Term
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Definition
| A state in which the immune system's ability to fight infections or malignancies is compromised or absent |
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Term
| 2 types of immunodeficiency disorders |
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Definition
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Term
| Primary immunodeficiency Disorders (2 types) |
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Definition
| Specific and Non specific |
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Term
| Primary Specific immunodeficiency disorders |
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Definition
| lumphocyte defects: T cell deficiencies, B cell deficiences, immunoglobulin deficiencies |
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Term
| Primary non specific immunodeficiency disorders |
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Definition
| phagocyte defects: neutropenia, chronic granulomatous disease, leukocyte adhesion deficiency, myeloperoxidase deficiency |
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Term
| Clinical features of Immunideficiency disorders |
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Definition
| Clinical features are common to all immunodeficiency disorders include frequent or unusual infections which may or may not respond well to antibiotic therapy |
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Term
| Classificiation of Nonspecific immunodeficiency disorders |
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Definition
1. Disorders of neutrophil #
2. Disorders of neutrophil function |
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Term
| Primary nonspecific immunodeficiency disorders: Disorders of neutrophil # |
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Definition
-acquired neutropenia
-Autoimmune neurtopenia of infancy (ANI)
-Severe congenital neutropenia (SCN) |
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Term
| Primary nonspecific immunodeficiency disorders: Disorders of neutrophil function |
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Definition
-chronic granulomatous disease (CGD)
-Leukocyte adhesion deficiency I (LADI)
-Leukocyte adhesion deficiency II (LAD II)
-Myeloperoxidase deficiency |
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Term
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Definition
| A reduction in the absolute number of circulating neutrophils below 1,500 cells/mm3 |
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Term
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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 |
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Term
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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) |
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Term
| Clinical manifestations of Neutropenia |
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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 |
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Term
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Definition
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Term
| Causes of Acquired Neutropenia |
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Definition
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Term
| Acquired Neutropenia - Bone Marrow Lesions |
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Definition
| Depression of hematopoiesis in the bone marrow (bone marrow hypoplasia) |
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Term
| Mechanisms of Acquired Neutropenia |
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Definition
A. Direct inhibition of myelopoiesis in most cases
B. Antibody production that destroy circulating granulocytes |
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Term
| Clinical manifestations of Acquired Neutropenia |
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Definition
| Fever, malaise, stomatitis, periodontitis, pharyngitis, gastrointestinal, skin, urinary infections |
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Term
| Involved bacteria in Acquired Neutropenia |
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Definition
Endogenous flora
-S. aureus in skin infections
-E. Coli and Pseudomonas in GI infections
-Mixed aerobes and anaerobes in oral infections |
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Term
| Drugs Associated with Neutropenia |
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Definition
-Analgesics (Acetaminophen)
-Cardiovascular Drugs (Captopril)
-Antibiotics (Cephalosporins)
-Diuretics (Acetazolamide)
-Anticonvulsants (Carbamazepine)
-Antithyroid agents (Carbimazole) |
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Term
| Hereditary Neutropenia - Autoimmune Neutropenia of Infancy (ANI) |
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Definition
| Characterized by increased destruction of neutrophils as a result of antineutrophil antibodies against human neutrophil antigen 1 |
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Term
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Definition
| Antineutrophil antibodies mediate peripheral destruction of the neutrophils |
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Term
| Etiology/Epidemiology of ANI |
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Definition
Etiology - cause of antibody production is unknown
Epidemiology - Incidence is 1 in 1 million population, avg. age of diagnosis is 8mos. |
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Term
| Clinical Manifestation of ANI |
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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 |
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Term
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Definition
| Benign condition, Neutropenia lasts only 6-24 mos., then antibodies disappear and WBC count spontaneously normalizes |
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Term
| Hereditary Neutropenia - Severe Congenital Neutropenia (SCN) |
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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 |
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Term
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Definition
| Mutations of the ELA2 gene encoding neutrophil elastase are responsible for most cases |
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Term
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Definition
| SCN is genetically hetergeneous. It can be autosomal dominant, autosomal recessive, X-linked recessive, and sporadic |
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Term
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Definition
| Incidence is 1 in 200,000 individuals. The avg age of diagnosis is 3 mos. |
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Term
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Definition
| Bone marrow reveals hyperplasia of neutrophil precursors but these cells cannot form mature neutrophils |
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Term
| SCN Clinical Manifestations |
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Definition
| Recurrent fever and life threatening infections (stomatitis, cellulitis, pneumonia, diarrhea, meningitis, peritonitis) caused by S. aureus, E. Coli and Pseusdomonas. |
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Term
| Chronic Granulomatous Disease |
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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 |
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Term
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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 |
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Term
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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. |
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Term
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Definition
-X-linked
-Autosomal recessive |
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Term
| Genetic forms of CGD - X-linked |
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Definition
| About 65% of cases. Males affected, females not. Caused by mutation of gp91phox gene |
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Term
| Genetic forms of CGD - Autosomal recessive |
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Definition
-25% caused by defects in p47phox gene
-5% caused by defects in p67phox gene
-1% caused by defects in p22phox gene |
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Term
| CGD Clinical manifestations |
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Definition
1. Recurrent infections
2. Catalast-positive pathogens
3. Granulomas
4.Failure to Thrive |
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Term
CGD Clinical manifestation
1. Recurrent infections |
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Definition
| CGD presents within first year of life with bacterial/fungal infections. Can affect every organ system (i.e., pneumonia, lymphadenopathy, hepatic abscesses, osteomyelitis) |
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Term
CGD Clinical Manifestations
2. Catalast-positive Pathogens
(types of pathogens) |
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Definition
| Most frequent include S. aureus, Aspergillus spp, enteric Gram - bacteria (Pseudomonas, Serratia marcescens and Salmonella spp) and Burkholderia cepacia |
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Term
CGD Clinical Manifestations
