PRELIM LEC: Leukocyte Development, Kinetics, and Functions Flashcards
also known as white blood cells, or WBCs
LEUKOCYTES
relatively colorless compared to red blood cells
LEUKOCYTES
develop from hematopoietic stem cells (HSCs) in the bone marrow, where most undergo differentiation and maturation
LEUKOCYTES
number of circulating leukocytes varies with sex, age, activity, time of day, and ethnicity; reacting to stress, being consumed, or being destroyed, and whether or not they are being produced by the bone marrow in sufficient numbers
LEUKOCYTES
Function: mediating immunity (innate or adaptive)
LEUKOCYTES
refers to the movement of cells through developmental stages, into the circulation, and from the circulation to the tissues and includes the time spent in
each phase of the cell’s life.
Kinetics
THE BODY COMPONENTS:
- BONE MARROW
- PERIPHERAL BLOOD
- TISSUES
WHERE WBC MATURE
BONE MARROW
MAIN COMPONENT OF WBC
PERIPHERAL BLOOD
TARGET SITES OF WBC
TISSUES
group of leukocytes whose cytoplasm is filled with granules with differing staining characteristics
GRANULOCYTES
nuclei are segmented or lobulated
GRANULOCYTES
3 GRANULOCYTES
- EOSINOPHILS
- BASOPHILS
- NEUTROPHILS
with granules containing basic proteins that stain with acid stains such as eosin.
Eosinophils
with granules that are acidic and stain with basic stains such as methylene blue;
Basophils
with granules that react with both acid and basic stains, which gives them a pink to lavender color.
Neutrophils
present in the peripheral blood in two forms according to whether the
nucleus is ______
NEUTROPHIL; SEGMENTED AND BAND FORM
make up the vast majority of circulating leukocytes.
Segmented neutrophils
Neutrophil Development Occurs in
BONE MARROW
Share a common progenitor with monocytes and distinct from eosinophils and basophils, known as the
granulocyte-monocyte progenitor (GMP)
The major cytokine responsible for the stimulation of neutrophil
production is
granulocyte colony-stimulating factor, or G-CSF.
There are three pools of developing neutrophils:
stem cell pool, proliferation
pool, and maturation pool
consists of HSCs hat are capable of self-renewal and differentiation.
stem cell pool
consists of cells that are dividing and includes (listed in the order of maturation)
The proliferation (mitotic) pool
The proliferation (mitotic) pool consists of cells that are dividing and includes (listed in the order of maturation):
- common myeloid progenitors (CMPs), also known as colony-forming units–granulocyte, erythrocyte, monocyte, and megakaryocyte (CFU-GEMMs);
- granulocyte-monocyte progenitors (GMPs);
- myeloblasts; promyelocytes; and myelocytes.
The third marrow pool is the
maturation (storage) pool
consisting of cells undergoing nuclear maturation that form the marrow reserve and are available for release
maturation (storage) pool
The third marrow pool is the maturation (storage) pool consisting of cells undergoing nuclear maturation that form the marrow reserve and are available for release:
metamyelocytes, band neutrophils, and segmented neutrophils.
