64 Disorders of Neutrophil Function Flashcards
1
Q
Part of a neutrophil used in locomotion
A
Lamellipodium - front
Uropod- back
2
Q
A pivotal mediator of actin dynamics
promotes filament severing and depolymerization, facilitating the breakdown of existing filaments in concert with actin-interacting protein 1 (AIP1, also known as WD40 repeat protein 1 WDR1)
A
Cofilin
3
Q
An actin monomer-binding protein, which, at low concentration, can act as an enhancer of actin filament assembly by shuttling actin monomers to the fast-growing (barbed) end of the actin filament
Mutation of this protein is associated with autosomal dominant form of Amyotrophic Lateral Sclerosis
A
Profilin
4
Q
An actin regulatory protein crucial for orchestrating the molecular events leading to proper endothelial barrier function and leukocyte recruitment in vivo, active in immune cells as well as the vascular lining
A
Cortactin
5
Q
Cortactin homologue that is only expressed in hematopoietic cells
Essential for T-cell activation
A
HS1
Human defects in cortactin or HS1 have not yet been reported.
6
Q
True or False
Locomotion is a prerequisite for ingestion
A
FALSE
Locomotion is NOT a prerequisite for ingestion: If neutrophils collide with a particle not secreting a chemotactic substance, pseudopodia form abruptly at the contact point and envelop the particle.
7
Q
Refers to loose and somewhat transient adhesion of neutrophils at site of inflammation
A
Tethering
8
Q
In macrophages,______________ act as phagocytic tentacles and pull bound objects toward the cell for subsequent phagocytosis
A
Filopodia
9
Q
Actin-binding proteins associated with neutrophil plasma membranes which are important for organization of microvilli on the surface of the cell
A
Moesin, ezrin, and p205 radixin
10
Q
These are primary adhesion proteins exposed on the microvilli
A
L-selectin and P-selectin glycoprotein ligand 1 (PSGL-1)
11
Q
Initiates neutrophil rolling
A
P-selectin
Interacts with the neutrophil PSGL-1 to initiate neutrophil rolling
12
Q
Only 1 inducible L-selectin counterreceptor has been identified on inflamed endothelium
Severs L-selectin from the surface of neutrophils and impairs their recruitment to endothelium.
A
ADAM17
Neutrophil PSGL-1 may also act as counterreceptor for L-selectin
13
Q
Serve as counterreceptors for the neutrophil P-selectin glycoprotein ligand-1
A
E-selectin and P-selectin
14
Q
Chemokine that specifically attracts neutrophils.
A
IL8
15
Q
IL-8 can be released by________or _________.
A
Histamine or thrombin
16
Q
β2-Integrins are recognized by counterligands on endothelial cells:
A
Intercellular adhesion molecule (ICAM) family, such as ICAM-1 and ICAM-2
17
Q
A minority of neutrophils exit by a transcellular route through so-called ________________.
A
Endothelial cups
18
Q
_____________are perivascular contractile cells that interact with endothelial cells and regulate vascular permeability
A
Pericytes
19
Q
Once out in tissues the forefront neutrophils release _________________ to recruit an additional swarm of neutrophils to the area and recruit later incoming monocytes and macrophages.
A
IL-8 and LTB4
20
Q
Examples of pattern recognition receptors (PRRs)
A
Membrane-bound: toll-like receptors (TLRs) and C-type lectin receptors
Cytosolic: nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and RIG-like receptors
21
Q
Examples of toll-like receptors (TLRs) and where it binds
A
TLR2: lipoproteins and lipopeptides in association with either TLR1 or TLR6
TLR3: double-stranded RNA
TLR5: flagellin
TLR7/8: viral single-stranded RNA
TLR9 :unmethylated GpC regions on DNA
TLR11: profilin-like proteins of protozoa
22
Q
Known as an LPS-binding protein but is not itself able to signal and presents LPS to TLR4.
A
CD14
23
Q
Human neutrophils do not express these TLRs:
A
TLR3, TLR7, TLR10, or TLR11
24
Q
Comprise a heterogeneous group of trans-membrane receptors that bind carbohydrates such as mannose, fucose, and β-glucans present on a variety of microbes, fungi in particular.
