Transcript plasma cells

#4 Anatomy of the Immune System II
Immunology 297
July 28, 2015
Ikuo Tsunoda, MD, Ph.D.
Associate Professor
Department of Microbiology and Immunology
LSUHSC
Homepage: http://tsunodalaboratory.web.fc2.com/
E-mail: [email protected]
Lymphoid organs
•Primary (central)
•Secondary (peripheral)
•Primary lymphoid tissues
•Lymphocytes are generated
and differentiate into mature
lymphocytes
•Bone marrow for B cells
•Thymus for T cells
•Secondary lymphoid tissues
•Tissues in which
lymphocytes are brought with
antigen and adaptive immune
responses are initiated
•Lymph nodes, spleen,
Peyer’s patches
Adaptive immunity
The adaptive responses
are divided into
humoral vs. cellmediated immunity
CD4
CD8
(Th cell)
(CTL)
Figure 1-2: Types of adaptive immunity.
In humoral immunity, B lymphocytes
secrete antibodies that prevent infections
and eliminate extracellular microbes. In
cell-mediated immunity, helper T
lymphocytes activate macrophages to kill
phagocytosed microbes, or cytotoxic T
lymphocytes directly destroy infected cells.
CD: cluster of differentiation
•The basis of a system for identifying cell
surface molecules of immune cells
•Each molecule is given a specific number
prefixed by CD
•Each molecules is usually recognized by a
group (=cluster) of monoclonal antibodies
•Used to classify cells
•CD3; T cell
•CD4; helper T (Th) cell
•CD8; cytotoxic T cell
or lymphocyte (CTL)
•CD20; B cell
The key stages of lymphocyte differentiation
(naïve, effector and memory cells)
naïve lymphocytes are
called small “resting” cells
T lymphocytes
B lymphocytes
naïve B cells
plasma cells
naive
effector
memory B cells memory
naïve CD4 T cells
naïve CD8 T cells
helper T cells
cytotoxic T cells
(Th1, Th2)
(CTL)
memory CD4 T cells
memory CD8 T cells
Naïve lymphocytes re-circulate until they
encounter their specific antigen
Figure 2-5: Maturation of lymphocytes.
Lymphocytes develop from bone marrow stem cells, mature in the generative lymphoid organs (bone marrow and thymus for B and T cells,
respectively), and then circulate through the blood to secondary lymphoid organs (lymph nodes, spleen, regional lymphoid tissues such as
mucosa-associated lymphoid tissues). Fully mature T cells leave the thymus, but immature B cells leave the bone marrow and complete their
maturation in secondary lymphoid organs. Naive lymphocytes may respond to foreign antigens in these secondary lymphoid tissues or return by
lymphatic drainage to the blood and recirculate through other secondary lymphoid organs.
Naïve B cells that encounter antigen differentiate into
effector B cells (plasma cells) that secrete antibodies
to protect against infection or memory B cells
Lymphocyte
Plasma cell
Three classes of effector T cells to deal with
multiple types of pathogens
Stimulate
macrophages
to kill
intracellular
pathogens.
Kill infected cells displaying foreign
antigen, typically virus infected cells.
Stimulate
antibody
production to
facilitate
elimination of
extracellular
pathogens.