2. Catalast-positive pathogens
(how they work) |
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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. |
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Term
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Definition
| Beaks down H2O2 into water and oxygen gas |
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Term
| Are CGD patients susceptible to catalase-negative bacteria? Why or why not? |
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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. |
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Term
CGD Clinical manifestations
3. Granulomas |
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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 |
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Term
CGD Clinical Manifestations
4. Failure to Thrive |
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Definition
| includes hepatosplenomegaly, lymphadenopathy and anemia |
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Term
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Definition
1. Nitroblue tetrazolium
2. Chemiluminescence assay |
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Term
| CGD Nitroblue tetrazolium test |
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Definition
| standard assay for phagocytic oxidase. The colorless compound NBT is reduced to blue formazan by the activity of NADPH oxidase |
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Term
| CGD Chemiluminescence Assay |
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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 |
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Term
| CGD Principles of Treatment |
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Definition
| Antimicrobial prophylaxis, early and aggressive treatment of infections, and the interferon-gamma = current therapy. Bone marrow transplant = cure but there are risks |
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Term
| Leukocyte Adhesion Deficiency Syndromes |
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Definition
| LAD results from failures of leukocytes to participate in inflammatory rxns because of missing surface adhesion molecules. |
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Term
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Definition
| neutrophils have a defect in tight adhesion, consistene with absent beta-2 integrin function |
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Term
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Definition
| neutrophils have a defect in rolling, implying impairment in selectin-mediated events. |
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Term
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Definition
| LAD I reported in fewer than 400 individuals, equal # of male/female, most present within first several months |
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Term
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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% |
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Term
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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 |
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Term
LAD I pathogenesis
1. First step: Rolling |
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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 |
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Term
LAD I Pathogenesis
2. Second Step: Adhesion |
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Definition
| Leukocytes bind to selectins and expose them to local chemokines, which active beta2-integrins on plasma membrane |
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Term
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Definition
| heterodimeric transmembrane glucoprotein containing two distinct chains called "alpha" and "beta" subunits |
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Term
LAD I Pathogenesis
3. Consequences of "beta"2-integrin deficiency |
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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 |
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Term
| LAD I Clinical manifestations |
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Definition
| recurrent bacterial infections primarily localized to skin and mucosal surfaces, sites of infections progressively enlarge and lead to septicemia |
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Term
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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 |
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Term
| LAD I - Delayed Umbilical Cord Separation |
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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. |
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Term
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Definition
| severity of clinical infections appear to be directly related to the degree of "beta"2-integrin deficiency |
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Term
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Definition
1. Severe deficiency
2. Moderate deficiency |
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Term
LAD I Phenotype
Severe Deficiency |
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Definition
| Patients exhibit less than 1% of normal surface expression of beta2-integrin and pts succomb to infections within the first year of life |
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Term
LAD I Phenotype
Moderate Deficiency |
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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 |
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Term
| LAD I - Principles of Treatment |
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Definition
| Only cure for pts is hematopoietic stem cell transplantation or bone marrow transplantation with all its risks |
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Term
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Definition
| results from generalized defect in fucose production causing absence of Sialyl Lewis-X component of the selectin glycoprotein ligans. Inherited autosomal recessive trait |
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Term
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Definition
| extremely rare condition with only 6 reported cases |
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Term
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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 |
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Term
| LAD II Deficiency - Pathogenesis |
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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 |
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Term
| LAD II - Clinical Manifestations |
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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) |
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Term
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Definition
| Confirmed by the analysis of peripheral blood leukocytes by flow cytometry using a monoclonal Ab to determine Sialyl Lewis-X expression |
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Term
| Myeloperoxidase (MPO) Deficiency |
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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 |
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Term
| MPO Deficiency - Genetics |
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Definition
| Autosomal recessive disease. Most pts are compound heterozygotes (different mutation on each allele of MPO gene, one from each parent) |
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Term
| MPO Deficiency - epidemiology |
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Definition
| Occurs 1 in every 2,000-4,000 individuals in general population |
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Term
| MPO Deficiency - Pathogenesis |
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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 |
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Term
MPO Deficiency - Pathogenesis
(structure) |
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Definition
| Dimer consisting of 2 light chains and 2 heavy chains bound to a prosthetic heme group (contains iron) |
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Term
| Capacity to kill ____________ is completely absent |
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Definition
| Candida albicans ans Aspergillus fumigatus |
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Term
| MPO Deficiency - Clinical manifestations |
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Definition
| benign immunodecifiency. 50% of pts = asymptomatic. Severe infections in less than 5%, usually fungal infections |
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Term
| MPO Deficiency - Clinical manifestations |
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Definition
| benign immunodecifiency. 50% of pts = asymptomatic. Severe infections in less than 5%, usually fungal infections |
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Term
| MPO Deficiency - Lab Studies |
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Definition
| presence/absence of myeloperoxidase can be determined using numerous techniques like: 1. histochemical staining 2. immunohistochemistry, 3. Flow cytometry |
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