Introduction to the Immune System

Kusworini Handono
The most important physiologic function of the immune
system is to prevent or eradicate infections
Role of the immune system
• Defense against microbes
• Defense against the growth of tumor cells
• kills the growth of tumor cells
• Homeostasis
• destruction of abnormal or dead cells
(e.g. dead red or white blood cells, antigen-antibody
complex)
Two types of immunity
1. Innate (non-adaptive) - non specific
• first line of immune response
• relies on mechanisms that exist before infection

2. Acquired (adaptive) - specific

• Second line of response (if innate fails)
• relies on mechanisms that adapt after infection
• handled by T- and B- lymphocytes
• one cell determines one antigenic determinant
Innate and adaptive immunity
 CELLS AND TISSUE
OF THE IMMUNE SYSTEM
Properties of the Immune System
1. Organs
2. Cells
3. Molecules
Organ of the immune system
• The central lymphoid organs
• the bone marrow and the thymus
• provide the environment for immune cell
production and maturation
• The peripheral lymphoid organs
• Lymph nodes, spleen, tonsils, appendix, Peyer’s
patches in the intestine, and mucosa-associated
lymphoid tissues in the respiratory,
gastrointestinal, and reproductive systems
• function to trap and process antigen and
promote its interaction with mature immune
cells
Hematopoiesis (within bone marrow)

IMMUNE
CELLS
Bone Marrow and Thymus :
Maturation of lymphocyte
The lymphatic system
Cells of the Immune system:
•Monocytes, Macrophages, Dendritics
•Granulocytes
• neutrophils
• eosinophils
• basophils
•Lymphocytes
• T-lymphocytes
• B-Lymphocytes, plasma cells
• natural killer lymphocytes
Cells of Innate
Immunity

13
Monocytes - Macrophages
• Macrophages are white blood cells that engulf and destroy
foreign (non-self) antigenic molecules, viruses or microbes
(phagocytosis) and then display small fragments of the
antigen on the outer surface of their plasma membrane
(APC)
• Macrophages are related to dendritic cells
Maturation of Monocytes
Neutrophil Function : Phagocytosis
 Neutrophils Function :
Neutropphil Extracelluler Traps / NETs
Natural Killer cells
• The NK cell is a nonspecific effector cell that can kill tumor cells and virus-infected
cells.
• They are called natural killer cells because, unlike T cytotoxic cells, they do not
need to recognize a specific antigen before being activated.
• NK cells kill after contact with a target cell. The NK cell is programmed
automatically to kill foreign cells.
• Programmed killing is inhibited if the NK cell membrane molecules contact MHC
self-molecules on normal host cells.
• The mechanism of NK cytotoxicity depends on production of pore-forming
proteins (i.e., NK perforins), enzymes, and toxic cytokines.
Natural Killer cell

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Cells of Adaptive
Immune System
Dendritic Cells
Presentation of antigen to helper T cell by
an
antigen-presenting cell (APC)
Lymphocyte
Lymphocytes Maturation
Maturation of T cells in the thymus
Classes of
lymphocytes
T Lymphocytes / T cells
• T cells are maturated in the thymus.
• There, they learn how to distinguish self from nonself. Only the T cells that ignore
self antigen molecules are allowed to mature and leave the thymus. Without this
training process, T cells could attack the body's cells and tissues.
• Mature T cells are stored in secondary lymphoid organs (lymph nodes, spleen,
tonsils, appendix, and Peyer's patches in the small intestine).
• These cells circulate in the bloodstream and the lymphatic system. After they first
encounter a foreign or abnormal cell, they are activated and search for those
particular cells.
• T cells consists of T helper (CD4+), T cytotoxic (CD8+), T regulatory
T helper lymphocytes subset
Types of T cells
• Th1 cells:
• secrete IL-2, IL-12, IFN gamma, TNF-beta;
• activate macrophages, amplifying their cytokine secretion capacity and
potential for presentation of antigens;
• activate synthesis of IgG but not IgE;
• are involved in delayed hypersensitivity reactions;
• are activated by signals from intracellular bacteria and viruses;
• Th2 cells:
• secrete IL-4, IL-5, IL-6, IL-10;
• activate the synthesis of IgE;
• stimulate proliferation and activation of eosinophils;
• are stimulated by allergens or parasite components.
Types of T cells
• Cytotoxic (Killer) T cells (CD8) attach to particular foreign or abnormal
(for example infected) cells. Killer T cells may kill these cells by making
holes in their cell membrane and injecting enzymes into the cells or by
binding with certain sites on their surface called death receptors.

