AL-AZHAR UNIVERSITY

FACULTY OF MEDICINE FOR GIRLS

MICROBIOLOGY DEPARTMENT

CELLS OF IMMUNE RESPONSE

THE SILENT ARMY OF THE BODY

Under the supervision of

PROF.DR:ASMAA ELGENDYDR:HANAN

PREPARED BY:

1) Ebthal Abd-elnaser Ahmed.

2) Arwa Essam Hussien.

3) Esraa Ahmed Fathy.

4) Esraa Elsied Mahmoud.

5) Esraa Abu-bakr Mohamed.

6) Esraa Ahmed Mohamed.

7) Esraa Gamal El-dien Yosef.

8) Esraa Arafaat Ahmed.

9) Esraa Abd-elsmee saied.

10) Esraa Ragab Abd-elkhalek.

بسم هللا الرحمن الرحيم

Points described in this research:

A. An overview of the immune system.

B. Components of the immune system.

C. Origin of immune cells.

D. Lymphocytes.

E. Granulocytes.

F. Phagocytic cells.

IMMUNOLOGY

is the science that studies immune system.

The main function of the immune system is to

prevent or limit infections by microorganisms such as bacteria, viruses,

fungi, and parasites.

First line

intact skin and mucus membrane.

Second line

innate immunity :it can function immediately upon entry of the microorganisms and it is not specific.

Third line

it takes several days to become fully functional and it is highly specific.

COMPONENTS OF THE IMMUNE

SYSTEM

Primary lymphoid organs:

1.bone marrow.

2.thymus gland

Secondary lymphoid

organs:

1.lumph nodes.

2.Spleen.

3.mucsa

associated lymphoid tissue.

Lymphocytes:

1.B lymphocytes.

2.T lymphocytes.

3.NK cells.

Granulocytes:

1.neutrophils.

2.esinophils.

3.basophils and mast cells.

Phagocytic cells:

1.monocytes.

2.macrophages.

3.dendritic cells.

Organs CELLS

CELLS OF IMMUNE RESPONSE

Origin of the immune cells:- During embryonic development, blood cell

precursors originate mainly in the fetal liver and yolk

sac.

-in postnatal life, the stem cells reside in the bone

marrow.

Then stem cells differentiate as the next figure:

DEVELOPMENT OF CELLS OF IMMUNE

RESPONSE:

A. LYMPHOCYTES:

The lymphocytes occupy a very special place among the leukocytes that participate in one way or another in immune reactions due to their ability to interact specifically with antigenic substances and to react to nonself antigenic determinants.

Lymphocytes differentiate from stem cells in the fetal liver, bone marrow, and thymus into two main functional classes T and B.

Their classification based on site of differentiation and on receptors:

-T cells and naturall killers T - in thymus -(TCR)

-B cells – bone marrow - (BCR)

(no cell surface specific receptors – NK cells)

They are found in the peripheral blood and in all lymphoid tissues.

1.T LYMPHOCYTES:

most important players of specific immunity.

T lymphocytes have a longer lifespan than B

lymphocytes. Long-lasting lymphocytes are particularly

important because of their involvement on

immunological memory.

Contain surface receptors :1)CD (cluster of differentiation) proteins-

molecules on the cells membrane, allow the

identification of cells.

2)TCR- receptor for antigen.

3)MHC gp I or II class.

1)CD PROTEINS:

allow an identification of T-cell subsets

CD 3 = important in intracellular signaling to initiate an immune response; closely associated with TCR.

CD 4,8 = are expresed on subclasses of mature T cells; CD4 reacts with MHC gp II.class),CD8 reacts with MHC gp I. class on macrophages.

CD 28- receptor for costimulator molecules CD80 and 86.

2)TCR RECEPTORS:

Antigen receptors are encoded by several gene segments that recombine during lymphocyte maturation.

Heterodimer consisting of 2 nonidentical polypeptide chains linked together by disulfide bonds.

TCR heterodimer is noncovalently associated with the γ,δ,ε chains of the CD3 molecule.

COMPLEX TCR- CD3 makes contact with both the Ag and MHC gp.

FUNCTION OF T LYMPHOCYTE:

1) regulation of immune responses and various

effector functions (cytotoxicity and lymphokine

production being the main ones) that are the

basis of cell-mediated immunity (CMI).