A
C-type lectin receptors
25
Receptors for Recognition of Microbes
**Toll-like receptors (TLRs)**
**C-type lectin receptors**: carbohydrates such as mannose, fucose, and β-glucans
**Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs)**: peptidoglycans of both Gram-positive and Gram-negative bacteria (NOD 1 and NOD 2)
26
Surface Components for Phagocytosis
For Immunoglobulins
Fcα receptor (CD89): immunoglobulin (Ig) A and IgG receptors
FcγRIIA (CD32)
FcγRIII (CD16)
Receptors for the complement component:
CD1qR
CR1 (CD35): binds CD3b, C4b, and C3bi
CR3 (CD11/CD18, Mac-1): binds C3bi
CR4
27
____________ serves as a marker for secretory vesicles and has allowed the identification of these as small intracellular vesicles that are scattered throughout the cytoplasm of neutrophils as is true for neutrophil granules
Albumin
28
TRUE OR FALSE
Secretory vesicles are not important for their cargo (plasma proteins), but for their membrane, which becomes fully incorporated into the plasma membrane of the neutrophil upon stimulation.
TRUE
29
First identified marker of secretory vesicles
Latent alkaline phosphatase
## Footnote
The first identified marker of secretory vesicles, latent alkaline phosphatase, is known to be **elevated in chronic myeloproliferative disorders** except for **chronic myelogenous leukemia (CML)**
30
Markers for secretory vesicles are _________and _______
CD10 (Neprilysin) and CD35 (CR1)
## Footnote
Neprilysin is also known as membrane metalloendopeptidase, neutral endopeptidase, or common acute lymphoblastic leukemia antigen.
31
Neutrophil granules
Peroxidase Positive: Azurophil granules: _____________: Primary granules
Peroxidase Negative: _____________: Myelocytes: ____________
Azurophil granules: promyelocytes: Primary granules: ** Peroxidase positive
Specific granules: Myelocytes: Secondary granules: ** Peroxidase negative
32
Azurophilic Granules
**Myeloperoxidase**
**Bacterial permeability-increasing (BPI) protein**
**Defensins**: 3 α-defensins; human neutrophil peptides (HNPs) 1–3
**Serine proteases of azurophil granules**: elastase, cathepsin G, proteinase 3, and neutrophil serine protease 4 (NSP4); azurocidin (CAP37 or heparin-binding protein [HBP]) is enzymatically inactive
**Lysozyme**
33
Specific Granules
Lactoferrin
Neutrophil gelatinase-associated lipocalin (NGAL) or siderochelin
hCAP-18
Neutrophil collagenase
Olfactomedin 4 (OLFM4)
Gelatinase
Leukolysin, which is distributed among of resting neutrophils
Cytochrome b558, (gp91phox, p22phox)
CD11b/CD18 (Mac-1, Mo1, CR3, αMβ2)
Pentraxin-3
Ficolin-1
Arginase 1
34
Tertiary granule subset was identified in human neutrophils and shown to mainly contain __________
Gelatinase
## Footnote
Active against type IV collagen
35
Defensins are also named
HNPs (human neutrophil peptides)
36
Peroxidase-negative granules can be divided into 3 subsets based on the distribution of the 2 marker proteins, ________ and __________
Lactoferrin and Gelatinase
## Footnote
(a) granules that contain lactoferrin, but no gelatinase (15%)
(b) granules that contain both proteins (60%)
(c) granules that are rich in gelatinase, but low in lactoferrin (25%)
37
TRUE OR FALSE
It is a characteristic of peroxidase-negative granules that the proteins present in their matrix are not proteolytically processed.
TRUE
It is a characteristic of peroxidase-negative granules that the proteins present in their matrix are not proteolytically processed.
38
TRUE OR FALSE
The biosynthesis of neutrophil granule proteins is controlled at the transcriptional and not the translational level
TRUE
The biosynthesis of neutrophil granule proteins is controlled at the transcriptional and not the translational level
39
TRUE OR FALSE
Lysozyme is retained during biosynthesis. This explains the low concentration of lysozyme in plasma.
FALSE
Lysozyme is **poorly retained** during biosynthesis. This explains the **high concentration of lysozyme in plasma**.