• Suppressor (regulatory) T cells produce substances that help end the

immune response or sometimes prevent certain harmful responses from
occurring.
B cells
• B cells are formed in the bone marrow. B cells have particular
sites (receptors) on their surface where antigens can attach.
• B cells are the major cells involved in the creation of antibodies
that circulate in blood plasma and lymph, known as humoral
immunity.
• In mammals there are five types of antibody IgA, IgD, IgE, IgG,
and IgM, differing in biological properties.
• Each has evolved to handle different kinds of antigens.
• Upon activation, B cells produce antibodies, each of which
recognizes a unique antigen, and neutralize specific pathogens.
Antibodies (immunoglobulins)
•Belong to the gamma-globulin fraction of
serum proteins
•Y-shaped or T-shaped polypeptides
• 2 identical heavy chains
• 2 identical light chains
• All immunoglobulins are not antibodies
•Five kinds of antibodies
• IgG, IgM, IgA, IgD, IgE
Effectors functions of antibodies
How can Innate Immunity attack microbes?
The two principal ways the innate immune system deals with microbes
is by inducing inflammation and by antiviral mechanisms.
• Inflammation: is triggered by all classes of microbes, is the
recruitment of circulating blood leukocytes (e.g., phagocytes and NK)
and various plasma proteins (e.g., complement, antibodies,
fibrinogen) to sites of infection, where they function to destroy the
microbes and repair damaged tissue.
• The antiviral mechanisms render host cells inhospitable for viral
infection and reproduction. These innate responses are often
sufficient to prevent infection within tissues or the blood.
How can the adaptive immune system combat
microbes?

• Secreted antibodies bind to extracellular microbes, block their ability

to infect host cells, and promote their ingestion and subsequent
destruction by phagocytes.
• Phagocytes ingest microbes and kill them, and helper T cells enhance
the microbicidal abilities of the phagocytes.
• Helper T cells recruit leukocytes to destroy microbes and enhance
epithelial barrier function to prevent the entry of microbes.
• Cytotoxic T lymphocytes kill cells infected by microbes.
Innate and Adaptive Immune System
Innate Immunity
• the first line of defense is provided by epithelial barriers of the skin
and mucosal tissues and by cells and natural antibiotics present in
epithelia, all of which function to block the entry of microbes.
• If microbes do breach epithelia and enter the tissues or circulation,
they are attacked by phagocytes, specialized lymphocytes called
innate lymphoid cells, which include natural killer cells, and several
plasma proteins, including the proteins of the complement system.

NK Cell Eosinophils Monocyte

Neutrophil Basophils &
Mast cells Macrophage
First Line of Defense : Skin and Mucous Membrane

1. Physical factors

2. Chemical factors

3. Normal microbiota
Physical factors
• The structure of intact skin
• The lacrimal apparatus
• Saliva  washes microorganisms
• Mucus  traps many microorganisms,
• The ciliary escalator move mucus up and out
• The flow of urine move microorganisms out
of the urinary tract
Chemical factors

• Sebum  contains unsaturated fatty acid  inhibit the growth of

pathogenic bacteria
• Lysozyme is found in tears, saliva, nasal secretions, and
perspiration
• The high acidity (pH 1.2 – 3.0) of gastric juice  prevents
microbial growth in the stomach
Normal microbiota

