64 Disorders of Neutrophil Function Flashcards
Part of a neutrophil used in locomotion
Lamellipodium - front
Uropod- back
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)
Cofilin
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
Profilin
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
Cortactin
Cortactin homologue that is only expressed in hematopoietic cells
Essential for T-cell activation
HS1
Human defects in cortactin or HS1 have not yet been reported.
True or False
Locomotion is a prerequisite for ingestion
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.
Refers to loose and somewhat transient adhesion of neutrophils at site of inflammation
Tethering
In macrophages,______________ act as phagocytic tentacles and pull bound objects toward the cell for subsequent phagocytosis
Filopodia
Actin-binding proteins associated with neutrophil plasma membranes which are important for organization of microvilli on the surface of the cell
Moesin, ezrin, and p205 radixin
These are primary adhesion proteins exposed on the microvilli
L-selectin and P-selectin glycoprotein ligand 1 (PSGL-1)
Initiates neutrophil rolling
P-selectin
Interacts with the neutrophil PSGL-1 to initiate neutrophil rolling
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.
ADAM17
Neutrophil PSGL-1 may also act as counterreceptor for L-selectin
Serve as counterreceptors for the neutrophil P-selectin glycoprotein ligand-1
E-selectin and P-selectin
Chemokine that specifically attracts neutrophils.
IL8
IL-8 can be released by________or _________.
Histamine or thrombin
β2-Integrins are recognized by counterligands on endothelial cells:
Intercellular adhesion molecule (ICAM) family, such as ICAM-1 and ICAM-2
A minority of neutrophils exit by a transcellular route through so-called ________________.
Endothelial cups
_____________are perivascular contractile cells that interact with endothelial cells and regulate vascular permeability
Pericytes
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.
IL-8 and LTB4
Examples of pattern recognition receptors (PRRs)
Membrane-bound: toll-like receptors (TLRs) and C-type lectin receptors
Cytosolic: nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and RIG-like receptors
Examples of toll-like receptors (TLRs) and where it binds
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
Known as an LPS-binding protein but is not itself able to signal and presents LPS to TLR4.
CD14
Human neutrophils do not express these TLRs:
TLR3, TLR7, TLR10, or TLR11
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.
C-type lectin receptors
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)
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
____________ 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
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
First identified marker of secretory vesicles
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)
Markers for secretory vesicles are _________and _______
CD10 (Neprilysin) and CD35 (CR1)
Neprilysin is also known as membrane metalloendopeptidase, neutral endopeptidase, or common acute lymphoblastic leukemia antigen.
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
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
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
Tertiary granule subset was identified in human neutrophils and shown to mainly contain __________
Gelatinase
Active against type IV collagen
Defensins are also named
HNPs (human neutrophil peptides)
Peroxidase-negative granules can be divided into 3 subsets based on the distribution of the 2 marker proteins, ________ and __________
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%)
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.
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
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.
MPO is efficiently retained; consequently, the plasma level of MPO is very low.
FUNCTION OF INDIVIDUAL GRANULE PROTEINS
TABLE 64-1
Marker of azurophil granules
MPO
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
Granule responsible for the binding of LPS and for the antimicrobial activity against Gram-negative microorganisms
Bacterial permeability-increasing
(BPI) protein
Only defensins found in human neutrophils and reside exclusively in azurophil granules
α defensins
Dominating proteins of azurophil granules
α Defensins
Only expressed in a subset of granules that are formed late in the promyelocyte stage
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
Serine protease that leads to autoantibodies against itself in Wegener granulomatosis, which is known as cytoplasmic antineutrophil cytoplasmic antibody
Proteinase 3
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
The dominating protein of specific granules
Lactoferrin
Protein with high affinity for iron and similar binding characteristics as ferritin
Lactoferrin
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
Protein that bind and sequester siderophores
NGAL, or lipocalin 2
Protein that binds enterochelin/ enterobactin with high affinity, and blocks growth of Escherichia coli
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.
