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THE IMMUNE RESPONSETHE IMMUNE RESPONSETHE IMMUNE RESPONSETHE IMMUNE RESPONSE

IMMUNOLOGY

MEL 1224

Lymphoid cells classes and subclasses

Biology of B and T lymphocytes

T and B cells cooperation.

Mononuclear phagocytic system and

Polymorphs.

Cytokines

Immune cells involved in the

Innate Immune system

Consist of:

Polymorphonuclear (PMN) leukocytes Polymorphonuclear (PMN) leukocytes

Macrophages

Dendritic cells

Natural Killer cells

PMN LEUKOCYTES

Also known as granulocytes.

Including basophils, mast cells, eosinophils,

and neutrohils.

These are phagocytic cells that contain These are phagocytic cells that contain

enzyme-rich lysosomes, which facilitate

destruction of infectious microorganisms.

Granulocytes are short-lived, and played an

major role in protection against infection.

MACROPHAGES

Macrophages are phagocytes which derived

from monocytes.

Example of macrophages:

Kupffer cells (Liver) Kupffer cells (Liver)

Alveolar macrophages (Lung)

Peritoneal macrophages

(white pulp of the spleen)

Microglial cells (CNS)

Although associated with diverse names and

locations, these macrophages shared some

common features:

Phagocytize microorgansisms and foreign

substances that invade the bloodstream and substances that invade the bloodstream and

various tissue.

These cells are most likely to make the first

contact with invading pathogens and

antigens.

DENDRITIC CELLS

They are long-lived and reside in an immature

state in most tissues.

Dendritic cells can be found as interdigitating

cells of thymus. Besides, they can also be cells of thymus. Besides, they can also be

found in the skin, called Langerhans cells.

They are capable of recognizing and

phagocytize pathogens and other antigens.

Besides, direct contact will pathogens also

leads to the maturation of the dendritic cells,

forming APC.

NATURAL KILLER CELLS

Natural killer (NK)cells are cytotoxic, plays an

important role in the early stages of viral

infection or tumorigenesis before activation of

T-cells.T-cells.

Unlike cytotoxic T lymphocytes which

recognize target cells in an antigen-specific

manner, NK cells lack antigen-specific

receptors.

NK cells kill potential target by determining its

MHC class I molecules (less specific)

Immune response in Innate

immunity

Endocytosis and Phagocytosis Endocytosis and Phagocytosis

Inflammation

Killing activity of the NK-cell

ENDOCYTOSIS

Endocytosis is the ingestion of

macromolecules present in extracellular fluid

by cells.

Endocytosis can occur by:

Pinocytosis

receptor mediated endocytosis

Pinocytosis involves only non-specific

membrane invagination.

Receptor mediated endocytosis is a process

involving selective binding of macromolecules

to the specific membrane receptors.to the specific membrane receptors.

In both cases, endocytic vesicle is generated

which later fused with endosomes (acidic

compartments) and lysosomes (degradative

enzymes).

PHAGOCYTOSIS

Phagocytosis is the ingestion of invading

foreign individual cells such as bacteria.

It is a critical protective mechanism of the

immune system.immune system.

Phagocytic cells can detect the bacteria by:

Substances released

Opsonins (factors that make the bacteria an

easier target, eg: Ab, complement protein.)

After ingestion, the bacteria is entrapped in

phagosome, which then fuse with lysosome

forming phagolysosomes.

The powerful enzyme in phagolysosome then

digest the bacteria.digest the bacteria.

INFLAMMATION

Damage to tissue by a physical injury (cut) or

by the entry of microorganisms triggers a

localized inflammatory response

(inflammation)(inflammation)

A series of events occurred (refer to the

diagram), causing the characterisitc of

inflammation: redness, edema, heat.

Chemotactic factors are released from

pathogens, whereas chemokines are

secreted by the endothelial cells of blood

vessels and monocytes.

KILLING ACTIVITY OF THE NK CELL

As mentioned previously, NK cells kill

potential target by determining its MHC class

I molecules.

MHC class I molecules are expressed on all MHC class I molecules are expressed on all

normal nucleated cells.

NK cells possess receptors called killer-cell

inhibitory receptors (KIRs) which bind to

MHC class I molecules expressed on normal

cells.

When KIRs bind to MHC class I molecules,

intracellular signals are generated and NK

cell is inhibited to destruct the target cells.

Virus-infected or transformed cells (tumour)

have significantly reduced or absent of MHC have significantly reduced or absent of MHC

class I molecules.

Thus, when such cells encounter NK cells,

the fail to binds with KIRs and NK-cells are

activated to destroy the target cells

Immune Cells involved in the

Adaptive Immune system

Consist of:

B-lymphocytes

T-lymphocytes

Development of B and T

lymphocytes

Both B-lymphocytes and T-lymphocytes are

produced in bone marrow, originating from a

common lymphoid progenitor.common lymphoid progenitor.

B cells differentiate and mature within the

bone marrow.

In contrast, T cells differentiate only partially

within bone marrow. It undergo final

maturation within the thymus gland (primary

lymphoid organ).

Mature B and T cells migrate through the

bloodstream and lymphatic system to the

peripheral lymphoid tissue, which is also

known as secondary lymphoid organ.

