Transcript Document

14. Macrophages, their ontogenesis and function.
15. T-lymphocytes, ontogenesis, surface markers. Subpopulations of Tlymphocytes and their functions.
16. The role of thymus. Positive and negative selection of T-lymphocytes.
17. B-lymphocytes - ontogenesis, surface markers, function.
18. Primary immune organs and their role in the immune system.
19. Secondary immune organs - structure and function of lymphatic node
and spleen.
20. Mucosal immune system.
Macrophages- ontogenesis
are a tissue- based phagocytic cells, derived from blood
monocytes
 play important roles in innate and adaptive immune
responses
 their development courses in the bone marrow
 an undifferentiated stem cell gives rise to the
myeloid and lymphoid progenitor
 myeloid progenitor cells differentiate into the
erythrocytic, granulocytic and monocytic cell lines
and megakaryocytes
Conversion
of the myeloid precursor cells into monocytes and
macrophages is affected by :
 GM-CSF: granulocyte-monocyte colony stimulating
factor – bone marrow (BM)stromal cells,
lymphocytes- production of monocytes from BM
 M-CSF: monocyte colony stimulating factor- stromal
cells, lymphocytes, endothelial cells, epithelial cellsproduction and maturation of monocytes
 IL-3 : lymphocytes- production of monocytes (other
blood cells) from BM
Macrophages- development
 Monocytes- in the blood
 Macrophages - in tissues
Macrophages - terminology
histiocytes
Macrophages
 a monocyte enter damaged tissue through the
endothelium of a blood vessel
 a monocyte is attracted to damaged site by chemokines,
triggered by stimuli including damaged cells, pathogens
and cytokines released by macrophages
 after migration of monocytes to the tissues they
differentiate into different form of macrophages
 macrophages survive several months
Macrophage surface molecules
 MHC gp class I, II assist in the presentation
of epitopes to T lymphocytes
 CD 35 - complement receptor 1 (CR 1),
binds complement C3b
 Receptor for the Fc portion of IgG
Function of macrophages
 Phagocytosis
 Production of monokines
 Presentation of epitops with MHC class II
 Presentation of epitops with MHC class I
Phagocytosis
 a foreign substances are ingested
 a living organisms are killed and digested
 follows sparing of antigenic epitopes and
their distribution on the cell membrane
Presentation epitopes with MHC
gp class II
 After endocytosis and degradation of the antigen,
preservation of its epitopes follows
 epitope is coupled with the MHC gp class II- moved
to the cell surface and contact the T-cell receptor
 MHC (major histocompatibility complex) = complex of
genes that governs the production of the major
histocompatibility antigens - in humans are termed
HLAs (human leukocyte antigens)
Presentation epitopes with MHC
gp class I
 intracelular parasites are degradeted in proteasomes
of macrophages
 their peptides are coupled to TAP (transporters
associated with antigen processing molecules 1,2)
that carry the epitope and MHC gp class I to the cell
surface- protect epitopes from phagocytic destruction
Monokines = cytokines produced by
macrophages
 IL- 1 α, ß- stimulate both T and B cells, IG synthesis,
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activation of other macrophages, sensitizing cells to IL-2
and IFN
TNF- α - similar in function to IL-1
IL- 8 - secreted by activated macrophages
- chemokine for neutrophils, T cells
IL-12 - promotes induction of Th1 cells, inhibits Th2 cells
IFN- α- activates host cells to induce enzymes that
inhibit protein synthesis needed for viral replication;
increases expression of MHC gp I class on host cells;
activates NK cells, T cells, other macrophages
Macrophage - functions
•Macrophages provide line of defense against tumor
cells and body cells infected with fungus or parasites.
• a T- cell becomes an activated effector cell after
recognition of an antigen on the surface of the APC,
releases chemical mediators that stimulate
macrophages into a more aggressive form
15. T-lymphocytes, ontogenesis, surface
markers. Subpopulations of T-lymphocytes
and their functions.