1-5 Major Histocompatibility Complex (MHC)
Molecules and the Detection of Infection
• T cells do not interact directly with intact
antigen
• T cells recognize fragments of antigen
carried to the cell surface by MHC
molecule
• Two classes of MHC
T cell responses initiate from interaction with
antigen + MHC molecules
MHC class I
Tissue Distribution
• Most cells
MHC class II
Tissue Distribution
• APCs
•
•
•
Macrophages
Dendritic cells
B cells
• Thymic epithelium
Function
• Antigen presentation
to CD8 + T cells
• Intracellular
(cytoplasmic) antigen
Function
• Antigen presentation
to CD4+ T cells
• Extracellular
(internalized) antigen
MHC = major histocompatibility complex
Antigen presenting cells (APCs)
APCs present antigen to CD4+ T cells on MHC class II molecules
T cell responses initiate from interaction with
antigen + MHC molecules
Recognition of viral
antigen and MHC class I
molecules by CD8+
cytotoxic T cells
Recognition of
internalized bacterial
antigen and MHC
class II molecules
on APCs by CD4+ T
cells
•CD4+ helper T (Th)1 cells
recognize fragments of
bacteria internalized by
macrophages
•Th1 cells activate
macrophage to destroy
the internalized bacteria
•CD4+ Th2 cells recognize
antigen fragments
internalized by B cells
•Th2 cells activate B cell
to proliferate and
differentiate into an
antibody-secreting
plasma cells
Two waves of the immune response
The innate immune response participates in
activation of the adaptive immune response
The innate immune response and the adaptive immune
response meet in the secondary lymphoid organs
The innate immune response participates in
activation of the adaptive immune response
The production of T-cell immune effector
responses requires the cooperative
function of both secondary and tertiary
lymphoid sites
Fundamental Immunology 4th edition chapter 10 Fig. 10
Initiation of adaptive immunity
The entire process is initiated by the capture of antigen by
APC, and the subsequent presentation of the antigen (on
MHC molecules) to T cells
Naïve lymphocyte:
• mature T or B cells
that have never
encountered
foreign antigen
• die after 1 to 3
months if they do
not recognize
antigens
•Lymphocytes mature in the bone marrow (B cells) and thymus (T cells)
and enter secondary lymphoid organs as naive lymphocytes
•Antigens are captured by dendritic cells and concentrated in lymph
nodes, where they activate naïve lymphocytes
•Effector T cells develop in the lymph nodes, enter the circulation, and
migrate to peripheral tissues
IV_8_2_Dendritic_Migration-H264
Janeway’s Immnobiology
Secondary lymphoid organs
Peripheral Lymph Nodes (500-600 in humans)
 connected to lymphatic network
 drain peripheral tissues – migration of antigen /
APCs into LNs
 compartments optimize antigen / lymphocyte
interactions
The lymphatic system
The lymphatic system collects extracellular fluid
from tissues and returns it to the blood. The fluid is
continuously produced by filtration from the blood.
It passes through the lymph nodes, drains into the
thoracic duct and is then returned to the blood.
The lymphatic system
Peripheral LNs are located at the points of convergence of lymphatic vessels.
Afferent lymphatic vessels drain fluid from the tissues into the LN.
Activated lymphocytes leave the LNs in the lymph fluid, which exits via the
efferent lymphatic vessels to return to the blood.
Antigens are
captured from a site
of infection, and
transported to the
draining lymph node,
where the immune
response is initiated
Figure 2-11: The lymphatic system.
The major lymphatic vessels, which drain into
the inferior vena cava (and superior vena cava,
not shown), and collections of lymph nodes are
illustrated. Antigens are captured from a site of
infection and the draining lymph node to which
these antigens are transported and where the
immune response is initiated.
http://study.com/academy/lesson/functions-of-the-lymphatic-system.html
In tissues, dendritic cells pick up antigen,
then migrate to regional lymph nodes via
lymphatics.
The lymph nodes are the sites where the lymph and
blood circulatory pathways come together
Peripheral lymph node structure
cortex
medulla
LNs are highly organized structures that are specialized to trap APCs for
presentation of antigen to circulating lymphocytes.
B cells are organized in follicles (some are germinal centers).
T cell are diffusely distributed in the paracortical areas – T cell zones.
Lymphocytes move from circulation into the lymph node
via extravasation in the post-capillary venules
Lymphocytes move from circulation into the lymph node
via extravasation in the post-capillary venules
The venules located in
lymphoid organs are
lined with specialized
endothelial cells.
Thus the vessels are
termed “high
endothelial venules
(vessels)” or HEVs.
•Lymphocytes move from
circulation into the lymph
node via the post-capillary
venules called high
endothelial venules (HEV)
•HEVs display certain
adhesion molecules and
chemokines on their
surfaces
Chemokine: small cytokines
whose main function is as
chemoattractants
A naïve T cells extravasates through HEVs using a
process termed ‘diapedesis’
Adhesion receptors and chemokines mediate this process
The lymph node is designed to bring T and B cells
into contact with APCs
• Naïve T and B cells
enter the node
through HEV
• Dendritic cells
– T cell zone
– Resident cells capture
antigen entering
through the afferent
lymphatic vessels
– Dendritic cells in the
periphery migrate into
the lymph node
• Follicular dendritic
cells
– B cell areas
– Capture antigen for B
cell recognition
• B cells are in
follicles
• Proliferating B
cells are
concentrated in
the germinal
center
• T cells in the
paracortical area
IV_10_5_Germinal_Centers
Janeway’s Immunobiology
Figure 2-12: Morphology of a lymph node.
A, Schematic diagram of a lymph node illustrating the T cell–rich and B cell–rich zones
and the routes of entry of lymphocytes and antigen (shown captured by a dendritic
cell). B, Light micrograph of a lymph node illustrating the T cell and B cell zones.