## Footnote
**MPO** is efficiently **retained**; consequently, the **plasma level of MPO is very low.**
40
FUNCTION OF INDIVIDUAL GRANULE PROTEINS
TABLE 64-1
41
Marker of azurophil granules
MPO
42
MPO is known for the anti-MPO autoantibodies that are characteristic of the __________ antibodies
**Perinuclear antineutrophil cytoplasmic antibodies** that are found in vasculitides, particularly those that primarily affect **kidneys**
43
Granule responsible for the **binding of LPS** and for the antimicrobial activity against **Gram-negative microorganisms**
Bacterial permeability-increasing
(BPI) protein
44
Only defensins found in human neutrophils and reside exclusively in azurophil granules
α defensins
45
Dominating proteins of azurophil granules
α Defensins
## Footnote
Only expressed in a subset of granules that are formed late in the promyelocyte stage
46
Unprocessed defensins
Secreted from **late promyelocytes and myelocytes** in the marrow and may serve as a **marker of normal myelopoietic activity**
A measure of normal higranulopoiesis which may be of clinical use in the setting of myeloablative treatment for acute leukemia
Prodefensins
47
Serine protease that leads to autoantibodies against itself in **Wegener granulomatosis**, which is known as **cytoplasmic antineutrophil cytoplasmic antibody**
Proteinase 3
48
Syndrome described as **lack cathepsin C activity** and are **not able to store serine proteases** in their neutrophils
The condition is characterized by **severe juvenile periodontitis and keratosis in hands and feet, but not by major systemic infections**
Papillon-Lefèvre syndrome
49
The dominating protein of specific granules
Lactoferrin
50
Protein with **high affinity for iron** and similar binding characteristics as ferritin
Lactoferrin
51
The antibacterial activity of lactoferrin does not depend exclusively on its ability to sequester iron because proteolytic fragments of lactoferrin, some of which are known as__________________, are directly bactericidal.
Lactoferricin
52
Protein that bind and sequester siderophores
NGAL, or lipocalin 2
53
Protein that **binds enterochelin/ enterobactin** with high affinity, and **blocks growth of Escherichia coli**
NGAL, or lipocalin 2
## Footnote
NGAL has been demonstrated to play a protective role in infections against **E. coli, Klebsiella pneumoniae, Salmonella typhimurium, and Mycobacterium tuberculosis.**
54
Protein that is an essential **resistance factor against mycobacterial infection**
Nramp1
55
Protein that cleaves peptidoglycan polymers of bacterial cell walls and displays bactericidal activity toward the **nonpathogenic Gram-positive bacteria Bacillus subtilis**
Lysozyme
56
A particular high serum level of this enzyme is characteristic for the **myelomonocytic leukemias**
Lysozyme
57
The only human member of a family of antimicrobial peptides known as **cathelicidins**.
**hCAP-18** also known as **LL-37190** or **CAMP**
58
Protein that has **angiogenic and endotoxin-neutralizing properties**
Stimulates neutrophil, monocyte, and T-cell chemotaxis via the formyl peptide receptor-like-1
hCAP-18/ LL-37
59
hCAP-18/ LL-37 counterpart in the testis is cleaved by _______
Gastricsin
60
Protein capable of capable of degrading major structural components of the extracellular matrix
Matrix metalloproteinase (MMPs)
Neutrophil collagenase (MMP-8 of 75 kDa), which is localized to specific granules,
Gelatinase (MMP-9 of 92 kDa), which resides predominantly in gelatinase granules
Leukolysin (MT6-MMP/MMP-25 of 56 kDa), which is mostly present in the secretory granules
61
Pattern-recognition molecules that binds the complement component **C1q** and mediates **activation of the classical complement cascade**.
