Ch02

Clinical Immunology & SerologyA 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.



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.

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.



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 SystemT-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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