Immunology

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					Immunology




             IMMUNOLOGY


              Sherko A Omer
               MB ChB, MSc., PhD




                                   1
Immunology



 Basic immunology
 Clinical immunology
 Diagnostic immunology

 Handout notes

 PowerPoint slides

 References

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Immunology


                WHY IMMUNOLOGY ?

 Pathology ..infection, allergy, autoimmune disorders

 Protection…. immunisation, tumour

 Diagnosis …Many fields…..

 Treatment …..allergic disorders,


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Immunology


                   DEFINITIONS

   Immunology …..the science

 Immunity .. state of protection against microorganisms,
toxic molecules and foreign cells

   Immunisation … induction of immunity




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Immunology


             TYPES OF IMMUNITY

1. Innate (natural, nonspecific) immunity



2. Adaptive (acquired, specific) immunity




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Immunology


               TYPES OF IMMUNITY

                  Innate        Adaptive
Specificity       Nonspecific   Specific

Memory            No            Yes

Time-dependency   No?           Yes?

Self/nonself      No            Yes

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Immunology




             7
Immunology




Physical and chemical
defence mechanisms.

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Immunology


      TYPES OF ADAPTIVE IMMUNITY

1. Active immunity… Body made e.g after infection or
active immunization

2. Passive immunity … Not made by host e.g maternal
immune transfer to the baby or passive immunisation




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Immunology


  ORGANISATION OF IMMUNE SYSTEM
1. Organs lymphoid organs such as thymus, spleen and
lymph nodes

2. Tissues lymphoid tissues such MALT

3. Cells lymphoid cells such as T cell, B cell, NK cells.
Other cells such as macrophage, neutrophils,

4. Proteins and peptides such as complement system
and cytokines
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Immunology


    CELLS OF THE ADAPTIVE IMMUNE
               SYSTEM
1. Lymphoid cells …T lymphocytes, B lymphocyte, NK cells.

2. The mononuclear phagocyte system cells.

3. Cells involved in the inflammatory phase of immune
response (Neutrophils, Basophils)…



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  Immunology




Hematopoietic and immune cell
differentiation                 12
Immunology


   CLUSTER OF DIFFERENTIATION(CD)
Lymphocytes, leukocytes and other body cells express a
large number of different macromolecules on their
surfaces; these macromolecules can be identified using
monoclonal antibodies (mAb) that bind them.

Theses macromolecules can serve either as surface
determinants specific to a particular cell type or
subpopulation (markers) or they serve as receptors.

http://prow.nci.nih.gov/

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   Immunology




T cell-APC interaction
at molecular level




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Immunology


              LYMPHOID CELLS
Lymphocytes are the predominant cells of immune
system.

Lymphoid cells makes 20% of total white blood cell count
and they are characterize by having a long life span,
their plasma membrane shows slow amoebic
movements.

Naive lymphocytes, cells that have not previously been
stimulated by antigens, are called small lymphocytes by
morphologists.
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Immunology


                   LYMPHOID CELLS
Main types of lymphocytes include:

 T lymphocytes
 B lymphocytes
 Natural killer cells (NK cells)
 Other cells, LAK




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Immunology


   Lymphocytes




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Immunology


T LYMPHOCYTES or T CELLS
Lymphocytes arise from maturation of steam cells in
thymus are called T (Thymus) lymphocytes.

In thymus, there is rearrangement and reproductive
expression of TCR (T cell receptors) genes and selection
of some antigen receptors that permits mature T cells to
recognize antigens.




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Immunology


T LYMPHOCYTES or T CELLS




 Development of CD4+ and CD8+ T cells in the thymus
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Immunology


T LYMPHOCYTES or T CELLS

T lymphocytes accounts for:
 65-75% of blood lymphocytes
 More than 95% of thymus lymphocytes
 70-80% of lymph node lymphocytes
 20-30% of spleen lymphocytes.




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Immunology


T LYMPHOCYTES or T CELLS
T cells that express CD4 are generally referred to as T
helper (TH) lymphocytes.