Pentraxin 3
## Footnote
Also binds **K. pneumoniae outer membrane protein A (KpOmpA)** from Gram-negative bacteria, especially the Enterobacteriaceae species, and binds **Aspergillus fumigatus conidia.**
62
Pattern-recognition molecules that binds **acetylated carbohydrate structures on Gram-positive bacteria** and can recruit **mannose-binding lectin-associated serine proteases and activate the lectin complement cascade**
Ficolin-1
63
Protein essential for essential for **collagen synthesis**
Proline
64
Protein that forms the membrane component of the **NADPH oxidase**
Cytochrome b558
## Footnote
Comprised of **gp91phox** and **p22phox**
65
Anaphylatoxin complement and receptors
Complement activation liberates the anaphylatoxins **C3a and C5a**, which activate 3 distinct GPCRs: **C3AR, C5AR1, and C5AR2** (or anaphylatoxin receptors)
66
A major proinflammatory component and the **most potent of the chemotactic proteins**
Induces neutrophil chemotaxis, degranulation, and superoxide generation
C5a
67
The major C5a receptor
C5AR1 (CD88)
68
IL-8 related receptors
CXCR1 and CXCR2
69
FcγRIIA/CD32 or FcγRIII/CD16
Most important immunoglobulin receptor for **clearing immune complexes**
FcγRIII
70
The reigning paradigm for fusion of biomembrane
**SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) hypothesis**
**v-SNAREs**:vesicles or granules
**t-SNAREs**: target plasma membranes
71
Neutrophil extracellular traps are extruded from neutrophils in a process called __________
NETosis
72
3 death programs of neutrophils:
Apoptosis, necrosis, and NETosis
73
The NADPH oxidase activity of stimulated neutrophils thus serves 2 purposes:
To generate reactive oxygen species for microbial killing
To induce formation of the bactericidal NETs
74
Condition where patients with **defective NADPH oxidase assembly**
Lack both the ability to generate microbicidal oxygen species and the ability to form the NETs
Chronic granulomatous disease [CGD]
75
Patients with the _________ syndrome **lack elastase** and are **incapable of generating NETs**
Patients do not have a major immune defect and their symptoms are largely related to periodontal infections
Papillon-Lefèvre syndrome
76
The most profound disturbances in signal mechanism as a result of Ab and complement defects
C3
77
Refers to the coating of pathogens by serum proteins such that they are more likely to be ingested
Opsonization
78
TRUE OR FALSE
Encapsulated pathogens characteristically are associated with neutropenic states.
FALSE
Encapsulated pathogens characteristically are NOT associated with neutropenic states.
79
DEGRANULATION ABNORMALITIES
Chédiak-Higashi syndrome
Specific granule deficiency
Specific granule deficiency with myelodysplasia
80
ADHESION ABNORMALITIES
Leukocyte adhesion deficiency type 1 (LAD-1)
LAD-2
LAD-3 (LAD-1 variant syndrome)
81
DEPRESSED MOTILE RESPONSES
Defects in the generation of chemotactic signals
Immune complexes
Intrinsic defects of the neutrophil, eg, leukocyte adhesion deficiency, Chédiak-Higashi syndrome (giant granules), neutrophil actin dysfunction,
and direct inhibition of neutrophil mobility by, eg, drugs
ARPC1B deficiency
MKL1 deficiency
WDR1 deficiency
RAC2 deficiency (D57N)
RAC2 deficiency (P34H and E62K)
RAC2 deficiency (G12R)
MOESIN deficiency
DOCK2
Hyperimmunoglobulin-E syndrome
82
MICROBICIDAL ACTIVITY
CGD
EROS deficiency (C17Orf62)
G6PD deficiency
Myeloperoxidase deficiency
RAC2 deficiency [D57N]
Deficiencies of glutathione reductase and glutathione synthetase
83
Example of Degranulation Abnormalities
Neurocutaneous disorders
Chédiak- Higashi syndrome (CHS)
Griscelli syndrome
Hermansky-Pudlak syndrome (HPS) subtypes
MAPBP-interacting protein deficiency syndromes
Hypopigmentation disorders that are associated with immunodeficiency feature both partial albinism of hair, skin, and eyes together with leukocyte defects
Autosomal recessive conditions
84
Among 10 currently defined subtypes of HPS, only type ____ and type ____are characterized by immunodeficiency.
Type 2 and Type 9
HPS2 : AP3B1 gene
HPS9: pallidin-encoding gene, PLDN
85
A long-term complication of CHS, but is uncommon in other syndromic albinisms
Neurologic disease
86
A feature of HPS2 in which AP-3 mediates trafficking of neutrophil elastase to lysosome-like granules, known as azurophilic granules.
