is the major site of immune responses to
blood-borne antigens

Morphology of a lymph node

Segregation of B cells and T cells in lymph node

Peripheral lymph node and lymphocytes

Function of peripheral lymphoid organ is to concentrate
antigens that are introduced through the common portals
of entry ( skin, GI and respiratory tracts )
Naive lymphocytes migrate through these organ, where
they recognise antigens and initiate immune responses
Effector and memory lymphocytes circulate in the blood,
home to peripheral sites of antigen entry, and are
efficiently retained at these sites

The lymphatic system

Lymphocytes
The only cells capable of specifically recognizing and
distinguishing different antigenic determinants and are
therefore responsible for the two characteristics of
adaptive immune response : specificity and memory
Lymphocytes consist of distinct subsets that are different
in their functions and protein products but are
morphologically indistuinghable

Lymphocytes classes
% total lymphocytes
blood Lymph Spleen
node

Classes

Functions

Markers

T helper
(Th1,
Th2,
Th17)

Stimuli for B cell growth

and differentiation
(humoral immunity)
M activation by secreted
cytokines (CMI)

CD3+,CD4+ ,
CD8-

50-60 50-60

50-60

T
cytolytic

Killing of virus infected

cells,tumor cells;rejection
of allograft ( CMI)

CD3+,CD4-,
CD8+

20-25 15-20

10-15

B cells

Antibody production
( humoral immunity)

Fc rec, MHC-II ,
CD19 ; CD21

10-15 20-25

40-45

T reg

Supression T cell and B cells CD3+, CD4+

activation
CD25+, FoxP3

NK cells

Killing of virus infected

cells,tumor cells; ADCC

-10

Rare

-10

Fc rec for IgG

Lymphocyte

Plasma cell

APC, dendritic cells and macrophages

APCs are cells specialized to capture microbial and other
antigens, display them to lymphocytes, and provide signals
that stimulate the proliferation and differentiation of the
lymphocytes. They are dendritic cell, macrophage, B cell
and folicular dendritic cell
Dendritic cells play important roles in antigen capture and
induction of T lymphocytes responses to protein antigens
Mononuclear phagocytes (macrophage) function as APCs in
T cell-mediated adaptive immune responses

Dendritic cells

Monocyte - Macrophage

Overview of
immune responses

Innate and Adaptive Immune

Response

Components of innate immunity

Component
Barriers

Principle function

Epithelial layers

Prevent microbial entry

Defensin

Microbial killing

Intraepithelial lymphocytes

Microbial killing

Circulating efector cells

Neutrophils

Early phagocytosis and killing

microbes

Macrophages

Early phagocytosis and killing

microbes, secretion of cytokines that
stimulate inflammation

NK cells

Lysis of infected cells, activation of

macrophages

Components of innate immunity

Circulating effector proteins
Complement

Killing microbes, opsonization of microbes,

activation of leukocytes

Membran binding lectin (collectin)

Opsonization of microbes, activation of

complement

C-reactive protein (pentraxin)

Opsonization of microbes, activation of

complement

Coagulation factors

Walling of infected tissues

Cytokines
TNF, IL-1, chemokines

Inflammation

IFN-

Macrophage activation

IL-12

IFN- production by NK cells and T cells

IL-15

Proliferation of NK cells

IL-10,TGF-

Control of inflammation

IFN-,

Resistance to viral infection

Functions of
epithelia in
innate
immunity

Phagocytosis and
intracelluler killing of
microbes

Function of Natural Killer cells

Mechanisms in Rheumatology 2001

Pathways of complement
activation

Adaptive (acquired) immunity

Defence against specific pathogenic agents expressing
specific antigens (proteins inducing an immune response)
Lymphocytes (T and B cells) respond selectively to antigens,
leading to specific memory that may last a lifetime