T cells that express CD8 are called T Cytotoxic Cells (Tc).

Both CD4 and CD8 cells can act as cytotoxic T lymphocytes
(CTL), depending on whether class II or class I MHC is
recognized, respectively.

A subset of T lymphocyte act as suppressor or regulatory
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cell T reg.
Immunology


T HELPER SUBSETS
TH can be subdivided into two categories, depending on their
function, response to various cytokines, and their ability to
secrete cytokines TH1 and TH2.

TH cells start as precursor cells that make IL-2. On initial
stimulation, these cells develop into TH0 cells, which can
secrete several cytokines, including IFN-, IL-2, IL-4, IL-5,
and IL-10.



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Immunology


T HELPER SUBSETS
TH0 cells can develop into either TH1 or TH2 cells, with IFN-
and IL-12 favouring the development of TH1 and IL-4 and IL-
10 favouring the development of TH2.

TH1 cells secrete IFN-, whereas TH2 cells secrete IL-4,
although both secrete several other cytokines (IL-3, GM-
CSF, TNF-) equally well.

TH1 favours the promotion of cellular immunity, whereas
TH2 favours the promotion of humoral immunity.
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Immunology


T HELPER SUBSETS




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Immunology


T CELL SURFACE MARKERS
CD2 which serve as receptor for sheep red blood
   corpuscles, mixing T lymphocytes with sheep RBCs
   results in formation of a rosette.
CD3 a hetropolymer that consists from 5 polypeptides, CD3
   play no role in antigen recognition but it involves in
   intracellular signalling to initiate a series of intracellular
   reaction.
CD5 present on all T lymphocytes and some B
   lymphocytes.


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Immunology


T CELL SURFACE MARKERS conti.
T lymphocytes that carry CD4 molecules called CD4+ or TH
    (helper).
T lymphocytes that carry CD8 molecules called CD8+ or TC
    (cytotoxic).
CD28, a receptor for the co-stimulatory B7 family of
    molecules present on B cells and other antigen
    presenting cells is present on mature T cells.
CD45, a signal-transduction molecule present on mature T
    cells.

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Immunology


T CELL SURFACE MARKERS conti.
T cell Receptor (TCR), these are antigen recognizing
molecules on T lymphocytes, each TCR is a heterodimer
that consist from two non identical polypeptides.

Two types of TCRs are exist; TCR which compose from 
chain and it is present in 5% of T lymphocytes and TCR
which compose from  chain and present in 95% of T
lymphocytes.

TCRs are associated with CD3 so there is either CD3/
or CD3/.
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  Immunology


  T CELL SURFACE MARKERS conti.




Development of αβ and γδ T cells from
lymphocyte stem cells (LSC). Two types
of T cells are produced in the thymus with
different TCRs (αβ and γδ). The classical
T cells (Th and Tc) utilize αβ for their TCR.


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Immunology


T CELL FUNCTIONS
T lymphocytes can recognize antigens through their
TCR/CD3 complex and this recognition is achieved in
CD4+ cells when the antigen is recognized in
association with class II MHC while CD8+ cells can
recognize antigen in association with class I MHC.


CD4+ can help both B cells and CD8+ cells in immune
response, it may also perform cytotoxicity while CD8+
cells perform cytotoxicity against virally infected cells,
tumour and allograft cells .
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Immunology


T CELL FUNCTIONS conti.
Activation of TH cells leads to production of cytokines like:
    IL-2 (Interleukin 2), serves as independent
        polyclonal proliferation factor for other T cells, TC/S
    and NK cells.
    IL-4, augments B cells and induce expression of Fc
        receptors on B cells.
    IL-3, -5, -10 and -12.
    GM-CSF.
     IFN (Gamma interferon).
    TNF (Tumour necrosis factor).
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Immunology


B LYMPHOCYTES or B CELLS
B lymphocytes arise from stem cells that migrate to
foetal liver and latter to bone marrow where there is
gene rearrangement and establishment of B cells
specific antigen receptors (mIg) and expression of
several markers.