T lymphocytes- ontogenesis
 The undifferentiated stem cell in BM gives rise to the
lymphoid precursor cell which matures into 3 types of
lymphocytes:
 T lymphocytes
 B lymphocytes
 Natural killer (NK) cell
 Pro-thymocytes come to the thymus where continue
the maturation into T lymphocytes
 Maturation of B lymphocytes continue in BM
Surface markers of T cells
 CD (cluster of differentiation) proteins-
molecules on the cells membrane, allow the
identification of cells
 TCR- receptor for antigen
 MHC gp I or II class
CD proteins
 allow an identification of T-cell subsets
 CD 2 = adhesion molecule
 CD 3 = important in intracellular signaling to initiate
an immune response; closely associated with TCR
 CD 5,7
 CD 4,8 = are expresed on subclasses of mature T
cells; CD4 reacts with MHC gp II.class),CD8 reacts
with MHC gp I. class on macrophages
 CD 28- receptor for costimulator molecules CD80
and 86
Maturation of T lymphocytes
Consist of three types of processes:
 Proliferation of immature cells
 Expression of antigen receptors genes
 Selection of lymphocytes that express useful
antigen receptor (TCR)
TCR
 Antigen receptors are encoded by several gene
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segments that recombine during lymphocyte maturation
Heterodimer consisting of 2 nonidentical polypeptide
chains linked together by disulfide bonds
> 95% T cells express the αß heterodimer, 5% γδ
TCR heterodimer is noncovalently associated with the
γ,δ,ε chains of the CD3 molecule
COMPLEX TCR- CD3 makes contact with both the Ag
and MHC gp
Subpopulation of T cells
 Subpopulation of T cells have been defined
according to their particular function and their CD
membrane markers
 Cytotoxic T lymphocytes = Tc;CD8+
- recognize the foreign epitope in association
with class I MHC molecules
 Helper T-lymphocytes = Th; CD4+
- recognize the epitopes in association with
class II MHC molecules
Cytotoxic T lymphocytes (Tc;CD8+)
 cause lysis of target cells; are active against tumors,
virus-infected cells, transplanted allogenetic tissue
 release TNF- depresses proteosynthesis
 recognize the foreign epitope in association with
class I MHC molecules
 destroy their target cells by releasing perforin (create
poresin the cell membrane and cytoplasm escapes)
and granzymes (degrading essential
macromolecules)
Helper T-lymphocytes
(Th; CD4+)
 recognize the epitopes in association with II
MHC p II.class
 help B cells to produce antibodies and help
phagocytes to destroy ingested microbes
 subsets of Th cells: Th1, Th2 cells
Th1 cells
secrete:
 INF-γ (gamma interferon) : activates macrophages to become
more effective at killing phagocytosed microbes, supresses the
development of Th2 cells
 IL- 2 : stimulates survival and proliferation of T cells, called Tcell growth factor
 TNF (tumor necrosis factor)- stimulates the recruitment of
neutrophils and monocytes to sites of infection, activates these
cells to eradicate microbes
 IL-3 : promotes expansion of immature marrow progenitors of all
blood cells
 GM-CSF : acts on progenitors in the bone marrow to increase
production of neutrophils and monocytes
Th2 cells
secrete:
 IL-4 : induces differentiation of Th2 cells from naive
CD4+ precursors, stimulation of IgE production by B
cells
 IL-5 : activates mast cells
 IL-6 : stimulates the synthesis of acute phase
proteins by hepatocytes
 IL-10 : inhibits activated macrophages, supresses
Th1 production
 IL-3, GM-CSF
Regulatory T cells
 Express CD4, CD25, FoxP3
 Regulate the activation or effector function of
other T cells
 Are necessary to maintain tolerance to self
antigens
16. The role of thymus.
Positive and negative selection
of T lymphocytes.
The role of thymus
 In the two thymic lobes, lymphocyte
precursors from the bone-marrow become
thymocytes, and subsequently mature into T
cells
 Once mature, T cells emigrate from the
thymus and constitute the peripheral T cell
repertoire responsible for directing many
facets of the specific immune system
Phases of thymocyte maturation
 A rare population of hematopoietic progenitors enters
the thymus from the blood, and expands by cell
division to generate a large population of immature
thymocytes
 Immature thymocytes each make distinct T cell
receptors by a process of gene rearrangement.
 This process is error-prone, and some thymocytes
fail to make functional T cell receptors, whereas other
thymocytes make T cell receptors that are
autoreactive
Positive and negative selection
 Immature thymocytes undergo a process of
selection, based on the specificity of their T
cell receptors.
