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WILLIAM'S HEMATOLOGY > 64 Disorders of Neutrophil Function > Flashcards

64 Disorders of Neutrophil Function Flashcards

1
Q

Part of a neutrophil used in locomotion

A

Lamellipodium - front
Uropod- back

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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

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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

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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

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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.

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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.

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7
Q

Refers to loose and somewhat transient adhesion of neutrophils at site of inflammation

A

Tethering

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8
Q

In macrophages,______________ act as phagocytic tentacles and pull bound objects toward the cell for subsequent phagocytosis

A

Filopodia

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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

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10
Q

These are primary adhesion proteins exposed on the microvilli

A

L-selectin and P-selectin glycoprotein ligand 1 (PSGL-1)

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11
Q

Initiates neutrophil rolling

A

P-selectin

Interacts with the neutrophil PSGL-1 to initiate neutrophil rolling

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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

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13
Q

Serve as counterreceptors for the neutrophil P-selectin glycoprotein ligand-1

A

E-selectin and P-selectin

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14
Q

Chemokine that specifically attracts neutrophils.

A

IL8

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15
Q

IL-8 can be released by________or _________.

A

Histamine or thrombin

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16
Q

β2-Integrins are recognized by counterligands on endothelial cells:

A

Intercellular adhesion molecule (ICAM) family, such as ICAM-1 and ICAM-2

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17
Q

A minority of neutrophils exit by a transcellular route through so-called ________________.

A

Endothelial cups

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18
Q

_____________are perivascular contractile cells that interact with endothelial cells and regulate vascular permeability

A

Pericytes

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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

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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

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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

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22
Q

Known as an LPS-binding protein but is not itself able to signal and presents LPS to TLR4.

A

CD14

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23
Q

Human neutrophils do not express these TLRs:

A

TLR3, TLR7, TLR10, or TLR11

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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

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25
Q

Receptors for Recognition of Microbes

A

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)

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26
Q

Surface Components for Phagocytosis

A

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

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27
Q

____________ 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

A

Albumin

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28
Q

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.

A

TRUE

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29
Q

First identified marker of secretory vesicles

A

Latent alkaline phosphatase

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)

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30
Q

Markers for secretory vesicles are _________and _______

A

CD10 (Neprilysin) and CD35 (CR1)

Neprilysin is also known as membrane metalloendopeptidase, neutral endopeptidase, or common acute lymphoblastic leukemia antigen.

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31
Q

Neutrophil granules

Peroxidase Positive: Azurophil granules: _____________: Primary granules

Peroxidase Negative: _____________: Myelocytes: ____________

A

Azurophil granules: promyelocytes: Primary granules: ** Peroxidase positive

Specific granules: Myelocytes: Secondary granules: ** Peroxidase negative

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32
Q

Azurophilic Granules

A

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

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33
Q

Specific Granules

A

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

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34
Q

Tertiary granule subset was identified in human neutrophils and shown to mainly contain __________

A

Gelatinase

Active against type IV collagen

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35
Q

Defensins are also named

A

HNPs (human neutrophil peptides)

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36
Q

Peroxidase-negative granules can be divided into 3 subsets based on the distribution of the 2 marker proteins, ________ and __________

A

Lactoferrin and Gelatinase

(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%)

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37
Q

TRUE OR FALSE

It is a characteristic of peroxidase-negative granules that the proteins present in their matrix are not proteolytically processed.

A

TRUE

It is a characteristic of peroxidase-negative granules that the proteins present in their matrix are not proteolytically processed.

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38
Q

TRUE OR FALSE

The biosynthesis of neutrophil granule proteins is controlled at the transcriptional and not the translational level

A

TRUE

The biosynthesis of neutrophil granule proteins is controlled at the transcriptional and not the translational level

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39
Q

TRUE OR FALSE

Lysozyme is retained during biosynthesis. This explains the low concentration of lysozyme in plasma.

A

FALSE

Lysozyme is poorly retained during biosynthesis. This explains the high concentration of lysozyme in plasma.

MPO is efficiently retained; consequently, the plasma level of MPO is very low.