B lymphocytes after were called after the Bursa of
Fabricious which is a lymphoepithelial organ near
the cloaca of birds.


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Immunology


B LYMPHOCYTES or B CELLS
 B lymphocytes accounts for :

  5-10% of blood lymphocytes
  Less than 15% of thymus lymphocytes
  10-20% of lymph node lymphocytes
  40-50% of spleen lymphocytes




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Immunology


B CELL SURFACE MARKERS
Membrane-bund Immunoglobulins (mIg), these are
monomeric surface IgM, IgD and to less extend surface IgG,
IgA or IgE, the mIg serve as antigen receptors (like TCR on
T lymphocytes), mIg can be detected by using fluorescent
labelled anti-human Immunoglobulin.

CD32, receptors for Fc portion of Immunoglobulin.

CD19, CD20

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Immunology


B CELL SURFACE MARKERS conti.
 CD5, present on some B lymphocytes (in some
 autoimmune disorders)

 CD35 which is a complement receptor (CR1) for C3b

 CD21 which is a complement receptor (CR2) for C3d
 and EB virus
 CD40
 Receptor for transferrin
 Class II MHC
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Immunology


B CELL FUNCTIONS
   Activation of these cells by specific antigen is
   achieved when the antigen binds to the mIg of B cells,
   this process may be helped by T cells or not, activation
   results in several intracellular chemical reactions and
   results in clonal expansion of B cells and development
   of either long lived memory cells or plasma cells.

   Some B lymphocytes may serve as antigen
   presenting cells APCs so they present antigens to T
   cells.

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Immunology




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Immunology


             PLASMA CELLS

 Cells that arise from B lymphocytes, they have an
 eccentric nucleus with large amount of basophilic
 cytoplasm (RNA).

 Each plasma cell produce and secrets one type of
 Immunoglobulin so plasma cells are antibody producing
 and secreting cells.


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Immunology


CHARACTERISTICS OF HUMAN B AND T CELLS




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Immunology


NATURAL KILLER CELLS or NK CELLS
These cells lack antigen receptors (TCR or mIg) so
different from both T and B cells.

Most NK cells appears as Large Granular
Lymphocytes (LGLs) or third population cells (TPCs),
they are larger than other lymphocytes.




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Immunology


NATURAL KILLER CELLS or NK CELLS
NK cytoplasm contain azurophilic granules and
eosinophic granules that stains for acid hydrolase.
Morphology and surface marker of NK cells are
intermediate between lymphocytes and monocytes
and they account for 10-15 % of total blood
lymphocytes or 1-2% of spleen lymphocytes.

Morphology and surface marker of NK cells are
intermediate between lymphocytes and monocytes
and they account for 10-15 % of total blood
lymphocytes or 1-2% of spleen lymphocytes.
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Immunology


NK CELL SURFACE MARKERS
CD2

CD3 (CD3ζ) is present in minority of NK cells

CD16 (Hum Fc R III) for IgG1 and IgG 3, present in
majority of NK cells

CD11b (CR3), CD11c (CR4)

CD56 adhesion molecule

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Immunology


NK CELL FUNCTIONS

NK cells are MHC-non restricted killer cells; they do
not require sensitization (previous exposure )to
express their killer functions

As these cells have no specific receptors so they act
as non specific cytotoxic cells (natural), they are
specialized in killing virally infected cells, they have
long been thought to be important in tumor surveillance
because they can kill some tumor cells as most tumors
lack MHC expression.
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Immunology


NK CELL FUNCTIONS conti.

NK cells can kill also through ADCC (Antibody Dependant
Cell Cytotoxicity) when they carry cytotoxicity on antibody
coated cells.

Production of cytokines such as IL-2, TNF-, IFN- and
GM-CSF. By secreting IFN-, NK cells can influence the
adaptive immune system by favouring the differentiation
of TH1 and inhibiting the differentiation of TH2.


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Immunology


MONOCYTE MACROPHAGE SYSTEM CELLS
 Steam cells that pass to bone marrow and under the
 effect of IL-3, GM-CSF and M-CSF develop to
 monocytes and latter differentiates to different
 macrophages. The series involve many cells:

 In Bone marrow monoblast, promonocyte and
 monocyte

 In blood, monocytes are present; they circulate for few
 days then migrate to tissues.
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Immunology


MONOCYTE MACROPHAGE SYSTEM CELLS
 In Tissue monocytes differentiate in to resident
 macrophages staying in tissues:

     Histiocytes… Connective tissue
     Histiocytes, Langerhans‘….skin
     Kupffer cells…..liver
     Alveolar and tissue macrophages…. lungs




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Immunology


MONOCYTE MACROPHAGE SYSTEM CELLS
  Microglial cells, CSF macrophages..CNS
  Red pulp macrophages…spleen
  Free or fixed macrophages, Interdigitating cells
 ...lymph nodes
  Oseoclast….bone
  Mesangial cells….kidney
  Macrophages….bone marrow, MALT, thymus, and
 endocrine glands



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Immunology


MONOCYTE MACROPHAGE SYSTEM CELLS




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Immunology


MONOCYTE MACROPHAGE SURFACE MARKER
 Class II HLA (HLA - DR, -DP, and -DQ)
 Complement receptors for C3: CR1 (CD 35),
CR3 (CD11 b), CR4 (CD 11C)
 Fc receptors like Hum Fc RI(CD 64), HuFc  RII
(CD32)
 Monocyte specific antigen CD14
 CD4 is present on monocytes
 On macrophages HumFc RIII (CD 16) are
present


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Immunology


MONOCYTE MACROPHAGE FUNCTIONS
 Phagocytosis both by non specific mechanisms or
 specific mechanisms (immune). They can ingest
 many microorganisms and digest them through
 oxygen independent mechanisms or oxygen
 dependent intracellular killing.


 These cells can act as APCs as they are rich in class
 II MHC.


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Immunology


MONOCYTE MACROPHAGE FUNCTIONS
 Cytokine production, several cytokines including
 like IL-1 (play role in the activation of T cells) and
 TNF.


 These cells can respond to certain molecules such as
 C5a, they are attracted toward C5a molecule, this
 phenomena is called chemotaxis.



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Immunology


ANTIGEN PRESENTING CELLS.. APCs

Functional group rather than morphological group

Cells that can process a proteinous antigens by
fragmenting them into peptides and present some of the
peptides on their surface in conjugation with class II
MHC (HLA) for interaction with proper TCR, so antigen
presenting cells is rather a function of certain cells that
can be called APCs


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 Immunology


ANTIGEN PRESENTING CELLS



Electron micrograph of an APC
(macrophage) associating with
a T lymphocyte




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Immunology


ANTIGEN PRESENTING CELLS




                  DCs development and scanning
                  Electron Micrograph.

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Immunology

 CELLS INVOLVED IN INFLAMMATORY
    PHASE OF IMMUNE RESPONSE
Cells involved in the inflammatory phase of
immune response include:

Neutrophils
Basophils
Eosinophils
Mast cells
Endothelial cells
Platelets ?

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Immunology


             NEUTROPHILS or (PMN)




90% of circulating granulocytes
10-15µm in diameter
Segmented or multi-lobed nucleus
Cytoplasmic granules (lysosomes)


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Immunology


             NEUTROPHIL or (PMN)
 Granules in PMN include:

 Primary (azurophilic) granules form 33% of the
 granules, these granules contains hydrolytic
 enzymes, myeloperoxidase and muramidaze
 (lysozyme).

 Secondary (specific) granules form 67% of the
 granules, they contain lactoferrine, lysozyme and
 alkaline phosphatase.

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Immunology


     NEUTROPHIL SURFACE MARKERS

 CD16 (low affinity Hum Fc  RIII)
 CD35 (CR1) and CD11 b (CR3)
 Receptors for C5a, which are responsible for chemotaxis
 CD11a; used for adherence to the endothelium
 Receptors for C3a, LT-B4, GM-CSF and G-CSF




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Immunology


          NEUTROPHIL FUNCTIIONS

Active phagocytic cells that maintain normal host
defense against microorganisms (non specific
mechanism).

