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Chronic Granulomatous Disease
Terms in this set (92)
What is a fungus that can result in this condition?
What is neutrophil's role in the innate immune response?
The bacterial specialist
Who are the specialist in inflammation?
What are the steps of neutrophil function?
1. Production of neutrophils in the bone marrow
4. Migration toward inflammatory area
5/ Phagocytosis of bacteria
6. Phagocytosis of bacteria
7. Intracellular killing
What do we call the production of neutrophils?
Myelopoesis specfically from the myoblast that develops from the differentiation of the common myeloid progenitor.
What can the common myeloid progenitor differentiate into (4 lines)?
myelocytes (like neutrophils)
What is the most numerous type of luekocyte?
Where are the neutrophils located?
2% in blood, the rest are in the tissues monitoring and chcking on things
What is rolling?
chemokines cause the neutrophils to be called to a certain area and slow down due to the activity of selectins on the endothelial cells and addressins on the neutrophil surface. These interactions result in the slowing down of the neutrophils
Are selectins always present?
Yes, they move out to the surface of the cell upon activation by cytokines. (trans mebrane glycoproteins)
What are Weibel-Palade bodies?
selectins are stored in this performed form in the endothelial cells until activation by cytokines
What are addresins?
the adhesion molecules on the neutrophils
What are the addressins
glycoproteins that are mucin like, and possess sialyl Lews X which binds to the lectin domain of the selectins
How do we ge complete adhesion?
Beta integrins on the neutrophils and molecules of the Ig family on endothelial cells interact
What are beta 2 integrins?
transmembrane proteins consisting ot two distinct chains termaed alpha and beta arrange as heterodimers, Beta 2 integrins bind 2 counter ligads on the endothelial surface
What are Icam-1 and VCAM -1
What the Beta 2 integrin binds to for adehsion.
What happens to beta 2 integrin in complete adhesion
the activation of them converts them to a high affinit state for the ICAMs when the cytokines are present
ICAM and VCAM are always epxessed on the endothelial surface but only activated by what?
How does Migration work?
Diapedesis through tight junctions between endothelial cells is related to PECAM-1, JAM. and CD99 expessed on both neutrophils and endothelial cells
What does PECAM-1 do?
platelet endothelial cell adhesion molecule is an Ig family member expressed on the sufrace of neutrophils and is also in high concentration on the endothelial cell intercellular junctions where they can squeeze through.
What is JAM?
localized to tight junctions between endothelial cells also expressed on neutrophils
What is CD99?
rather samll membrane protein that is not related to any known protein family. IT is expressed on the leukocyte surface and endothelial junction.
What occurs after extravasation in migration?
neutrophils emigrate toward the site of injury via chemotaxis
What are chemotactic agents?
formyl peptides, Complement 3a and 5a, chemokins and leukotrienes presented within the tissue (these two are most important in getting leukocytes to the aea)
WHy is polymerization of Beta actin important?
Signals iniated from receptors moobilize the actin so taht the cell can use filopodia to move.
What is the phagosome?
bacteria adheres to the leukocyte sufrace (facilitated by opsonization( and the leukocyte englufs the bacterium, forming the phagosome or phagocytic vacuole
What is the phagyolsome?
The cytoplasmic granules discharge their content into the phagosome as a funcion of the granule mebrane with the phagosome making it the phagolysome
What is degranulation?
the process by which the phagysome releases antimicrobial cytotoxic molecules from granules found inside the neutrophils into the phagolysomes.
What are the three types of granules?
Specific (secondary) granules
and GElatinase granules
What is the Oxygen dependent mechanisms of intracellular killing?
Oxygen dependent intracellular killing involes activation of NADPH in the cells that is part of a rapid oxygen uptake and works to give a lethal dose of free radicals
What is the NADPH oxidase complex?
enzyme that is responsible for free radical production and is activated to assemble in the membranes during phagocytosis
What are the steps in oxygen dependent killing?
1. superoxide formed
2. spontaneous dismutation to hydrogen peoxide
3. hydroxyl radical fromed from hydrogen peroxide by reduced metal oxidation
What is myeloperoxidase?
Large quarternary protein that carries two heme prosethetics and is abundant in asurophilic granules. causes the reaction of CL- and H2O2 to form HOCl
What are the types of neutrophil granules? (10+descrption)
A defensins- small peptides, form membrane pores
2. BPI- cytotoxic against LPS
3. Lactoferrin- antibacterial, deprives them of growth element
4. Serprocidins- 4 cerine proteases that target all bacteria and fungi
5. hCAP-18- neutralizes effect of LPS
6. NGAL- bacterostatic activity through sequestration of iron
7. Lysosome- destroys peptidoglycan of cell wall hydrolizing glycosidic bonds
8. NRAMP1- sequesters divalent metal ions necessary for bacteria growth
9/10. GElatinase and leukolysin-metalloproteinases capable of degrading major extracellular matrix structures.
