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Pathology VCOM 2014
Chronic Granulomatous Disease
82
Pathology
Graduate
09/17/2010

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Term
Immunodeficiency
Definition
A state in which the immune system's ability to fight infections or malignancies is compromised or absent
Term
2 types of immunodeficiency disorders
Definition
Primary and Secondary
Term
Primary immunodeficiency Disorders (2 types)
Definition
Specific and Non specific
Term
Primary Specific immunodeficiency disorders
Definition
lumphocyte defects: T cell deficiencies, B cell deficiences, immunoglobulin deficiencies
Term
Primary non specific immunodeficiency disorders
Definition
phagocyte defects: neutropenia, chronic granulomatous disease, leukocyte adhesion deficiency, myeloperoxidase deficiency
Term
Clinical features of Immunideficiency disorders
Definition
Clinical features are common to all immunodeficiency disorders include frequent or unusual infections which may or may not respond well to antibiotic therapy
Term
Classificiation of Nonspecific immunodeficiency disorders
Definition
1. Disorders of neutrophil #
2. Disorders of neutrophil function
Term
Primary nonspecific immunodeficiency disorders: Disorders of neutrophil #
Definition
-acquired neutropenia
-Autoimmune neurtopenia of infancy (ANI)
-Severe congenital neutropenia (SCN)
Term
Primary nonspecific immunodeficiency disorders: Disorders of neutrophil function
Definition
-chronic granulomatous disease (CGD)
-Leukocyte adhesion deficiency I (LADI)
-Leukocyte adhesion deficiency II (LAD II)
-Myeloperoxidase deficiency
Term
Neutropenia
Definition
A reduction in the absolute number of circulating neutrophils below 1,500 cells/mm3
Term
Normal WBC count...
Definition
is 5,000 to 10,000/mm3. Neutrophils in the differential count account for 55-70% of the total WBC count, which correspond to an absolute number of 2,500-8,000/mm3
Term
Severity of Neutropenia
Definition
-Mild (absolute # of neutrophils is 1,000-1,500 cells/mm3)
-Moderate (500 -1,000 cells/mm3)
-Severe (less than 500 cells/mm3)
-Agranulocytosis (less than 100 cells/mm3)
Term
Clinical manifestations of Neutropenia
Definition
-Increased risk of bacterial infections: fever pulmonary, gastrointestinal, skin infections, and sepsis
-Risk of bacterial infections is proportional to both the severity and duration of the neutropenia
-There is no increased risk for parasitic and viral infections
Term
Causes of neutropenia
Definition
1. Acquired
2. Hereditary
Term
Causes of Acquired Neutropenia
Definition
Drugs and Chemicals
Term
Acquired Neutropenia - Bone Marrow Lesions
Definition
Depression of hematopoiesis in the bone marrow (bone marrow hypoplasia)
Term
Mechanisms of Acquired Neutropenia
Definition
A. Direct inhibition of myelopoiesis in most cases
B. Antibody production that destroy circulating granulocytes
Term
Clinical manifestations of Acquired Neutropenia
Definition
Fever, malaise, stomatitis, periodontitis, pharyngitis, gastrointestinal, skin, urinary infections
Term
Involved bacteria in Acquired Neutropenia
Definition
Endogenous flora
-S. aureus in skin infections
-E. Coli and Pseudomonas in GI infections
-Mixed aerobes and anaerobes in oral infections
Term
Drugs Associated with Neutropenia
Definition
-Analgesics (Acetaminophen)
-Cardiovascular Drugs (Captopril)
-Antibiotics (Cephalosporins)
-Diuretics (Acetazolamide)
-Anticonvulsants (Carbamazepine)
-Antithyroid agents (Carbimazole)
Term
Hereditary Neutropenia - Autoimmune Neutropenia of Infancy (ANI)
Definition
Characterized by increased destruction of neutrophils as a result of antineutrophil antibodies against human neutrophil antigen 1
Term
Pathogenesis of ANI
Definition
Antineutrophil antibodies mediate peripheral destruction of the neutrophils
Term
Etiology/Epidemiology of ANI
Definition
Etiology - cause of antibody production is unknown
Epidemiology - Incidence is 1 in 1 million population, avg. age of diagnosis is 8mos.