Neutrophil elastase is required for normal differentiation of myeloid progenitor cells to mature neutrophils.
Severe chronic neutropenia
87
Disorder of generalized cellular dysfunction characterized by **increased fusion of cytoplasmic granules** and one in which neutrophils, monocytes, and lymphocytes contained **giant cytoplasmic granules**
Chédiak-Higashi Syndrome
88
Features of Chedak Higashi
Neutropenia, thrombocytopathy, NK cell abnormalities, and peripheral neuropathies
89
Patients with Chédiak-Higashi Syndrome often suffer this fatal condition caused by a viral infection known as the accelerated phase, occurring months from birth to several years later
Lymphohistiocytic infiltration (HLH)
90
The primary morphologic feature of CHS
**Giant lysosomes**
## Footnote
Only cells relying on the secretion by these lysosomes manifest pathologic defects
91
Gene that is mutated in CHS
CHS1 (synonym: LYST) found on chromosome 1q
92
The pathognomonic feature in CHS that can be seen in neutrophils.
Giant peroxidase-positive granules
93
A microscopic examination of hair shafts of patients with CHS reveal
Large, speckled pigment clumps
94
Most commonly infecting organism in CHS
Staphylococcus aureus
95
Reason for prolonged bleeding times with normal platelet counts in CHS
**Impaired platelet aggregation** associated with a **deficiency of the storage pools of ADP and serotonin**
96
Rare disorder, arising from mutations in the **RAB27A gene**, and is defined by **partial ocular and cutaneous albinism**, variable cellular and humeral immunodeficiency, variable neurologic involvement, and the development of the accelerated phase
Unlike CHS, it **lack giant granules in neutrophils** and have **large pigment clumps in hair shafts**.
Griscelli syndrome
97
Disorder of **ocular and cutaneous albinism, bleeding diathesis arising from platelet dysfunction**, and deposition of **ceroid lipofuscin in various organs**
In contrast to CHS, it lack giant granules and the patients are not predisposed to recurrent infections.
Hermansky-Pudlak syndrome (HPS)
98
TRUE OR FALSE
In CHS, prophylactic antibiotics do not prevent infections
TRUE
In CHS, prophylactic antibiotics do not prevent infections
99
The only potential for curative therapy for preventing the accelerated phase in CHS
**Marrow transplantation**
## Footnote
*If the patient is actively in the accelerated phase, stem cell transplantation from a matched unrelated donor is associated with a poor prognosis*
*Ocular and cutaneous albinism are not corrected after transplantation, nor does transplantation prevent progressive neuropathies from occurring.*
100
Autosomal recessive disorder
Characterized by **absence of specific granules**, the **nuclei of the neutrophils are bilobed**
Specific granule deficiency (SGD)
## Footnote
*The disorder is a global defect in phagocytic granules rather than limited to specific granules, as suggested by its name*
101
The most commonly observed pathogens in SGD
S. aureus and Pseudomonas aeruginosa
102
Gene that is mutated in Specific granule deficiency (SGD)
C/EBPε
103
The diagnosis of SGD is suggested by the presence of
Neutrophils devoid of specific granules but containing azurophilic granules on the blood film
104
Specific granule deficiency (SGD) can be confirmed by demonstrating a severe deficiency in either ______ or _________
Lactoferrin or hCAP-18
105
Gene that is mutated in Specific granule deficiency (SGD) with myelodysplasia
SMARCD2
106
An acquired form of SGD can be observed in
Thermally injured patients or in individuals with myelodysplasia
107
Autosomal recessive disorder of leukocyte function characterized clinically by **recurrent soft-tissue infections, delayed wound healing, and severely impaired pus formation**, despite striking blood neutrophilis
Leukocyte adhesion deficiency type I (LAD-1)
108
Gene that is mutated in Leukocyte adhesion deficiency type I (LAD-1)
CD11/ CD18 complex (also referred to as the β2-integrin family of leukocyte adhesion proteins)
109
Diagnosis can be considered in infants with a **paucity of neutrophils at sites of infection despite blood neutrophilia** and have a **history of delayed separation of the umbilical cord**
Leukocyte adhesion deficiency type I (LAD-1)
110
Refers to chemotaxis that occurs despite blockade of CD11/CD18
Chimneying
111
Diagnosis of LAD can be made through
Flow cytometric measurement of surface **CD11b**
112
TRUE OR FALSE
In LAD, there is a paucity of neutrophils in inflammatory skin windows and biopsies of infected tissues.
