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Lymphoid Organs
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Hematopoiesis the formation of red and white blood cells
Occurs via pluripotent hematopoietic stem cells (HSCs)
Self renewing
Yolk sac --> Liver --> Spleen -- (adulthood) --> Bone
Marrow (BM) Present at low concentrations in BM (less than 1-in-
5x104)
High proliferative capacity
HSCs differentiate towards a myeloidor lymphoid
lineage
Stem cells differentiate into committed progenitor cells
(which do not self-renew)
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Fig. 2-1
Generation
of Leukocytes,
Platelets and
Erythrocytes
from HSCs
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Growth and Death of HSCs
In the BM, HSCs require stromal cells
(stroma) to growGrowth of HSCs is dependent on
hematopoietic growth factors and cytokines
IL-3 M-CSF, G-CSF, GM-CSF
Erythropoietin (EPO)
Differentiation is regulated by hematopoiesisgenes
Cell number is limited by programmed cell
death (apoptosis)
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Primary Lymphoid Organs - sites
of lymphocyte maturation; include
the BM and thymus
Secondary Lymphoid Organs -
sites where antigen is trapped,
and brought into contact with
lymphocytes (differentiation)
Lymphatic System network of
vessels which collect fluidcomponent of blood after it has
drained to tissues; collects
antigen from tissues and brings it
to secondary lymphoid organs
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Thymus Bi-lobed organ sits
above the heart Site of maturationand selection of Tcells
Thymocytes which
cannot recognizeself MHC proteins,or which bind selfantigen, are deletedby apoptosis
Medulla containsmature T cells
Cortex containsmainly of immaturecells
Atrophies with age(thymic involution)
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Thymus
T Cell Development and Thymic Maturation
Thymocyte
TCR
TCR
CD4
TCR
CD8
Approximately 90 - 95% of all thymocytes
die in the thymus!!!
TCR
CD4
CD4
T Cell(Helper T Cell)
TCR
CD8
CD8
T Cell
(Cytotoxic(killer)
T Cell)
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Bone Marrow
Site of generation,maturation and
selection of B cells B cells interact directly
with stromal cellsduring selection
Mature, immunocom-petent B cells exit BMand migrate tosecondary lymphoidorgans (only ~ 10%)
Site of generation of Tprogenitor cells
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Secondary Lymphoid Organs Consist of lymph nodes (LN), spleen, and
mucosal-associated lymphoid tissue (MALT) whichinclude tonsils, Peyers patches and appendix
Antigen in tissues is transported by lymphaticsystem to secondary lymphoid organs where it istrapped
Newly-developed, immunocompetent lymphocytes(T and B) migrate to secondary lymphoid organswhere they interact with antigen, becomeactivated, differentiate and mutate, divide and
multiply
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Lymph Node
Spleen
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SpleenLargest secondary lymphoid organ
Major organ in the body in which antibodiesare synthesized and from which they arereleased into the circulation
Function: filters blood and traps blood-borne antigens; can respond to systemicinfection
Consists of white and red pulp
50% of cells are B cells, 30 40% are T cellsand the remaining population are plasma
cells and macrophages
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Lymph Nodes located along lymphatic ducts and serve as central
collecting joints for lymph fluid from adjacenttissues
main function is filtration; ideal site forphagocytosis
Medulla consist mainly of plasma cells while thecortex contains T cells and macrophages
where the blast transformation of B cells take place(germinal center)
plasma cells, memory cells are also present in thegerminal center
its primary function is the generation of B cellmemory
contains immobile B lymphocytes
Oth L h id Ti
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Other Lymphoid Tissues Includes GUT-associated lymphoid
tissues and MALT
At MALT macrophages and lymphocytesare localized at some of the main portalsof entry for foreign organisms
Peyers patches specialized type ofMALT, located at the lower ileum ofthe intestinal tract
Oth L h id Ti
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Other Lymphoid Tissues Tonsils small masses of
lymphoid tissue found in themucous membrane lining of theoral and pharyngeal cavities
Appendix also consideredMALT
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Lymphoid Cells
Approximately 1011 lymphocytes in thehuman body
Three main types of lymphocytes:
B Cells
T Cells
Null Cells (Large granular lymphocytes (LGLs)
or Natural Killer (NK) Cells)Transition through cell cycle from small
lymphocytes (nave) --> lymphoblasts -->
effector cells or memory cells
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Fig. 2-7
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Clonal Selection of B Cells is Caused by Antigenic Stimulation
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Humoral Response to T Dependent Antigens
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B Lymphocytes
Distinguishing cell-surface markers include:
B220 (CD45), MHC Class II, CD80 (B7-1) and
CD86 (B7-2), CD40, CD19, CD21, etc.
