Download NATIONAL CHENG KUNG UNIVERSITY MEDICAL COLLEGE

NATIONAL CHENG KUNG UNIVERSITY MEDICAL COLLEGE
DEPARTMENT OF MEDICAL TECHNOLOGY
Wednesday, February 27, 2008, 10:10-12:00 a.m.
CELLS, TISSUES, AND ORGANS OF THE IMMUNE SYSTEM
Yee-Shin Lin, Ph.D.
A. BACKGROUND
Leukocytes, the cells of the immune system, traverse the entire body via the circulatory system. Accumulations
of white blood cells are known as the thymus, spleen, lymph nodes, tonsils, Peyer’s patches, and appendix.
Each leukocyte has its own specific tasks to perform.
Reading: Male, Brostoff, Roth & Roitt [chapter 2]
B. LECTURE SUMMARY
CELLS INVOLVED IN THE IMMUNE RESPONSE
The cells of the immune system arise from pluripotent hemopoietic stem cells through two main lines of
differentiation:
1. Lymphoid lineage: T cells, B cells, and NK cells
2. Myeloid lineage: monocyte/macrophage, neutrophil, eosinophil, basophil/mast cell, platelets
The cells involved in the immune response can be divided into 3 general categories: lymphocytes, phagocytes,
and accessory cells. [see also Fig. 2.1, 2.2]
CELLS OF THE INNATE IMMUNE SYSTEM
Differentiation of cells in the innate immune system [Fig. 2.6]
MONOCYTES [Fig. 2.4]: ImmunoSynonyms -- macrophages, Langerhans’ cells of the epidermis, histiocytes,
and cells of the mononuclear phagocyte system. These are the scavengers or garbage collectors of the body.
They pick up cellular debris, foreign cells and particles, etc., and enzymatically degrade it.
Distinguishing surface characteristics of monocyte/macrophage:
1.
FcR -- surface receptor for Fc portion of Ig molecule, i.e., CD64, CD32, CD16
2.
CR -- surface receptor for the 3rd component of complement, i.e., CR1 (CD35)
3.
MHC class II molecules (HLA-D for human and I-A/I-E for mouse) -- important in presentation of
antigens to T cells and functionally important in the regulation of the immune response
4.
Other markers: e.g. LFA-1 (CD11a/CD18), CD14, CD23(FcRII)
POLYMORPHONUCLEAR GRANULOCYTES
Neutrophils [Fig. 2.5]: the most prominent leukocytes in the circulation, accounting for over 90% of the
circulating granulocytes or 60-70% of the circulating leukocytes. Possess two main types of granules. Ingested
organisms are contained within vacuoles termed phagosomes which fuse with the enzyme-containing granules
(lysosomes) to form phagolysosomes. An increase in the numbers of circulating neutrophils indicates acute
bacterial infection.
Eosinophils [Fig. 2.7]: comprise 2-5% of blood leukocytes. They are capable of phagocytosing and killing
ingested microorganisms, can be triggered to degranulate by appropriate stimuli. Often found at sites of
parasitic infections.
Basophils [Fig. 2.8]: found in circulation (less than 0.2% of leukocytes), may be equivalent of mast cells found
in tissue. Large basophilic granules contain heparin, SRS-A (slow reactive substance of anaphylaxis), ECF-A
(eosinophil chemotactic factor of anaphylaxis) and histamine. Bear FcR for IgE. IgE is important in immediate
hypersensitivity reactions (also called allergic reactions). A comparison of characteristics between basophils
and mast cells is listed in Fig. 2.10.
Natural Killer Cells [Fig. 2.13]: NK cells have been defined by morphology as large granular lymphocytes
(LGL). They comprise up to 15% of the peripheral blood lymphocytes and express neither T nor B cell antigen
receptors. The surface markers of human NK cells are CD16/CD56. At least 2 distinct types of killing are
known:
1.
2.