Components of innate and adaptive

immunity
Innate

Adaptive

Physical and chemical

barriers

Skin, mucosal epithelial, anti

microbial chemical

Lymphocytes in
epithelia; antibodies
secreted at epithelial
surface

Blood protein

Complement, Acute Phase

Protein, Cytokines

Antibodies

Cells

Phagocytes ( macrophages,
Lymphocytes T, B
neutrophils) , natural killer cells Activated Macrophage

Types of adaptive immunity

Humoral Immune Response

Mechanisms in Rheumatology 2001

Cells Mediated Immune Response

Click here to run the animation

Mechanisms in Rheumatology 2001

Immune cells in adaptive immunity

Macrophages engulf foreign objects
Inform T lymphocytes that a specific antigen is present
Helper T cells produce and secrete chemicals which
promote large numbers of effector and memory cells
Cytotoxic T cells T lymphocytes that eliminate infected
body cells and tumour cells
B cells produce antibodies (secrete them in the blood or
position them on their cell surfaces)

Cardinal features of Adaptive Immune Responses

Feature

Functional significance

Specificity

Ensure that distinct antigens elicit specific

response

Memory

Leads to enhanced responses to repeated

exposure to the same antigens

Specialization

Responses to distinct microbes are

optimized for defense against these
microbes

Self limitation

Allows immune system to respond to

newly encountered antigens

Non reactivity to self antigens Prevents injurious immune responses

against host cells and tissues

Phases of adaptive immune responses

Function of Dendritic Cell

The capture and

display of
microbial antigens

The capture and

presentation of
protein antigens
by dendritic cells.

The Structure and Function of

MHC molecules

The Major Histocompatibility Complex

(MHC) molecules
Membrane protein on APCs or target cells that display
peptide antigens for recognition by T lymphocytes
Human MHC molecules are called Human Leucocyte
Antigens (HLA)
There are 2 types : Class I and Class II MHC molecules
The genes encoding these molecules are MHC Region of
highly polymorphic genes on 6p21 chromosome
MHC genes are codominantly expressed
The MHC locus in human is designated HLA locus

The Importance of MHC molecules

Play a central role in immune responses to protein antigen
Play a central role in clonal selection of T lymphocyte in
thymus
Play an important role in the transplantation of organ and
tissue, when organs are transplanted across major HLA locus
differences between donor and recipient, graft rejection is
prompt
Play a major role in conferring susceptibility to many
autoimmune diseases

Class I HLA Molecules

Contain two separate polypeptide chain : chain 44 kD
and chain 12 kD
The chain is divided into three region : an extracellular,
transmembrane and cytoplasmic region
The extracellular region has been subdivided into 1, 2,
and 3 domain
The chain, 2 microglobulin, encoded by a gene outside
the MHC, on chromosome 15
Distribution : all nucleated cells of the body
The principal function : to bind and present of intracellular
antigen to specific CD8 lymphocytes

Class II HLA Molecules

Composed of two non-covalently associated polypeptide
chains : chain 34 kD and chain 32 kD
Both polypeptide chains are divided into three regions : an
extracellular, transmembrane and cytoplasmic region
The extracellular region of both the and chains have
been subdivided into two domains, 1, 2 and 1, 2
Distribution : Dendritics, B lymphocytes, macrophages and
a few other cell types
The principal function : to bind and present of extracellular
antigen to specific CD4 lymphocytes

Molecules involved in the immune response

Immunoglobulins
Complement
Cytokines

Immunoglobulins
Human
immunoglobulin is
composed of two light
chains (lambda or
kappa) and two heavy
chains (alpha, delta,
gamma, epsilon or mu)

Antibody isotype : specific effector function

Ig G : Neutralization, Opsonization
Activation of classical pathway of complement
ADCC mediated by NK cells
Neonatal immunity
IgM : Activation of classical pathway of complement
Ig A : Mucosal immunity
Ig E : ADCC mediated by eosinophils
Mast cell degranulation
Ig D : B cell receptor

Effectors functions of antibodies

Antibody mediated opsonization and

phagocytosis of microbes

The Complement system

Complement is a group of
proteins in the blood that
influence the
inflammatory process and
serve as the primary
mediator in antigen
antibody reactions of the
B cell mediated immune
response