• Normal microbiota change the environment, which can prevent

the growth of pathogens:
- by competing with them for nutrients
- by producing substances  harmful to the pathogens
- by altering conditions  pH and oxygen availability
Second Line of Defense
If a microbe penetrates the first line of defense it
encourages production of:
- phagocytes,
- inflammation,
- fever,
- and antimicrobial substances.
 Phagocytes
• Phagocytosis is the ingestion of
microorganisms or particulate
matter by a cell.
• Phagocytosis is performed by
phagocytes, certain types of
white blood cells or their
derivatives.
Inflammation
• Inflammation is a bodily response to cell
damage; it is characterized by redness, pain,
heat, swelling, and sometimes the loss of
function  confine and destroy microbes and
initiates tissue repair
• Acute inflammation is a short, intense
response to infection;
• Chronic inflammation is a prolonged
response.
Fever
• Fever is an abnormally high body temperature
produced in response to a bacterial or viral infection.
• Bacterial endotoxins, interleukin-1 (IL-1), and
alpha-tumor necrosis factor (TNF-α) can induce
fever.
• A chill indicates a rising body temperature; crisis
(sweating) indicates that the body's temperature is
falling.
Adaptive immunity : mechanisms
• Cell-mediated immune response (CMIR)
• T-lymphocytes
• eliminate intracellular microbes that survive within
phagocytes or other infected cells
• Humoral immune response (HIR)
• B-lymphocytes
• mediated by antibodies
• eliminate extra-cellular microbes and their toxins

Plasma cell
(Derived from B-
lymphocyte, produces
antibodies)
 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 Prevents injurious immune responses

antigens against host cells and tissues
Types of adaptive immunity
 Cells Mediated Immune Response

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 Humoral Immune Response

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Phases of adaptive immune responses
 MHC
Major Histocompatibility Complex
Structure and Function
Introduction
• Adaptive immune responses: initiated by the recognition of antigens by
antigen receptors of lymphocytes.
• The antigen receptors of most T lymphocytes (TCR), can see only peptide
fragments of protein antigens, and only when these peptides are presented
by specialized molecules (MHC) that bind peptides generated inside a host
cell and then display them on the cell surface.
• Therefore, T cell–mediated immune responses may be generated only
against protein antigens that are either produced in or taken up by host
cells.
Innate and adaptive immunity
Antigen Recognized by T lymphocytes

The majority of T lymphocytes recognized peptide antigen

that are bound to and displayed by the MHC molecules on
Antigen Precenting Cell (APCs) or target cells

The specialized cells that capture microbial antigen and

display them for recognition by T lymphocytes are called APC
(dendritic cells, macrophages and B cells)
Antigen recoqnized by T lymphocytes
The Structure and Function of MHC molecules
 The Major Histocompatibility Complex (MHC) molecules

• Membrane protein on APCs 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 Human Leucocyte Antigen / HLA locus
 The Function of MHC molecules

• The physiologic function of MHC molecules is to display peptides

derived from protein antigens to antigen-specific T lymphocytes
• Class I and class II MHC molecules are membrane protein that each
contains a peptide-binding cleft
• The peptide-binding clefts of MHC molecules bind peptides derived
from protein antigens and display these peptides for recognition by T
cells
• Each MHC molecule can present only one peptide at a time, but each
MHC molecule is capable of presenting many different peptides
 CLASS I HLA MOLECULES

• Contain two separate polypeptide chain : α chain 44 kD and β chain 12 kD

• The α chain is divided into three region : an extracellular, transmembrane and
cytoplasmic region
• The extracellular region has been subdivided into α1, α2, and α3 domain
• The β chain, β 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+T lymphocytes ( T cytotoxic)
(Abbas et al., 2016)
 CLASS II HLA MOLECULES
• Composed of two non-covalently associated polypeptide chains : α chain 34
kD and β chain 32 kD
• Both polypeptide chains are divided into three regions : an extracellular,
transmembrane and cytoplasmic region
• The extracellular region of both the α and β chains have been subdivided into
two domains, α1, α2 and β1, β2
• Distribution : Dendritics, B lymphocytes, macrophages and a few other cell
types
• The principal function : to bind and present of extracellular antigen to specific
CD4+T lymphocytes (T helper)
(Abbas et al., 2016)
 The Importance of MHC molecules