2) carry an antigen-recognition unit on their

membranes, known as T-cell receptors.

3) Several subpopulations of T lymphocytes with

separate functions will be dicussed later.

SURFACE RECEPTORS OF T LYMPHOCYTE:

All T cells contain CD3 and TCR.

T cells are subdivided into two major categories on

the basis of whether they have CD4 or CD8

proteins on their surface. Mature T cells have either

CD4 or CD8 proteins but not both.

CD4 T cells: CD8 T cells:

1) 2/3 of all T cells containging CD3

2) CD4 cell surface molecule

– recognise part of MHC II

molecule that is not part

of peptid binding site

3) Functionally – helper

1) 1/3 of all T cells containing CD32) CD8 cell surface molecule

– recognise part of MHC Imolecule that is not designated to bind peptids

3) Functionally : Tc cytotoxic – eliminate virus or i.c.bacteria infected cells

Ts supreesor – increase and control reactions of specific immunity

T CELL SUBPOPULATIONS:

Subpopulations of T cells have been defined

according to their particular function and their CD

membrane markers.

They are:

1) Helper:CD4 (T helper 1 and T helper 2).

2) Cytotoxic:CD8.

3) Regulatory.

4) Memory.

1) T HELPER(CD4):

recognize the epitopes in association with class II

MHC

help B cells to produce antibodies and help

phagocytes to destroy ingested microbes

subsets of Th cells: Th1, Th2 cells in the next table:

a) T helper 1 b) T helper 2

secrete: 1)INF-γ (gamma interferon) : activates

macrophages to become more effective at killing phagocytosed microbes, supresses the development of Th2 cells.

2)IL- 2 : stimulates survival and proliferation of T cells, called T-cell growth factor.

3)TNF (tumor necrosis factor)- stimulates the recruitment of neutrophils and monocytes to sites of infection, activates these cells to eradicate microbes.

4)IL-3 : promotes expansion of immature marrow progenitors of all blood cells.

5)GM-CSF : acts on progenitors in the bone marrow to increase production of neutrophils and monocytes.

Th1 based immune reaction:

1)Th1 cells stimulate phagocytes to

eliminate ingested microbes.

2)Interferon gamma is the main Th1

cytokine.

secrete: 1)IL-4 : induces differentiation of Th2

cells from naive CD4+ precursors, stimulation of IgE production by B cells.

2)IL-5 : activates mast cells.3)IL-6 : stimulates the synthesis of

acute phase proteins by hepatocytes.4)IL-10 : inhibits activated

macrophages, supresses Th1 production.

5)IL-3, GM-CSF.

Th2 based immune reaction:

1)Th 2 response provide help for B

cells and are essential for antibody-

mediated immunity.

2)Antibodies are needed to control

extracellular pathogens.

3)The Th2 - type cytokines include IL

4, 5, and 13.

2)T CYTOTOXIC (CD8):

cause lysis of target cells; are active against tumors, virus-infected cells, transplanted allogenetic tissue

release TNF- depresses proteosynthesis

recognize the foreign epitope in association with class I MHC molecules

destroy their target cells by releasing perforin (create poresin the cell membrane and cytoplasm escapes) and granzymes (degrading essential macromolecules)

3)T REGULATORY:

Express CD4, CD25, FoxP3.

Regulate the activation or effector function of other

T cells.

Are necessary to maintain tolerance to self

antigens.

4)T MEMORY:

Memory T cells, as the name implies, endow our host defenses with the ability to respond rapidly and vigorously for many years after the initial exposure to a microbe or other foreign material.

This memory response to a specific antigen is due to several features:

(1) many memory cells are produced, so that the secondary response is greater than the primary response, in which very few cells respond.

(2) memory cells live for many years or have the capacity to reproduce themselves.

(3) memory cells are activated by smaller amounts of antigen and require less costimulation than do naïve, unactivated T cells.

(4) activated memory cells produce greater amounts of interleukins than do naïve T cells when they are first activated.

2.B LYMPHOCYTES:

Origin:1) During embryogenesis, B-cell precursors are

recognized first in the fetal liver.

2) they migrate to the bone marrow, which is their main location during adult life. Unlike T cells, they do not require the thymus for maturation.

3) Pre-B cells lack surface immunoglobulins and light chains but do have heavy chains in the cytoplasm.

