MODULE 2 UNIT 4: LEUKOCYTOSIS Flashcards by Arriane Camacho

Q

are a heterogenous group.

A

Leukocytes

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Q

2 types of Leukocytes

A

granulocytes and agranulocytes

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Q

The granulocytes together with the monocytes share the (?) while the lymphocytes have their (?).

A

same lineage with the red cells (CFU-GEMM)
own (CFU-L)

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Q

pertains to the production and development of the three granulocytes.

A

Ganulopoiesis

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Q

Give the three granulocytes.

A

neutrophils, eosinophils and basophils

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Q

Give the three granulocytes.

A

neutrophils, eosinophils and basophils

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Q

The maturation sequence is almost similar for the three types of cells, except for the (?) that influence production and differentiation.

A

cytokines

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Q

Maturation Sequence of Neutrophil Development

A

I. Stem cell pool
II. Mitotic pool
III. Maturation pool
IV. Neutrophil

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Q

Pluripotential hematopoietic stem cell

A

Stem cell pool

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Q

Mitotic pool
Progenitors:

A

a. CFU-GEMM (Common Myeloid Progenitor)
b. CFU-GM (Granulocyte-Macrophage Progenitor)
c. CFU-G

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Q

Mitotic pool
Precursors:

A

d. Myeloblast
e. Promyelocytes
f. Myelocytes

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Q

Maturation pool
Precursors:

A

a. Metamyelocytes
b. Neutrophilic band

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Q

MYELOBLAST

Size (um)
N:C ratio
Nucleus Shape
Chromatin
Nucleoli
Staining
Granules

A

14 to 20
8:1 to 4:1
Round to oval
Homogenous, delicate, fine euchromatin
2 to 4
Slightly basophilic
No Granules

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Q

PROMYELOCYTE

Size (um)
N:C ratio
Nucleus Shape
Chromatin
Nucleoli
Staining
Granules

A

16-25
3:1 to 2:1
Round to oval
Heterochroma tin Slightly coarse
1-3
Basophilic
Formation of PRIMARY/ Azurophilic granules

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Q

PROMYELOCYTE

Size (um)
N:C ratio
Nucleus Shape
Chromatin
Nucleoli
Staining
Granules

A

16-25
3:1 to 2:1
Round to oval
Heterochroma tin Slightly coarse
1-3
Basophilic
Formation of PRIMARY/ Azurophilic granules

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Q

MYELOCYTE (“Dawn of Neutrophilia”)

Size (um)
N:C ratio
Nucleus Shape
Chromatin
Nucleoli
Staining
Granules

A

12-18
1:1
Oval or round
Coarser and condensed
NONE
Mixture of basophilic and acidophilic
Formation of SECONDARY / Specific granules “Dawn of Neutrophilia ”

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Q

METAMYELOCYTE

Size (um)
N:C ratio
Nucleus Shape
Chromatin
Nucleoli
Staining
Granules

A

15-18
1:1
KIDNEY-SHAPED
Coarse & clumped
NONE
Beige/ salmon
Formation of TERTIARY/ Gelatinase granules

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Q

BAND/STAB

Size (um)
N:C ratio
Nucleus Shape
Chromatin
Nucleoli
Staining
Granules

A

9-15
1:1 to 1:2
Elongate/ band (C or S)
Coarse & clumped
NONE
Beige/ salmon
Continuous formation of tertiary granules Formation of SECRETORY GRANULES (vesicles)

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Q

Cellular Activity of MYELOBLAST

A

0-3% of nucleated cells in BM

Classification:
Type I blasts: No visible granules
“Granular blasts” Rare in normal marrow

Type II blasts: < 20 visible primary or azurophilic granules

Type III blasts: >20 visible primary or azurophilic granules

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Q

Cellular Activity of PROMYELOCYTE

A

1-5% BM Hof/ Paranuclear halo surrounding the nucleus

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Q

Cellular Activity of MYELOCYTE (“Dawn of Neutrophilia”)

A

6-17% BM
LAST STAGE CAPABLE OF MITOSIS

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Q

Cellular Activity of METAMYELOCYTE

A

3-20% BM

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Q

Formed during the promyelocyte stage
Last to be released (Exocytosis)

