Cells and Organs of the Immune System 2015 SV(1

Cells and Organs of the Immune System:

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Cells and Organs of the Immune System:
• Immune System = network of cells and organs that extends
throughout body and functions as the last line of defense
against infection (also called Lymphoid System)
• Lymph = interstitial fluid derived from blood plasma
• Leukocytes = white blood cells; participate in immune
response; carried within blood and lymph and populating the
lymphoid organs

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Types of Leukocytes (WBC):
1. Granulocytes: contain obvious cytoplasmic granules
• Neutrophils
• Basophils
• Mast cells
• Eosinophils
2. Myeloid Antigen-Presenting Cells (APC):
• Monocytes / macrophages
• Dendritic cells
3. Megakaryocytes / Platelets
4. Lymphocytes:
• B cells, T cells, natural killer (NK) cells, NKT cells

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Granulocytes
• Irregularly-shaped, multi-lobed nucleus
• Granules containing anti-microbial chemicals and
enzymes
• Subdivided into 4 categories based on cellular
morphology and staining characteristics of granules:
a) Neutrophils
b) Basophils
c) Mast cells
d) Eosinophils

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Neutrophils
• Multi-lobed nucleus
• Granulated cytoplasm
• Stain with acidic or basic dyes
• Only live a few days
• 50 to 70% of leukocytes in circulation
• Often called polymorphonuclear leukocyte (PMN)
• Perform phagocytosis (cellular uptake of particulate
matter by engulfment - more later)
• Among the first cells recruited to the site of infection
– Leukocytosis = transient increase in # circulating WBC
– Neutrophilia = indication of infection (increase may be
2-3 fold)
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Basophils
• Lobed nucleus
• Heavily granulated cytoplasm
• Stain blue with basic methylene blue
• <1 % of circulating leukocytes
• Not phagocytic
• Undergo degranulation (discharge contents of cytoplasmic
granules following appropriate stimulus)
– Release pharmacologically active substances from
cytoplasmic granules (ex. histamine) → defense against
larger parasites (ex. helminths) and allergic response
(Allergy = malfunction of body’s defense in which
harmless agents (ex. pollen) → inappropriate immune
reaction)
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Mast Cells
• Share many features with basophils
• Large numbers cytoplasmic granules
• <1 % of circulating leukocytes
• Precursors form in bone marrow, are released into blood
and differentiate when enter tissue
• Found in skin, connective tissue of various organs, mucosal
epithelial tissue (respiratory, genitourinary, digestive)
• Important in activation of inflammatory response
(degranulate to release inflammatory mediators)
• Release pharmacologically active substances → allergic
response (more later)
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Eosinophils
• Bilobed nucleus
• Granulated cytoplasm
• Stain red with acidic dye Eosin Red
• 1 to 3% of circulating leukocytes
• Phagocytic (minor role)
• Important in defense against parasites which are too
large to be phagocytosed (secreted contents of
eosinophilic granules damages parasite membrane)
– Ex. defense against protozoal parasites, fungi, worms

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Myeloid Antigen-Presenting Cells
• Phagocytic cells that have professional antigenpresenting cell function
– Monocytes
– Macrophages
– Dendritic cells
• Professional antigen-presenting cells (APCs) ingest
pathogen, digest pathogenic proteins into peptides,
then present these peptide antigens on their
membrane surfaces to activate other immune cells
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Monocytes / Macrophages:
• Compact nucleus
• Phagocytic
• Monocytes are generated in the bone marrow and can
migrate to the tissues to differentiate into macrophages
or dendritic cells
• Macrophages are 5 to 10 times larger than
monocytes, have increased number and complexity of
organelles, and are more immunologically active

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Monocyte Development:
Granulocyte / monocyte progenitor
(in bone marrow)
↓
Promonocyte
↓
Enters blood and circulates ~ 8 hours while
differentiating into mature monocyte

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• Two types of monocytes:
1. Inflammatory monocytes (more common): enter tissues
quickly in response to infection
– Once in the tissue, monocytes can differentiate into
macrophages or dendritic cells
2. Patrolling monocytes (less common): crawl along blood
vessels; provide reservoir for tissue-resident monocytes in
absence of infection; may quell rather than initiate immune
responses

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Macrophages:
•
•
•
•

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Phagocytic
May survive months in tissue
Wandering macrophages travel to infected tissue
Fixed macrophages reside permanently in a particular
tissue
– Alveolar macrophages (lung)
– Microglial cells (brain)
– Osteoclasts (bone)