The complement system

Mechanisms in Rheumatology 2001

Complement system:
MAC compromise cellular integrity
MAC* pores insert
into the membrane
of the target cell,
compromising
membrane integrity
and causing cell lysis

*MAC = membrane-attack complexes

Biologic functions of complement

Cytokines
Cytokines are secreted proteins that induce cells to
Proliferate
Differentiate to mediate some immune function
Proliferate and differentiate
Cytokine is a generic term referring to soluble factors
produced by any type of cell
For example, cytokines produced by lymphocytes are
called lymphokines, while those produced by
monocytes or macrophages are monokines

General functions of cytokines

Mechanisms in Rheumatology 2001

Balance between pro-inflammatory and antiinflammatory cytokines

Mechanisms in Rheumatology 2001

Anti-inflammatory cytokines :
mechanisms of action

Inflammation

Inflammatory response
Mechanism by which all required elements of the immune
system are recruited to the site of invasion
End result of the inflammatory response is destruction of
pathogen by lysis or by being engulfed and digested
Inappropriate activation of the immune system can lead to
disorders such as allergies and autoimmune disease

Intra vascular cells and connective tissue matrix

and cells involved in the inflammatory response

Chemical mediators of inflammation

Mediators derived from neutrophil activation

Mechanisms in Rheumatology 2001

Recruitment of cells to inflammatory sites

Mechanisms in Rheumatology 2001

Cellular mechanisms of inflammation

Mechanisms in Rheumatology 2001

Cytokines involved in the inflammatory response

Cytokine

Producing cells

Role

IFN-, IFN-

Neutrophils (IFN-) , fibroblasts (IFN-)

Pro-inflammatory

TNF

Monocytes and macrophages

Pro-inflammatory

IL-1

Cells of the monocytemacrophage

lineage

IL-6

CD4+ TH, endothelial and monocytic cells

IL-8

Monocytes

Pro-inflammatory

Bone marrow stromal cells and

macrophages

Anti-inflammatory

IL-10,
IL-11

Pro-inflammatory and
promotes specific
immune responses
Pro-inflammatory and
promotes specific
immune responses

Vaso active amines

Histamin.
Causes dilation and increased vascular permeability. Mostly
come from mast cell, but also found in basophil and platelets,
in response to:
Physical injury ( trauma, cold,or heat).
Immune reactions involving binding of Ab to mast cells.
Fragments of complement called anaphylatoxins ( C3a, C5a)
Histamin-releasing proteins derived from leucocytes.
Neuropeptides ( eg substance P).
Cytokines (IL-1,IL-8)
Serotonin. Present only in platelets and enterochromaffin cells.

Oxygen Derived Free radicals

Oxygen-derived free radicals may be released extracellularly

from leukocytes after exposure to chemotactic factors, immune
complexes or phagocytic challenge

Low levels of these potent mediators can increase the expression

of chemokines ( e.g IL8 ), cytokines, and endothelial leukocyte
adhesion molecules

At higher levels can be damaging to the host :

Endothelial cell damage, with resultant increased vascular
permeability.

Inactivation of antiproteases , such as a1-antitrypsin.

Injury to other cell types ( tumor cells, red cells, parenchymal

cells )

Most likely mediators in inflammation

Vasodilation ------ CALOR, RUBOR
Prostaglandins, nitric oxide
Increased vascular permeability ------ RUBOR, TUMOR
Vasoactive amines, C3a and C5a (through liberating
amines), bradykinin, leukotrienes C4, D4, E4, PAF,
substance P
Chemotaxis, leukocyte activation
C5a, leukotriene B4, chemokines, bacterial products
Fever
IL-1, IL-6, TNF, prostaglandin
Pain ------ DOLOR
Prostaglandin, bradykinin
Tissue damage -------- FUNCTIO LAESA
Neutrophil and macrophage lysozomal enzymes, oxygen
metabolites, nitric oxide