Qualitative Functional WBC defects
Overview of neutrophil microbicidal activity
Migration of leukocyte into tissue
- Tethering
- Rolling: E selectin is to L selectin
- Adhesion: ICAM is to integrin
- Transmigration
- Diapedesis
- Chemotaxis
Phagocytosis of organisms
→ Production of bactericidal substances
Schwachman Syndrome
One of the earliest congenital abnormality of neutrophil
Defect in neutrophil chemotaxis and deficient random mobility of neutrophils
→ Direct and random mobility- innate /intrinsic characteristic
Blood neutrophils cannot migrate at the site of tissue injury
Phagocytic and bactericidal activities are normal
In vivo demonstrated that the abnormalities in migration are intrinsic to the granulocyte
Alteration in the structure or function of micro-filamentous protein of the granulocyte membrane
Disorder of membrane leading to altered deformability
Disordered function of the micro filamentous protein of the cell membrane
Excessive or undue rigidity of neutrophils
→ This rigidity of the neutrophils explains the clinical pathologic features of the disease
Impaired mobility
Failure of egress from the bone marrow
Appearance of Lazy leukocyte syndrome in scanning electron microscopy (micro
filamentous protein of the granulocyte membrane)
✓ Normal = fine and filmy ruffles
✓ Abnormal = replaced by irregular knob like projection pattern
✓ Amoeboid forms
,CLINICAL PATHOLOGICAL FINDINGS: LAZY LEUKOCYTE SYNDROME
✓ Recurrent stomatitis
✓ Otitis
✓ Gingivitis
✓ Presence of low-grade fever
✓ Blood count of patients with LLS a severe peripheral neutropenia is observed
→ But there is a normal number of mature and morphologically normal neutrophils in the bone marrow
Note: Neutrophils from peripheral blood or bone marrow have normal phagocytic and bactericidal activities but
almost no chemotactic activity.
Rare genetic disorder which affects many organs, and particularly the immune system
In CHS, mutation in the LYST gene result in abnormal function of the lysosomal trafficking regulator protein
which affect the size and function of lysosomes
→ LYST gene is sometimes called CHS1 gene
The defects result in the progression of viral and bacterial infections
→ Start at infancy or early childhood which are in some cases life threatening
→ Few people with this condition can live to adulthood
IMMUNODEFICIENCY IN CHS
Giant granules result from abnormal fusion of primary granules with secondary granules azurophilic and specific
granules respectively)
The presence of giant granules in neutrophils impairs chemotaxis and killing of ingested microbes.
✓ CHS neutrophil - giant and several granules
✓ Normal neutrophil - normal granulation
CLINICAL MANIFESTATIONS: CHEDIAK-HIGASHI SYNDROME
✓ All because of the large granules in variety of cells:
Hypopigmentation or partial albinism
→ Impaired packaging of melanin into giant melanosome granules disturb
melanin traffic
→ Fair skin, pale retina, and light blond frosted or silvery hair (Oculocutaneous
albinism- prominent feature of CHS)
→ Most patients die in early childhood of overwhelming infection, hemorrhage,
or a lymphoma-like process
→ more than 50% die before the end of the first decade of life
Severed immunodeficiency
→ impaired release of lytic secretory granules by NK cells, neutrophil defects
→ affected individuals have recurrent infections typically begin in infancy period
→ more susceptible to bacterial and fungal infections (staphylococcal, strep., pneum.)
Neurologic abnormalities
→ Cytoplasmic inclusions, resembling large lysosomes were present in all types of neurons; it could lead
to peripheral and cranial neuropathy
, EVALUATION OF CHS
Diagnosis with light microscopy of peripheral blood smear
→ With the demonstration of large intracytoplasmic granules → Eosinophilic peroxidase-positive giant
granules in neutrophils and platelets
Bone marrow smear
→ Giant lysosomes in leukocyte precursor cells
→ CBC showing pancytopenia (all of the blood cell counts are abnormally decreased)
Mild coagulation defects
→ Prolonged bleeding time
Large azurophilic granules:
A – eosinophil
B - Lymphocyte
C – Neutrophil
D - Monocyte
Recurrent fungal and bacterial infections similar with CHS since both involved immunodeficiency or malfunction
of immune system; but it differs in its etiology.
Have areas of inflammation in various tissues = Granuloma formation
Particularly appear in childhood and symptoms appear later in life
Inability of phagocytes to produce superoxide and reactive oxygen species
→ No phagocytosis then there is no respiratory burst that is normally the production of the antimicrobial
agents
Mutation in any of the 4 genes for NADPH oxidase
→ One or more mutation in the genes: Nicotinamide Adenine Dinucleotide Phosphate - in a reduce form.
Inability of phagocytes to produce superoxide and reactive oxygen species
Mutations in any of 4 genes for NADPH oxidase
Nitroblue tetrazolium reduction test
→ Normal PMN - reduce the yellow water soluble nitroblue tetrazolium to a dark blue insoluble formazan
Recall that under normal conditions, phagocytosis of foreign organism usually leads to phosphorylation and binding
of the cytosolic proteins p47 and p67 and also with p40 in some books (purple circle 2nd pic). The phosphorylation
and binding of the cytosolic proteins will initiate the activation of NADPH OXIDASE COMPLEX.