Compromise 0% to 3% of the nucleated cells in the bone marrow
MYELOBLAST
14 to 20 um in diameter
MYELOBLAST
subdivided into type I, type II, and type III myeloblasts
MYELOBLAST
N:C OF MYELOBLAST:
6:1
(N:C) ratio of 8:1 to 4:1 (the nucleus occupies most of the cell, with very little cytoplasm)
Type I
slightly basophilic cytoplasm
Type I
fine nuclear chromatin
Type I
two to four visible nucleoli
Type I
no visible granules when observed under light microscopy with Romanowsky stains
Type I
presence of dispersed primary (azurophilic) granules in the cytoplasm
Type II
the number of granules does not exceed 20 per cell
Type II
darker chromatin and a more purple cytoplasm
Type III
they contain **more than **20 granules that do not obscure the nucleus
Type III
rare in normal bone marrows, but they can be seen in certain types of acute myeloid leukemias. PATHOLOGIC
Type III
Mufti and colleagues proposed combining type II and type III blasts into a single category of “granular blasts” because of the difficulty in distinguishing type II blasts from type III blasts
Type III
comprise 1% to 5% of the nucleated cells in the bone marrow
PROMYELOCYTES
relatively larger than the myeloblast
PROMYELOCYTES
6 to 25 um in diameter
PROMYELOCYTES
Nucleus is round to oval and is often eccentric
PROMYELOCYTES
A paranuclear halo or “hof” is usually seen in normal promyelocytes but not in the malignant promyelocytes of acute promyelocytic leukemia
PROMYELOCYTES
The cytoplasm is evenly basophilic and full of primary (azurophilic) granules
PROMYELOCYTES
The nucleus is similar to that described earlier for myeloblasts except that chromatin clumping (heterochromatin) may be visible, especially around the edges of the nucleus
PROMYELOCYTES
One to three nucleoli can be seen but may be obscured by the granules
PROMYELOCYTES
These granules are the first in a series of granules to be produced during neutrophil maturation
primary (azurophilic) granules
6% to 17% of the nucleated cells in the bone marrow
MYELOCYTES
final stage in which cell division (mitosis) occurs.
MYELOCYTES
During this stage, the production of primary granules ceases and the cell begins to manufacture secondary (specific) neutrophil granules.
MYELOCYTES
This stage of neutrophil development is sometimes divided into early and late
myelocytes.
MYELOCYTES
**Early myelocytes **may look very similar to the promyelocytes (described earlier) in size and nuclear characteristics except that patches of grainy pale pink cytoplasm representing secondary granules begin to be evident in the area of the Golgi apparatus.
MYELOCYTES
Secondary neutrophilic granules slowly spread through the cell until its cytoplasm is more lavender-pink than blue.
MYELOCYTES
As the cell divides, the number of primary granules per cell is decreased and their membrane chemistry changes so that they are much less visible.
MYELOCYTES
Late myelocytes are somewhat smaller than promyelocytes (15 to 18 mm), and the nucleus has considerably more heterochromatin. Nucleoli are difficult to see by light microscopy
MYELOCYTES
has D-SHAPED HOF
MYELOCYTES
NEUTRAL STAINING
MYELOCYTES
DEFINITE PRODUCTION OF SECONDARY GRANULES
MYELOCYTES
patches of grainy pale pink cytoplasm representing secondary granules
dawn of neutrophilia
WHAT CD MARKER SEEN IN ACUTE MYELOTIC LEUKEMIA (AML)?
CD34
WHAT CD MARKER SEEN IN acute promyelocytic leukemia (APL)?
CD64
constitute 3% to 20% of nucleated marrow cells.
METAMYELOCYTES
the cells are no longer capable of division and the major morphologic change is in the shape of the nucleus.
METAMYELOCYTES
The nucleus is indented (kidney bean shaped or peanut shaped), and the chromatin is increasingly clumped.
METAMYELOCYTES
Nucleoli are absent.
METAMYELOCYTES
Synthesis of **tertiary granules **(also known as gelatinase granules) may begin during this stage.
METAMYELOCYTES
The size of the metamyelocyte is slightly smaller than that of the myelocyte
(14 to 16 mm).
METAMYELOCYTES
The cytoplasm contains very little residual ribonucleic acid (RNA) and therefore little or no basophilia
METAMYELOCYTES
ALSO KNOWN AS JUVENILE CELL
METAMYELOCYTES
MOST ABUNDANT
METAMYELOCYTES
make up 9% to 32% of nucleated marrow cells and 0% to 5% of the nucleated peripheral blood cells.
BANDS
All evidence of RNA (cytoplasmic basophilia) is absent, and tertiary granules continue to be formed during this stage.