Non-specific killing by NK cell -- are responsible for immunity against spontaneously arising tumors, thus
acting as an immune surveillance mechanism. They are also cytotoxic for virus-infected cells. NK cells do
not require Ag priming although NK activity is enhanced by IFN and IL-2. [see also Fig. 10.1]
ADCC -- sees Ab bound to foreign cell surfaces and lyses them. This complement (C) independent process
is called antibody-dependent cell-mediated cytotoxicity (ADCC) and is mediated through the receptor for
IgG. It is also known as killer (K) cell activity. [see also Fig. 10.6]
APCs LINK THE INNATE AND ADAPTIVE IMMUNE SYSTEMS
Antigen-presenting cells (APCs) are a heterogeneous population of leukocytes. Among them, dendritic cells
(DCs) process and present foreign protein antigens to T cells, and follicular dendritic cells (FDCs) passively
present foreign antigens in the form of immune complexes to B cells [Fig. 2.14]. Macrophages engulf (by
phagocytosis) foreign particles, dead cells, etc., enzymatically degrade this matter (antigen processing), and
display the enzymatically degraded material on their cell membranes. T cells must see both processed antigen
and the MHC class II molecule as the necessary initiation step in an immune response. [see also Fig. 2.15, 2.17]
CELLS OF THE ADAPTIVE IMMUNE SYSTEM
LYMOHOCYTES: The average human adult has about 1012 lymphocytes. Lymphoid cells represent about
20% of the total leukocytes present in the circulation. Two distinct types of resting lymphocytes can be
distinguished in the circulation: The first is relatively small, agranular, and has a higher N:C ratio (i.e., T and B
cells). The second type is larger, has a lower N:C ratio, and contains granules (i.e., LGL) [Fig. 2.19]. While the
T and B cells look alike by both light and electron microscopy, they differ widely in function. Different
categories of lymphocytes are based upon their embryological origin and this relates to their function and
distinguishing surface molecules (markers).
T cells: originate in the bone marrow as prothymocytes. They migrate via the circulation to the thymus.
Lymphocytes within the thymus (thymocytes) are indoctrinated ("educated") by the mechanisms including
positive and negative selections, such that they have the ability to distinguish self from non-self (foreign). T
cells comprise 60-70% of all peripheral blood lymphocytes. Collectively, T cells display a number of diverse
functions: [will be detailed in subsequent lectures]
1.
2.
Regulate humoral immune response, they can heighten or diminish an immune response.
Regulate cellular immune responses (immune responses directly mediated by cells not Ab such as items
3-6 below).
3.
Delayed-type hypersensitivity (DTH): an example of this type of response would be the cellular infiltration
causing swelling following a tuberculin skin test.
Contact sensitivity (CS): cellular infiltration causing swelling and itching following exposure to poison ivy.
Related to DTH.
Transplantation immunity: graft rejection is usually mediated by T cells.
Cytotoxic T lymphocyte (CTL) activity: when activated this T cell comes into contact with another cell
and causes its lysis, the "kiss of death".
4.
5.
6.
Distinguishing surface characteristics of T cells: [Fig. 2.20; Appendix 2]
1. T cell receptor (TCR) and CD3 -- T cells have the ability to specifically recognize every epitope in the
antigenic universe. This means that there are at least 106 to 107 distinct T cells resident in the immune system.
The cell surface structure is called the T cell receptor. Approximately 90-95% of blood T cells express TCR,
and the remaining around 5% express TCR [Fig. 2.21]. TCRs are associated with the CD3 complex to give
the TCR-CD3 complex [see chapter 5].
2. CD4 and CD8. These surface molecules are important in determining functionally different T cell subsets.
The CD4+ T cells have been further divided into subsets [Fig. 2.21, chapter 11].
3.
Other markers: e.g. CD5, CD28, CTLA-4 (CD152), CD45RO, and CD45RA.
B cells are responsible for the production of immunoglobulins (antibodies). An organ in birds, a blind cloacal
sac called the bursa of Fabricius, serves as the indoctrination site for these precursors of antibody secreting
cells (plasma cells). Mammals do not have this organ, but bone marrow serves as the equivalent
differentiation site. The term "B" cell is a mnemonic for the bursal or bone marrow origin of these cells. B cells
normally comprise 5-15% of the peripheral blood lymphocytes.
Distinguishing surface characteristics of B cells: [Fig. 2.20]
1.
Surface Ig and Ig(CD79a)/Ig(CD79b) -- B cells express both surface and cytoplasmic Ig. The pre-B
cells express cytoplasmic but not surface Ig. Cells that secrete Ig are termed plasma cells. Moreover, B
cells are specific, that is they produce Ig of only one Ab specificity that recognizes only one epitope. Like
CD3 in the TCR-CD3 complex of T cells, Ig and Ig are involved in cellular activation.
2.
MHC class II molecules -- they are specifically recognized by T cells and are functionally important in the
regulation of the immune response, i.e. I-A and I-E in mouse, and HLA-DP, DQ and DR in human.
3.
CR1 (CD35) and CR2 (CD21) -- surface receptors for complement, which are associated with activation
and possibly "homing" of the cells.
4.
FcR -- a surface receptor for the Fc portion of the Ig molecule (FcRII, CD32), which play a role in
negative signaling to the B cells. [see chapter 11]
5.
Other markers: e.g. CD5, CD19, CD20, CD22, CD40, and CD72.