Overview of neutrophil microbicidal activity
Migration of leukocyte into tissue
- Tethering
- Rolling: E selectin is to L selectin
- Adhesion: ICAM is to integrin
- Transmigration
- Diapedesis
- Chemotaxis
Phagocytosis of organisms
→ Production of bactericidal substances
Schwachman Syndrome
One of the earliest congenital abnormality of neutrophil
Defect in neutrophil chemotaxis and deficient random mobility of neutrophils
→ Direct and random mobility- innate /intrinsic characteristic
Blood neutrophils cannot migrate at the site of tissue injury
Phagocytic and bactericidal activities are normal
In vivo demonstrated that the abnormalities in migration are intrinsic to the granulocyte
Alteration in the structure or function of micro-filamentous protein of the granulocyte membrane
Disorder of membrane leading to altered deformability
Disordered function of the micro filamentous protein of the cell membrane
Excessive or undue rigidity of neutrophils
→ This rigidity of the neutrophils explains the clinical pathologic features of the disease
Impaired mobility
Failure of egress from the bone marrow
Appearance of Lazy leukocyte syndrome in scanning electron microscopy (micro
filamentous protein of the granulocyte membrane)
✓ Normal = fine and filmy ruffles
✓ Abnormal = replaced by irregular knob like projection pattern
✓ Amoeboid forms
,CLINICAL PATHOLOGICAL FINDINGS: LAZY LEUKOCYTE SYNDROME
✓ Recurrent stomatitis
✓ Otitis
✓ Gingivitis
✓ Presence of low-grade fever
✓ Blood count of patients with LLS a severe peripheral neutropenia is observed
→ But there is a normal number of mature and morphologically normal neutrophils in the bone marrow
Note: Neutrophils from peripheral blood or bone marrow have normal phagocytic and bactericidal activities but
almost no chemotactic activity.
Rare genetic disorder which affects many organs, and particularly the immune system
In CHS, mutation in the LYST gene result in abnormal function of the lysosomal trafficking regulator protein
which affect the size and function of lysosomes
→ LYST gene is sometimes called CHS1 gene
The defects result in the progression of viral and bacterial infections
→ Start at infancy or early childhood which are in some cases life threatening
→ Few people with this condition can live to adulthood
IMMUNODEFICIENCY IN CHS
Giant granules result from abnormal fusion of primary granules with secondary granules azurophilic and specific
granules respectively)
The presence of giant granules in neutrophils impairs chemotaxis and killing of ingested microbes.
✓ CHS neutrophil - giant and several granules
✓ Normal neutrophil - normal granulation
CLINICAL MANIFESTATIONS: CHEDIAK-HIGASHI SYNDROME
✓ All because of the large granules in variety of cells:
Hypopigmentation or partial albinism
→ Impaired packaging of melanin into giant melanosome granules disturb
melanin traffic
→ Fair skin, pale retina, and light blond frosted or silvery hair (Oculocutaneous
albinism- prominent feature of CHS)
→ Most patients die in early childhood of overwhelming infection, hemorrhage,
or a lymphoma-like process
→ more than 50% die before the end of the first decade of life
Severed immunodeficiency
→ impaired release of lytic secretory granules by NK cells, neutrophil defects
→ affected individuals have recurrent infections typically begin in infancy period
→ more susceptible to bacterial and fungal infections (staphylococcal, strep., pneum.)
Neurologic abnormalities
→ Cytoplasmic inclusions, resembling large lysosomes were present in all types of neurons; it could lead
to peripheral and cranial neuropathy
, EVALUATION OF CHS
Diagnosis with light microscopy of peripheral blood smear
→ With the demonstration of large intracytoplasmic granules → Eosinophilic peroxidase-positive giant
granules in neutrophils and platelets
Bone marrow smear
→ Giant lysosomes in leukocyte precursor cells
→ CBC showing pancytopenia (all of the blood cell counts are abnormally decreased)
Mild coagulation defects
→ Prolonged bleeding time
Large azurophilic granules:
A – eosinophil
B - Lymphocyte
C – Neutrophil
D - Monocyte
Recurrent fungal and bacterial infections similar with CHS since both involved immunodeficiency or malfunction
of immune system; but it differs in its etiology.
Have areas of inflammation in various tissues = Granuloma formation
Particularly appear in childhood and symptoms appear later in life
Inability of phagocytes to produce superoxide and reactive oxygen species
→ No phagocytosis then there is no respiratory burst that is normally the production of the antimicrobial
agents
Mutation in any of the 4 genes for NADPH oxidase
→ One or more mutation in the genes: Nicotinamide Adenine Dinucleotide Phosphate - in a reduce form.
Inability of phagocytes to produce superoxide and reactive oxygen species
Mutations in any of 4 genes for NADPH oxidase
Nitroblue tetrazolium reduction test
→ Normal PMN - reduce the yellow water soluble nitroblue tetrazolium to a dark blue insoluble formazan
Recall that under normal conditions, phagocytosis of foreign organism usually leads to phosphorylation and binding
of the cytosolic proteins p47 and p67 and also with p40 in some books (purple circle 2nd pic). The phosphorylation
and binding of the cytosolic proteins will initiate the activation of NADPH OXIDASE COMPLEX.