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40
Q

FUNCTION OF INDIVIDUAL GRANULE PROTEINS

A

TABLE 64-1

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41
Q

Marker of azurophil granules

A

MPO

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42
Q

MPO is known for the anti-MPO autoantibodies that are characteristic of the __________ antibodies

A

Perinuclear antineutrophil cytoplasmic antibodies that are found in vasculitides, particularly those that primarily affect kidneys

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43
Q

Granule responsible for the binding of LPS and for the antimicrobial activity against Gram-negative microorganisms

A

Bacterial permeability-increasing
(BPI) protein

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44
Q

Only defensins found in human neutrophils and reside exclusively in azurophil granules

A

α defensins

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45
Q

Dominating proteins of azurophil granules

A

α Defensins

Only expressed in a subset of granules that are formed late in the promyelocyte stage

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46
Q

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

A

Prodefensins

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47
Q

Serine protease that leads to autoantibodies against itself in Wegener granulomatosis, which is known as cytoplasmic antineutrophil cytoplasmic antibody

A

Proteinase 3

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48
Q

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

A

Papillon-Lefèvre syndrome

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49
Q

The dominating protein of specific granules

A

Lactoferrin

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50
Q

Protein with high affinity for iron and similar binding characteristics as ferritin

A

Lactoferrin

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51
Q

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.

A

Lactoferricin

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52
Q

Protein that bind and sequester siderophores

A

NGAL, or lipocalin 2

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53
Q

Protein that binds enterochelin/ enterobactin with high affinity, and blocks growth of Escherichia coli

A

NGAL, or lipocalin 2

NGAL has been demonstrated to play a protective role in infections against E. coli, Klebsiella pneumoniae, Salmonella typhimurium, and Mycobacterium tuberculosis.

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54
Q

Protein that is an essential resistance factor against mycobacterial infection

A

Nramp1

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55
Q

Protein that cleaves peptidoglycan polymers of bacterial cell walls and displays bactericidal activity toward the nonpathogenic Gram-positive bacteria Bacillus subtilis

A

Lysozyme

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56
Q

A particular high serum level of this enzyme is characteristic for the myelomonocytic leukemias

A

Lysozyme

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57
Q

The only human member of a family of antimicrobial peptides known as cathelicidins.

A

hCAP-18 also known as LL-37190 or CAMP

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58
Q

Protein that has angiogenic and endotoxin-neutralizing properties

Stimulates neutrophil, monocyte, and T-cell chemotaxis via the formyl peptide receptor-like-1

A

hCAP-18/ LL-37

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59
Q

hCAP-18/ LL-37 counterpart in the testis is cleaved by _______

A

Gastricsin

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60
Q

Protein capable of capable of degrading major structural components of the extracellular matrix

A

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

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61
Q

Pattern-recognition molecules that binds the complement component C1q and mediates activation of the classical complement cascade.

A

Pentraxin 3

Also binds K. pneumoniae outer membrane protein A (KpOmpA) from Gram-negative bacteria, especially the Enterobacteriaceae species, and binds Aspergillus fumigatus conidia.

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62
Q

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

A

Ficolin-1

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63
Q

Protein essential for essential for collagen synthesis

A

Proline

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64
Q

Protein that forms the membrane component of the NADPH oxidase

A

Cytochrome b558

Comprised of gp91phox and p22phox

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65
Q

Anaphylatoxin complement and receptors

A

Complement activation liberates the anaphylatoxins C3a and C5a, which activate 3 distinct GPCRs: C3AR, C5AR1, and C5AR2 (or anaphylatoxin receptors)

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66
Q

A major proinflammatory component and the most potent of the chemotactic proteins

Induces neutrophil chemotaxis, degranulation, and superoxide generation

A

C5a

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67
Q

The major C5a receptor

A

C5AR1 (CD88)

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68
Q

IL-8 related receptors

A

CXCR1 and CXCR2

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69
Q

FcγRIIA/CD32 or FcγRIII/CD16

Most important immunoglobulin receptor for clearing immune complexes

A

FcγRIII

70
Q

The reigning paradigm for fusion of biomembrane

A

SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) hypothesis

v-SNAREs:vesicles or granules
t-SNAREs: target plasma membranes

71
Q

Neutrophil extracellular traps are extruded from neutrophils in a process called __________

A

NETosis

72
Q

3 death programs of neutrophils:

A

Apoptosis, necrosis, and NETosis

73
Q

The NADPH oxidase activity of stimulated neutrophils thus serves 2 purposes:

A

To generate reactive oxygen species for microbial killing

To induce formation of the bactericidal NETs

74
Q

Condition where patients with defective NADPH oxidase assembly

Lack both the ability to generate microbicidal oxygen species and the ability to form the NETs

A

Chronic granulomatous disease [CGD]

75
Q

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

A

Papillon-Lefèvre syndrome

76
Q

The most profound disturbances in signal mechanism as a result of Ab and complement defects

A

C3

77
Q

Refers to the coating of pathogens by serum proteins such that they are more likely to be ingested

A

Opsonization

78
Q

TRUE OR FALSE

Encapsulated pathogens characteristically are associated with neutropenic states.

