14. macrophages, their ontogenesis and function
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14. Macrophages, their ontogenesis and function. 15. T-lymphocytes, ontogenesis, surface markers. Subpopulations of T-lymphocytes and their functions. 16. The role of thymus. Positive and negative selection of T-lymphocytes. 17. B-lymphocytes - ontogenesis, surface markers, function. - PowerPoint PPT PresentationTRANSCRIPT
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14. Macrophages, their ontogenesis and function.
15. T-lymphocytes, ontogenesis, surface markers. Subpopulations of T-lymphocytes 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.
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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
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Macrophages- development
Monocytes- in the blood
Macrophages - in tissues
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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
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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
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Function of macrophages
Phagocytosis Production of monokines Presentation of epitops with MHC class II Presentation of epitops with MHC class I
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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
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15. T-lymphocytes, ontogenesis, surface markers. Subpopulations of T-lymphocytes and their functions.
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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
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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
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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
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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)
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TCR
Antigen receptors are encoded by several gene 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
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Subpopulations 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
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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)
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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
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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 T-cell 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
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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
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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
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16. The role of thymus. Positive and negative selection of T lymphocytes.
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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
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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
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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)
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Thymus – positive selection of T - cells
1. 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%)
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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
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17. B-lymphocytes - ontogenesis, surface markers, function.
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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
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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 Ig-
positive B lymphocytes IgM, IgD - antigen receptors = BCR MHC class II - antigen-presenting molecules
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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
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18. Primary immune organs and their role in the immune system.
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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
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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 B-cell 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
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Differentiation in the BM
Differentiation from the stem cell is influenced by:
membrane interaction between the stem
cells and the stromal cells cytokines (CSF, IL-3, trombopoetin,
erytropoetin)
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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
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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
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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
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19. Secondary immune organs - structure and function of lymphatic node and spleen.
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Secondary immune organs
spleenlymphatic nodes tonsils appendix
Peyer´s patchesMALT
• 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
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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
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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
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Contains lymphoid folicles = acumulation of B-lymphocytes and folicular dentritic cells
When a lymphocyte recognizes an antigen, B cells become activated and migrate to germinal centers = to the secondary nodule
Lymphatic node- cortex
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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
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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
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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
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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
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DC: dendritic cells, IEC: intestinal epithelial cell (Nu-nucleus), MC: M cell, IEL: intra epithelial lymphocytes, PP: Peyer’s patches, MØ: macrophages
Pv: particulate Ag in pinocytic vesicle of M cell
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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
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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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