• Play role in eliminating bacteria during early stages of
infection (via phagocytosis -- see section on
phagocytosis under “non-specific interior defenses”)
• Very efficient at scavenging dead cells and debris during
inflammatory repair
• Macrophages activated by various stimuli (phagocytosis,
cell to cell contact, chemical stimulus) → active
macrophage with increased phagocytic, killing, and
secretory capability)
• Also participate in body’s SPECIFIC IMMUNE
DEFENSES as antigen presenting cells (phagocytose
Ag, then present the Ag on their surface to “show”
Ag to other immune cells (T) → increased response)
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Dendritic Cells:
• Covered in maze of long membrane extensions (resemble
dendrites of nerve cells)
• There are many types of dendritic cells
– Derive from either myeloid or lymphoid lineage
• All dendritic cells except follicular are antigen-presenting
cells
• Note: Follicular dendritic cells
– Do not arise in bone marrow
– Are involved in maturation of B cells (Ab-producing
cells – more later)
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Megakaryocytes:
• Reside in bone marrow
• Very large cells that produce platelets by cytoplasmic
budding
• Platelets = small anucleate cells or cell fragments that
contain vasoactive substances and clotting factors –
important in formation of blood clots
• Platelets are also called thrombocytes
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Lymphocytes:
• = Primary cells of the adaptive immune system
• 20-30% of circulating white blood cells
• Three types of lymphocytes
– B cells
– T cells
– Natural killer (NK) cells
• Smooth, round, relatively small, lack visible granules
• B cells and T cells are difficult to distinguish
morphologically and may appear identical under
microscopy

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Lymphocytes:
• One way to tell them apart is to look at the surface
protein expressed:
– CLUSTER OF DIFFERENTIATION (CD) = a
collection of monoclonal antibodies that all recognize
an antigen found on a particular differentiated cell
type or types – each of the antigens recognized by such a
collection of antibodies is called a “CD Marker” and is
assigned a unique identifying number
– Ex. CD4 T cells
– Ex. CD8 T cells
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Lymphocytes: B Cells
• Agents of Humoral or Ab-mediated Immunity
• Arise and mature in bone marrow
• Each express a unique antigen-binding receptor (B-cell
receptor or BCR) on its membrane
– BCR = membrane bound immunoglobulin (antibody)
– Each of the ~1.5x105 molecules of Ab on the membrane of
a single B cell is identical
• Respond to antigen by dividing rapidly to create memory B
cells and effector B cells called plasma cells (plasma cells
produce a secreted form of the antibody)
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Lymphocytes: T Cells
• Agents of Cell-mediated Immunity
• Arise in bone marrow, but migrate to thymus for
maturation
• Mature T cells express a unique antigen-binding molecule
(T-cell receptor or TCR) on their membrane
– TCR must recognize antigen in association with a
“self” molecule (Major Histocompatibility Complex
or MHC)
• Respond to Ag by directly killing marked cells (TC) or
indirectly by regulating immune system (TH)
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• Two major types of T cells:
– T helper (TH) cells
– CD4+
– T cytotoxic (TC) cells
– CD8+
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Lymphocytes: Natural Killer (NK) Cells
• Large, granular (grainy appearance under microscope)
• Part of innate immune system
• 5-10% of lymphocytes in human peripheral blood
• Display cytotoxic activity against wide range of tumor
cells and against cells infected with viruses
• Do not have T- or B-cell receptors (must recognize
abnormal cells in a different way – more later)

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Lymphocytes: NKT
• NKT cells have characteristics of both T cells and
NK cells
– Have a TCR
• But, not a lot of diversity between TCRs of
different NKTs (unlike regular T cells)
– Some express CD4 (like TH cells)
– Have some of the receptors associated with NK
cells (more later)
– Not well understood (area of active research)
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All Blood Cells (RBC, WBC) Arise from
Hematopoietic Stem Cells (HSC)
– Self-renewing by cell division
– Can differentiate into other cell types
– Display enormous proliferative and
differentiative capacity

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Hematopoiesis:
• Hematopoiesis: formation & development of red & white
blood cells
• Via stem cell differentiation
• Location of development of stem cells into mature immune
cells:
– Bone marrow: HSCs primarily reside here and give rise
to all cell type progenitors in this location
– Thymus: Where T cells complete their maturation (T
cell precursors travel via blood from bone marrow to
thymus where they complete maturation)
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• Early in hematopoiesis, HSC differentiates along one of
two pathways:

