FUNCTIONAL DISORDERS OF

NEUTROPHILS AND MONOCYTES

Presented By: Group 4

AML5
Faculty of Life Sciences
University of Central Punjab
CONTENTS
• INTRODUCTION TO MONOCYTES AND NEUTROPHILS
 Neutrophils
•abundant type of granulocyte and play a crucial role in the
innate immune response.
•first responders to sites of infection or tissue damage, quickly
migrating to the affected area through chemotaxis.
• - Neutrophils are phagocytes, meaning they engulf and
destroy pathogens such as bacteria and fungi.
•contribute to inflammation by releasing cytokines and other
signaling molecules that recruit additional immune cells to the
site of infection.
Types of Neutrophil Disorders

• Neutrophil disorders can result from a reduced number of

cells (Neutropenias) or defective function.
• Neutropenias are a result of one or more defects in the
diferentiation or proliferation in the bone marrow, or
increased peripheral destruction.
• Functional disorders include disorders of chemotaxis,
adhesion, phagocytosis, and the respiratory burst.
FUNCTIONAL DISORDERS
• Chronic Granulomatous Disease (CGD)
• Myeloperoxidase (MPO) Deficiency
• Glutathione Synthetase Deficiency
• Severe Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
• Leukocyte Adhesion Deficiency (LAD)
• Chediak-Higashi Syndrome
• Specific Granule Deficiency
Chronic Granulomatous Disease (CGD)
• Absent or Reduced Function of Respiratory Burst: Neutrophils in
CGD lack the ability to generate reactive oxygen species (ROS) via
the respiratory burst mechanism, compromising their ability to kill
pathogens.
• Importance of Oxygen Free Radicals for Intracellular Killing:
ROS play a crucial role in the intracellular killing of bacteria and fungi
by neutrophils. In CGD, this mechanism is impaired, leading to
recurrent infections.
CAUSES

• Congenital Defects in Components of NADPH Oxidase Enzyme:

CGD arises from mutations in genes encoding the subunits of the
NADPH oxidase enzyme complex, which is responsible for ROS
production.
• Heterogeneous Mutations: CGD exhibits genetic heterogeneity, with
mutations occurring in various genes encoding NADPH oxidase
components.
Clinical Features

• Presentation in Early Childhood with Recurrent Bacterial and

Fungal Infections: CGD typically manifests in early childhood, with
patients experiencing frequent and severe infections caused by
organisms such as Staphylococcus aureus, Aspergillus species, and
enteric Gram-negative bacteria.
• Presence of Granulomas, Hepatosplenomegaly, Failure to Thrive:
CGD can lead to the formation of granulomas in various organs,
hepatosplenomegaly (enlargement of the liver and spleen), and failure
to thrive due to chronic illness.
Diagnosis
• Bacterial Killing Test
• PMA-NBT Slide Test
• Flow Cytometric Analysis
• Genotypic Analysis for Subgroups
Management
• Oral Hygiene, Regular Dental Care, Prophylactic Antibiotics
• Treatment of Infections with Appropriate Antibiotics
• Potential Use of Corticosteroids, Bone Marrow Transplantation
Leukocyte Adhesion Deficiency (LAD)
• LAD is characterized by impaired leukocyte adhesion to the
endothelium, resulting in compromised immune cell recruitment to
sites of infection or inflammation.
• Proper leukocyte adhesion is crucial for immune cell migration and
tissue infiltration, essential for effective pathogen clearance.
CAUSES
• Genetic Mutations in Adhesion Molecule Genes
• Autosomal Recessive Inheritance
Clinical Features
• Patients with LAD experience recurrent and severe bacterial
infections, often involving the skin, respiratory tract, and mucous
membranes.
• Delayed Umbilical Cord Separation, Omphalitis: Neonates with
LAD may exhibit delayed umbilical cord separation and develop
omphalitis (infection of the umbilical cord stump) due to impaired
immune cell migration.
Diagnosis
• Flow Cytometry for Leukocyte Surface Markers particularly
integrins and selectins, can aid in the diagnosis of LAD by identifying
abnormalities in leukocyte adhesion molecules.
• Functional Assays for Leukocyte Adhesion such as leukocyte
adhesion tests, help assess the ability of leukocytes to adhere to
endothelial cells under controlled conditions.
Management
• Antibiotic Therapy for Infections
• Hematopoietic Stem Cell Transplantation (HSCT)
• Gene Therapy
Chediak-Higashi Syndrome (CHS):

