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Clinical Immunology & Serology
A Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis CompanyCopyright © 2010 F.A. Davis Company
The Lymphoid System
Chapter Two

Copyright © 2010 F.A. Davis Company
The Lymphoid System
 Lymphocytes represent between 20 and 40
percent of the circulating white blood cells.
 The typical small lymphocyte is between 7 and
10 μm in diameter with a rounded nucleus that
may be somewhat indented.
 The nuclear chromatin is dense and tends to
stain purple.

The Lymphoid System
 The lymphocyte’s cytoplasm is sparse,
contains few organelles with no specific
granules, and stains a lighter blue.
 Lymphocytes rise from a hematopoietic stem
cell in the bone marrow and then are further
differentiated in the primary lymphoid organs.
 The primary lymphoid organs in humans are
the bone marrow and the thymus.

The Lymphoid System
 The secondary organs in the lymphoid
system include the spleen, lymph nodes,
appendix, tonsils, and other mucosal-
associated lymphoid tissue (MALT).
 It is in the secondary organs that the main
contact with foreign antigens takes place.
 The spleen serves as a filtering mechanism
for removing antigens from the bloodstream.

The Lymphoid System
 The lymph nodes filter interstitial fluid from
the tissues.
 Mucosal surfaces in the respiratory and
alimentary tracts are backed with lymphoid
tissue as an additional means of contacting
foreign antigens as they enter the body.
 Circulation of the lymphatic fluid is complex
and promoted by skeletal and smooth muscle
contractions.

The Lymphoid System
 T lymphocytes are effector cells that serve a
regulatory role.
 B lymphocytes produce antibodies.
 Both T and B lymphocytes recirculate
continuously from the bloodstream to the
secondary lymphoid organs and back, to
increase contact with foreign antigens.

The Lymphoid System
 A third type of lymphocyte, the NK cell, is
large, somewhat granular, and plays a role as
a surveillance cell in both the innate and
adaptive immune response.

The Lymphoid System
 T, B, and NK cells arise from a
common precursor known as the
common lymphoid precursor
(CLP) (see Fig. 2-2).
 Lymphocyte precursors:
lymphoblast, prolymphocyte
 The bone marrow functions as
the center for antigen-
independent lymphopoiesis.

The Lymphoid System
 Following release from the marrow,
lymphocyte precursors are further developed
in the primary lymphoid organs.
 One subset goes to the thymus and develops
into T cells.
 B-cell maturation takes place within the bone
marrow itself.

The Lymphoid System
 In the peripheral blood, approximately 10–20
percent of all lymphocytes are B cells, 61–89
percent are T cells, and up to 22 percent are
NK cells.20%

The Lymphoid System
 T cells develop their
identifying
characteristics in the
thymus (see Fig. 2-3).
 Surface markers (CD
markers) are acquired as
the lymphocytes travel
from the cortex to the
medulla in the thymus
over a period of 2–3
weeks.
 Mature T lymphocytes
are then released from
the medulla.

The Lymphoid System
 Once differentiation occurs, mature T and B
lymphocytes are released from the bone
marrow and the thymus. They migrate to
secondary lymphoid organs and become part
of a recirculating pool.

The Lymphoid System
 The secondary lymphoid
organs include the spleen,
lymph nodes, tonsils,
appendix, Peyer’s patches
in the intestines, and other
mucosal-associated
lymphoid tissue (MALT; see
Fig. 2-3).
 Lymphocytes in these
organs travel through the
tissue via the lymphatic
vessels and return to the
bloodstream by way of the
thoracic duct.

The Lymphoid System
 When lymphopoiesis, or reproduction of
lymphocytes, occurs in the secondary tissue, it
is strictly dependent on antigenic
stimulation.specifically by MHC
 Formation of lymphocytes in the
bone marrow is antigen independent.

The Lymphoid System
 Most naïve or resting lymphocytes die within a
few days after leaving the primary lymphoid
organs unless activated by the presence of a
foreign antigen.
 Lymphopoiesis following antigenic stimulation
gives rise to long-lived memory cells and
shorter-lived effector cells that are
responsible for the generation of the immune
response.plasma cell

The Lymphoid System
 The spleen is the largest secondary lymphoid
organ.
 The red pulp makes up more than one-half
of the total splenic volume; its function is to
destroy old red blood cells and constantly
search for infectious agents or other foreign
matter.