4) The maturation of B cells has two phases:

a) the antigen-independent phase consists of stem cells, pre-B cells, and B cells.

b) the antigen-dependent phase consists of the cells that arise subsequent to the interaction of antigen with the B cells.

MATURATION OF B LYMPHOCYTES:

FUNCTION OF B LYMPHOCYTES:

1) interact with antigenic epitopes, using their

immunoglobulin receptors.

2) subsequently develop into plasma cells, secreting

large amounts of specific antibody.

3) circulate as memory cells.

4) present antigenic peptides to T cells, consequent

upon interiorization and processing of the original

antigen.

CLONAL SELECTION OF B LYMPHOCYTES:

clonal selection, accounts for antibody formation.

Each individual has a large pool of B lymphocytes (about 107).

Each immunologically responsive B cell bears a surface

receptor (either IgM or IgD) that can react with one antigen (or

closely related group of antigens); i.e., there are about 107

different specificities.

An antigen interacts with the B lymphocyte that shows the best

"fit" with its immunoglobulin surface receptor. After the antigen

binds, the B cell is stimulated to proliferate and form a clone of

cells. These selected B cells soon become plasma cells and

secrete antibody specific for the antigen.

Plasma cells synthesize the immunoglobulins with the same antigenic

specificity (i.e., they have the same heavy chain and the same light chain) as

those carried by the selected B cell.

* Immature B cells express IgM receptors on the surface

* Mature B cells express IgM, IgD molecules on surfaces

* IgM and IgD molecules serve as receptors for antigens

* Memory B-cells express IgG or IgA or IgE on the surface

* B-cells bear receptors for Fc portion of IgG and a receptor for C3 component

of the complement

* They express an array of molecules on their surfaces that are important in

B-cells interactions with other cells such as MHC II, B7 and CD40

ACTIVATION OF B LYMPHOCYTES:

• THE END RESULT OF ACTIVATION OF B LYMPHOCYTE IS:

1)Plasma cells 2)Memory cells

Most activated B cells form plasma

cells.

produce large amounts of

immunoglobulins specific for the

epitope.

secrete thousands of antibody

molecules per second for a few days

and then die.

Some activated B cells form memory

cells.

can remain quiescent for long periods

but are capable of being activated

rapidly upon reexposure to antigen.

Most memory B cells have surface IgG

that serves as the antigen receptor, but

some have IgM.

The presence of these cells explains

the rapid appearance of antibody in the

secondary response.

Memory T cells secrete interleukins

that enhance antibody production by

the memory B cells.

3.NATURAL KILLER CELL: Large granular lymphocytes which lack most surface markers of B

and T-cells

* They comprise 5-10% of the peripheral lymphocytes

They are called "natural" killer cells because they are active without prior exposure to the virus, are not enhanced by exposure, and are not specific for any virus.

* They function mainly in innate immunity

* They have spontaneous non-specific cytotoxic activity on virus infected cells, tumour cells and graft cells by secreting cytotoxins (perforins and granzymes) similar to those of cytotoxic T lymphocytes and by participating in Fas-Fas ligand-mediated apoptosis.

* They are not MHC restricted and MHC I inhibits their killing functions

NATURAL KILLER CELL:

They can kill without antibody, but antibody (IgG) enhances

their effectiveness, a process called antibody-dependent

cellular cytotoxicity (ADCC). IL-12 and gamma interferon are

potent activators of NK cells.

• Lack T-cell receptor, CD3 proteins, and surface IgM

and IgD

Thymus not required for development

• Normal numbers in Severe Combined

Immunodeficiency Disease (SCID) patients

• Activity not enhanced by prior exposure

B. GRANULOCYTES:

Granulocytes are a collection of white blood cells

with segmented or lobulated nuclei and granules in

their cytoplasm, which are visible with special

stains.

Because of their segmented nuclei, which assume

variable sizes and shapes, these cells are

generically designated as polymorphonuclear

neutrophil leukocytes (PMN).

CLASSIFICATION:

•Classified according to cell morphology and cytoplasmic

staining

•Neutrophils: stains with BOTH acid and basic dyes

called ‘PMN’ for lobed nucleus; 50% of circ

leukocytes

•Eosinophils: stain with ACID dye (Eosin-red);

bilobed nucleus;1-3% of leuko’s

•Basophils: stain with BASIC dye (Methylene blue);

<1% of leuko’s

1.NEUTROPHILS:

• Circulate in peripheral blood 7-10 hr before migrating into tissue; live only a few days.

