10-Immune Response and Cells New a - Copy Yara

8/8/2019 10-Immune Response and Cells New a - Copy Yara

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Immune responseImmune response

Characteristics of the specificCharacteristics of the specific

immune responseimmune response


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1-It includes the combination of bothhumoral and cellularresponse.

2-It is a physiological reaction.

3- It does not pre exist but it is acquired

by contact and adaptation to the inducingagent.

4- It is undergenetic control. The immuneresponse genes are located in the DRregion of chromosome no. 6 in man.


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5- It develops a memory called anamnesticresponse for protection.

6- Feed back regulation due to antibodies,

lymphoid cells, and cytokines. 7- Various hormones influence the immune

response.

8- High doses of antigen paralyze the lymphoid

cells so they are unable to produce specificantibodies to these antigens, this is calledimmunological tolerance.


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Lymphoid tissuesLymphoid tissues

They are filtering systems to remove foreign antigens from the blood streamand lymph.

Central lymphoid tissue (Bone marrow)

Lymphoid erythromyeloid megakaryocyte

Progenitor progenitor progenitor

T Nul B Myeloid Erythroid Platelets progenitor Cell progenitor progenitor

Monocytes granulocytes erythrocytes platelets

Macrophages neutrophils Basophils eosinophils


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Primary lymphoid tissue Thymus Bone marrow, fetal

(T) (B) liver& spleen Secondary lymphoid Encapsulated Unencapsulated

Tissue

L.N. Spleen MALT, GALT, SALT, BALT

Immune response in tissues blood mucosal surface

T cells: paracortical in L.N., periarteriolar in spleen. B cells: germinal follicles in L.N. and spleen. APC: in dendritic cells in thymus and medulla.


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Phases of immune responsePhases of immune response::

1- Recognition (cognitive) binding of peptide

to receptors on T cells

LPS to receptors on B cells.

2- Activation: Phospholipase C mechanism

intracellular calcium.

3-EffectorAb, CMI Killing, cytokine


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Ag C.M R

Phosphoinositol diphosphate

Phospholipase C

DAG IP3 Cytoplasm Ca

Arachidonic protein kinase

5HPETE

Guanyl cyclase

cGMP Nucleus RNA& protein synthesis (Transcription IL2)


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Cells concerned in immuneCells concerned in immune

responseresponse

1-Macrophages and other accessory cells aslangerhans and dendritic cells.

2-T lymphocytes.

3-B lymphocytes 4-Null cells:

Natural killer (NK cells)

Killer cells (K cells)

lymphokine activated killer (LAK cells)

Tumor infiltrating lymphocytes.


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MacrophagesMacrophages

Functions:

1-They play a very important role in

process ofphagocytosis,

2- Present antigen to lymphocytes.

3- Secrete factors termed monokines: IL1,

TNF, IL6, IL8, IL10, 12, 15. 4- ADCC: Abs, C3b.


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Surface receptors ofSurface receptors of

macrophagemacrophage

I)Immune receptors:

1- fc part of immunoglobulin

2 complement

c3b c3d

3 lymphokines: for activation and proliferation.

4 HLA class II, class I.

5- Toll like receptors.

6- CD14


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II) Non immune receptors: Regulate CHO and lipidsmetabolism. Clear debris of infl.products.

1) Hormone receptors Colony stimulating factor (c s f)

Insulin Thrombin 2) Lactoferrin 3) Transferrin 4) Fibrin- fibrinogen 5) Fibronectin 6) Alpha2 macroglobulin- proteinase complexes 7) Lipoprotein receptors


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Secreted products ofSecreted products of

macrophagesmacrophages

Enzymes:

1- Plasminogen activator

2- Elastases, collagenases andgelatinases

3-Lysozyme

4- Arginase

5- Lipoprotein lipase

6- Matrix metalloproteinase


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Plasma proteins:

1-Alpha 2 macrglobulin

2- Fibronectin

3- Coagulation proteins

4- Complement components

- C1 C2 C3 C4 C5

5- Factor B D I H

6- Properdin


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Nucleotide metabolites:

-cAMP -Uracil -Thymidine - Uric

acid

Bioactive lipids:

1-Prostaglandin E2

2-Thromboxane 3-Leukotriene C (slow reacting

substance of anaphylaxis)


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Monokines:

1- Interleukin -1, 3, 6, 8, 10, 12, 15, 18

2- Interferons. 3- Granulocyte monocyte- colony

stimulating factors (GM-CSF).

4- Tumoricidal and microbicidal factors


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The process of phagocytosisThe process of phagocytosis

1) Chemotaxis:

- Substances chemotactic for macrophges include:-

1- Complement factor particularly C5a, C3a.

2- Bacterial products: bacterial endotoxin 3- Products from stimulated B and T

lymphocytes.

4- Factors produced by fibroblasts, collagen, elastin.

5- cAMP, leukotriens, PG.