The Lymphoid System
 Lymph nodes are located along lymphatic
vessels and serve as central collecting points
for lymph fluid from adjacent tissues.
 Lymph fluid arises from passage of fluids and
low-molecular-weight solutes out of blood
vessel walls and into the interstitial spaces.
 Lymph nodes are especially numerous near
joints and where the arms and legs join the
body (axillary and inguinal nodes)

The Lymphoid System
 Filtration is a main function
of the lymph nodes.
 The lymph nodes contain
sinuses, which are lined
with macrophages,
creating an ideal location
for phagocytosis to take
place.
 The tissue is organized
into an outer cortex, a
paracortex, and an inner
medulla (see Fig. 2-5).

The Lymphoid System
 The outermost layer, the cortex, contains
macrophages and aggregations of B cells in
primary follicles similar to those found in the
spleen.
 These B lymphocytes are mature, resting B
cells that have not yet been exposed to
antigen.

The Lymphoid System
 Secondary follicles consist of antigen-
stimulated proliferating B cells.
 The interior of a secondary follicle is known as
the germinal center, where blast
transformation of B cells takes place.
 Blastogenesis is triggered by IL-2, secreted by
T helper cells.

The Lymphoid System
 Plasma cells, which actively secrete
antibody, and B memory cells, carrying
membrane-bound antibody, are present in
the germinal center.

The Lymphoid System
 Particulate antigens are removed by
macrophages, processed, and presented to
the lymphocytes as the fluid travels across the
lymph node from cortex to medulla.
 Fluid and lymphocytes exit by way of the
efferent lymph vessels.
 These eventually connect with the thoracic
duct and the venous system.

The Lymphoid System
 Additional areas of lymphoid tissue include
the MALT, tonsils, appendix, and cutaneous-
associated lymphoid tissue.
 MALT(mucosal-associated lymphoid
tissue) is found in the gastrointestinal,
respiratory, and urogenital tracts.
 Peyer’s patches represent a specialized type
of MALT and are located at the lower ileum of
the intestinal tract.

The Lymphoid System
 The tonsils are another area of lymphoid
tissue found in the mucous membrane lining of
the oral and pharyngeal cavities.
 An additional location of lymphoid tissue is the
appendix at the juncture of the small and
large intestines.

The Lymphoid System
 Within each of these secondary organs, T and
B cells are segregated.
 B cells differentiate into memory cells and
plasma cells and are responsible for humoral
immunity or antibody formation.
 T cells play a role in cell-mediated immunity
and produce sensitized lymphocytes that
secrete cytokines.

The Lymphoid System
 B cells are derived from a multipotential
progenitor cell (stem cell) , a lymphoid-myeloid
precursor that differentiates to become either a
common myeloid progenitor or an early
lymphocyte progenitor.

The Lymphoid System
 Early lymphocyte progenitors become T-cell,
B-cell, NK-cell, or dendritic cell precursors
depending on exposure to different cytokines
(see Fig. 2-6).

The Lymphoid System
 The earliest B-cell precursor can be
recognized by the presence of a surface
molecule called CD45R (common to all wbcs).
 B-cell precursors go through a developmental
process that prepares them for their role in
antibody production and restricts the types of
antigens to which the cell can respond.
 This part of B-cell development is known as
the antigen-independent phase.

The Lymphoid System
 Under the influence of growth factors and
cytokines, rearrangement of genes occurs that
will code for the heavy and light chains of an
antibody molecule.
 At this stage the cell is called a pro-B cell.

The Lymphoid System
 The pro-B cell has distinctive markers that
include surface antigens CD19, CD45R,
CD43, CD24, and c-Kit. Intracellular proteins
at this stage include TdT, necessary for gene
rearrangement (marker of immature cells).
 Differentiation of pro-B cells into pre-B cells
occurs upon successful rearrangement of
heavy-chain genes.

The Lymphoid System
 When synthesis of the heavy chain part of the
antibody molecule occurs, the pre-B stage
begins.
 Pre-B cells lose the CD43 marker as well as c-
Kit and TdT.
 Mu (μ) chains accumulate in the cytoplasm.

The Lymphoid System
 It appears that only pre-B cells expressing the
μ heavy chains in association with surrogate
light chains survive and proceed to further
differentiation.
 Although these cells have complete IgM
molecules on the cell surface, they are still
immature.