 This involves selection of T cells that are
functional (positive selection), and
elimination of T cells that are autoreactive
(negative selection)
Thymus – positive selection of T - cells
precursor T cells enter thymus from the blood
2. they are presented with self-antigens complexed
with MHC molecules on the surface of cortical
epithelial cells
3. only those thymocytes which bind the MHC/antigen
complex with adequate affinity will receive a vital
"survival signal"
4. the other thymocytes die (>95%)
1.
Thymus – negative selection of T - cells
1. thymocytes that survive positive selection migrate
towards the boundary of the thymic cortex and
thymic medulla
2. they are again presented with self-antigen in
complex with MHC molecules on antigen-presenting
cells
3. thymocytes that interact too strongly with the
antigen receive an signal for apoptosis
17. B-lymphocytes - ontogenesis, surface
markers, function.
B-lymphocytes
are an essential component of the innate immune
system
 Maturation of B cells course in the BM
 B cells ordinate from stem cells and need to be in
touch with the stromal cells in the bone marrow
 Stromal cells produce SCF (stem cell factor) needed
for development at early period, IL-7 needed at later
period of maturation
 Ig gene rearrangements and the appearance of
surface markers identify the stage of B-cell
development
Development of B lymphocytes
 Lymphoid progenitor gives rise to precursors of B cells =
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pro- B cells
During maturation from the pro-B cells into the pre-B
cells – Ig genes of the heavy chain recombine; pre-B
cells express pre-BCR
During maturation from the pre-B cells into the
B cells – Ig genes of the light chain recombine
Immature B cells express membrane IgM
Mature B cells express membrane IgM and IgD = BCR
and are able to respond to antigen in peripheral
lymphoid tissues
Negative selection
 If an immature B cell binds an antigen in the bone
marrow with high affinity- further maturation is
stopped and B cell dies by apoptosis
 Negative selection eliminates potentially dangerous
cells that can recognize and react against self
antigens
 B cells that survive this selection process leave the
bone marrow through efferent blood vessels
B-lymphocytes – surface markers
 CD 10 - immature B cells, malignant cells
 CD 35 - receptor for the C3b of the
complement
 CD 19 - a characteristic marker of B cells
 CD 20 - a typical surface antigen of Igpositive B lymphocytes
 IgM, IgD - antigen receptors = BCR
 MHC class II - antigen-presenting molecules
B-lymphocytes – functions
 After stimulation B lymfocytes convert into the
plasma cells and produce antibodies
against soluble antigens
 Other functions are :
antigen presentation
cooperation with complement
18. Primary immune organs and their role in
the immune system.
Primary immune organs
 Bone marrow
 Thymus
 are places of development, differenciation and
maturation of immunocompetent cells and
elimination of autoreactive cells
 T and B lymphocytes mature and become
competent to respond to antigens in PIOs
Bone marrow
is the central cavity of bone that is the site of
generation of all circulating blood cells in the adult,
including immature lymphocytes, and the site of Bcell maturation.
 The pluripotent stem cell gives rise to the
progenitor of all immune cells
 Production of cells course in the places
divided by vascullar sinuses
 Endothelial cells of the sinuses produce
cytokines
 Sinuses are borded by reticular cells
Differentiation in the BM
 Differentiation from the stem cell is influenced
by:
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membrane interaction between the stem
cells and the stromal cells
cytokines (CSF, IL-3, trombopoetin,
erytropoetin)
Thymus
 is located between the sternum and
the major vessel trunks
 It consist of two lobes
 Each lobe is surrounded by a
capsule and is divided into lobules,
which are separated from each other
by strands of connective tissue =
trabeculae
Structure of the thymus
Each lobule is organized into two compartments:
- the cortex (outer compartment) – contains
lymphocytes that proliferate
- the medulla (inner compartment)- mature
lymphocytes, Hassall´s bodies
Thymus - morphology
stromal cells composed of:
 thymic epithelial cells – produce thymulin,
thymopoetin, thymosin that influence the maturation
of T cells
 dendritic cells
 macrophages
 The thymus contain a large number of blood vessels
and efferent lymphoid vessels that drain into the
mediastinal lymph nodes
19. Secondary immune organs - structure and
function of lymphatic node and spleen.