• very important component of our innate host defenses, and severe bacterial infections occur if they are too few in number (neutropenia) or are deficient in function, as in chronic granulomatous disease.

• increased # (leukocytosis) used as an indicator of infection

• extravasate in inflam rxn

• attracted by chemotactic factors

• Use both O2-dep and O2-indep digestive mech’s

• Produce high levels of defensins

granules are lysosomes, which contain a variety of degradative enzymes that are important in the bactericidal action of these cells.

Neutrophils have receptors for IgG on their surface so

IgG is the only immunoglobulin that opsonizes, i.e.,

makes bacteria more easily phagocytosed. Note that

neutrophils do not display class II MHC proteins on their

surface and therefore do not present antigen to helper T

cells. This is in contrast to macrophages that are also

phagocytes but do present antigen to helper T cells.

Neutrophils can be thought of as a "two-edged" sword.

The positive edge of the sword is their powerful

microbicidal activity, but the negative edge is the tissue

damage caused by the release of degradative enzymes.

An excellent example of the latter is the damage to the

glomeruli in acute post-streptococcal glomerulonephritis.

The damage is caused by enzymes released by

neutrophils attracted to the glomeruli by C5a activated by

the antigen–antibody complexes deposited on the

glomerular membrane.

2.ESINOPHILS:

are white blood cells with cytoplasmic granules that

appear red when stained with Wright stain. The red

color is caused by the negatively charged eosin dye

binding to the positively charged major basic

protein in the granules.

The eosinophil count is elevated in two medically

important types of diseases: parasitic diseases,

especially those caused by nematodes and

hypersensitivity diseases, such as asthma and

serum sickness. Diseases caused by protozoa are

typically not characterized by eosinophilia.

• The function of eosinophils has not been clearly established. It seems

likely that their main function is to defend against the migratory larvae of

nematodes, such as Strongyloides and Trichinella. They attach to the

surface of the larvae and discharge the contents of their granules, which

in turn damages the cuticle of the larvae. Attachment to the larvae is

mediated by receptors on the eosinophil surface for the Fc portion of the

heavy chain of IgG and IgE.

• Another function of eosinophils may be to mitigate the effects of

immediate hypersensitivity reactions because the granules of eosinophils

contain histaminase, an enzyme that degrades histamine, which is an

important mediator of immediate reactions. However, the granules of the

eosinophils also contain leukotrienes and peroxidases, which can

damage tissue and cause inflammation. The granules also contain major

basic protein that damages respiratory epithelium and contributes to the

pathogenesis of asthma.

• Eosinophils can phagocytose bacteria but they do so weakly and are not

sufficient to protect against pyogenic bacterial infections in neutropenic

patients. Although they can phagocytose, they do not present antigen to

helper T cells. The growth and differentiation of eosinophils is stimulated

by interleukin-5.

3.BASOPHILS AND MAST CELLS:

Basophils are white blood cells with cytoplasmic granules that appear blue when stained with Wright stain. The blue color is caused by the positively charged methylene blue dye binding to several negatively charged molecules in the granules. Basophils circulate in the bloodstream, whereas mast cells, which are similar to basophils in many ways, are fixed in tissue, especially under the skin and in the mucosa of the respiratory and gastrointestinal tracts.

Basophils and mast cells have receptors on their surface for the Fc portion of the heavy chain of IgE. When adjacent IgE molecules are cross-linked by antigen, immunologically active mediators, such as histamine, and enzymes, such as peroxidases and hydrolases, are released. These cause inflammation and, when produced in large amounts, cause severe immediate hypersensitivity reactions such as systemic anaphylaxis.

Mast cells also play an important role in the innate

response to bacteria and viruses. The surface of mast

cells contain Toll-like receptors that recognize bacteria

and viruses. The mast cells respond by releasing

cytokines and enzymes from their granules that mediate

inflammation and attract neutrophils and dendritic cells

to the site of infection. Dendritic cells are important

antigen-presenting cells that initiate the adaptive

response. The role of mast cells in inflammation has

been demonstrated in rheumatoid arthritis. These cells

produce both inflammatory cytokines and the enzymes

that degrade the cartilage in the joints.

C. PHAGOCYTIC CELLS:

1) Macrophage.

2) Monocyte.