BANDS
Secretory granules (also known as secretory vesicles) may begin to be formed during this stage.
BANDS
nucleus is highly clumped, and the nuclear indentation that began in the metamyelocyte stage now exceeds one half the diameter of the nucleus, but actual segmentation has not yet occurred
BANDS
7% to 30% of nucleated cells in the bone marrow.
SEGMENTED NEUTROPHILS
Secretory granules continue to be formed during this stage.
SEGMENTED NEUTROPHILS
morphologic difference between segmented neutrophils and bands is the presence of between two and five nuclear lobes connected by thread-like filaments
SEGMENTED NEUTROPHILS
present in the highest numbers in the peripheral blood of adults
SEGMENTED NEUTROPHILS
are of significant importance in allowing neutrophils to marginate as well as exit the blood and enter the tissues by a process
known as diapedesis
Integrins and selectins
make up 1% to 3% of nucleated cells in the bone marrow.
EOSINOPHILS
slightly more than a third are mature, a quarter are eosinophilic metamyelocytes, and the remainder are eosinophilic promyelocytes or eosinophilic myelocytes.
EOSINOPHILS
similar to neutrophils
EOSINOPHILS
arise from the CMP
EOSINOPHILS
Eosinophil lineage is established through the interaction between the cytokines:
interleukin-3 (IL-3), IL-5 (induced by IL-33), and GM-CSF
*
3 TRANSCRIPTION FACTORS OF EOSINOPHILS:
GATA-1 (hematopoietic transcription factor), PU.1, and
c/EBP.
are critical for eosinophil growth and survival
IL-5 and IL-33
Eosinophilic promyelocytes can be identified cytochemically because of the presence of
Charcot-Leyden crystal protein
presence of large (resolvable at the light microscope level), pale, reddish-orange secondary granules, along with azure granules in blue cytoplasm.
EOSINOPHIL MYELOCYTES
The nucleus is similar to that described for neutrophil myelocytes.
EOSINOPHIL MYELOCYTES
Transmission electron micrographs of eosinophils reveal that many secondary eosinophil granules contain an electron-dense crystalline core
EOSINOPHIL MYELOCYTES
resemble their neutrophil counterparts with respect to their nuclear shape.
EOSINOPHIL METAMYELOCYTES AND BANDS
Secondary granules increase in number, and a third type of granule is generated called the secretory granule or secretory vesicle.
EOSINOPHIL METAMYELOCYTES AND BANDS
The secondary granules become more distinct and refractory.
EOSINOPHIL METAMYELOCYTES AND BANDS
Electron microscopy indicates the presence of two other organelles: lipid bodies and small granules
EOSINOPHIL METAMYELOCYTES AND BANDS
The time from the last myelocyte mitotic division to the emergence of mature
eosinophils from the marrow is about ___
3.5 days
Survival time of eosinophils in human tissues ranges from
2 to 5 days
4 Eosinophil Functions:
- Classical exocytosis
- Compound exocytosis
- Piecemeal degranulation
- Cytolysis
granules move to the plasma membrane, fuse with the plasma membrane, and empty their contents into the extracellular space.
Classical exocytosis
exocytosis is a second mechanism in which granules fuse together within the eosinophil before fusing with the plasma membrane.
Compound exocytosis
in which secretory vesicles **remove
specific proteins **from the secondary granules. These vesicles then migrate to the plasma membrane and fuse to empty the specific proteins into the extracellular space
Piecemeal degranulation
that occurs when extracellular intact granules are deposited during cell lysis. SPLILLING OF CELLULAR CONTENTS
Cytolysis
*
OTHER NAME OF PIECEMEAL DEGRANULATION
EOSINOPHIL SUMBRERO VESICLE
HALLMARK OF ALLERGY
EOSINOPHIL
EASILY ACTIVATED FROM BASOPHILS
EOSINOPHIL
________ are true leukocytes because they mature in the bone marrow and circulate in the blood as mature cells with granules,
basophils
____________ precursors leave the bone marrow and use the blood as a transit system to
gain access to the tissues where they mature.
mast cell
least numerous of the WBCs, making up between 0% and 2% of circulating
leukocytes and less than 1% of nucleated cells in the bone marrow.