• Naïve T and B cells enter
through an artery, and
are drawn to different
areas of the node by
chemokines
• Dendritic cells enter
through afferent
lymphatic vessels, and
migrate to the T cell-rich
area
III_7_2_Lymph_Node_Dev
Janeway’s Immunobiology
Peripheral Lymph Node Structure
IV_10_1_The_Immune_Response-H264
Janeway’s Immunobiology
Secondary lymphoid organs
Spleen (1)
 acts as a filter of antigen from the blood
 white pulp is structurally similar to peripheral LNs
 compartments optimize antigen/lymphocyte
interactions
Blood borne antigens are picked up by antigen presenting cells
(eg, macrophages, dendritic cells) in the spleen
Spleen structure
The spleen functions as a ‘filter’ for the blood – removes pathogens,
collects antigens for presentation, and collects/disposes of old RBCs.
The bulk of the spleen is the red pulp – the site of RBC disposal.
Lymphoid cells are organized in the white pulp.
The spleen is the major site
of immune responses to
blood-borne antigens
•White pulp
•Lymphocyte-rich region
•Periarteriolar lymphoid
sheaths around central
arteries: T cell zone
•B cell zone
•Marginal zone
•Marginal zone B cell
•Red pulp
•Erythrocytes,
macrophages, dendritic
cells, lymphocytes,
plasma cells
Spleen structure
• Antigens enter the spleen via arterioles (instead of lymphatics)
• Sinuses pass through the white pulp where the lymphocytes reside.
• Antigens are trapped in the marginal zone by resident APCs.
• Lymphocytes and antigen meet in the periarteriolar lymphoid sheath
(PALS).
T cells in the spleen
B cells in the spleen
Spleen structure
The PALS is primarily
composed of T cells
The B cells are located
in the germinal center
and B cell corona
The marginal zone
contains macrophages
and MZ B cells
Antigen enters mucosal
lymphoid tissues through
specialized cells
• Antigen is delivered to
mucosal lymphoid tissues
through M cells
• M cells deliver viruses and
bacteria to dendritic cells
• B cell follicles of gut
lymphoid tissue are active
with germinal centers
Mucosa-associated lymphoid tissue
(MALT)
MALT are specialized areas of tissue beneath mucosal surfaces that are
designed to collect antigen and stimulate localized adaptive immune
responses to protect the mucosal surfaces.
The architecture is different from LNs, but employs the same basic process –
trap antigen and present it to lymphocytes in organized follicles.
Gut-associated lymphoid tissue
(GALT)
A subdivision of MALT – most important tissues are the Peyer’s
patches. These are large, highly organized areas of lymphoid tissue
found along the small intestine. Antigen is collected from the GI
epithelial surface by specialized M cells.
Cutaneous immune system
•Langerhans cells in the epidermis; immature dendritic cells, capture
antigens
•Intraepithelial T cells, gd T cells
•Dermal dendritic cells
•T cells
Thymus
•The site of T cell maturation
•Thymocyte: lymphocytes in
the thymus at various
stages of maturation
•Immature T cell lineage
cells enter the cortex
through the blood vessels
•As thymocytes mature, they
migrate toward the medulla
and exit the thymus and
enter the blood
•Cortex
•Medulla
•Hassall’s corpuscle
Maturation of T cells in the thymus
Table 10-1. Importance of Antimicrobial Defenses for Infectious Agents
Bacteria
+++
++++
+++
+++*
++++
+
++
Fungi
+++
++
+
++
+++
+++
++
+
+++
++
+
++++
++
++
++ (IgE)†
Extracellular Intracellular
NK cells
CD4 Th1,
DTH
CD8 CTL
Antibody
-
Complement
Interferon-α/β
Neutrophils
Macrophages
Viruses
-
*By activation of macrophages.
†Immunoglobulin E and mast cells are especially
important for worm infections.
CTL, cytotoxic T lymphocytes; DTH, delayed type
hypersensitivity; NK, natural killer; Th1, T helper
Parasites
++
+
1-1 Cells of the Immune System:
Differentiation in the Bone Marrow
1. Which of the following cells belong to the myeloid lineage?
a)
macrophages
b)
neutrophils
c)
mast cells
d)
NK cells
2. Which of the following statements are true?
a)
Hematopoietins do not stimulate the production of myeloidlineage cells.
b)
Growth factors required for the production of different
types of hematopoietic cells are produced both
consititutively by some tissue cells and inducibly by tissue
cells and immune cells in response to infection.
c)
Interleukins are cytokines that signal between immune cells
and can also serve as growth factors for specific cell types.