Eg of secondary lympoihd organ: Eg of secondary lympoihd organ:

Lymph nodes (major)

Spleen (major)

Tonsils

Peyers patches

The secondary lymphoid organs have two

major function:

They are highly efficient in trapping and

concentrating foreign substances

The are the main sites of production of The are the main sites of production of

antibodies and induction of antigen-specific

T lymphocytes.

Circulation of lymph and fate of

antigen after penetration through:

Blood stream

Skin

GI tract or

respiratory

tract

Immune response in Adaptive

immunity

In cell-mediated immunity:

Helper T- cells (TH)

Cytotoxic T- cells (TC)

What is MHC molecules?

They are cell surface glycoproteins

There are 2 main types of MHC molecules:

MHC class I

(can be found on almost all nucleated body

cells)

MHC class II

(can be found on specialized cell types eg:

macrophages, B cells, activated T-cells, etc.)

In immune response, MHC molecules

function display the antigen fragments

present in the infected cells on cell surface,

forming Antigen Presenting Cells.

TH have receptors that bind to antigen TH have receptors that bind to antigen

fragments displayed by MHC Class II

molecule .

Tc have receptors that bind to antigen

fragments displayed by MHC Class I

molecule .

Function of Helper T-Cell in both CELL-

MEDIATED and HUMORAL immune

response

1. Macrophages engulf a bacterium and

transports the fragment to the cell surface and

displayed by MHC class II molecule, forming

APC.

2. A specific TH cell is activated by binding to

the MHC-antigen complex.

3. The activated TH cell proliferates, giving rise

to a clone of identical cells . These cells

secrete cytokines.

4. The cytokines further stimulate the TH cells

and also help activate B cells and TC cells.

Function of Cytotoxic T-Cell in cell-mediated

immune response

1. An infected cell (or cancer cell) displays an

antigen fragment on its surface by MHC class

I molecule.

2. A specific TC cell is activated by binding to

the MHC-antigen complex.

3. The activated T cell discharges perforin 3. The activated TC cell discharges perforin

molecules, which function to create pores in

the membrane of the infected cells

4. Water and ions flow into the infected cell, and

the cell lyses.

Cytokines

History of Cytokines

The activity of cytokines was first discovered

in 1960s.in 1960s.

At that time, cytokines was believed to be

present with the presence of antigen, to

elevated the proliferative responses of T-cells

Soon afterward, it was determined that this

factor was produced by T cells, and also by

monocytes and macrophages.

Several names were given to cytokines

produced by different cells.

For example:

T-cell growth factor (TCGF)

Lymphocyte-activating Factor (LAF)

Lymphokines Lymphokines

Interleukins (IL)

Interferon (IFN)

Monokines (monocytes and macrophages)

Chemokines

Tumour Necrosis Factor (TNF)

GENERAL PROPERTIES OF CYTOKINES

Most cytokines have very short half lives.

Cytokines facilitate communication between

cells at very low concentrations

Cytokines may act:

Locally

(autocrine; paracrine)

Systematically

(endocrine)

Autocrine: act on

the same cell that

secreted it

Paracrine: act on

other cellsother cells

Endocrine:

systematically

General properties of Cytokines

Cytokines exert their functional effects by

binding to specific receptor on target cells.

Hence, the target cell must be expressing the

receptor for cytokines.receptor for cytokines.

The response of the target cell depends on the

quantity and the type of cytokines which it is

exposed to.

Some cytokines behave antagonistically:

inhibiting each others action on a target cell.

CATEGORIES AND FUNCTIONS OF

CYTOKINES

Cytokines can be divide into:

Cytokines that faciliate innate immune

responsesresponses

Cytokines that promote inflammatory

responses

Cytokines that regulate adaptive immune

responses

Cytokines that affect leukocyte movement

Etc.

Cytokines that faciliate innate immune

responses

Eg: IL-1, IL-6, TNF-

They are produced by phagocytes, and are

capable of causing fever, promoting capable of causing fever, promoting

inflammation, enhancing phagocytosis

(opsonin)

Elevated body temperature is beneficial to

host defenses: pathogens grow less

efficiently at raised temperature, intensing

adaptive immune responses.

Cytokines that promote inflammatory

responses

Eg: IL-1, IL-6, IL-23, TNF-

They cause increased vascular

permeability, leading to swelling and permeability, leading to swelling and

redness associated with inflammation.

Cytokines that regulate adaptive immune

responses.

Eg: IL-1, IL-2

Depending on the cytokines involved, the

regulation can be positive or negative.regulation can be positive or negative.

Ultimately, cytokines regulate the intensity

and duration of immune responses.

Cytokines tend to act on antigen-activated

lymphocytes .

Cytokines that affect leukocyte movement.

Chemokines: attractors for various

leukocytes.

Eg: IL-8

IL-8 is produced by macrophages, T-cell, IL-8 is produced by macrophages, T-cell,

etc.

It activates and attracts neutrophils to the

site of tissue, promoting inflammatory

response and wound healing.

ROLES OF CYTOKINES AND CYTOKINE

RECEPTORS IN DISEASE

Cytokines have complex regulatory properties.

Hence, over-expression or under-expression

of cytokines or cytokine receptors have been

implicated in many disease:

Toxic-shock syndrome

Bacterial septic shock

Cancers (Follicular lymphoma)

Autoimmunity (SLE) Autoimmunity (SLE)

Asthma