Term
Clinical Manifestation of ANI
Definition
-Recurrent mild infections in 80% of patients consisting of pyoderma, otitis media, upper respiratory infections
-Severe infections in 20% of patients such as pneumonia, memingitis, sepsis
Term
Outcome of ANI
Definition
Benign condition, Neutropenia lasts only 6-24 mos., then antibodies disappear and WBC count spontaneously normalizes
Term
Hereditary Neutropenia - Severe Congenital Neutropenia (SCN)
Definition
SCN is a rare disorder characterized by severe neutropenia present at birth and an arrest of granulocytic differentiation at the promyelocyte or myelocyte stage
Term
SCN Genetics
Definition
Mutations of the ELA2 gene encoding neutrophil elastase are responsible for most cases
Term
SCN Inheritance
Definition
SCN is genetically hetergeneous. It can be autosomal dominant, autosomal recessive, X-linked recessive, and sporadic
Term
SCN Epidemiology
Definition
Incidence is 1 in 200,000 individuals. The avg age of diagnosis is 3 mos.
Term
SCN Morphology
Definition
Bone marrow reveals hyperplasia of neutrophil precursors but these cells cannot form mature neutrophils
Term
SCN Clinical Manifestations
Definition
Recurrent fever and life threatening infections (stomatitis, cellulitis, pneumonia, diarrhea, meningitis, peritonitis) caused by S. aureus, E. Coli and Pseusdomonas.
Term
Chronic Granulomatous Disease
Definition
CGD is a rare disorder characterized by absent or reduced function of the respiratory burst in neutrophils which produces oxygen free radicals important for intracellular killing of bacteria
Term
CGD Cause
Definition
Represents a group of genetic disorders, caused by genetic defects in each of 5 components of enzyme NADPH oxidase, leads to failure of phagocytes to undergo respiratory burst. Superoxide is converted to more potent free radicals such as peroxide and hypochlorous
Term
CGD - NADPH Oxidase
Definition
Enzyme complex composed of 5 proteins. Activation requires several proteins normally present in the cytosol. Translocation to the membrane of phagocytic vacuole and help assemble active complex. Once active complex assembled, ET system operates and generates superoxide in vacuole lumen.
Term
Genetic Forms of CGD
Definition
-X-linked
-Autosomal recessive
Term
Genetic forms of CGD - X-linked
Definition
About 65% of cases. Males affected, females not. Caused by mutation of gp91phox gene
Term
Genetic forms of CGD - Autosomal recessive
Definition
-25% caused by defects in p47phox gene
-5% caused by defects in p67phox gene
-1% caused by defects in p22phox gene
Term
CGD Clinical manifestations
Definition
1. Recurrent infections
2. Catalast-positive pathogens
3. Granulomas
4.Failure to Thrive
Term
CGD Clinical manifestation
1. Recurrent infections
Definition
CGD presents within first year of life with bacterial/fungal infections. Can affect every organ system (i.e., pneumonia, lymphadenopathy, hepatic abscesses, osteomyelitis)
Term
CGD Clinical Manifestations
2. Catalast-positive Pathogens
(types of pathogens)
Definition
Most frequent include S. aureus, Aspergillus spp, enteric Gram - bacteria (Pseudomonas, Serratia marcescens and Salmonella spp) and Burkholderia cepacia
Term
CGD Clinical Manifestations
2. Catalast-positive pathogens
(how they work)
Definition
Organisms are catalast-positive; produce catalase, considered a virulence determinant allowing bacteria to resist intracellular killing by H2O2. This activity is defense against H2O2 produced in phagocytic vacuoles.