What is the most significant disease that can inherent neutrophil function and at what step?
Chronic granulomatous disease interferes with intracellular killing
What is neutropenia?
reducion of absolute blood neutrophil count below 1500 cells/mm3
What is the etiology of neutropenia?
What is tthe pathogenic classification? (2)*** IMPORTANT
Decreased production of neutrophils in t he bone marrow- marrow failure OR
peripheral destruction of neutrophils which will give you hyperplastic bone marrow +peripheral blood neutropenia
What is clinical presentation of neutropenia?
fever, infections all over, sepsis, risk of bacterial infections is proportional to severity and duration of neutropenia
What causes 85% of neutropenic infections?
naturally occuring microorganisms in the patient's own systems.
Is there an increased risk of viral and parasitic infections in neutropenia?
What do we see with pateints who have bone marrow failure(infection wise)
sepsis, often do to staph aureus, pseudomonas, Klebsiella, and E coli.
What infections do we see in patients with peripheral neutropenia?
Recurrent sinusitis, stomatitis, ginigivitis, periodontii, anorectal abcess
What is postinfectious neutropenia?
seen after viral infections
What is Drug-induced neutropenia?
develops because of two mechanisms: Direct cytotoxic effect to bone marrow or via immune mediated destruction of neutrophil
What is hypersplenism?
Overactive spleen that destroys rapidly and prematurely white and red blood cells. Spleen is blood cell cemetary, marrow is hyperplastic
What is chronic benign neutropenia of infancy and childhood?
Peripheral destruction of neutrophils as a result of formation of antibodies against human neutrophil antigen. Patients usually infants, Bone marrow is hyperpplastic and condition resolves by 2 or 3 yo
Benign ethnic neutropenia?
Seen in individuals of African American descent (25-50%) have neutrophol couints lower than 1500 and has been suggested that there is a factor that interferes with neutrophil egression from the bone marrow via the interaction of SDF1 (cytokine)
What is the leukocyte adhesion deficiency type I?
Deficiency of Beta integreins change which makes it so that there are no integrins on the surface of the cell. SInce there is no combination of the alpha and beta chains. Children are prone to infections of the skin and oral cavity
What is the pathogenesis and Leukocyte adhesion deficiency type I?
The absent expression of Beta 2 integrins, results in the failure of neutrophils to emigrate from the blood stream to sites of infection.
What is the clinical presentation of LAD I? (2 types)
Severe and moderate phenotypes
What is severe LAD I? What is moderate?
diagnosis is 1 month in age,
Moderate: Cutaneous abcesses, ginigvitis, stomatitis, and aggressive perionditis
What is severe? moderate symptoms plus: delayed umbilical cord separation, anorectal abcess, severe ulcerative stomatitis, and bacterial sepsis
How can LAD I be diagnosed?
Can be done early when there is a delayed umbilical cord separation (occuring after 3 weeks)
What is the pathology of LAD I?
A striking feature is that abcesses and other site of infection are devoid of pus despite the marked neutrophilia because neutrophils are unable to migrate to tissue.
How do you diagnose LAD I?
flow cytometry measurement of surface Beta 2 integrins in unstimulated and stimulated neutrophils using monoclonal antibodies directed against Beta subunits.
What is prognosis?
Patients with severe phenotypes succumb to infections within the first year of life. Moderate phenotype survive into adulthood.
What is LAD II caused by?
Defect in selectin mediated rolling due to a deficiency in the Sialyl lewis X component of the addressins. LAD II is inherited in autosomal recessive trait.
What is the incidence of LAD II?
Very rare clinical syndrome, only 5 cases world wide
What is the etiology of LAD II?
Cause of LAD II is a mutation in the gene encoding GDP fucose mebrane transporter. This transporter leads to a failure to convert mannose to fucose, which won't let the Sialyl Lewis X is absent (no fucoslyated carbs).
What is the clinical presentation of LAD II?
neutrophilia, recurrent bacterial infections, associated with developmental abnormalities. Dysmorphiv features in facial appearnces, depressed nasal bridge, simial crease, dorsally positioned second toe, mental retardation
How do you diagnose LAD II?
made by flow cytometry measurement of Sialyl Lewis expression using monoclonal antibodies
What are the principes of treatment
(increase selectin binding by 20% if the nromal level and normalizes WBC count
What is Beta actin deficiency?
Autosomal dominant disease, consisting of deficiency Beta actin polymerization, hindering cell motility. Note that alpha actin is a muscle protein involved in contraction
What is the etiology of Beta actin deficiency?
mutation in the ACTB gene, located in the chromosome 7p15-p12
What is pathogenesis of Beta actin deficiency?
Beta actin deficiency is a neutrophil migration disease, associated with poor chemoteaxis.
What is the clinical presenation of beta actin deficiency?
REccurent bacterial and fungal infections without pus formation, mental retardation and photosensitivity. SOme patients have early tooth loss
What is localized juvenile periodontitis?