1-2 Cells of the Immune System: Functional
Characteristics
Work through the following questions, checking all the correct answers. For each
question there may be more than one correct answer.
1. Which of the following are phagocytic cells?
a)
eosinophils
b)
macrophages
c)
dendritic cells
d)
basophils
2. Which of the following statements are true?
a)
Plasma cells are naïve lymphocytes that circulate
through blood and lymph before they have encountered
antigen.
b)
Neutrophils, basophils, mast cells and eosinophils all
store inflammatory mediators in cytoplasmic granules.
c)
The two major classes of effector T lymphocytes are T
helper cells and cytotoxic T cells.
d)
T helper cells activate B cells and macrophages.
1-3 Macrophage and Dendritic Cell Subsets
1. Which of the following are specialized properties of
macrophages?
a)
Ingestion and destruction of microorganisms
b)
Tissue maintenance and repair
c)
Migration to lymphoid tissues in the presence of infection
d)
Activation of naïve T cells
2. Which of the following statements are true?
a) Dendritic cells can differentiate from either lymphoid or myeloid
precursors.
b) Dendritic cells have a sentinel role as immature dendritic cells in
lymphoid as well as peripheral tissues.
c) Dendritic cells include specialized cells known as Kupffer cells.
d) Dendritic cells are especially abundant at epithelial surfaces.
1-5 Major Histocompatibility Molecules and
the Detection of Infection
a)
MHC molecules are highly variable because they must
recognize the variable receptors of T lymphocytes.
b)
MHC molecules are highly variable because they must
bind antigenic fragments of diverse and variable
pathogens.
c)
MHC class I molecules are specialized to bind antigen
fragments generated in the cytoplasmic compartment of
cells.
d)
MHC class I molecules are particularly important for
presenting antigenic fragments of viruses.
e)
MHC class I molecules are recognized by T lymphocytes
bearing CD4 coreceptor molecules.
1-6 The Lymphoid System and Lymphocyte
Circulation
1. Peyer's patches are:
a) the lymphoid areas of the spleen.
b) regions of highly organized lymphoid tissue in the small intestine.
c) the T cell areas of the lymph nodes.
2. Which of the following statements are true?
a) The primary lymphoid tissues are the bone marrow and thymus.
b) Naïve lymphocytes enter lymph nodes from the lymphatic
vessels.
c) Germinal centers are the regions in secondary lymphoid tissue
where T lymphocytes are activated by dendritic cells.
d) In the spleen, the lymphoid tissues ensheath arterioles.
1-7 Architecture of Secondary Lymphoid
Tissues
1. Which of the following are routes of entry for
antigen into secondary lymphoid tissues?
a)
Afferent lymphatic vessels.
b)
The marginal sinus of the spleen.
c)
High endothelial venules (HEV).
d)
M cells in mucosal epithelia.
2. Which of the following statements are true?
a)
The marginal zone of the spleen contains B cells specialized
to respond rapidly to blood-borne bacteria.
b)
Follicular dendritic cells are dendritic cells that activate T cells
that migrate into B cell follicles.
c)
Germinal centers are present throughout the lymphoid tissues
of the small intestine.
d)
Intact microorganisms can enter gut-associated lymphoid
tissues through M cells.
Cells and Tissues of the Immune System
Question 1
• The cells labeled 1, 2, and 3 shown in the figure are:
A) 1, plasma cell; 2, monocyte; 3, resting lymphocyte
B) 1, monocyte; 2, plasma cell; 3, resting lymphocyte
C) 1, plasma cell; 2, resting lymphocyte; 3, monocyte
D) 1, resting lymphocyte; 2, monocyte; 3, plasma cell
E) 1, resting lymphocyte; 2, plasma cell; 3, monocyte
Resting lymphocytes can be found in blood
and tissues and may be naïve or memory
cells. They are 8 to 10 μm in diameter and
have a large nucleus with dense nuclear
chromatin and little visible cytoplasm.
Plasma cells, which are differentiated
antibody-secreting B lymphocytes, are
found in tissues. They are larger than
resting lymphocytes and have eccentric
nuclei with heterogeneous chromatin
staining and abundant cytoplasm with a
distinct perinuclear halo.
The plasma cell has an
eccentric, largely
heterochromatic nucleus
with central nucleolus and
heterochromatin clumped
in a "clockface" or "wagon
wheel" arrangement
around the inner face of
the nuclear membrane.
There is extensive rER.