A

Primary (Azurophilic) Granules

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Q

Contain:
• Myeloperoxidase
• Acid-β- glycerophosphate
• Cathepsins
• Defensins
• Elastase
• Proteinase-3
• Others

A

Primary (Azurophilic) Granules

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Formed during myelocyte and metamyelocyte stages Third to be released

Secondary (Specific) Granules

Contain: • β2- microglobulin • Collagenase • Gelatinase • Lactoferrin • Neutrophil gelatinase- associated lipocalin • Transcobalamin I • Others

Secondary (Specific) Granules

Formed during metamyelocyte and band stages Second to be released

Tertiary Granules

Contain: • β2- microglobulin • Collagenase • Gelatinase • Lysozyme • Acetyltransferase

Tertiary Granules

Formed during the band and segmented neutrophil stages First to be released (fuse to plasma membrane)

Secretory Granules (Secretory Vesicles)

Contain (attached to the membrane): • CD11b/ CD18 • Alkaline phosphatase • Vesicle-associated membrane-2 • CD10, CD13, CD14, CD16 • Cytochrome b558 • Complement 1q receptor • Complement receptor-1

Secretory Granules (Secretory Vesicles)

are also known as polymorphonuclear cells (PMNs) or segmenters.

Neutrophils

Neutrophils are the cells that respond to (?).

bacterial infection

Neutrophils average size ranges from (?) microns.

9 to 15 microns

The nucleus presents with (?) lobes with highly condensed chromatin.

2-5 lobes

The cytoplasm will contain continuously forming (?) secretory granules.

pink to rose-violet

- Normal values: o Bone marrow: o Relative value in peripheral blood: o Absolute value:

o Bone marrow: 7-30% of nucleated cell population o Relative value in peripheral blood: 50-70% of WBCs o Absolute value: 1.7-7.5 x 109/ L

Neutrophil kinetics: o Production: o Mitotic pool: o Maturation pool: o Once in the peripheral blood, neutrophils are divided randomly into a (?) and a (?). The ratio of CNP and MNP is roughly equal. o Majority of the MNP are in the (?) of the lungs.

o Production: 0.9-1.0 x 109 cells/ kg per day o Mitotic pool: 2.11 x 109 cells/ kg o Maturation pool: 5.6 x 109 cells/ kg o Once in the peripheral blood, neutrophils are divided randomly into a circulating neutrophil pool (CNP) and a marginated neutrophil pool (MNP). The ratio of CNP and MNP is roughly equal. o Majority of the MNP are in the capillaries of the lungs.

Transit time: o HSC to myeloblast: o Myeloblast to maturation pool: o Neutrophil half-life in blood: o It takes about (?) from the blast stage to the release of mature granulocytes.

o HSC to myeloblast: 6 days o Myeloblast to maturation pool: 4 to 6 days o Neutrophil half-life in blood: 6-8 hours o It takes about 14 days from the blast stage to the release of mature granulocytes.

Neutrophil Function: a. Phagocytosis Steps

Chemical signals from damaged cells leading to chemotaxis → Margination (sticking to capillary endothelium) → Diapedesis → Recognition of pathogen→ Attachment (Toll-like receptor of phagocyte attaching to PAMPs) → Ingestion → Pathogen in phagosome → Formation of phagolysosome→ Digestion & killing

Respiratory burst through the activation of NADPH oxidase. H2O2 and peroxidase are produced

Oxygen dependent Digestion

The pH within the phagosome becomes alkaline and then neutral, the pH at which digestive enzymes work.