→ Lymphoid progenitor cell (gives rise to B, T, natural killer
cells, dendritic cells)
→ Myeloid progenitor cell (gives rise to RBC, neutrophils,
eosinophils, basophils, monocytes / macrophages,
megakaryocytes / platelets, dendritic cells)
• These lymphoid and myeloid progenitor cells are:
– No longer self-renewing
– Committed to particular cell lineage
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Regulation of Hematopoiesis:
• Hematopoiesis is continuous process that must
maintain a steady state (production of blood cells
equals loss)
• Failure to regulate may contribute to development of
some leukemias
• Lifespan of blood cells depends on type (ex.
Neutrophils (as little as 1 day); RBC (~120 days);
some T lymphocytes (20-30 years)

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• Steady-state regulation of hematopoiesis achieved
through:
1. Regulation by cytokines (chemical messengers) that
stimulate proliferation and / or differentiation of
various hematopoietic cells
2. Regulation of expression of receptors for cytokines
in stem and progenitor cells
3. Removal of some cells by controlled induction of
cell death (apoptosis)

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Programmed Cell Death (Apoptosis):
• Induced, ordered process in which cell actively brings
about its own demise
• Cells undergoing programmed cell death often exhibit
distinctive morphological changes referred to as
apoptosis
– Decrease in cell volume
– Modification of cytoskeleton → membrane blebbing
– Condensation of chromatin
– Degradation of DNA
– Shedding of tiny membrane-bounded apoptotic
bodies

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• Apoptotic bodies and cells in advanced apoptosis are
phagocytosed (taken up) by macrophages (avoids release
of cellular enzymes which may cause local damage and
inflammatory response)

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Laboratory Count Definitions:
• Complete blood cell count (CBC) = total count
WBC and RBC
• Leukocyte differential count = # of each type of
leukocyte (given as % of total # of leukocytes)
• Diagnostic as acute infection can increase #
leukocytes (especially neutrophils)

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Lymphoid Organs:
Primary Lymphoid Organs:
•

Provide appropriate
microenvironment for
development and maturation of
lymphocytes
• Two primary lymphoid organs:
– Bone marrow
– Thymus
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Secondary Lymphoid Organs:
•

Trap antigen, generally from nearby tissues or
vascular spaces
• Mature B and T cells congregate and interact within
these organs
• Sites where mature lymphocytes can interact
effectively with antigen
• Three types of secondary lymphoid organs:
– Lymph nodes
– Spleen
– Mucosal-associated lymphoid tissue (MALT)
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Primary Lymphoid Organs: Bone Marrow
• Where hematopoietic stem cells produce progenitors
of all blood cell types
• Site of B cell origin and development in humans, mice
(bursa of Fabricius in birds; intestinal area called Peyer’s
patch in cattle and sheep)
• A selection process within bone marrow eliminates B
cells with self-reactive Ab receptors (important)

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Primary Lymphoid Organs: Thymus
• Flat, bilobed organ situated above heart
• Immature T cells formed in bone marrow migrate to
thymus to differentiate
• Stromal-cell network (epithelial cells, dendritic cells,
macrophages) in thymus contributes to growth and
maturation of T cells
• A selection process within thymus eliminates T cells with
self-reactive receptors
• Aging → decline in thymic function (average thymus in
child ~30g; average thymus in elderly ~3g) – this may
account for some of decline in immune function in elderly
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Lymphatic System:
• As blood circulates under pressure, its fluid component
(plasma) seeps through thin wall of capillaries into
surrounding tissue (= interstitial fluid)
– Permeates all tissues and bathes the cells
• Interstitial fluid that does not return to blood through
capillary membranes is called lymph, & flows from spaces
in connective tissue into network of tiny open lymphatic
capillaries, then into series of progressively larger collecting
vessels called lymphatic vessels
• Lymphatic Circulation = system of vessels that collects
excess lymph from tissues and returns it to bloodstream
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Lymphatic capillaries pick up interstitial fluid, particulate and soluble
proteins, as well as immune cells from the tissue surrounding the
blood capillaries

Most of the body’s lymphatics
eventually drain into the thoracic
duct which empties into the left
subclavian vein near the heart to
return lymph to blood.
However, vessels draining right arm
and right side of head converge to
form the right lymphatic duct, which
empties into the right subclavian
vein.
Primary organs (thymus, bone
marrow) in red.
Secondary organs and tissues in blue.
Lymphatic vessels in purple.