Localized juvenile periodontitis is an rapidly progressive 10-13 years. IAutosomal recessive inheritance.
What is the clinical presentation of periodontitis?
Periodontium is the tissue that surrounds and supports the teeth. Characterized by gingivival recession resulting in apparent lengthening of teeth, loss of attachment of the teeth,
What is the pathogenesis of localized periodontitis?
Disorder is associated with impaired neutrophil chemotaxis toward bacterial formul peptides (They have formyl peptide receptors which are defective in this disease).
What is Chediak-Higashi syndrome?
CHS is a rare hereditary disorder characterized by defect in membrane fusion of azurophilic granules with phagosomes. The delivery of the content of azurophilic granules into the phagosomes is delayed
Clinical presentation of CHS?
Manifested by oculocutaneous albinism, reccurent Staph aureaus infections in the URT and skin, gina granules in neutrophils, and progressive neurologic impairment. patients have sensory deficiency, ataxia, progressive parkinsonism
What is the etiology of CHS?
ARises from mutation in the Lyst Gene regulates intracellular trafficking of lysosomes and vacuoles. Azurophilic granules of neutrophils, melanosomes of melanocytes, dense bodies of platelets are larger in size indicating that intracelleular trafficking of vacuoles is affected.
What is teh diagnosis of CHS?
giant granules in neutrophils
What is the prognosis of CHS?
Lethal disease, patients who do not succumb to bacterial infections, develop a leukemia-lymphoma like syndrome called "accelerated phase" Consists of lymphocytes due to viral infections, with leukocytosis over 20,000, consisting of 90% of lymphocytes and enlargement of liver and spleen (due to lymphocytic inflitration)
What is specific granule deficiency?
SGD rare disorder that is the absense of specific granules in the cytoplasm of neutrophils
What is the clinical presentation of SGD?
suffer from recurrent bacterial and fungal infections, primarily in the skin ears and lungs. Major pathogens are S aureus, Psuedomonas, enterig gram negative bacteria, Candida ablicans
What is the pathogenesis of SGD?
neutrophil structure with Bilobed nuclei, absense of specific granules. Azurophilic granules are normally present but lack defensins. Eosinophils lack eosinophilic cationic proteins in their cytoplasmic granules. Monocytes are functionally defective
What is CGD?
genetically heterogenous defects that share in common the failure of neutrophils to undergo a respiratory burst and generate superoxide. The absence of respiratory burst results in life threatening bacterial and fungal infections that are recurrent. associated with the formation of inflammatory granules
What is the incidence of CGD
1-20,000 to-50,000 in the US. 90% are male
WHat is the pathogenesis of CGD?
Mutation in any of the 4 genes encoding essential subunits of NADPH oxidase, the oxidase subunits have been give the designation phox for phagocytic oxidase
What are the genes affected by CGD
CYBB, CYBA, NCF1, NCF2
What are the genotype/phenotype correlations of CGD?
severe form of the disease begin to suffer reccurent infections during infancy and recur every 6 months
intermediate severity have superoxide production that is 1% of normal and have infections every 3 to 10 years.
What is the clinical presentation of CGD?
First year of life is when onset begins, recurrent purulent bacterial and fungal infections, lungs and skins are most severely affected, S aureus, enteric gram negatives, Serratia marcescens, burkholdia cepacia, ASpergiullus, these pathogens are Catalase positive
What does catalase do?
2H2O2 to 2H2O and O2
What are common diseases (not the causative agents) that are a result of CGD?
pneumonia, cutaneous infections, hepatic abcess, lymphadenitis, osteomyelitis, septicemia
What is the pathology of CGD?
granuloma formation the inefficient neutrophils cannot control the acute purulent, so they are surronded by macrophages then become granulomatous.
HOw do you diagnose chronic granulomatous disease?
nitroblue tetrazolium test. assay for oxidase activity. Drop of blood place on microscope slides, coated with an activaitn agent like LPS or phorbol ester. Neutrophils activate their NADPH oxidase and undergo the respiratory burst. Normal neutrophils will test positive and turn blue, while CGD ones will turn negative
What is myeloperoxidase deficiency?
MPO deficiency by lack of activity, enzyme found in phagocytic cells, the defect is associated with higher susceptibility to infection. Autosomal recessive inheritance
What kind of mutation causes MPO deficiency?
R569W missense mutation tryptophan substituted for arginine at codon 569, MPO is enzymatically inactive, undelivered to the azurophilic granules
What is MPO deficiency occurence?
1 in 2,000 individuals in the general population
WHat is the pathogenesis of MPO deficiency?
HOCl formation relies on this enzyme (MPO), diminished poduction of this slows the killing of bacterial and halts the
What is the clinical presentation of MPO deficiency?
Usually clinically silent, remarkable lack of clinical affected persons, disseminated candidiasis occurs only in 5% of patients who also suffer from diabetes.
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