TRUE
In LAD, there is a paucity of neutrophils in inflammatory skin windows and biopsies of infected tissues.
113
Genetic defect in LAD-2 or congenital disorder of glycosylation type IIc (CDG-IIc)
**Fucosylation of ligands for selectins and other glycoconjugates.**
## Footnote
The LAD-2 neutrophils express **normal levels of CD18 integrins**, but are **deficient in the carbohydrate structure sLex**, which renders the cells unable to roll on activated endothelial cells expressing E-selectin
114
Blood phenotype of patients (of Arab, Turkish, Pakistani, and Brazilian origin) who had **neutrophilia, recurrent bacterial infections, and an inability to form pus**, similar to LAD
Bombay blood phenotype (deficiency in H blood group integrins)
115
TRUE OR FALSE
In contrast to LAD-1, the patients’ NK cell activity is abnormal.
FALSE
In contrast to LAD-1, the patients’ NK cell activity is normal
116
The LAD-2 neutrophils express normal levels of CD18 integrins, but are deficient in the carbohydrate structure
sLex
117
The diagnosis of LAD-2 can be made by
Flow cytometry analysis of **CD15s (sLex)** expression
118
2 major hallmarks of LAD-3 or LAD-1 variant syndrome
A moderate LAD-1–like syndrome and severe Glanzmann-like bleeding diathesis
## Footnote
Inability to form pus at sites of microbial infections, as well as a severe bleeding tendency
119
Gene that is mutated in LAD-3 or LAD-1 variant syndrome
FERMT3 which encodes kindlin-3
120
Condition where neutrophils from the patient had **defects in both adhesion and chemotaxis**
Compared with other LAD, has the added feature of **reduced respiratory burst**
Mutation in the Rac2 GTPase
121
Treatment of choice in case of severe LAD-1 or LAD-like syndromes
Hematopoietic stem cell transplantation (HSCT)
122
The severity of infectious complications in LAD correlates with the degree of ___________ deficiency.
β2 deficiency
123
Moderately severe LAD-1 is characterized clinically by ________________
Severe periodontal disease that results in premature loss of teeth.
124
An autosomal recessive disorder characterized by **recurrent pyogenic infections** from birth as a result of **defective chemotactic and phagocytic response**
Morphologically, the neutrophils displayed **thin, filamentous projections of membrane with an underlying abnormal cytoskeletal structure**
Neutrophil Actin Dysfunction
NAD47/89
125
Defect in Neutrophil Actin Dysfunction
Overexpression of this resulted in **bundling of actin** in cells, leading to an abnormal cytoskeletal structure and motility defects
LSP-1 (lymphocyte-specific protein-1)
126
This condition indicates the requirement for the **Arp2/3 complex** as a major factor in actin polymerization in human blood cells.
Has a strong **allergy** aspect, which is atypical and often less severe in Wiskott-Aldrich syndrome, but may be very similar to patients with DOCK8 deficiency
ARPC1B deficiency
127
Disease with **recurrent invasive infections** caused by Gram-positive and Gram-negative bacteria, **impaired wound healing**, and a **severe stomatitis with acquired microstomia and remarkable oral stenosis**
Patients had **mild neutropenia, defective neutrophil mobilization, nuclear lobe herniation with regionally agranular cytoplasm** caused by **increased F-actin**, and abnormal migration.
WDR1 Deficiency
“lazy leukocyte syndrome”
128
Disease on patients with WDR1 Deficiency having an acute-phase response, thrombocytopenia, hyperferritinemia, high serum IgA levels and constitutively increased IL-18 levels.
Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (APFIT) syndrome
129
An X-linked combined immune deficiency characterized by **defects of T-cell function** associated with **hypogammaglobulinemia and (fluctuating) neutropenia**
Moesin Deficiency
## Footnote
Affected individuals suffered from **recurrent bacterial infections**, mainly of the **respiratory tract**, along with unusually **severe varicella-zoster infections and molluscum contagiosum**
130
Clinical features of this disease include autoimmune cytopenias, viral skin (molluscum contagiosum, warts, and perioral herpetic infection) and bacterial infections, mild onychomycosis, mild atopic and seborrheic dermatitis, lymphopenia (particularly CD4 lymphopenia), but also intermittent mild neutropenia.
STK4 (or MST1) Deficiency
131
Drugs and Extrinsic Agents That Impair Neutrophil Motility
**Ethanol**- inhibitor of PLD
**Glucocorticoids**- inhibit neutrophil locomotion, ingestion, and degranulation
**Epinephrine (cyclic adenosine monophosphate)** can depress neutrophil adherence
**Immune complexes (RA, autoimmune diseases)**: inhibit neutrophil movement by binding to neutrophil Fc receptors
132
TRUE OR FALSE
Administration of glucocorticoids on alternate days does not interfere with neutrophil movement.
TRUE
Administration of glucocorticoids on alternate days does not interfere with neutrophil movement.
133
Autosomal dominant disorder characterized by markedly **elevated serum IgE levels, chronic dermatitis, and serious recurrent bacterial infections**
The skin infections in these patients are remarkable for their **absence of surrounding erythema, leading to the formation of “cold abscesses.”**
Hyperimmunoglobulin E Syndrome
“Job syndrome.”
134
Gene that is mutated in Autosomal dominant hyperimmunoglobulin E syndrome (HIES)
STAT3
135
Gene that is mutated in autosomal recessive hyperimmunoglobulin E syndrome (HIES)
DOCK8
136
Distinguishing features of AD-HIES
Pneumatoceles in the lung, subcutaneous abscess formation, lack of viral skin disease (in contrast to DOCK8 deficiency), and facial features
137
Disease features include coarse facial features, including a **prominent forehead, deep-set eyes, a broad nasal bridge, a wide fleshly nasal tip, mild prognathism facial asymmetry, and hemihypertrophy**
**Blood and sputum eosinophilia**
Autosomal dominant hyperimmunoglobulin E syndrome (HIES)
138
Characteristic skin features of AD-HIES
Chronic **eczematoid rashes**, which are typically papular and pruritic
The rash generally involves the **face and extensor surfaces** of arms and legs; skin lesions are frequently sharply demarcated and usually **lack surrounding erythema**.
By 5 years of age all patients have had a history of **recurrent skin abscess** formation with **recurrent pneumonias**, along with **chronic otitis media and sinusitis**.
139
The major offending pathogen in AD-HIES
S. aureus
140
TRUE OR FALSE
AD-HIES has an increased risk of both Hodgkin and non-Hodgkin lymphoma
TRUE
AD-HIES has an increased risk of both Hodgkin and non-Hodgkin lymphoma
141
TRUE OR FALSE
Patients with AR-HIES have more symptomatic neurologic disease than STAT3 deficiency
TRUE
Patients with AR-HIES have **more symptomatic neurologic disease** than STAT3 deficiency
142
A humanized recombinant monoclonal antibody against IgE
Omalizumab (Xolair)
143
An **X-linked** genetic disorder affecting the function of neutrophils and monocytes and involving one of several genes encoding a component of the **NADPH oxidase**
**" defective respiratory burst"**
Chronic Granulomatous Disease
144
The respiratory burst is accompanied, not by mitochondrial respiration, but by a unique electron transport chain called the
NADPH oxidase
145
The most frequent (70%) form of CGD mutation involves what gene
These mutations lead to the X-linked form of the disease
**gp91phox gene (CYBB)** which is located on **chromosome Xp21.1**
146
Forms of autosomal recessive CGD
p47phox (NCF1)- majority
p67phox (NCF2)
147
TRUE OR FALSE
H2O2 is produced by CGD neutrophils, and any generated by the microbes themselves may be destroyed by their own catalase
FALSE
**H2O2 is NOT produced by CGD neutrophils**, and any generated by the microbes themselves may be destroyed by their own catalase.
## Footnote
Thus, catalase-positive microbes can multiply inside CGD neutrophils more easily, where they are protected from most circulating antibiotics, and can be transported to distant sites and released to establish new foci of infection.