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2) Retension:

1-lymphokines macrophage migration

inhibitory factor (MIF) macrophage

activation factor (MAF)

2- Proteolytic enzymes produced during

activation of complement

(Factor Bb) and of the fibrinolytic system

(plasmin)


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3) Ingestion:

Ingestion is accompanied by:

1- Sharp rise in 02 uptake. 2- Hexose monophosphate shunt activity

increases 10 folds NADPH.

3- NADPH is used to reduce O2 intosuperoxide ions, hydrogen peroxide.


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4) Microbial killing: A) Myeloperoxidase system

(O2 dependent killing):

1 - Halogenation of microbial surface componentsloss of function. 2- Carboxylation of amino acid aldehydes,

ammonia & CO2.

3- Production of singlet O2

Singlet O2 can attack double bounds in carbonchains leading to lethal damage of biologicalsystem


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(B)O2independent killing mechanisms:

1) Acidity

2) Lysozyme. 3) Lactoferrin.

4) Cationic protein:

Bacteria ve charged, bind to +vecharged cationic protein: bactericidal.


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Opsoninsare:

Complements,

Immunoglobulins,

Tuftsin, Fibronectin,

Products of B &T lymphocytes:

MAF,TNF,CSF,IL1. Acute phase protein:CRP, antitrypsin, macroglobulin.


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OpsonizationOpsonization


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OpsoninsOpsonins


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OpsonizationOpsonization


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LymphocytesLymphocytes

Thymus- derived lymphocytes (T cells)

Effectors functionsinclude reactivitysuch as: delayed hypersensitivity, allograft

rejection, tumor immunity and graft-versus- host reactivity, these effectorsfunctions reflect 2 general properties of Tlymphocytes their ability to secreteproteins (termed lymphokines) and theirability to kill other cells (cytotoxicity),


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The regulatory function:

cell-mediated cytotoxicity by other

T cells and immunoglobulinproduction by B cells.


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Certain molecules expressed on their surface.The most important of these are:

CD3:3 molecules associated with antigenreceptor (Ti)

CD4 (T4) involved in recognizing class II MHCmolecules

CD8 (T8) involved in recognizing class I

MHC molecules.

CD25 (TAC) receptor for IL-2

Ti heterodimer that recognizes antigen plusMHC gene products.

HLA-DR on all mitogen activated T cells. CD= Cluster of differentiation.


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T cell ontogenyT cell ontogeny::

The appearance of mature, functional T

cells in the peripheral lymphoid tissue

represents the culmination of a series of

differentiation steps occurring in thethymus.


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Stem cells migrate to the thymus and thenmove from the cortex to the medulla and outinto the periphery, a journey that takes 3

days. During intrathymic development, thymocytes

acquire functional maturity as shown bychanges in their cell surface phenotype as

reflected by the expression of the cellsurface molecules.


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One of the main functions of thymicdifferentiation is to produce a population ofcells that can discriminate between self

antigens and foreign antigens such asthose expressed on microorganisms orthe cells of unrelated individuals.

During their differentiation within thethymus, T cells capable of recognizing theselfclass I or IIMHC molecules.


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Congenital lacking of thymus gland:

-Recurrent infection: fungal.

-Impaired CMI. -Impaired graft rejection.

-Impaired humoral response.


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T cell activationT cell activation

At least 2 signals are required for T cellactivation.

1-One is transmitted through interaction between

antigen receptor /CD3 complex on the T cell andantigen plus MHC gene.

2- This interaction generates 2 biologically activemetabolites from membrane inositol. The first is

inositol triphosphate. The second isdiacylglycerol, which activates the enzymeprotein kinase c.


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3- IL-I released from accessory cell "antigenpresenting cell".

Signal transduction: JAK/STAT (Janus kinasesand signal transduction and activated

transcription) IL1 IL1-R Janus kinases

STAT protein (kinases) nucleus transcription


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These three stimuli increase transcription

of lymphokine genes IL-2 and IL-2

receptor synthesis are initiated.

Since IL-2 is a T cell growth factor, this

leads to a brief burst of cell proliferation.


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B- LYMHOCYTESB- LYMHOCYTES

Various receptors are detectable on B cells:

1) Immunoglobulins: Ig, M, D.

2) Fc receptors for fc portion of IgM, G, A, E.

3) C3b, C3d, and C4 .

4) EBV, Epstein Barr virus receptors.

5) A, B, C, D: histocompatiblity antigens.


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Mature human B-lymphocytes perform

many functions including antibody

secretion, Ag presentation, preservation of

memory for Ag and lymphokine secretion .


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Products of cellsProducts of cells

Th1:IL2, IFN , TNF, TNF

Th2:IL4, 5, 6, 10, 13.

Th3:IL10,TGF ,IL 35 B: IL 2, 4, 5, 6,10, 13.

Monocyte: IL1, TNF, IL6, 8, 10, 12, 15,

18.


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Null cellsNull cells

They are lymphoid cells that lack B, T cell

features. These cells are large

lymphocytes that can be distinguished by

characteristic azurophilic granules in theircytoplasm.

Their azurophilic granules contain

perforins, Lymphotoxins, TNF, NKCF (NKcytotoxic factor), and IFN.