Golgi complexes are
typically visible. Fawcett DW,
The Cell: An Atlas of Fine Structure,
WB Saunders, Philadelphia, 1966, p.
153.
Monocytes are the circulating precursors of
tissue macrophages. They are 10 to 15 μm
in diameter and have a typically beanshaped (kidney-shaped) nucleus and
abundant cytoplasm.
Question 2. A 52-year-old man who receives
radiation therapy and cytotoxic drugs for treatment
of cancer sustains significant damage to his bone
marrow. Which of the following changes will most
likely occurs?
A) Decreased production of B lymphocytes but not T lymphocytes
B) Decreased production of T lymphocyte but not B lymphocytes
C) Decreased production of neutrophils and monocytes but not B
or T lymphocytes
D) Decreased production of B lymphocytes and T lymphocytes
E) Normal production of all blood cells due to compensatory
extramedullary hematopoiesis. Decreased production of
histiocytes (macrophages) but not other cell type.
Question 4. Tissue macrophages are derived from
which type of circulating blood cell?
A) Polymorphonuclear leukocyte
B) Small lymphocyte
C) Monocyte
D) Basophil
E) Lymphoblast
Question 5. A 5-year old boy with recurrent
infections is discovered to have a genetic defect
that impairs B cell maturation. Which of the
following abnormalities is most likely to be found in
this patient?
A) Small thymus
B) Absence of follicles in lymph nodes
and spleen
C) Enlarged tonsils
D) Diminished parafollicular zones in
lymph nodes
E) Hypocellular bone marrow
1.
Which of the following cells serve as antigenpresenting cells that travel from the site of an
infection to the lymph system to activate cells in
the adaptive immune system?
Dendritic cells
Macrophages
B-cells
Mast cells
1.
2 The role of Toll-like receptors is
. to: *
Im
mun
olog
y
Revi
ew
I:
Cell
s of
the
Im
mun
e
Syst
em
Which of the following is a
phagocytic cell of the innate
immune system that circulates
through the bloodstream until
"summoned"? *
a. Helper T-cell
a. Present a gathered antigen to Tcells
b. Recognize molecular patterns
characteristic of common pathogens
c. Provide a binding site for antibody
and cognate antigen
d. None of the above
Post
test
Inst
ruct
ions:
To
rece
ive
cred
it for
y our
parti
cipat
ion
in
this
activ
ity ,
plea
se
com
plete
the
follo
wing
steps
:
1.Pa
rtici
pate
in
the
onlin
e
activ
ity .
2.Co
mple
te
the
Postt
est,
sele
cting
the
most
appr
opri
ate
resp
onse
to
each
ques
tion.
3.Co
mple
te
the
Eval
uatio
n (P
leas
e be
sure
to
indic
ate
how
long
it
took
to
com
plete
this
activ
ity .
The
amo
unt
of
time
you
atte
st to
on
this
eval
uati
on
will
be
refl
ecte
d on
your
cert
ifica
te.)
b. Macrophage
c. Neutrophil
d. Mast cell
3 Which of the following cells serve as antigen-presenting
. cells that travel from the site of an infection to the lymph
system to activate cells in the adaptive immune system? *
4.Pri
nt
out
y our
certi
ficat
e.
* All
Que
stion
s
Are
Req
uire
d
a. Dendritic cells
1.
Which of the following is a
phagocytic cell of the
innate immune system that
circulates through the
bloodstream until
"summoned"? *
a. Helper T-cell
b. Macrophage
c. Neutrophil
d. Mast cell
b. Macrophages
c. B-cells
d. Mast cells
Question 1 (10 points).
DRAW AND DESCRIBE the basic structure of a lymph node. Use
the following terms:
afferent
efferent
cortex
medulla
germinal center
HEV
Where are B cells located in your lymph node?
Where are T cells located in your lymph node?
How would the antigen get there?
How would the T cells get there?
Question 2 (3 points).
1
2
5
6
3
4
7
8
These are different cell types from blood (1-7) or tissue (8). What are their name
and their lineage (lymphoid, myeloid or erythroid)?
Question 3 (2 points).
Some tissues contain specialized resident macrophages and dendritic cells. What
are their names ?
Question 4 (2 points)
Fill out the table using the following key words: class I, class II, extracellular,
intracellular, cytotoxic, helper
MHC restriction
Recognized
antigen
Function
CD4 T cells
CD8 T cells
Class II
Class I
extracellular
intracellular
helper
cytotoxic
Question 5 (3 points)
Explain “inflammation”, using the following key words: rubor (redness), color
(heat), tumor (swelling) and dolor (pain)