Protein that is an essential resistance factor against mycobacterial infection
Nramp1
Protein that cleaves peptidoglycan polymers of bacterial cell walls and displays bactericidal activity toward the nonpathogenic Gram-positive bacteria Bacillus subtilis
Lysozyme
A particular high serum level of this enzyme is characteristic for the myelomonocytic leukemias
Lysozyme
The only human member of a family of antimicrobial peptides known as cathelicidins.
hCAP-18 also known as LL-37190 or CAMP
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
hCAP-18/ LL-37 counterpart in the testis is cleaved by _______
Gastricsin
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
Pattern-recognition molecules that binds the complement component C1q and mediates activation of the classical complement cascade.
Pentraxin 3
Also binds K. pneumoniae outer membrane protein A (KpOmpA) from Gram-negative bacteria, especially the Enterobacteriaceae species, and binds Aspergillus fumigatus conidia.
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
Protein essential for essential for collagen synthesis
Proline
Protein that forms the membrane component of the NADPH oxidase
Cytochrome b558
Comprised of gp91phox and p22phox
Anaphylatoxin complement and receptors
Complement activation liberates the anaphylatoxins C3a and C5a, which activate 3 distinct GPCRs: C3AR, C5AR1, and C5AR2 (or anaphylatoxin receptors)
A major proinflammatory component and the most potent of the chemotactic proteins
Induces neutrophil chemotaxis, degranulation, and superoxide generation
C5a
The major C5a receptor
C5AR1 (CD88)
IL-8 related receptors
CXCR1 and CXCR2
FcγRIIA/CD32 or FcγRIII/CD16
Most important immunoglobulin receptor for clearing immune complexes
FcγRIII
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
Neutrophil extracellular traps are extruded from neutrophils in a process called __________
NETosis
3 death programs of neutrophils:
Apoptosis, necrosis, and NETosis
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
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]
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
The most profound disturbances in signal mechanism as a result of Ab and complement defects
C3
Refers to the coating of pathogens by serum proteins such that they are more likely to be ingested
Opsonization
TRUE OR FALSE
Encapsulated pathogens characteristically are associated with neutropenic states.
FALSE
Encapsulated pathogens characteristically are NOT associated with neutropenic states.
DEGRANULATION ABNORMALITIES
Chédiak-Higashi syndrome
Specific granule deficiency
Specific granule deficiency with myelodysplasia
ADHESION ABNORMALITIES
Leukocyte adhesion deficiency type 1 (LAD-1)
LAD-2
LAD-3 (LAD-1 variant syndrome)
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
MICROBICIDAL ACTIVITY
CGD
EROS deficiency (C17Orf62)
G6PD deficiency
Myeloperoxidase deficiency
RAC2 deficiency [D57N]
Deficiencies of glutathione reductase and glutathione synthetase
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
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
A long-term complication of CHS, but is uncommon in other syndromic albinisms
Neurologic disease
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
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
Features of Chedak Higashi
Neutropenia, thrombocytopathy, NK cell abnormalities, and peripheral neuropathies
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)
The primary morphologic feature of CHS
Giant lysosomes
Only cells relying on the secretion by these lysosomes manifest pathologic defects
Gene that is mutated in CHS
CHS1 (synonym: LYST) found on chromosome 1q
The pathognomonic feature in CHS that can be seen in neutrophils.
Giant peroxidase-positive granules
A microscopic examination of hair shafts of patients with CHS reveal
Large, speckled pigment clumps
Most commonly infecting organism in CHS
Staphylococcus aureus
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
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
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)
TRUE OR FALSE
In CHS, prophylactic antibiotics do not prevent infections
TRUE
In CHS, prophylactic antibiotics do not prevent infections
The only potential for curative therapy for preventing the accelerated phase in CHS
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.
Autosomal recessive disorder
Characterized by absence of specific granules, the nuclei of the neutrophils are bilobed
Specific granule deficiency (SGD)
The disorder is a global defect in phagocytic granules rather than limited to specific granules, as suggested by its name
The most commonly observed pathogens in SGD
S. aureus and Pseudomonas aeruginosa
Gene that is mutated in Specific granule deficiency (SGD)
C/EBPε
The diagnosis of SGD is suggested by the presence of
Neutrophils devoid of specific granules but containing azurophilic granules on the blood film
Specific granule deficiency (SGD) can be confirmed by demonstrating a severe deficiency in either ______ or _________
Lactoferrin or hCAP-18
Gene that is mutated in Specific granule deficiency (SGD) with myelodysplasia
SMARCD2
An acquired form of SGD can be observed in
Thermally injured patients or in individuals with myelodysplasia
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)
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)
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)
Refers to chemotaxis that occurs despite blockade of CD11/CD18
Chimneying
Diagnosis of LAD can be made through
Flow cytometric measurement of surface CD11b
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.