A

FALSE

Encapsulated pathogens characteristically are NOT associated with neutropenic states.

79
Q

DEGRANULATION ABNORMALITIES

A

Chédiak-Higashi syndrome
Specific granule deficiency
Specific granule deficiency with myelodysplasia

80
Q

ADHESION ABNORMALITIES

A

Leukocyte adhesion deficiency type 1 (LAD-1)
LAD-2
LAD-3 (LAD-1 variant syndrome)

81
Q

DEPRESSED MOTILE RESPONSES

A

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
Q

MICROBICIDAL ACTIVITY

A

CGD
EROS deficiency (C17Orf62)
G6PD deficiency
Myeloperoxidase deficiency
RAC2 deficiency [D57N]
Deficiencies of glutathione reductase and glutathione synthetase

83
Q

Example of Degranulation Abnormalities

A

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
Q

Among 10 currently defined subtypes of HPS, only type ____ and type ____are characterized by immunodeficiency.

A

Type 2 and Type 9

HPS2 : AP3B1 gene
HPS9: pallidin-encoding gene, PLDN

85
Q

A long-term complication of CHS, but is uncommon in other syndromic albinisms

A

Neurologic disease

86
Q

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.

A

Severe chronic neutropenia

87
Q

Disorder of generalized cellular dysfunction characterized by increased fusion of cytoplasmic granules and one in which neutrophils, monocytes, and lymphocytes contained giant cytoplasmic granules

A

Chédiak-Higashi Syndrome

88
Q

Features of Chedak Higashi

A

Neutropenia, thrombocytopathy, NK cell abnormalities, and peripheral neuropathies

89
Q

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

A

Lymphohistiocytic infiltration (HLH)

90
Q

The primary morphologic feature of CHS

A

Giant lysosomes

Only cells relying on the secretion by these lysosomes manifest pathologic defects

91
Q

Gene that is mutated in CHS

A

CHS1 (synonym: LYST) found on chromosome 1q

92
Q

The pathognomonic feature in CHS that can be seen in neutrophils.

A

Giant peroxidase-positive granules

93
Q

A microscopic examination of hair shafts of patients with CHS reveal

A

Large, speckled pigment clumps

94
Q

Most commonly infecting organism in CHS

A

Staphylococcus aureus

95
Q

Reason for prolonged bleeding times with normal platelet counts in CHS

A

Impaired platelet aggregation associated with a deficiency of the storage pools of ADP and serotonin

96
Q

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.

A

Griscelli syndrome

97
Q

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.

A

Hermansky-Pudlak syndrome (HPS)

98
Q

TRUE OR FALSE

In CHS, prophylactic antibiotics do not prevent infections

A

TRUE

In CHS, prophylactic antibiotics do not prevent infections

99
Q

The only potential for curative therapy for preventing the accelerated phase in CHS

A

Marrow transplantation

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
Q

Autosomal recessive disorder
Characterized by absence of specific granules, the nuclei of the neutrophils are bilobed

A

Specific granule deficiency (SGD)

The disorder is a global defect in phagocytic granules rather than limited to specific granules, as suggested by its name

101
Q

The most commonly observed pathogens in SGD

A

S. aureus and Pseudomonas aeruginosa

102
Q

Gene that is mutated in Specific granule deficiency (SGD)

A

C/EBPε

103
Q

The diagnosis of SGD is suggested by the presence of

A

Neutrophils devoid of specific granules but containing azurophilic granules on the blood film

104
Q

Specific granule deficiency (SGD) can be confirmed by demonstrating a severe deficiency in either ______ or _________

A

Lactoferrin or hCAP-18

105
Q

Gene that is mutated in Specific granule deficiency (SGD) with myelodysplasia

A

SMARCD2

106
Q

An acquired form of SGD can be observed in

A

Thermally injured patients or in individuals with myelodysplasia

107
Q

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

A

Leukocyte adhesion deficiency type I (LAD-1)

108
Q

Gene that is mutated in Leukocyte adhesion deficiency type I (LAD-1)

A

CD11/ CD18 complex (also referred to as the β2-integrin family of leukocyte adhesion proteins)

109
Q

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

A

Leukocyte adhesion deficiency type I (LAD-1)

110
Q

Refers to chemotaxis that occurs despite blockade of CD11/CD18

A

Chimneying

111
Q

Diagnosis of LAD can be made through

A

Flow cytometric measurement of surface CD11b

112
Q

TRUE OR FALSE

In LAD, there is a paucity of neutrophils in inflammatory skin windows and biopsies of infected tissues.