3) Dentritic cell.

1.MACROPHAGE :2.MONOCYTE:

Monocytes and macrophages are believed to be closely related.

The monocyte is considered a leukocyte in transit through the blood, which when fixed in a tissue will become a macrophage.

Monocytes and macrophages, as well as granulocytes are able to ingest particulate matter (microorganisms, cells, inert particles) and for this reason are said to have phagocytic functions.

The phagocytic activity is greater in macrophages (particularly after activation by soluble mediators released during immune responses) than in monocytes

• Macrophages, monocytes, and related cells play an important role in the

inductive stages of the immune response by processing complex antigens

and concentrating antigen fragments on the cell membrane. In this form,

the antigen is recognized by helper T lymphocytes For this reason, these

cells are known

as antigen-presenting cells (APC).

• APC include other cells sharing certain functional properties with

monocytes and macrophages present in skin (langerhans cells), kidney,

brain

(microglia), capillary walls, and lymphoid tissues.

• Langerhans cells can migrate to the lymph nodes, where they interact with

T lymphocytes and assume the morphological characteristics

of dendritic cells(will discussed later).

• All antigen-presenting cells express one special class of histocompatibility

antigens,designated as class II MHC or la (I region–associated) antigens.

• The expression of MHC-II molecules is essential for the interaction with

helper T lymphocytes.

• Antigen-presenting cells also release cytokines, which assist the

proliferation of antigenstimulated lymphocytes, including interleukins (IL)-1,

-6, and -12.

MECHANISMS OF MACROPHAGE FUNCTION:

function mechanism

Phagocytosi

s

Ingestion and killing of microbes in phagolysosomes. Killing caused

by reactive oxygen intermediates such as superoxides, reactive

nitrogen intermediates such as nitric oxide, and lysosomal enzymes

such as proteases, nucleases, and lysozyme.

Antigen

presentation

Presentation of antigen in association with class II MHC proteins to

CD4-positive helper T cells. Also displays B7 protein, which acts as a

costimulator of helper T cells.

Cytokine

production

Synthesis and release of cytokines such as IL-1 and TNF, and

chemokines such as IL-8.

3.DENDRETIC CELLS:

are a third type of cell that function as "professional" antigen-presenting cells (macrophages and B cells are the other two); i.e., they express class II MHC proteins and present antigen to CD4-positive T cells.

They are particularly important because they are the main inducers of the primary antibody response.

The name "dendritic" describes their many long, narrow processes (that resemble neuronal dendrites), which make them very efficient at making contact with foreign material.

Dendritic cells are primarily located under the skin and the mucosa, e.g., Langerhans' cells in the skin.

Dendritic cells migrate from their peripheral location under the skin and mucosa to local lymph nodes, where they present antigen to helper T cells.

4 types: Langerhans, Interstitial DC’s, Myeloid DC’s, Lymphoid DC’s.

major role as APC to TH.

MATURATION OF DENDERTIC CELLS:

Loss of endocytic and phagocytic receptors

Increased expression of MHC

Up -regulation of co-stimulatory molecules (CD80

and CD86) required for T-cell stimulation

Up-regulation of CD40 and adhesion molecules

ICAM-1 and LFA-3

Fc receptors (endocytosis) decrease.

DEVELOPMENTAL PATHWAY OF DCS

FOLLICULAR DENDERITIC CELLS:

monocyte-derived cell.

have a similar appearance to the dendritic cells but are quite different from them in their location and function.

Follicular dendritic cells (FDCs) are located in the B-cell-containing germinal centers of the follicles in the spleen and lymph nodes.

They do not present antigen to helper T cells because they do not produce class II MHC proteins. Rather, they capture antigen–antibody complexes via Fc receptors located on their surface.

The antigen–antibody complexes are then detected by activated B cells.

The antibody produced by these B cells undergoes affinity maturation. (Affinity maturation is the improvement in the affinity of an antibody for the antigen that occurs upon repeated exposure to the antigen.).

In addition, FDCs produce chemokines that attract B cells to the follicles in the spleen and lymph nodes.

REFERENCES:

A) Medical Immunology Fifth Edition,

edited by: Gabriel Virella ,Medical University of South Carolina .Charleston, South Carolina.

B) Cellular and molecular immunology by:Abul K. Abbas and Andrew H. Lichtman.

C) W.W.W.

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