Bursa of
fabricius
First identified in the Bursa of Fabricius in
birds
In humans, B cells develop in the Bone
Marrow
Can be divided into memoryandplasma B
cells
Primary effectors of humoral immunity, viaantibody production
Recognize antigen by means of surface-expressed antigen receptor
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T Lymphocytes
Distinguishing cell-surface markers include TCR,
CD3, CD2, CD4 or CD8, CD28, and CD45
T cells derive from stem cells in the bone marrow,
mature in the thymus, and then are released into the
periphery
Similarities between T and B cells: Antigen receptor on surface (T cell receptor or TCR)
Recognize single, specific antigen
Expand through clonal selection
Some T cells exist as long-lived memory cells
Primary effectors of cellular immunity
Can be divided (broadly) into helperT cells (Th) and
cytotoxicT cells (Tc), usually found in a 2:1 ratio
70% T cells (5 10% B cells and 10 15% are nulls cells)
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T lymphocytes have the ability to bind sheep erythrocytes, the
clumps of cells formed are called E-rosettes (E+ cells) progenitor T cells appear in fetus as early as 8 weeks
of gestation
surface characteristics:
ability to bind to certain lectins ability to interact with the measles virus
exhibit receptors for FC portion of IgM and IgG
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Antigen Processing and PresentationUnlike B cells, T cells cannot recognize free antigen; it must be:
Presented on the surface of APCs in the context of MHC (major
histocompatibility complex) proteins
Processed (digested) in to smaller fragments within special
antigen presenting cells (APCs)
APCMHC
+
Ag
TCR
APC
T Cell
APC
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Table 2-4CD - Cluster of Differentiation
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T cell subsetsActivator T cells (Ta)
amplify killer to cell differentiation Helper T cell (Th)
helps the B cell to produce antibody in response toantigen
activation of B cell and their differentiation intoantibody-secreting plasma cells
Suppressor T cells (Ts) inhibits initiation or expression of the response of T and
B cells to antigen
Cytotoxic T cells (Tc) or killer cells causes death of the cell and destroy the inciting antigen
against which they specifically sensitized
Delayed type of hypersensitivity (Td or Tdth) res onsible for dela ed t e of h ersensitivit reaction
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Helper T CellsHelper T cells (CD4 T cells) produce proteins(cytokines) which act on B cells, stimulating them to
produce antibodies
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T Helper (TH) Cells: Central role in
immune response. Most are CD4+
Recognize antigen on the surface of
antigen presenting cells (e.g.:macrophage).
Activate macrophages
Induce formation of cytotoxic T cells Stimulate B cells to produce
antibodies.
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Central Role of Helper T Cells
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Cytotoxic (Killer) T Cells
Cytotoxic T cells (CD8 T cells) attack theirtarget cells (e.g. virally-infected cells) and kill
them directly..
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Cytotoxic (Killer) T Cells
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Cytotoxic T (Tc) Cells: Destroy target cells.
Most are CD4 negative (CD4 -).
Recognize antigens on the surface of all cells:
Kill host cells that are infected with virusesor bacteria.
Recognize and kill cancer cells. Recognize and destroy transplanted tissue.
Release protein calledperforinwhich formsa pore in target cell, causing lysis of infected
cells. Undergo apoptosiswhen stimulating antigen
is gone.
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Cytotoxic T Cells Lyse Infected Cells
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Null Cells
Referred to as Null cells because they are
lymphocytes, but lack typical B cell or T cell markers ontheir surface
Also known as large granular lymphocytes (LGLs) ornatural killer(NK) cells
Demonstrate cytotoxicity against tumor cells and somevirus-infected cells
most effect as killer cells in antibody-independentCytotoxic reactions
Not specific. Dont require antigen stimulation.
Not phagocytic, but must contact cell in order to lyse it.
NK1-T cell - Recently identified subset displaying someT cell markers (e.g. TCR), functions
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Other Cells
Plasma cells (Plasmocyte) known as mature antibody-producing cells contain large includsion bodies called Russelbodies
derived from B lymphocytes
Monocytes (peripheral blood)/Macrophage(tissues)
formed in bone marrow, spleen and tissues ofRES function in amoeboid movement and
phagocytosis (immune response)
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GranulocytesNeutrophils important in the bodys defense(phagocytosis & destruction of microorganisms)
process facilitated by complement and antibody
Basophils and Mast cells contain heparin important in immediate hypersensitivity
reactions
found in large numbers in some cell.-mediateddelayed reactions: skin graft or tumor reject,hypersensitivity
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GranulocytesEosinophils has a specialized role in immunity to helminth
infections found in tissues at sites of immune response or
reaction that have been triggered by IgEantibodies
activated when antigen triggers IgE coated mastcells to release an eosinophil chemotactic factorof anaphylaxis
attracted to antigen-antibody complex and can
phagocytize them contain a number of enzymes that can degrade
mediators of immediate hypersensitivity Histamine slow reacting substance of anaphylaxis
PAF (Platelet Aggregating Factor) control ordiminish such hypersensitivity
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Mast Cells
Found in a wide variety of tissues,including:
skin
connective tissues mucosal epithelial tissues of the respiratory,
genitourinary and digestive tracts
Heavily granulated
Granules contain histamine; degranulation
of mast cells results in histamine release,
allergic/inflammatory response
Generation
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Fig. 2-1
Generation
of Leukocytes,
Platelets and
Erythrocytes
from HSCs
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Mononuclear Cells Consist of monocytes (in blood) and
macrophages (in tissues)
Macrophages (ms) are larger,more complex, and produce morehydrolytic enzymes
There are multiple types ofmacrophages, defined by location:
Alveolar macrophages (lungs) Histiocytes (connective tissues)
Kupffer cells (liver)
Mesangial cells (kidney)
Microglial cells (brain)
Osteoclasts (bone)
Splenic macrophages (spleen) Peritoneal macrophages (peritoneal
fluid)
Dendritic cells (lymph nodes)
Langerhans cells (dendritic cells in theskin)
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Functions of Macrophages
Phagocytosis Chemotaxis
Formation ofpseudopodia
Opsonization (by antibody)
Antimicrobial and cytotoxic
activities Antigen processing and
presentation
Protein secretion
Interleukin 1 (IL-1)
IL-6
Complement proteins
TNF-a
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Dendritic Cells
Lineage/origin is not
entirely understood Express high levels of
MHC class II and B7
molecules, making them
extremely potent APCs
Multiple different types,
based on location (similar
to m) Langerhans cells found in
skin and mucous
membranes