BASOPHILS
derived from progenitors in the bone marrow and spleen, where they differentiate under the influence of a number of cytokines, including
BASOPHILS; including IL-3 and
TSLP (thymic stromal lymphopoietin)
Two basophil populations are identified:
- IL-3 elicited basophils that are immunoglobulin **E (IgE) **dependent and
- **non-IgE **dependent TSLP elicited
basophils.
Nucleoli may or may not be apparent.
IMMATURE BASOPHILS
have round to somewhat lobulated nuclei with only slightly condensed chromatin.
IMMATURE BASOPHILS
The cytoplasm is blue and contains large blue-black secondary granules
IMMATURE BASOPHILS
Primary azure granules may or may not be seen.
IMMATURE BASOPHILS
Basophil granules are water soluble and therefore may be dissolved if the blood film is washed too much during the staining process.
IMMATURE BASOPHILS
Actual nuclear segmentation with visible filaments occurs rarely. The cytoplasm is colorless and contains large numbers of the characteristic large blue-black granules.
MATURE BASOPHILS
If any granules have been dissolved during the staining process, they often leave a reddish-purple rim surrounding what appears to be a vacuole
MATURE BASOPHILS
The chromatin pattern, if visible, is clumped.
MATURE BASOPHILS
contain a lobulated nucleus that is often obscured by its granules.
MATURE BASOPHILS
This life span of basophils is relatively longer than that of the other granulocytes:
60 hours
This has been attributed to the fact that when they are activated by _______, antiapoptotic pathways are initiated that prolong the basophil life span.
IL-3 and IL-25
functions in both innate and adaptive immunity.
BASOPHILS
are capable of releasing large quantities of subtype 2 helper T cell (TH2) cytokines such as IL-4 and IL-13 that regulate the TH2 immune
response.
BASOPHILS
also induce B cells to synthesize IgE.
BASOPHILS
are the effectors of IgE-mediated chronic allergic inflammation
MAST CELLS
________function as initiators of the allergic inflammation through the release of preformed cytokines.
basophils
not considered to be leukocytes.
MAST CELLS
They are tissue effector cells of allergic responses and inflammatory reactions.
MAST CELLS
(1) their precursors circulate in the peripheral blood for a brief period on their way to their tissue destinations, and
MAST CELLS
have several phenotypic and functional similarities with both basophils and eosinophils.
MAST CELLS
originate from the bone marrow and spleen
MAST CELLS PROGENITORS
The progenitors are then released to the blood before finally reaching tissues such as the intestine and lung, where they mediate their actions.
MAST CELLS
The major mast cell cytokine responsible for mast cell maturation and differentiation is
KIT ligand (stem cell factor)
can have antiinflammatory and immunosuppressive functions, and thus they can both enhance and suppress features of the immune response
Mast cells
They may act as immunologic “gatekeepers” because of their location in mucosal surfaces and their role in barrier function.
Mast cells
categorized into monocytes and lymphocytes.
MONONUCLEAR CELLS
These cells have nuclei that are not segmented but are round, oval, indented, or folded.
MONONUCLEAR CELLS
similar to neutrophil development because both cell types are derived from
the GMP
MONOCYTES
is the major cytokine responsible for the growth and differentiation of monocytes.
Macrophage colony-stimulating factor (M-CSF)
The nucleus may be round, oval, or** kidney** shaped but more often is deeply indented (horseshoe shaped) or folded on itself.
MONOCYTES
The chromatin pattern is looser than in the other leukocytes and has sometimes been described as lace-like or stringy.