148
When CGD neutrophils ingest __________________, these organisms generate enough H2O2 to result in a microbicidal effect
Pneumococci or streptococci
149
Most prevalent infectious complication in CGD (both x-linked recessive and autosomal recessive)
Pneumonia
150
Sign/symptom in a patient with CGD
Recurrent lymphadenitis
## Footnote
Additionally, patients with **bacterial hepatic abscesses, osteomyelitis at multiple sites or in the small bones of the hands and feet, a family history of recurrent infections, or unusual microbial infections** all require clinical evaluation for this disorder.
151
TRUE OR FALSE
Perirectal abscess, suppurative adenitis, and bacteremia/fungemia are twice as common in the autosomal recessive CGD
FALSE
Perirectal abscess, suppurative adenitis, and bacteremia/fungemia are twice as common in the **X-linked recessive CGD**
152
Most common cause of infections in CGD in the initial cases
**Staphylococcus**
Klebsiella and E. coli: next most common pathogens
153
The majority of patients with CGD (76%) are diagnosed before the age of ______ years
5 years
154
Most prominent organism causing pneumonia and leading cause of death in CGD
**Aspergillus**
## Footnote
2nd: Burkholderia cepacia
3rd: Serratia marcescens
155
Histologically, presence of ________ is helpful in establishing the diagnosis of CGD
Pigmented histiocytes
156
Tests to diagnose CGD
Flow cytometry using dihydrorhodamine-123 fluorescence
NBT test
Spectrophotometric assay- measures cytochrome b558 content
157
Difference of G6PD deficiency from CGD
G6PD has **hemolytic anemia** and **erythrocyte activity is markedly reduced**
158
Therapeutics for CGD
IFN-γ (50 mcg/m2, 3 times per week, SQ)
Anti–IL-1 agents
Infliximab
159
A novel **CGD-like disorder** has been most recently identified in 8 homozygote individuals from **Iceland** with **colitis, rare infections**, and a severely impaired **phorbol 12-myristate 13-acetate (PMA)-induced neutrophil oxidative burst**
Has a distinct profile of infections (**Legionella pneumophila and Streptococcus pneumoniae**, and the clear absence of S. aureus and Aspergillus species)
CYBC1 (C17orf62/EROS) Deficiency
160
The first known inherited condition predisposing to **extrapulmonary Aspergillus** infection with an unexpected **sparing of the lungs**.
CARD9 Deficiency
161
# CARD9 Deficiency
In contrast to the retardation of bactericidal activity, candidacidal activity in MPO-deficient neutrophils is (present or absent).
In contrast to the retardation of bactericidal activity, **candidacidal activity** in MPO-deficient neutrophils is **ABSENT**
162
The most significant clinical manifestation in a few patients with diabetes mellitus and MPO deficiency has been severe infection with
C. albicans
163
Most patients with MPO deficiency have a __________ mutation in the gene that results in replacement of arginine 569 with_______________.
Missense mutation
Tryptophan
164
Acquired disorders associated with MPO deficiency
**Lead intoxication, ceroid lipofuscinosis, myelodysplastic syndromes, and acute myelogenous leukemia**
## Footnote
Half of untreated patients with acute myelogenous leukemia and 20% of patients with CML may have MPO deficiency.
165
A soluble enzyme that converts superoxide to a H2O2
Superoxide dismutase
166
Disease associated with impaired neutrophil bactericidal activity
Associated with hemolysis under conditions of oxidative stress
Deficiencies of Glutathione Reductase and Glutathione Synthetase
167
Serves as an **antioxidant** to **prevent damage to the surface** of activated neutrophils when releasing H2O2
Vitamin E
168
TRUE OR FALSE
Like patients with MPO-deficient neutrophils, the patients with glutathione reductase deficiency and glutathione synthetase deficiency are not unusually susceptible to bacterial infections.
TRUE
Like patients with MPO-deficient neutrophils, the patients with **glutathione reductase deficiency and glutathione synthetase deficiency** are NOT unusually susceptible to bacterial infections.
169
Genetic mutations in **NOD2 **which are associated with C**rohn disease and familial sarcoidosis**
Blau syndrome