A

TRUE

In LAD, there is a paucity of neutrophils in inflammatory skin windows and biopsies of infected tissues.

113
Q

Genetic defect in LAD-2 or congenital disorder of glycosylation type IIc (CDG-IIc)

A

Fucosylation of ligands for selectins and other glycoconjugates.

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
Q

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

A

Bombay blood phenotype (deficiency in H blood group integrins)

115
Q

TRUE OR FALSE

In contrast to LAD-1, the patients’ NK cell activity is abnormal.

A

FALSE

In contrast to LAD-1, the patients’ NK cell activity is normal

116
Q

The LAD-2 neutrophils express normal levels of CD18 integrins, but are deficient in the carbohydrate structure

A

sLex

117
Q

The diagnosis of LAD-2 can be made by

A

Flow cytometry analysis of CD15s (sLex) expression

118
Q

2 major hallmarks of LAD-3 or LAD-1 variant syndrome

A

A moderate LAD-1–like syndrome and severe Glanzmann-like bleeding diathesis

Inability to form pus at sites of microbial infections, as well as a severe bleeding tendency

119
Q

Gene that is mutated in LAD-3 or LAD-1 variant syndrome

A

FERMT3 which encodes kindlin-3

120
Q

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

A

Mutation in the Rac2 GTPase

121
Q

Treatment of choice in case of severe LAD-1 or LAD-like syndromes

A

Hematopoietic stem cell transplantation (HSCT)

122
Q

The severity of infectious complications in LAD correlates with the degree of ___________ deficiency.

A

β2 deficiency

123
Q

Moderately severe LAD-1 is characterized clinically by ________________

A

Severe periodontal disease that results in premature loss of teeth.

124
Q

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

A

Neutrophil Actin Dysfunction

NAD47/89

125
Q

Defect in Neutrophil Actin Dysfunction

Overexpression of this resulted in bundling of actin in cells, leading to an abnormal cytoskeletal structure and motility defects

A

LSP-1 (lymphocyte-specific protein-1)

126
Q

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

A

ARPC1B deficiency

127
Q

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.

A

WDR1 Deficiency
“lazy leukocyte syndrome”

128
Q

Disease on patients with WDR1 Deficiency having an acute-phase response, thrombocytopenia, hyperferritinemia, high serum IgA levels and constitutively increased IL-18 levels.

A

Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (APFIT) syndrome

129
Q

An X-linked combined immune deficiency characterized by defects of T-cell function associated with hypogammaglobulinemia and (fluctuating) neutropenia

A

Moesin Deficiency

Affected individuals suffered from recurrent bacterial infections, mainly of the respiratory tract, along with unusually severe varicella-zoster infections and molluscum contagiosum

130
Q

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.

A

STK4 (or MST1) Deficiency

131
Q

Drugs and Extrinsic Agents That Impair Neutrophil Motility

A

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
Q

TRUE OR FALSE

Administration of glucocorticoids on alternate days does not interfere with neutrophil movement.

A

TRUE

Administration of glucocorticoids on alternate days does not interfere with neutrophil movement.

133
Q

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.”

A

Hyperimmunoglobulin E Syndrome

“Job syndrome.”

134
Q

Gene that is mutated in Autosomal dominant hyperimmunoglobulin E syndrome (HIES)

A

STAT3

135
Q

Gene that is mutated in autosomal recessive hyperimmunoglobulin E syndrome (HIES)

A

DOCK8

136
Q

Distinguishing features of AD-HIES

A

Pneumatoceles in the lung, subcutaneous abscess formation, lack of viral skin disease (in contrast to DOCK8 deficiency), and facial features

137
Q

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

A

Autosomal dominant hyperimmunoglobulin E syndrome (HIES)

138
Q

Characteristic skin features of AD-HIES

A

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
Q

The major offending pathogen in AD-HIES

A

S. aureus

140
Q

TRUE OR FALSE

AD-HIES has an increased risk of both Hodgkin and non-Hodgkin lymphoma

A

TRUE

AD-HIES has an increased risk of both Hodgkin and non-Hodgkin lymphoma

141
Q

TRUE OR FALSE

Patients with AR-HIES have more symptomatic neurologic disease than STAT3 deficiency