Oxygen independent Digestion

▪ Nuclear & organelle membrane dissolves → DNA release → DNA + cytoplasmic enzymes → Cell membrane ruptures → NET release

NETs

▪ Extracellular threadlike structures believed to represent chains of nucleosomes from DNA

NETs

▪ Have enzymes from neutrophil granules

NETs

▪ Have been shown to be able to trap and kill gram-positive and gramnegative bacteria as well as fungi

NETs

NETs are generated at the time that neutrophils die as a result of antibacterial activity

“NETosis”

• Transcobalamin I/R binder (needed for Vitamin B12 absorption) • Variety of cytokines

Secretory Function

Maturation Sequence of Eosinophil Development

I. Pluripotential hematopoietic stem cell II. Progenitors III. Precursors IV. Eosinophil

Eosinophil Development Maturation Sequence II. Progenitors:

a. CFU-GEMM (Common Myeloid Progenitor) b. CFU-Eo

Eosinophil Development Maturation Sequence III. Precursors:

a. Myeloblast b. Promyelocytes c. Myelocytes d. Metamyelocytes e. Eosinophilic band

o Not fully characterized

A. Eosinophilic myeloblasts

o Cytochemical identification only

B. Promyelocytes

o PRIMARY GRANULE: Charcot-Leyden crystal protein

B. Promyelocytes

o Similar to neutrophil myelocytes

Myelocytes

o Large, pale, reddish-orange SECONDARY GRANULES

Myelocytes

o Resemble their neutrophil counterpart

Metamyelocytes & Band Forms

o Formation of SECRETORY GRANULE/ VESICLE

Metamyelocytes & Band Forms

o Two other organelles are also present: Lipid bodies and Small lysosomal granules

Metamyelocytes & Band Forms

Formed during the promyelocyte stage

Primary Granules

Contain: • Charcot-Leyden crystals

Primary Granules

Formed throughout remaining maturation stages

Secondary (Specific) Granules

Contain: • Major basic protein (core) • Eosinophil cationic protein (matrix) • Eosinophil- derived neurotoxin (matrix) • Eosinophil peroxidase (matrix) • Lysozyme (matrix) • Catalase (core and matrix) • β-Glucuronidase (core and matrix) • Cathepsin D (core and matrix) • Interleukins 2,4, and 5 (core) • Interleukin- 6 (matrix) • Granulocyte- and Macrophage colony-stimulating factor (core) • Others

Secondary (Specific) Granules

• Acid phosphatase • Arylsulfatase B • Catalase • Cytochrome b558 • Elastase • Eosinophil cationic protein

Small Lysosomal Granules

• Cyclooxygenase • 5-Lipoxygenase • 15-Lipoxygenase • Leukotriene C4 synthase • Eosinophil peroxidase • Esterase

Lipid Bodies

Carry proteins from secondary granules to be released into the extracellular medium

Storage Vesicles

can also be classified as larger or smaller granules

Eosinophil specific granules

MAJOR BASIC PROTEIN, Acid hydrolase, Peroxidase, Phospholipase, Cathepsin, Eosinophil cationic protein, Eosinophil-derived neurotoxin

Larger granules

Arylsulfatase, Peroxidase, Acid phosphatase

Smaller granules

Eosinophils have bilobed nucleus measuring around (?) microns.

9-15

They possess refractile, orange-red granules and are involved in allergic and parasitic infections.

Eosinophils

Eosinophils - Normal values: o Relative value: o Absolute value:

o Relative value: 1-3% of WBC in peripheral blood o Absolute value: 0-0.3 x 109/ L

Production of eosinophil from last myelocyte division:

3.5 days

Eosinophil kinetics: o Turnover of eosinophils: o Large storage pool: o Half-life in circulation: o Survival in tissues:

o Turnover of eosinophils: 2.2 x 108 cells/ kg o Large storage pool: 9-14 x 108 cells/ kg o Half-life in circulation: 18 hours o Survival in tissues: 2-5 days (columnar epithelial cells of the respiratory, genitourinary, and gastrointestinal tracts)

Eosinophil Function: a. Eosinophil degranulation

i. Classical exocytosis ii. Compound exocytosis iii. Piecemeal degranulation

▪ Granules move to plasma membrane → Fuse with cell membrane → Emptying of contents to extracellular fluid (ECF)

Classical exocytosis

▪ Granules fuse together within eosinophils → Fuses with cell membrane → Emptying to ECF

Compound exocytosis

▪ Secretory vesicles remove specific CHONs from 20 granules → Secretory vesicles migrate to plasma membrane → Emptying to ECF