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.Natural killer cellsare usually null cells with

surface marker CD 16 which bind to the Fc portion

of the IgG, and thereby destroy it. NK-cells do

immune surveillance, attack pathogens and

abnormal cells. members of null cells are NK cells,antigen dependent cytotoxic cells(ADCC), and the

lymphokine activated killer(LAK)cells.
http://en.wikipedia.org/wiki/Natural_killer_cellhttp://en.wikipedia.org/wiki/Natural_killer_cell


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1-KILLER CELLS (K.cells):

They have receptors for the Fc portion of

the antibody and appear to recognize

immune complexes specifically. Target

cells are killed. This phenomenon is called

antibody- dependent cell- mediated

cytotoxicity (ADCC).


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The exact killing mechanisms are

unknown, but it involves cell to cell

contact, and in some of the effector cell

types involved might result from therelease oflysosomal enzymes.


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2) NATURAL KILLER (NK- cells):

The main function associated with NK

cells is the non-specific killing of tumour

cells and virally infected cells.

NK cells do not require recognition of

antigens in association with MHC products

in contrast to cytotoxic T cells.


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"perforins and granzymes" : a protease

cascade is initiated, activate caspases,

cleave critical molecule such as

cytoskeleton, DNA and chromatin proteindeath of the target and apoptotic

bodies formation which are phagocytosed

by macrophages.


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Cell death results in the same way as with

late complement components by loss of

cellular contents through the pores.


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Granzymes&Perforins.

Fas binds to Fas ligand.

TNF

+ Caspases

Apoptosis


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ADCC by NK CellsADCC by NK Cells


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3) LYMPHOKINE ACTIVATED KILLER

cells (LAK):

IL - 2 enhances their non-specific killing

capacity to many tumor targets.

4) TIL: 100 times potent in killing tumors,

+by IL2.


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Major events taking place inMajor events taking place in

specific immune responsespecific immune response


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1-Antigen processing and presentation:

The antigen presenting cell takes up the

foreign antigen, internalizes it, and breaks it

into small fragments, then presents it in asimple form on its surface complexed with

MHC class II molecule to be recognized by

the receptor on the surface of the specific T-

helper cell. The macrophage also secretes IL-1 which activates the T-helper cell.


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Other cells can also act as antigen

presenting cells such as langerhans

cells of the skin, dendritic cells, and B

lymphocytes.


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2- Activation of the T- helper cell

The T-helper cell is activated when it

recognizes its specific antigen presented

to it by the antigen presenting cell, and

also by the cytokines produced by the

macrophage.


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It undergoes proliferation and produces a

number ofcytokines (e.g.IL-2, IL-4 and IL-

6) which act on other cells of the immune

system as T- cytotoxic cells, B-cells andmacrophages causing their proliferation

and activation.


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3- Activation of T-cytotoxic cells

T-cytotoxic cells become activated when

they recognize their antigen on the

surface of a target cell, complexed with

MHC class I molecule and also by the

effect ofcytokines produced by the

activated T-helper cell.


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The activated T-cytotoxic cell then

releases cytotoxins which kill the target

cell e.g. virus-infected cell; this represents

the cellular or cell-mediated immuneresponse.


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4- Activation of B-cells

When B-cells recognize their specificantigen by surface membrane Ig

receptors, and are acted upon by the

cytokines released by the activated T-helper cells, they will become activated

and will undergo proliferation and

differentiation into antibody producingplasma cells.


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These cells will secrete antibodies specific

to the antigen which induced the

response.These antibodies can lyse

bacteria or prepare them for phagocytosisby osponisaton, they can neutralize toxins

and neutralize viruses rendering them non-

infective. This represents the humoral orantibody-mediated immune response.


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5- Some activated B and T-cells become

memory cells which can respond to

subsequent encounters with the same

antigen.


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6- The usual outcome of the immune

response is the elimination of the

offending antigen. After that the response

is down-regulated by suppressor T-cellsto prevent unnecessary activation of

lymphocytes and unregulated production

of antibodies.


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Antigen processing and presentationAntigen processing and presentation

T helper cell

33Activation of cytotoxic TActivation of cytotoxic T


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33--Activation of cytotoxic TActivation of cytotoxic T

cellscells

Activated T

helper cell

Memory Tc Effector Tc

T c


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A Cytotoxic T Cell Attacking and KillingA Cytotoxic T Cell Attacking and Killing

a Virus-Infected Target Cella Virus-Infected Target Cell

Here, the smaller cytotoxic T cell or Tc (arrow) is attacking and killing

a much larger virus-infected cell. The T cell will survive while the

infected cell is destroyed.

CELLS alive!

4- B-cell activation and4- B-cell activation and


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4- B-cell activation and4- B-cell activation and

differentiationdifferentiation

Activated T

helper cell

Antibodies


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Activated T helper

cell

Memory Tc Effector Tc Lysis

APC T helper cell

Antiodi Cell-mediated immunity

Humoral immunity


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10-Immune Response and Cells New a - Copy Yara