A

TRUE

Patients with AR-HIES have more symptomatic neurologic disease than STAT3 deficiency

142
Q

A humanized recombinant monoclonal antibody against IgE

A

Omalizumab (Xolair)

143
Q

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”

A

Chronic Granulomatous Disease

144
Q

The respiratory burst is accompanied, not by mitochondrial respiration, but by a unique electron transport chain called the

A

NADPH oxidase

145
Q

The most frequent (70%) form of CGD mutation involves what gene

These mutations lead to the X-linked form of the disease

A

gp91phox gene (CYBB) which is located on chromosome Xp21.1

146
Q

Forms of autosomal recessive CGD

A

p47phox (NCF1)- majority
p67phox (NCF2)

147
Q

TRUE OR FALSE

H2O2 is produced by CGD neutrophils, and any generated by the microbes themselves may be destroyed by their own catalase

A

FALSE

H2O2 is NOT produced by CGD neutrophils, and any generated by the microbes themselves may be destroyed by their own catalase.

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
Q

When CGD neutrophils ingest __________________, these organisms generate enough H2O2 to result in a microbicidal effect

A

Pneumococci or streptococci

149
Q

Most prevalent infectious complication in CGD (both x-linked recessive and autosomal recessive)

A

Pneumonia

150
Q

Sign/symptom in a patient with CGD

A

Recurrent lymphadenitis

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
Q

TRUE OR FALSE

Perirectal abscess, suppurative adenitis, and bacteremia/fungemia are twice as common in the autosomal recessive CGD

A

FALSE

Perirectal abscess, suppurative adenitis, and bacteremia/fungemia are twice as common in the X-linked recessive CGD

152
Q

Most common cause of infections in CGD in the initial cases

A

Staphylococcus

Klebsiella and E. coliwere- next most common pathogens

153
Q

The majority of patients with CGD (76%) are diagnosed before the age of ______ years

A

5 years

154
Q

Most prominent organism causing pneumonia and leading cause of death in CGD

A

Aspergillus

2nd: Burkholderia cepacia
3rd: Serratia marcescens

155
Q

Histologically, presence of ________ is helpful in establishing the diagnosis of CGD

A

Pigmented histiocytes

156
Q

Tests to diagnose CGD

A

Flow cytometry using dihydrorhodamine-123 fluorescence

NBT test
Spectrophotometric assay- measures cytochrome b558 content

157
Q

Difference of G6PD deficiency from CGD

A

G6PD has hemolytic anemia and erythrocyte activity is markedly reduced

158
Q

Therapeutics for CGD

A

IFN-γ (50 mcg/m2, 3 times per week, SQ)
Anti–IL-1 agents
Infliximab

159
Q

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)

A

CYBC1 (C17orf62/EROS) Deficiency

160
Q

The first known inherited condition predisposing to extrapulmonary Aspergillus infection with an unexpected sparing of the lungs.

A

CARD9 Deficiency

161
Q

CARD9 Deficiency

In contrast to the retardation of bactericidal activity, candidacidal activity in MPO-deficient neutrophils is (present or absent).

A

In contrast to the retardation of bactericidal activity, candidacidal activity in MPO-deficient neutrophils is ABSENT

162
Q

The most significant clinical manifestation in a few patients with diabetes mellitus and MPO deficiency has been severe infection with

A

C. albicans

163
Q

Most patients with MPO deficiency have a __________ mutation in the gene that results in replacement of arginine 569 with_______________.

A

Missense mutation

Tryptophan

164
Q

Acquired disorders associated with MPO deficiency

A

Lead intoxication, ceroid lipofuscinosis, myelodysplastic syndromes, and acute myelogenous leukemia

Half of untreated patients with acute myelogenous leukemia and 20% of patients with CML may have MPO deficiency.

165
Q

A soluble enzyme that converts superoxide to a H2O2

A

Superoxide dismutase

166
Q

Disease associated with impaired neutrophil bactericidal activity

Associated with hemolysis under conditions of oxidative stress

A

Deficiencies of Glutathione Reductase and Glutathione Synthetase

167
Q

Serves as an antioxidant to prevent damage to the surface of activated neutrophils when releasing H2O2

A

Vitamin E

168
Q

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.

A

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
Q

Genetic mutations in NOD2 which are associated with Crohn disease and familial sarcoidosis

A

Blau syndrome

170
Q

First known inherited condition predisposing to extrapulmonary Aspergillus infection with an unexpected sparing of the lungs.

A

CARD9 Deficiency

WILLIAM'S HEMATOLOGY (89 decks)

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