Piecemeal degranulation

Eosinophils delete double-positive thymocytes, act as antigen-presenting cells, promote proliferation of effector T cells, initiate Type 1 or Type 2 immune response and regulate mast cells

Regulation of immune responses

can trigger mast cell degranulation

▪ Major basic protein & other cytokines

is needed for mast cell survival

▪ Nerve growth factor

In the peripheral blood, eosinophil concentration correlates with severity of disease

Hallmark of allergic disorders

They secrete HISTAMINASE, IL-5 that function for airway inflammation and mucosal cell damage, and eosinophil-derived fibrogenic growth factors that function for airway remodeling

eosinophil concentration

Maturation Sequence Basophil Development

I. Pluripotential hematopoietic stem cell II. Progenitors a. CFU-GEMM (CMP) b. CFU-Baso III. Immature basophil IV. Mature basophil

Formed throughout remaining maturation stages

Secondary (Specific) Granules

Secondary (Specific) Granules

• Histamine • Platelet-activating factor • Leukotriene C4 • Interleukin-4 • Interleukin-13 • Vascular endothelial growth factor A • Vascular endothelial growth factor B • Chondroitin sulfates (e.g. Heparin)

possess unsegmented or bilobed nucleus with condensed chromatin.

Basophils

The (?) almost obscure the nuclear material of the cell.

blue-black water-soluble granules

Basophils are further characterized by:

Normal values Basophil kinetics Basophil functions

Normal values Relative value: Absolute value:

0-2% 0-0.2 x 109/ L

- Basophil kinetics:

Poorly understood Life span of 60 hours

- Basophil functions

(ALLERGIC OR HYPERSENSITIVITY REACTION)

Basophils possess (?). They regulate Th2 response (IL-4 & IL ), induce B cells to synthesize IgE, mediate allergic processes (production of HISTAMINE, Granzymes B, retinoic acid) and promote angiogenesis (Vascular endothelial growth factor production)

surface IgE receptors

are erroneously called tissue basophils.

Mast cells

They are not true leukocytes; they are cells from the BM that uses blood as transit system to gain access to tissues where they mature.

Mast cells

They function as effector cells in allergic reactions by stimulating IgE receptors and inflammatory reactions by an IgE receptor-independent process.

Mast cells

They can also act as antigen presenting cells that induce Th2 differentiation.

Mast cells

They are known for their anti-inflammatory and immunosuppressive functions

Mast cells

MONOPOIESIS Maturation sequence (Table 2-2):

I. Pluripotential hematopoietic stem cell II. Progenitors: a. CFU-GEMM (CMP) b. CFU-GM c. CFU-M III. Precursors: a. Monoblasts b. Promonocyte IV. Monocyte V. Tissue spaces: Macrophage

Size (um): 12-20 N:C ratio: 4:1 to 3:1 Nucleus Shape: Round to oval Chromatin: Delicate Nucleoli: 1-2 Cytoplasm Staining: Basophilic Cytoplasm Granules: No Granules Cellular Activity Carries out 2 mitotic divisions in 60 hours to produce 8 monocytes Can carry out 4 mitotic divisions in 60 hours under increased demand

MONOBLAST

Size (um): 12-18 N:C ratio: 3:1 to 2:1 Nucleus Shape: Slightly indented or folded Chromatin: Delicate Nucleoli: > 1 Cytoplasm Staining: Blue-gray Cytoplasm Granules: Formation of AZUROPHILIC GRANULES Cellular Activity Carries out 2 mitotic divisions in 60 hours to produce 8 monocytes Can carry out 4 mitotic divisions in 60 hours under increased demand

PROMONOCYTE

LARGEST CELL IN PERIPHERAL BLOOD

MONOCYTE

Size (um): 15-20 N:C ratio: 2:1 to 1:1 Nucleus Shape: Oval or round KIDNEY/ HORSE-SHOE May be folded, showing brain-like convolutions Chromatin: Looser (Lace-like/ Stringy Nucleoli: NONE Cytoplasm Staining: Blue-gray Cytoplasm Granules: Many fine azurophilic granules having GROUNDGLASS APPEARANCE (frosted) Cellular Activity Enter tissues and mature to macrophages

MONOCYTE