Term
Catalase enzyme
Definition
Beaks down H2O2 into water and oxygen gas
Term
Are CGD patients susceptible to catalase-negative bacteria? Why or why not?
Definition
Not susceptible (catalase-negative includes Streptococcus and Pneumococcus). Produce H2O2, when ingested by neutrophils, bacteria supply missing chemical needed by the phaagocytes for normal killing.
Term
CGD Clinical manifestations
3. Granulomas
Definition
Hallmark of disease, caused by granulomatous response to the pathogen. Prominent in GI and lower urinary tract with thickening of gastric, rectal, and urinary bladder walls
Term
CGD Clinical Manifestations
4. Failure to Thrive
Definition
includes hepatosplenomegaly, lymphadenopathy and anemia
Term
CGD Testing types
Definition
1. Nitroblue tetrazolium
2. Chemiluminescence assay
Term
CGD Nitroblue tetrazolium test
Definition
standard assay for phagocytic oxidase. The colorless compound NBT is reduced to blue formazan by the activity of NADPH oxidase
Term
CGD Chemiluminescence Assay
Definition
produced by direct transformation of chemical energy into electromagnetic energy (light). Detects formation of oxygen radicals by neutrophils. Used to assess neutrophil respiratory burst
Term
CGD Principles of Treatment
Definition
Antimicrobial prophylaxis, early and aggressive treatment of infections, and the interferon-gamma = current therapy. Bone marrow transplant = cure but there are risks
Term
Leukocyte Adhesion Deficiency Syndromes
Definition
LAD results from failures of leukocytes to participate in inflammatory rxns because of missing surface adhesion molecules.
Term
LAD I
Definition
neutrophils have a defect in tight adhesion, consistene with absent beta-2 integrin function
Term
LAD II
Definition
neutrophils have a defect in rolling, implying impairment in selectin-mediated events.
Term
LAD I epidemiology
Definition
LAD I reported in fewer than 400 individuals, equal # of male/female, most present within first several months
Term
LAD I etiology
Definition
Autosomal recessive disease caused by mutations in the gene that codes for the beta-chain (i.e., CD18) of beta2-integrins mapped to chromosome 21q22.3. 50% are point mutations of CD18; missense, nonsense and splice mutations = other 50%
Term
LAD I Pathogenesis
Definition
migration of leukocytes from the bloodstream to the tissue during inflammation occurs in several distinct steps: 1. Rolling 2. Adhesion 3. Consequences of beta2-integrin deficiency
Term
LAD I pathogenesis
1. First step: Rolling
Definition
Selectin translocated to plasma membrane where it functions as a receptor for monocytes and neutrophils. endothelial selectins bind to leukocytes through corresponding selectin glycoprotein ligands once activated
Term
LAD I Pathogenesis
2. Second Step: Adhesion
Definition
Leukocytes bind to selectins and expose them to local chemokines, which active beta2-integrins on plasma membrane
Term
Beta2-integrins
Definition
heterodimeric transmembrane glucoprotein containing two distinct chains called "alpha" and "beta" subunits
Term
LAD I Pathogenesis
3. Consequences of "beta"2-integrin deficiency
Definition
Adhesion is severely limited when neutrophils have deficient "beta"2 integrin expression; restricting neutrophil movement out of blood vessels and markedly reducing the ability of the host to combat infectious organisms
Term
LAD I Clinical manifestations
Definition
recurrent bacterial infections primarily localized to skin and mucosal surfaces, sites of infections progressively enlarge and lead to septicemia
Term
LAD I Pathology
Definition
Infections are indolent and necrotic. Serosanguinolent exudate is present but not pus. Biopsies demonstrate inflammation totally devoid of neutrophils. This is in contrast with marked peripheral blood leukocytosis
Term
LAD I - Delayed Umbilical Cord Separation
Definition
Normal range of separation is 7-14 days. Cord normally clamped 1-5 mins after birth. Cord separation is chiefly due to migration of neutrophils into the area, with digestion and necrosis of cord. Separation after 3 weeks is considered abnormal.