MONOCYTES
Their cytoplasm is blue-gray, with fine **azure granules **often referred to as azure dust or a ground-glass appearance.
MONOCYTES
There is **no storage pool of mature **monocytes in the bone marrow, and unlike neutrophils, monocytes are released immediately into the circulation upon maturation.
TRUE
Monocytes/macrophages recognize a wide range of bacterial pathogens by means of pattern recognition receptors (**Toll-like
receptors) **that stimulate inflammatory cytokine production and phagocytosis.
TRUE
ARE RECEPTORS THAT CAN DETECT PAMP (PATHOGEN ASSOCIATED MOLECULAR PATTERN)
Toll-like receptors
These include removal of debris and dead cells at sites of infection or tissue damage, destruction of senescent red blood cells
MONOCYTE
LYMPHOCYTES divided into three major groups:
T cells, B cells, and natural killer (NK) cells
are major players in adaptive immunity.
T and B cells
make up a small percentage of lymphocytes and are part of innate immunity.
NK cells
Participate in humoral immunity by producing
antibodies; develop in the bone marrow.
B lymphocytes (B cells)
Participate in cellular immunity by attacking foreign organisms or cells directly; develop in the thymus.
T lymphocytes (T cells)
Contribute to cellular immunity; develop in both the bone marrow and the thymus.
Natural Killer (NK) cells
Not End Cells
LYMPHOCYTES
Occurs in the bone marrow (B cells) and thymus (T cells).
Antigen-Independent Phase
Central or primary lymphatic organs involved.
Antigen-Independent Phase
Occurs in secondary lymphatic organs: spleen, lymph nodes, tonsils, mucosa-associated lymphoid tissue (e.g., Peyer’s patches).
Antigen-Dependent Phase
Secondary lymphatic organs are sites for antigen exposure and lymphocyte activation.
Antigen-Dependent Phase
IMMATURE B CELLS CD MARKERS
- CD21
- CD40
- MHC CLASS II
PRO B CELLS CD MARKERS
- CD19
- CD43
MATURE B CELLS HAS WHAT IMMUNOGLOBULINS:
IgG and IgD
MATURE B CELLS BECOME?
MARGINAL ZONE B CELLS AND FOLECULAR B CELLS
PRE B CELLS HAS?
MU HEAVY CHAINS AND SOME LIGHT CHAINS
B CELLS THAT CAME IN CONTACT WITH ANTIGEN
ACTIVATED B CELLS
SUEFACE ANTIGENS/CD MARKERS OF NK CELLS:
CD56, CD16, CD3-, CD7
RECEPTOR OF FC REGION OF LYMPHOCYTE?
CD16
WHO ACTIVATE THESE SURFACE ANTIGENS/CD MARKERS OF NK CELLS?
IL-15
Primary Function: Antibody production.
- Other Roles:
o Antigen presentation to T cells, aiding CD4 activation.
o Cytokine production to regulate T cell and antigen-presenting cell functions.
B Lymphocytes (B Cells)
SUBTYPES OF T LYMPHOCYTE:
TH1
TH2
TH17
TREG CELLS
Mediate immune responses against intracellular pathogens.
TH1 cells
Defend against extracellular parasites (e.g., helminths); contribute to asthma and allergic disease induction.
TH2 cells
Combat extracellular bacteria and fungi.
TH17 cells
Maintain self-tolerance by regulating immune responses TOGETHER WITH EOSINOPHIL
Treg cells (CD4+CD25+ Regulatory T Cells)
Kill target cells by:
o Secreting granules containing granzyme and perforin.
o Activating apoptotic pathways in target cells.
CD8+ T Cells (Cytotoxic T Lymphocytes)
- Function as part of innate immunity.
- Capable of killing:
o Certain tumor cells.
o Virus-infected cells without prior sensitization. - Modulate the functions of other immune cells (e.g., macrophages and T cells).
Natural Killer (NK) Cells