• Giant Inclusion Bodies in Leukocytes: CHS is characterized by the

presence of giant inclusion bodies in leukocytes, which impair cellular
function and lead to immune system dysfunction.
• Defective Intracellular Vesicle Trafficking: CHS results from
mutations in the LYST gene, which impairs intracellular vesicle
trafficking and fusion, leading to abnormal lysosome formation.
Causes
• LYST Gene Mutations: inherited in an autosomal recessive pattern.
These mutations disrupt lysosome-related organelles' function and
compromise cellular homeostasis
Clinical Features

• Oculocutaneous Albinism
• Recurrent Infections
• Giant Granules in Leukocytes
• Neurological Manifestations
Diagnosis
• Peripheral Blood Smear: Examination of peripheral blood smears
reveals the presence of giant inclusion bodies within leukocytes,
characteristic of CHS.
• Genetic Testing: Molecular genetic testing can confirm the diagnosis
by identifying mutations in the LYST gene associated with CHS.
Management
• Infection Prevention:
• Hematopoietic Stem Cell Transplantation (HSCT)
• Symptomatic Treatment
Myeloperoxidase (MPO) Deficiency
• Deficiency of Myeloperoxidase Enzyme: MPO deficiency is
characterized by reduced or absent activity of the myeloperoxidase
enzyme in neutrophils, impairing their ability to generate microbicidal
reactive oxygen species.
• Importance of Myeloperoxidase in Microbial Killing:
Myeloperoxidase plays a crucial role in microbial killing by
generating hypochlorous acid and other reactive oxygen species,
which are essential for neutrophil-mediated host defense.
Causes
• MPO deficiency results from genetic mutations affecting the MPO
gene, which encodes the myeloperoxidase enzyme. These mutations
can lead to decreased enzyme activity or impaired enzyme function.
• Autosomal Recessive Inheritance
Clinical Features

• Increased Susceptibility to Infections Individuals with MPO

deficiency are more susceptible to bacterial and fungal infections,
particularly those involving the skin, respiratory tract, and soft tissues.
• Absence of Green Pus the absence of green pus in infected wounds,
as the green color is attributed to the presence of myeloperoxidase-
generated reactive oxygen species.
• Possible Association with Inflammatory Disorders a potential
association between MPO deficiency and inflammatory disorders,
such as rheumatoid arthritis and inflammatory bowel disease.
Diagnosis
• MPO Activity Assays: Laboratory testing for MPO activity in
neutrophils can confirm the diagnosis of MPO deficiency. Reduced or
absent MPO activity indicates enzyme deficiency.
• Genetic Testing: Molecular genetic testing can identify mutations in
the MPO gene associated with MPO deficiency, providing further
confirmation of the diagnosis.
Management
• Antibiotic Therapy for Infections
• Avoidance of Oxidative Stress
• Regular Monitoring and Supportive Care
Specific Granule Deficiency (SGD)
• SGD is characterized by the absence or reduction of specific granules
in neutrophils, resulting in impaired storage and release of certain
antimicrobial proteins and enzymes.
• Specific granules play a crucial role in neutrophil function by storing
and releasing antimicrobial proteins, such as lactoferrin, lysozyme,
and collagenase, which are essential for microbial killing and tissue
remodeling.
Causes
• SGD arises from genetic mutations affecting proteins involved in
specific granule formation and function, such as CEBPE
(CCAAT/enhancer-binding protein epsilon) and neutrophil elastase.
• Autosomal Recessive Inheritance
Clinical Features

• Patients with SGD experience recurrent bacterial infections,

particularly those caused by Staphylococcus aureus and Gram-
negative bacteria, due to impaired neutrophil antimicrobial function.
• Delayed Wound Healing
• Association with Inflammatory Disorders such as inflammatory
bowel disease or autoimmune conditions, highlighting the complex
interplay between neutrophil dysfunction and immune dysregulation.
Diagnosis
• Neutrophil Morphology and Granule Staining
• Genetic Testing
Management
• Antibiotic Therapy for Infections
• Supportive Care and Wound Management
• Use of Hematopoietic Stem Cell Transplantation (HSCT)