LYMPHOID TISSUES AND ORGANS
The immune system is highly dynamic. This is especially true for lymphocytes. Approximately one half of the
lymphocytes recirculate as individual cells in the blood and lymph. Lymphoid tissues can be classified as
organs (thymus, spleen and lymph nodes) and lymphoid accumulations (mucosa-associated lymphoid tissues
such as Peyer’s patches and lymphocytes within the lamina propria, etc.). Two major types of lymphoid organs
are found: primary (central) and secondary (peripheral) lymphoid organs and tissues [Fig. 2.26]. Primary
lymphoid organs are the major sites of lymphocyte development. Thymus and bone marrow are primary
lymphoid organs. The secondary lymphoid organs trap and concentrate antigens and they are where specific
immune reactions are generated.
THYMUS GRAND [Fig. 2.29]: This bilobed organ is the first lymphoid organ to develop during ontogeny. It
increases in size during fetal and neonatal life and progressively involutes following puberty.
A stem cell, derived from the bone marrow (prothymocyte) and committed to the T cell lineage, migrates via
the circulation to the thymic cortex (cell is now called a cortical thymocyte). Subsequently, it migrates through
the cortico-medullary border into the medulla to mature. The mature thymocyte enters the circulation and is
known as a T cell. It takes about 3 days for a prothymocyte to mature to a T cell.
T-cell differentiation:
1. Phenotypic changes during T-cell maturation [Fig. 2.31]
2. Positive and negative selection in the thymus [Fig. 2.32, 2.33]
3. Extrathymic T-cell development [p. 46]
B-cell differentiation:
1.
Mammalian B cells develop in the bone marrow and fetal liver [p. 46, Fig. 2.35].
2.
Expression of Ig and other markers: [Fig. 8.1]
SPLEEN: Clears particulate matter from the blood and concentrates blood-borne Ag. Histologically divided
into the lymphocyte-rich white pulp and erythrocyte-rich red pulp. Lymphocytes are organized around small
arteries and arterioles. Immediately surrounding the arteriole is a T-cell rich area. The B cells are organized into
either primary or secondary follicles. [Fig. 2.38]
LYMPH NODES: small round- or oval-shaped peripheral of secondary lymphoid organs. They function as a
filter to purify lymph and as sites of initiation of the immune response. The lymph node system and structure
are shown in Fig. 2.39, 2.42. Anatomically the node is divided into the cortex and medulla. The reticulum or
"framework" of the organ is composed of phagocytes (macrophages) and specialized kinds of reticular or
dendritic cells. Lymphocytes are distributed mainly in two areas of the cortex:
cortex (B cell area) -- closely packed clusters of lymphocytes forming nodules of follicles. Sometimes called
the T-independent area. Contains mostly B cells. When an immune response takes place, the follicles develop a
central area with large proliferating cells termed a germinal center. [Fig. 2.48]
paracortex (T-dependent area) -- T cell-rich area.
Antigen trapping. Antigen is trapped either in the sinuses or paracortex by the reticular cells. This is an
important step in the induction of immune responses. Most of the Ag taken up by the macrophage is readily
enzymatically digested, but a few molecules escape total break down and these are the ones that interact with
lymphocytes.
As soon as Ag is taken up by macrophage or reticuloendothelial cell, inductive events occur whereby
lymphocytes recognize and interact with some of the trapped antigen molecules. This is manifest 24 h after Ag
enters the node. There follows a marked decrease in the number of lymphocytes leaving the node. Presumably,
lymphocytes keep entering the node from the postcapillary venules.
2 to 5 d later, lymphocytes leaving the node increase in number and more lymphocytes enter the node from the
postcapillary venules. Lymphocytes specifically reactive with the Ag remain in the node. Cellularity of the
node increases, often resulting in a swelling (something that the physician looks for during physical diagnosis).
Proliferation becomes abundant in the cortex and the first Ab-containing cells appear. Development of the
cortex proceeds and germinal centers become evident. The germinal centers and interfollicular areas are
abundant with plasma cells.
After another 5 d (8 to 11 d elapsed time), total numbers of cells leaving the node are reduced. However,
lymphocytes that have reacted with Ag (called primed or activated cells) now leave the node and are
disseminated throughout the tissues.
THE MUCOSAL LYMPHOID SYSTEM: M cells, lamina propria lymphocytes (LPL), intraepithelial
lymphocytes (IEL) [see Fig. 2.53, 2.52]
LYMPHOCYTE TRAFFIC: [see Fig. 2.54, 2.57]
C. ImmunObjectives -- a self assessment
1.



Define:
leukocytes -- granular, agranular
lymphoid lineage
myeloid lineage


mononuclear phagocyte system
T cell -- its functions, surface markers, and differentiation

B cell -- its functions, surface markers, and differentiation
2.
What is meant by primary and secondary lymphoid organs, what is the function of each.
3. Describe the lymph node in terms of structure and function. You should know cortex, paracortex, medulla,
afferent and efferent lymphatics and blood supply. What types of cells populate each area and how do they
function in antigen trapping and initiation of an immune response?