• Play a central role in immune responses to protein antigen (activate

adaptive IR)
• Play a central role in clonal selection/maturation of T or B lymphocyte
in thymus and bone marrow
• Play an important role in the transplantation of organ and tissue;
MHC/HLA molecules is antigen of tissue donor that recognized by
recipient’s immune system. 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 diseases
(autoimmune, cancer, infection etc)
The Role of MHC molecules in activate
Humoral Immune Response
The Role of MHC molecules in activate
Cellular Immune Response
Distribution of
MHC molecules

Profesional APC
 Genetic organization of the HLA

• The HLA region, ± 4.000 kb, on the 6p21.3, is divided into class I, II and III regions
• The class I region encoded : HLA-A, B and C molecules (classical molecules) and HLA-
E, F,G, H, J (non classical molecules)
• The class II region encoded : HLA-DR, DQ and DP molecules (classical molecules) and
HLA-DM and DO (non classical molecules).
• The class III region include : C2, C4, properdine factor B, TNF-α, TNF-β, HSP70, 21-
hydroxylase.
 Chromosome 6
MHC/HLA locus

Centromer DP DQ DR B C A

ClassII ClassII Class I

I
HLA Locus
HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX REGION

CLASS II CLASS III CLASS I

21-OH B1 HSP70
TNF B C E J A H G F
GLO COL11A2 HLA-D B C4BA C4ARD C2 A B

DQ G7a

DP DN DM DO DQ DR
A1 A1 A A LMP LMP A2 A1 A
2 7

B2 B1 B TAP TAP B B2 B1 B1B2B3B4B5

1 2 B6
B7 Functional Gene
Pseudogene
(Abbas et al., 2016)
Polimorfisme MHC
HLA Nomenclature

Nomenclature of HLA relied on :

Serologically based typing (for molecules) : serologic
specificities defined by alloantibodies, as HLA-A, B, C,
DR and DQ types.
Eq : HLA-A2 ; HLA-B27 ; HLA-DR4 etc

DNA based typing (for genetic) : detect variability on

DNA sequences (alleles). An allele is named first by its
locus, followed by an asterisk and its allele number.
Eq : HLA-A*0201 ; HLA-B*2705 ; HLA-DR*0401 etc
 HLA Type and Alleles
Locus Serology Based DNA Based
Class I
HLA-A 21 151
HLA-B 43 301
HLA-C 10 83
Class II
HLA-DR 18
DRA 2
DRB 282
HLA-DQ 9
DQA 20
DQB 43
HLA-DP
DPA 18
DPB 47
Properties of MHC Genes
and Proteins

MHC genes are

codominantly expressed,
meaning that the alleles
inherited from both parents
are expressed equally

(Abbas et al., 2016)

The HLA Molecules
Inheritance of HLA
HLA Associations with Autoimmune Rheumatic Diseases
Disease Specificity Allele RR
Ankylosing B27 B*2702, *2704, *2705 80-90
spondylitis
Reiter’s syndrome B27 40
Psoriatic arthritis B27 10
Behcet’s disease B51 B*5101 3
Rheumatoid arthritis DR4 DRB*0401, *0404 6
Seropositive JRA DR4 DRB*0401, *0404 7
Pauciarticular JRA A2 2-4
DR5 DRB1*1101, *1104 3-7
DR8 DRB1*0801 4-8
DPw2.1 DPB1*0201 3-6
SLE DR3 3-6
DR2 DRB1*1501 2
Sjogren’s syndrome DR3 DRIB5* 0101 6