• Flow of lymph through lymphatic system is achieved
as lymph vessels are squeezed by movements of body
muscles (heart does not pump lymph)
• Series of one way valves along lymphatic vessels
ensures one-way flow
• Various types of organized lymphoid tissue located
along vessels of lymphatic system (ex. lymph nodes)
• Lymphatic system is means of transporting
lymphocytes and Ag from connective tissues to
organized lymphoid tissues where immune response
may be activated

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Secondary Lymphoid Organs:
• Lymph nodes - located throughout body on lymphatic
vessels
• Spleen
• Mucosal-associated lymphoid tissue (MALT) in
various body sites:
• Adenoids (nose)
• Tonsils (throat)
• Appendix (intestine)
• Peyer’s patches (intestinal wall)
• Within mucous membranes lining upper
airways, bronchi, urogenital tract
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Secondary Lymphoid Organs: Lymph Nodes
• Encapsulated bean-shaped structures containing network
packed with lymphocytes, macrophages, dendritic
cells
• Clustered at junctions of lymphatic vessels → therefore
are first organized lymphoid structure to encounter Ag
that enter tissue
• Provide ideal environment for filtration of foreign Ag
& subsequent interaction of Ag with lymphocytes
• Antigenic stimulation within node causes proliferation
of lymphocytes as well as migration of existing
lymphocytes from blood into node → visible swelling of
node in response to infection
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Lymph Node Structure:

Three Zones:
1.Cortex (contains lymphocytes
(mostly B cells), macrophages, and
follicular dendritic cells arranged in
“follicles”)
2.Paracortex (contains mostly T cells)
3.Medulla (site where lymphocytes,
plasma cells and Ab exit)

Secondary Lymphoid Organs: Spleen
• Large, ovoid organ situated high in left abdominal cavity
• Specializes in filtering blood and trapping blood-borne
Ag (thus responds to systemic infection)
– Blood-borne Ag and lymphocytes enter via spenic
artery
– Blood leaves via spenic vein
• Presents trapped Ag to lymphocytes populating /
circulating through spleen
• Splenectomy → increase in blood-borne bacterial
infections (sepsis / bacteremia)
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Three Zones:
1.Red pulp (network of sinusoids populated by macrophages and RBCs; site of
destruction of old and defective RBCs)
2.Marginal zone (between red and white pulp; contains mainly macrophages and
B cells)
3.White pulp (surrounds the arteries, forming a periarteriolar lymphoid sheath
(PALS) – populated mainly by T cells and B cell follicles)

Laparoscopic Splenectomy
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Secondary Lymphoid Organs:
Mucosal-Associated Lymphoid Tissue (MALT)
• Mucous membranes lining digestive, respiratory, urogenital
tracts have large surface area (~400 m²)
– Major site of entry of for most pathogens
• These vulnerable surfaces defended by MALT
– BALT = bronchus-associated lymphoid tissue
– GALT = gut-associated lymphoid tissue
– NALT = nasal-associated lymphoid tissue
• Structurally range from loose, barely organized clusters of
lymphoid cells (in intestinal villi) to well-organized
structures (tonsils, appendix, Peyer’s patches)
• Has large population of Ab-producing B cells
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• M Cells:
– In mucus membranes of digestive, respiratory and
urogenital tracts
– Flattened epithelial cells lacking the microvilli that
characterize rest of mucosal epithelium
– Function = endocytose and transport antigen
from lumen across epithelium and deliver it to
clusters of lymphocytes and APCs (often dendritic
cells)
– Specific B cells are then activated and differentiate
into plasma cells which produce and secrete
antibody (of the IgA isotype) into the lumen of the
tract
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Skin Also Contains Lymphoid Tissue
• Skin = largest organ in human body
• Critical anatomic barrier against pathogens
• Outer layer of skin composed largely of specialized
epithelial cells called keratinocytes
– Secrete cytokines → local inflammatory response
• Langerhans cells (type of skin-resident dendritic cell)
phagocytose Ag, then migrate to regional lymph nodes
to act as Ag-presenting cells → activate immune
response
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“Tertiary” Lymphoid Tissues:
• = Tissues that are the sites of infection
• Lymphocytes activated by Ag in secondary lymphoid
tissue can return to these organs (ex. lung, liver, brain) as
effector cells and can also reside there as memory cells
• Tertiary lymphoid tissues can generate defined
microenvironments that organize the returning lymphoid
cells

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Evolutionary Distribution of Lymphoid Tissues: