Pharmacodynamics

1. Cells & Tissues of the Immune
System

2. Introduction
• The cells, tissues and organs of the immune system
are found throughout the body carrying out specific
functions.
• Organs are grouped into two groups being primary
and secondary lymphoid organs.
• Cells are carried within the blood and the lymph and
populate lymphoid organs.
• These cells are the white blood cells and are
referred to as leukocytes.
• The blood and lymph are the important body fluids
that connect the cells, tissues and organs of the
immune system.

3. BLOOD:
• Flows in the circulatory system of the body.
• In mammals, the functions of blood can be
divided into two:
- Transport functions: mainly connected with the
supply of food materials and oxygen and the
removal of waste products from body cells.
In terms of immune transport importance it is
involved in transporting various protein
molecules secreted by immune cells such as
cytokines and chemokines that can then be
collected in serum.

4. It is also involved in transporting cells as some of
these are found circulating through the blood.
- Homeostatic functions: these include
haemotopoiesis, the regulation of tissue fluid,
pH, distribution of heat and defence against
disease and repair of damaged tissues (wound
healing and repair).
LYMPH:
• Antigens are transported to lymph nodes mainly
in lymphatic vessels
• Lymph is fluid absorbed and drained from spaces
between tissue cells (made of plasma filtrate)

5. • Lymph flows through lymphatic capillaries into
larger lymphatic vessels which merge into
afferent lymph vessels that drain into the
subcapsular sinuses of lymph nodes
• The lymphatic system functions to collect
antigens from various portals of entry and
delivering them to lymph nodes
• Microbes enter through the skin and mucous
membranes which are lined by epithelia that
contain dendritic cells (DCs) and are all drained
by lymphatic vessels

6. • DCs capture antigens and enter lymphatic migrate
vessels whilst other antigens enter the lymphatics
in free-form, soluble inflammatory mediators
such as chemokines also enter the lymphatics
• All these are delivered to the draining lymph
nodes

7. Whole Blood
Plasma (55%) Cellular Components (45%)
Plasma Proteins Serum RBCs Leukocytes Platelets
Albumin Globulins Fibrinogen Granular Agranular
Immunoglobulins Neutrophils Monocytes
(Antibodies) Eosinophils Lymphocytes
Basophils

8. • Blood does not normally clot in intact blood vessels
due to the action of a number of anticoagulants such
as heparin which circulate in the blood stream.
• Intact endothelium (inner lining of blood vessels)
also produce molecules which inhibit clotting.
• Blood clots quickly when exposed to air due to the
absence of an endothelium and a lack of
anticoagulants.
• Thus in clinical diagnosis and research,
anticoagulants such as
EDTA(Ethylenediaminetetraacetic) are used to
prevent clotting of blood in studies that require the
use of non-clotted blood e.g. when looking at
immune cells such as peripheral blood mononuclear
cells (PBMCs).

9. • For instance, if a sample of blood treated with an
anticoagulant is placed in a test tube and allowed
to stand, it separates into plasma and formed
elements.
• Formed elements, comprise of cellular
components, settle to the bottom leaving a layer
of plasma.
• Serum is obtained when blood is left to clot that
is not treated with anticoagulants.
• When blood cells die, the release all their
granular contents and hence it is important to
analyse blood samples as soon as possible in
terms of serum content

10. Haematopoiesis
• All blood cells arise from a common type of cell
referred to as a hematopoietic stem cell (HSC).
• Stem cells are cells that are able to differentiate
into other cell types.
• These cells are self-renewing and maintain their
population levels by cell division.
• In humans haematopoiesis refers to the
formation and development of blood cells
including red and white blood cells and begins in
the embryonic yolk sac during the first weeks of
development.

11. • Yolk sac stem cells differentiate into primitive
erythroid cells that contain embryonic
haemoglobin.
• By the third month of gestation, haematopoietic
stem cells have migrated from the yolk sac to the
fetal liver and then colonise the spleen.
• The liver and spleen have major roles in
haematopoiesis from the third to the seventh
months of gestation.
• After this, the differentiation of HSCs takes place
in the bone marrow and this becomes the major
site such that by birth little or no haematopoiesis
takes place in either liver or spleen.

12. • In haematopoiesis, a multipotent stem cell
differentiates along one of two pathways giving
rise to either a lymphoid or myeloid progenitor
cell.
• Progenitor cells have lost the capacity for self-
renewal and are committed to a particular cell
lineage.
• Lymphoid progenitor cells give rise to B, T, NK
and NKT cells whilst myeloid progenitor cells
generate red blood cells, leukocytes and platelet-
generating cells termed megakaryocytes.

13. • In the bone marrow, haematopoietic cells and
their progeny grow, differentiate and mature on a
mesh framework of stromal cells that include fat
cells, endothelial cells, fibroblasts and
macrophages.
• These stromal cells are able to influence the
differentiation of HSCs by providing the right
microenvironment referred to as a
haematopoietic-inducing microenvironment
consisting of a cellular matrix and factors that
promote growth and differentiation.

14. • Some of these growth factors are soluble agents
that arrive at their target cells by diffusion
whereas some are membrane-bound molecules
on the surface of stromal cells that require a cell-
to-cell contact between the responding cells and
the stromal cells.
• Examples of growth factors include the cytokines
Interleukin (IL)-3 and Granulocyte macrophage-
colony stimulating factor (GM-CSF) which gives
rise to a myeloid progenitor cell.
• During infection, haematopoiesis can be induced
to give rise to an increased number in particular
cell populations.

16. Homeostatic Haematopoiesis
• Haematopoiesis is a steady-state process in which
mature blood cells are produced at the same rate as
they are lost with the principal reason for loss being
due to aging.
• The average erythrocyte has a life span of 120days
before it is phagocytosed and digested by
macrophages in the spleen.
• Neutrophils on the other hand have a life span of
about a day (24hours) whilst memory T or B cells
can circulate for as longs as 20-30years.
• On average a normal human being produces about
3.7X1011 leukocytes a day and this is highly
regulated by complex mechanisms that affect all the
different individual cell types.

17. • Ultimately the number of cells in a
haematopoietic lineage is a tight balance
between the number of cells removed by cell
death and the number that arise from division
and differentiation.
• Hence it is a highly regulated system involving a
combination of regulatory factors which can
affect rates of cell reproduction and
differentiation.
• The homeostatic mechanisms of haematopoiesis
include programmed cell death.

18. Proliferation & Differentiation
• When a TCR or BCR interact with their potential
antigen, they are activated and undergo the cell
cycle
• The y produce clones that have the same TCR or
BCR as the one that responded to the antigen
• They also differentiate into different cell types.
• For the B cell, it differentiates into a plasma cell
that will continuously produce antibodies and
memory B cell that will respond to a second
encounter with the eliciting antigen
• For the T cell, it differentiates into effector T cells
and memory T cells

20. • Cell cycle promotes growth of cell populations
and is the interval between each cell division and
is the process of cell growth and division.
• When a cell is proliferating it begins by entering
the cell cycle which produces 2 cells and the
numbers of cell divisions or end products formed
depends on the strength of the signal that
stimulated the proliferation in the first place.
• For CD8+ T cells the effector T cell will effect it
cytotoxic effects on target cells whilst the CD4+ T
cell will produce the appropriate cytokines that
will bring about the activation and effector
functions of other cell types

21. Cell Proliferation
• This refers to the process by which cells divide and
reproduce and in normal tissue this is regulated so
that the numbers of cells are kept in balance.
• In terms of cell proliferation, the different cell types
of the body can be divided into 3 categories:
• Terminally differentiated cells: these include cells
such as the neuron and cells of the skeletal and
cardiac muscle that are unable to divide and
reproduce.
• Partially differentiated cells: these continue to divide
and reproduce such as blood cells, skin cells and liver
cells.

22. • Undifferentiated cells: these can be triggered
to enter the cell cycle and produce large
numbers of parent cells when the need arises.
• The rate of proliferation of these cells varies
greatly.
• For instance leukocytes and cells of the
gastrointestinal tract lining must be replaced
constantly.
• In most tissues, the rate of proliferation is
greatly increased when tissue is injured or
lost.

23. Cell Differentiation
• This refers to the process of specialisation whereby
new cells develop the structure and function of the
cell they replace.
• So it is a process where proliferating cells are
transformed into different and more specialised cell
types.
• This process leads to a fully or well differentiated
adult cell that has achieved its specific set of
structural, functional and life expectancy
characteristics.
• Cell differentiation is thus a process that is controlled
by a system that switches particular genes on and off
and involves the formation of different types of cells
and the deposition of these cells into particular
tissues.

24. • The size of cell populations is regulated by a
balance of cellular signals that stimulate or
inhibit proliferation and differentiation.
• Cell growth involves both cell proliferation
and differentiation.
• Proliferation on the one hand is an inherent
mechanism for replacing body cells when
old cells die or additional cells are needed
whilst differentiation on the other hand
involves specialisation whereby cells
develop the structure and function of the
cells they replace.

26. Lymphoid Cell Types
1. B cells
• Produce antibodies and express
immunoglobulin as an antigen-specific receptor
as well as MHC and CD19
• They have a large nucleus surrounded by a
small rim of cytoplasm
• Also function as antigen presenting cells and
combat extracellular infections by the
production of antibodies
• Stimulated by antigen to form plasma cells
whose primary function is to produce Abs

28. 2. T cells
• These resemble unstimulated B cells
morphologically and can be stimulated by
antigen to become lymphoblasts with more
cytoplasm and organelles
• T cells consist of 2 major subsets: CD4+ helper T
cells and CD8+ cytotoxic T cells
• CD8+ T cells also bear a TCR and are they major
source of antigen-specific protection against
viral infections and intracellular infections

30. CD4+ T Cells
• Th1 T-bet+: produce IFNg and other pro-
inflammatory
• Th2 GATA-3+ : predominate subset during a
helminth infection and produce IL-4, IL-5, Il-10,
IL-13 cytokines amongst others and also
promote the production of IgE by B cells.
• Th17 RORgt+: produce IL-17, IL-22 and IL-23 and
are involved in inflammation
• Tregs FOXP3+: produce IL-10, TGFb and are
responsible for the regulation on an immune
response

32. T cell Education/Priming
• T cells develop in the thymus and enter circulation
to various sites in various peripheral lymphoid
organs
• Migrate through lymphoid tissue via the
lymphatics and re-enter into the circulation to
effector sites
• The characteristics of these circulating T cells is
that they are mature, have undergone various
gene rearrangements to form a functioning TCR in
the thymus, but have not yet encountered antigen
and are thus referred to as being naive

33. • Naïve T cells must encounter specific antigen
for them to participate in an immune response
• Once they encounter the antigen:MHC complex
on an APC, they are activated, proliferate and
differentiate into effector and memory T cells –
primary cell-mediated response
• Effector T cells respond rapidly to enable
remove of the eliciting antigen and act only on
target cells that exhibit that particular antigen
• Memory T cells enable a fast recall response
and remain circulating for a second encounter
with their specific antigen

35. 3. Natural Killer Cells (NK cells)
• These cells do not have clonally distributed
antigen-specific receptors
• They part of the innate immune system and lyse
certain virally infected cells and some tumour
cells
• They carry KIR receptors that are specific for
molecules expressed on infected cells or cells
altered in other ways e.g. expressing tumour-
specific antigens

36. 4. Natural Killer T cells
• These are a small population of lymphocytes
that share characteristics of both NK and T cells
• They express αβ antigen receptors (TCR) that
are encoded by somatically recombined genes
but lack diversity
5. γδ T cells
• Express a similar but structurally distinct type of
TCR
6. B-1 B cells
• These lack diversity in their BCR

37. Myeloid Cell Types
1. Neutrophils
• These exhibit phagocytic and cytotoxic activities
and are the first cell type that migrates to the
site of infection and inflammation in response
to chemotactic factors
• They contain primary and secondary granules
which are loaded with lysosomal enzymes,
lysozyme and collagenase etc
• They are referred to as polymorphonuclear
neutrophils (PMNs) as they have nuclei with 2-5
lobes

38. • Their major role is the first line of defence against
bacterial infections
2. Eosinophils
• These are characterised by a nucleus with 2 or 3
lobes
• They have large specific granules which contain
heparin as well as peroxidase and other
hydrolytic enzymes
• They have phagocytic and cytotoxic activity and
express Fc receptors
• These cells function to combat certain parasitic
infections particularly worms

40. 3. Mast Cells
• Mature mast cells have large granules that
contain heparin and histamine but do not contai
hydrolytic enzymes
• They express Fc receptors and have important
roles in allergic responses: activated via IgE
specific Fc receptors to release the granule
contents
4. Monocytes/Macrophages
• Monocytes are the largest blood cells and
contain many granules and have a lobular-
shaped nucleus

41. • Monocytes phagocytose, have bacteriocidal
activity and can carry out antibody-mediated
cell-mediated cytotoxicity (ADCC)
• Monocytes migrate out of the blood into the
tisssues and become tissue macrophages:
Intestinal macrophages; Alveolar macrophages;
Histiocytes; Kupfer cells; Mesengial cells;
Microglial cells; Osteoclasts
• Express CD14 as their designated marker protein
• Macrophages have a central role in the antigen
processing and presentation

43. 4. Dendritic Cells
• These are irregularly shaped with many
branchlike extentions
• They are motile in blood and lymph and in most
organs
• There are a variety of DCs which are critical in
antigen-capture and uptake in peripheral tissues
• In the presence of infection and under the
influence of cytokines, they mature and migrate
to lymphoid organs where they present antigen,
activate T cells and help develop a protective
adaptive immune response

45. Organs & Tissues
• Organs and tissues of the immune system are
divided into 2 subsets:
- Primary lymphoid organs: where lymphocytes
develop and are produced
- Secondary lymphoid organs: where antigen
presentation takes place, clonal expansion and
maturation of effector cells
• In embryonic human the primary lymphoid
organs are initially the yolk sac, then the fetal
liver and spleen and finally the bone marrow and
thymus

46. • In adult humans the bone marrow and thymus are
the primary lymphoid organs
• Human secondary lymphoid organs are
considered to be the spleen, lymph nodes and
mucosa-associated lymphoid tissue (MALT) lining
the GIT, RT and URT.
• The skin is also considered a secondary lympoid
organ (cutaneous immune system)
• Lymphocytes are dispersed to almost all tissue
sites however, some sites are immunologically
privileged e.g. eyes, testis and brain