The Lymphoid System
 Other surface proteins that appear on the
immature B cell include CD21, CD40, and
major histocompatibility complex (MHC) class
II molecules.

The Lymphoid System
 CD21 acts a receptor for a breakdown product
of the complement component C3, known as
C3d.
 This enhances the likelihood of contact
between B cells and antigen, because antigen
frequently becomes coated with complement
fragments during the immune response.

The Lymphoid System
 CD40 and MHC class II are important for
interaction of B cells with T cells.
 Self-reactive B cells are deleted from the
marrow by the process of programmed cell
death, or apoptosis.
 Immature B cells leave the bone marrow and
proceed to seed the spleen and other
secondary lymphoid organs.

The Lymphoid System
 In the spleen, immature B cells develop into mature B-
cells
 These B cells remain in the spleen to respond quickly to
any bloodborne pathogens they may come into contact
with.
 Other immature B cells become follicular B cells, which
are found in lymph nodes and other secondary organs.
 The end result is a B lymphocyte programmed to produce
a unique antibody molecule, consisting of two identical
light chains and two identical heavy chains.

The Lymphoid System
 In addition to IgM, all
mature B cells exhibit IgD,
another class of antibody
molecule, on their surface
(see Fig. 2-6D).IgD may
prolong the life span of
mature B cells in the
periphery, and regulates
isotype switching.
 Unless contact with antigen
occurs, the life span of a
mature B cell is typically
only a few days.

The Lymphoid System
 If a B cell is stimulated by antigen, it
undergoes transformation to a blast stage,
which eventually forms memory cells and
antibody-secreting plasma cells.
 This process is known as the antigen-
dependent phase of B-cell development.
 These B cells have a half-life of more than 6
weeks.

The Lymphoid System
 Antigen-dependent activation of B cells takes
place in the primary follicles of peripheral
lymphoid tissue.
 Activated B cells exhibit identifying markers,
including CD25, which is found on both
activated T and B cells and acts as a receptor
for interleukin- 2 (IL-2), a growth factor
produced by T cells.

The Lymphoid System
 Plasma cells are
spherical or ellipsoidal
cells between 10 and
20 μm in size with an
eccentric nucleus and
abundant deep blue
cytoplasm containing
immunoglobulin and
little to no surface
immunoglobulin (see
Fig. 2-8).

The Lymphoid System
 Plasma cells are not normally found in the
blood but are located in germinal centers in
the peripheral lymphoid organs.
 Plasma cells are nondividing, and after several
days of antibody production, they die without
further proliferation.

The Lymphoid System
 Memory cells (see Fig.
2-7) are also found in
germinal centers and
have a much longer life
span than a resting B
cell.
 They remain in an
activated state for
months or years, ready
to respond again to the
initial antigen.

The Lymphoid System
T-Cell Differentiation
 60 to 80 percent of circulating lymphocytes in
the peripheral blood are T cells, and these
become differentiated in the thymus.
 Lymphocyte precursors called thymocytes
enter the thymus from the bone marrow.

The Lymphoid System
 This process is driven by chemokines..
 There is an orderly rearrangement of the
genes coding for the antigen receptor (TCR).
 At the same time, distinct surface markers
appear during specific stages of development.

The Lymphoid System
 Two chains of the TCR, the
alpha (α) and beta (β)
chains, contain variable
regions that recognize
specific antigens (see Fig.
2-10)
 The remaining four chains
comprise a complex called
CD3 which is involved in
signal transduction.

The Lymphoid System
 The appearance of a functional β chain on the
cell surface sends a signal to suppress any
further β chain gene rearrangements.
 Signaling by the β chain also triggers the
thymocyte to become CD4-positive (CD4+)
and CD8-positive (CD8+).

The Lymphoid System
 At this second stage, when thymocytes
express both CD4 and CD8 antigens, they are
called double-positive cells.
 Double-positive thymocytes proliferate and
then begin to rearrange the genes coding for
the alpha chain.
 Only double-positive T cells with functional
TCR complexes will survive this positive
selection process.

The Lymphoid System
 Any thymocytes that are unable to recognize
self-MHC antigens die without leaving the
thymus.
 This negative selection process takes place
among the surviving double-positive T cells.
 Strong reactions with self-peptides send a
signal to delete the developing T cell by
means of apoptosis.