Secondary immune organs
• consist of the spleen, the lymph nodes, the mucosal and
cutaneous immune system
• are organized to optimize interactions of antigens, APCs
and lymphocytes
• are places of the development of adaptive immune
responses
spleen
lymphatic
nodes
tonsils
MALT
appendix
Peyer´s
patches
hatic node
 are nodular aggregates of
lymphoid tissues located along
lymphatic channels throughout
the body
 Lymph comes from tissues and
most parenchymal organs to
the lymph nodes
 Lymph contains a mixture of
substances absorbed from
epithelia and tissues
 as the lymph passes through
lymph nodes, APCs in the LN
are able to sample the
antigens of microbes that may
enter through epithelia into
tissues
Lymphatic node
• lymph circulates to the lymph
node via afferent lymphatic vessels
and drains into the node just
beneath the capsule in a space
called the subcapsular sinus
• the subcapsular sinus drains into
trabecular sinuses and finally into
medullary sinuses
• the sinus space is criss-crossed
by the pseudopods of
macrophages which act to trap
foreign particles and filter the lymph
• the medullary sinuses converge
at the hilum and lymph then leaves
the lymph node via the efferent
lymphatic vessel
Lymphatic node- medulla
The medullary cords are cords of lymphatic
tissue, and include plasma cells and T cells
• The medullary sinuses are vessel-like spaces
separating the medullary cords; contain
histiocytes (= immobile macrophages) and
reticular cells.
• Lymph flows to the medullary sinuses from
cortical sinuses, and into efferent lymphatic
vessels
Lymphatic node- cortex
Contains lymphoid folicles = acumulation of Blymphocytes and folicular dentritic cells
When a lymphocyte recognizes an antigen, B cells
become activated and migrate to germinal centers =
to the secondary nodule
Spleen
is a secondary lymphoid organ positioned high in the left abdominal
cavity
 is surrounded by a capsule, which sends trabeculae into the
interior to form a compartmentalized structure
 there are two types of compartments -red pulp and white pulp
with a marginal zone in between
 is NOT supplied by afferent lymphatics
Spleen
 Red pulp : place of mechanical filtration and
elimination of senescent red and white blood cells
and microbes
 White pulp : T lymphocytes CD4+,CD8+ are around
arterioles (periarteriolar lymphoid sheaths), B
lymphocytes are in the folicles; final maturation of B
lymphocytes course in germinal center of secondary
folicles
Mucosal immune system
 MALT = mucosal-associated lymphoid tissue
 GALT = gut-associated lymphoid tissue
 BALT = bronchus-associated lymphoid tissue
 digestive, respiratory, and urogenital systems are
lined by mucous membranes
 includes loose clusters of lymphoid cells in lamina
propria of intestinal villi
 contains a very large population of plasma cells that
synthetize IgA antibodies
M cells
 are epithelial cells that are specialized for the transport antigen from
the lumen of the respiratory, digestive, and urogenital tracts to the
underlying MALT
 contain a characteristic pocket filled with B cells, T cells, and
macrophages
 are found at inductive sites that overlie organized lymphoid follicles
in the lamina propria
 antigens are endocytosed and transported within vesicles from the
luminal membrane to the pocket membrane, where the vesicles fuse
and deliver their contents to antigen-presenting cells
DC: dendritic
cells, IEC:
intestinal
epithelial cell (Nunucleus), MC: M
cell, IEL: intra
epithelial
lymphocytes, PP:
Peyer’s patches,
MØ:
macrophages
Pv: particulate Ag in
pinocytic vesicle of M cell
Secretory IgA
 daily production of secretory IgA into mucous
secretions exceeds that of any other class of
immunoglobulin (5-15 g each day)
 is an important line of defense for mucosal surfaces
against bacteria
 binding of secretory IgA to bacteria and viruses also
prevents attachment to mucosal epithelial cells,
thereby inhibiting infection and colonization
Cutaneous immune system
 Epidermis contains keratin cells that produce
IL-1, 6 and TNF during inflamation; and IL-10,
TGF-β during healing
 Dermis contains fibroblasts that produce
collagen, remove apoptotic cells
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