Term
LAD 1 Phenotype
Definition
severity of clinical infections appear to be directly related to the degree of "beta"2-integrin deficiency
Term
LAD I Two Phenotypes
Definition
1. Severe deficiency
2. Moderate deficiency
Term
LAD I Phenotype
Severe Deficiency
Definition
Patients exhibit less than 1% of normal surface expression of beta2-integrin and pts succomb to infections within the first year of life
Term
LAD I Phenotype
Moderate Deficiency
Definition
-Pts exhibit 2-30% of normal surface expression of beta2-integrin
-may have normal cord separation
-fewer serious life-threatening infections
-survive into adulthood
Term
LAD I - Principles of Treatment
Definition
Only cure for pts is hematopoietic stem cell transplantation or bone marrow transplantation with all its risks
Term
LAD II
Definition
results from generalized defect in fucose production causing absence of Sialyl Lewis-X component of the selectin glycoprotein ligans. Inherited autosomal recessive trait
Term
LAD II Epidemiology
Definition
extremely rare condition with only 6 reported cases
Term
LAD II Etiology
Definition
genetic mutation in guanosine diphosphate transporter gene (located on chromosome 11). Mutation leads to failure to convert mannose to fucose. Sialyl-Lewis X (selectin ligand) is another fucosylated carb that is absent in these individuals
Term
LAD II Deficiency - Pathogenesis
Definition
Absence of Sialyl-Lewis X (mediates neutrophil recruitement for rolling) which results in impaired emigrations of leukocytes from the blood vessels to the site of infection which requires adhesion of leukocytes to the endothelium
Term
LAD II - Clinical Manifestations
Definition
No delay in cord separation. Pts suffer from early life from recurrent episodes of bacterial infections, mainly pneumonia, periodontitis, otitis media and cellulitits. Infections are not life-threatening and usually treated in outpatient setting (comparable to moderate LAD I)
Term
LAD II - Diagnosis
Definition
Confirmed by the analysis of peripheral blood leukocytes by flow cytometry using a monoclonal Ab to determine Sialyl Lewis-X expression
Term
Myeloperoxidase (MPO) Deficiency
Definition
genetic disorder featuring lack of myeloperoxidase activity. Myeloperoxidase is enzyme found in phagocytic cells (esp. neutrophils). Associated with higher susceptibility to infection and higher incidence of neoplasm
Term
MPO Deficiency - Genetics
Definition
Autosomal recessive disease. Most pts are compound heterozygotes (different mutation on each allele of MPO gene, one from each parent)
Term
MPO Deficiency - epidemiology
Definition
Occurs 1 in every 2,000-4,000 individuals in general population
Term
MPO Deficiency - Pathogenesis
Definition
Lysosomal enzyme found in azurophilic granules in leukocytes and monocytes. Major role to aid in microbial killing. Enzyme catalyzes formationo f highly potent antimicrobial agents by reacting with H2O2 and Cl- to form HOCl
Term
MPO Deficiency - Pathogenesis
(structure)
Definition
Dimer consisting of 2 light chains and 2 heavy chains bound to a prosthetic heme group (contains iron)
Term
Capacity to kill ____________ is completely absent
Definition
Candida albicans ans Aspergillus fumigatus
Term
MPO Deficiency - Clinical manifestations
Definition
benign immunodecifiency. 50% of pts = asymptomatic. Severe infections in less than 5%, usually fungal infections
Term
MPO Deficiency - Clinical manifestations
Definition
benign immunodecifiency. 50% of pts = asymptomatic. Severe infections in less than 5%, usually fungal infections
Term
MPO Deficiency - Lab Studies
Definition
presence/absence of myeloperoxidase can be determined using numerous techniques like: 1. histochemical staining 2. immunohistochemistry, 3. Flow cytometry
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