The Lymphoid System
 Survivors of selection exhibit only one type of
marker, either CD4 or CD8, and they migrate to
the medulla of the thymus.
 CD4+ cells, termed T-helper or inducer cells,
represent ~ 2/3 of peripheral T cells. They
recognize antigen bound to MHC class II
protein.CD 8+ cells, termed T-cytotoxic cells,
represent ~ 1/3 of peripheral T cells. They
recognize antigen linked to MHC class I proteins.

The Lymphoid System
 These mature T cells are released from the
thymus and seed peripheral lymphoid organs.
 Resting T cells have a life span of up to
several years in these peripheral organs.
 Th1 cells produce interferon gamma (IFN-γ)
and tumor necrosis factor-beta (TNF-β), which
protect cells against intracellular pathogens.

The Lymphoid System
 Th2 cells produce a variety of interleukins,
including IL-4, IL-5,IL-10, and IL-13.
 The essential role of the Th2 cells is to help B
cells produce antibody against extracellular
pathogens.
 A third class of T cells, regulatory cells (T reg),
possess CD4 antigen and CD25 antigens.
 Treg cells produce IL-10 which switches off
the immune response (down-regulates genes)

The Lymphoid System
 T regulatory cells prevent autoimmune
reactions in any surviving T cells that can react
with self-antigens.

The Lymphoid System
 Antigen activation occurs next.
 Antigen must be transported to the T-cell
zones of the secondary lymphoid tissue.
 When antigen recognition occurs, the
activated lymphocytes are transformed into
lymphoblasts.
 Activated T lymphocytes express receptors for
IL-2 (CD 25), as activated B cells do.

The Lymphoid System
 T lymphoblasts differentiate into functionally
active small lymphocytes that produce
cytokines.
 Activities of specific cytokines include
assisting B cells, killing target cells, promoting
blast cell division, etc.
 In addition to effector cells, T memory cells are
also generated. They are able to proliferate
faster than naïve T cells.

The Lymphoid System
 T memory cells also express a broader array
of cytokines and appear to persist for years.
 All the activities of T cells constitute cell-
mediated immunity.
 Table 2-2 summarizes the differences
between T cells and B cells in structure and
function.

The Lymphoid System
 Natural killer cells are a small percentage of
lymphocytes that do not express the markers of
either T cells or B cells (double neg. cells). Cell
markers are CD 16, which acts as a receptor for
the Fc end of Ig, and CD 56.
 These large, granular lymphocytes make up 5 to
10 percent of the circulating lymphoid pool found
mainly in the spleen and peripheral blood.

The Lymphoid System
 NK cells lack specificity in their response; this is
essential to their function as early defenders
against viral pathogens and tumor cells. They
have the ability to mediate cytolytic reactions
(TNF) and kill target cells without prior
exposure to them. They do not require MHC-
processed antigen. Part of "natural immunity".
 This gives time for the acquired response of
specific T and B cells to be activated.

The Lymphoid System
 NK cells arise from the common lymphocyte
precursor (CLP) and differentiate into a T/NK
cell that can become a T cell or an NK cell.
 T/NK cells in the bone marrow respond to IL-
15 and become NK cells.
 T/NK cells in the thymus become T cells.

The Lymphoid System
 NK-cell activity is based on a balance of
inhibitory and activatory signals.
 NK cells are stimulated by exposure to
cytokines such as interleukin-12, interferon
gamma, and interferon beta.
 The inhibitory signal is based on recognition of
MHC class I protein, expressed on all healthy
self cells.

The Lymphoid System
 Diseased and cancerous cells tend to lose
their ability to produce MHC proteins.
 NK cells are thus triggered by a lack of MHC
antigens, sometimes referred to as recognition
of “missing self" antigen
 If an inhibitory signal is not received at the
same time as the activatory signal, then NK
cells release substances called perforins and
granzymes. (See Figure 2-12 in text.)

The Lymphoid System
 NK cells can also recognize and lyse antibody-
coated cells through a process called
antibody-dependent cell cytotoxicity.
 Binding occurs through the CD16 receptor for
IgG (Fc fragment).
 Any target cell coated with IgG can be bound
and destroyed.

The Lymphoid System
 Laboratory identification of T and B
lymphocytes utilizes flow cytometry.
 CD2, CD3, CD4,CD7, and CD8 are
recognized on T cells.
 CD19, CD20, CD21, CD22, and surface
immunoglobulin are recognized on B cells.
 CD 16,56 are found on NK cells

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