Genetic defect in LAD-2 or congenital disorder of glycosylation type IIc (CDG-IIc)
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
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)
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
The LAD-2 neutrophils express normal levels of CD18 integrins, but are deficient in the carbohydrate structure
sLex
The diagnosis of LAD-2 can be made by
Flow cytometry analysis of CD15s (sLex) expression
2 major hallmarks of LAD-3 or LAD-1 variant syndrome
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
Gene that is mutated in LAD-3 or LAD-1 variant syndrome
FERMT3 which encodes kindlin-3
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
Treatment of choice in case of severe LAD-1 or LAD-like syndromes
Hematopoietic stem cell transplantation (HSCT)
The severity of infectious complications in LAD correlates with the degree of ___________ deficiency.
β2 deficiency
Moderately severe LAD-1 is characterized clinically by ________________
Severe periodontal disease that results in premature loss of teeth.
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
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)
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
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”
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
An X-linked combined immune deficiency characterized by defects of T-cell function associated with hypogammaglobulinemia and (fluctuating) neutropenia
Moesin Deficiency
Affected individuals suffered from recurrent bacterial infections, mainly of the respiratory tract, along with unusually severe varicella-zoster infections and molluscum contagiosum
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
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
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.
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.”
Gene that is mutated in Autosomal dominant hyperimmunoglobulin E syndrome (HIES)
STAT3
Gene that is mutated in autosomal recessive hyperimmunoglobulin E syndrome (HIES)
DOCK8
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
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)
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.
The major offending pathogen in AD-HIES
S. aureus
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
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
A humanized recombinant monoclonal antibody against IgE
Omalizumab (Xolair)
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
The respiratory burst is accompanied, not by mitochondrial respiration, but by a unique electron transport chain called the
NADPH oxidase
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
Forms of autosomal recessive CGD
p47phox (NCF1)- majority
p67phox (NCF2)
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.
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.
When CGD neutrophils ingest __________________, these organisms generate enough H2O2 to result in a microbicidal effect
Pneumococci or streptococci
Most prevalent infectious complication in CGD (both x-linked recessive and autosomal recessive)
Pneumonia
Sign/symptom in a patient with CGD
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.
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
Most common cause of infections in CGD in the initial cases
Staphylococcus
Klebsiella and E. coli: next most common pathogens
The majority of patients with CGD (76%) are diagnosed before the age of ______ years
5 years
Most prominent organism causing pneumonia and leading cause of death in CGD
Aspergillus
2nd: Burkholderia cepacia
3rd: Serratia marcescens
Histologically, presence of ________ is helpful in establishing the diagnosis of CGD
Pigmented histiocytes
Tests to diagnose CGD
Flow cytometry using dihydrorhodamine-123 fluorescence
NBT test
Spectrophotometric assay- measures cytochrome b558 content
Difference of G6PD deficiency from CGD
G6PD has hemolytic anemia and erythrocyte activity is markedly reduced
Therapeutics for CGD
IFN-γ (50 mcg/m2, 3 times per week, SQ)
Anti–IL-1 agents
Infliximab
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
The first known inherited condition predisposing to extrapulmonary Aspergillus infection with an unexpected sparing of the lungs.
CARD9 Deficiency
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
The most significant clinical manifestation in a few patients with diabetes mellitus and MPO deficiency has been severe infection with
C. albicans
Most patients with MPO deficiency have a __________ mutation in the gene that results in replacement of arginine 569 with_______________.
Missense mutation
Tryptophan
Acquired disorders associated with MPO deficiency
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.
A soluble enzyme that converts superoxide to a H2O2
Superoxide dismutase
Disease associated with impaired neutrophil bactericidal activity
Associated with hemolysis under conditions of oxidative stress
Deficiencies of Glutathione Reductase and Glutathione Synthetase
Serves as an antioxidant to prevent damage to the surface of activated neutrophils when releasing H2O2
Vitamin E
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.
Genetic mutations in NOD2 which are associated with Crohn disease and familial sarcoidosis
Blau syndrome