Neutrophil adhere and move alone the endothelium
(pavement) and they pass between endothelial
cells of capillaries (diapedesis) and moves to
tissues attracted by C5a, endotoxin, leukotrienes
B4 and N-formylmethinoine.

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Immunology


       NEUTROPHIL FUNCTIIONS conti.

At the site of infection or inflammation neutrophils
engulf microorganisms non specifically or
specifically (microorganisms coated with
antibodies (IgG) or complement protein (C3b) in to
a phagosome, lysosomes then fuse with the
phagosome forming phagolysosome and later
intracellular digestion of the ingested materials will
take place by different mechanisms



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  Immunology


                      EOSINOPHIL




1-3% of blood leukocytes

2-17µm in diameter bilobed nucleus
Cytoplasm contain huge numbers of
specific granules that contain
preoxidase and three basic proteins
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Immunology


      EOSINOPHIL SURFACE MARKER
   Low affinity IgE receptors (Fc RII)
   IgG receptors
   Complement receptors (CR1, CR3 and
  C5a) in some cells




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Immunology


           EOSINOPHIL FUNCTIONS
 Stimulation of eosinophil leads to fusion of their
 cytoplasmic granules with the cell membrane
 and releasing the granule contents outside the
 cell (degranulation) so these cells can use their
 granules against larger organisms (helminthes)
 which can’t be phagocytosed.




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Immunology


        EOSINOPHIL FUNCTIONS conti.
 Eosinophil have role in some inflammatory
 reactions like allergy. The major basic proteins
 when liberated are toxic for respiratory epithelium.

 They also secret histaminase, arylsulfate, slow
 reactive substances of anaphylaxis which may
 damp the inflammatory process.

 They engulf bacteria, fungi, mycoplasma and inert
 particles in vitro.

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Immunology


                     BASOPHIL
Smallest blood granulocytes
5-7 µm un diameter
Bilobed nucleus

Cytoplasmic glycogen that
appear as electron dense
aggregate




                                65
Immunology


                      BASOPHIL

  On their surface high affinity Fc RI, Hum Fc RIII
  (CD16) and complement receptors for C5a, C3a are
  present.

  Basophils are found in variety of inflammatory
  diseases but their role in immunity and
  hypersensitivity are uncertain although their granules
  contain histamine.


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Immunology


                   MAST CELLS
 Tissue cells that occurs predominantly in skin, lungs,
 gastrointestinal and nasal mucosa.

 They are 10-15µm in diameter with eccentric nucleus
 rounded or oval in shape.

 Two types of mast cells are exist according to the
 content of their granules these are T mast cell
 (Tryptase) and TC mast cell (Tryptase and Chymase).


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Immunology


                  MAST CELLS
 The surface makers of mast cell are Fc RI, CD16,
 C5a receptor, CR1 and CR3

 Mast cells play prominent role in IgE mediated
 inflammation and their granules contain histamine,
 and heparin which cause smooth muscle contraction,
 increasing vascular permeability and mucous
 secretion.



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Immunology


                     PLATELETS
Circulating bodies, they are of 2µm in diameter, have
role in blood clotting.

They are involved in inflammatory phase of immune
response, they express class I HLA, Fc RII and low
affinity Fc RII.

Activation leads to changes in their morphology,
aggregation and generation of arachidonic acid
metabolites (PG- G2, PG- H2-thromboxane A2) and
secretion of their granules.
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Immunology


                  ENDOTHEILUM
 Endothelial cells have receptors for many cytokines
 and when they are activated by inflammatory
 cytokines (IL-1, TNF) they become more adhesive
 to inflammatory cells (monocytes, neutrophils.

 This is important in migration of these inflammatory
 cells to inflammatory sites, endothelial cells can also
 secrets cytokines such as IL-1 and GM-CSF.



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Immunology




       You've broken down my immune system
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