STUDY - Technical - New Dacian's Medicine
Pathological
Changes of Granulocytes and Monocytes (3)
Translation Draft
I will continue by addressing the functional anomalies of neutrophils (as announced). The types of inherited and acquired abnormalities of phagocyte function (grouped after its impairment) are represented by: 1. adhesion-aggregation function (a. drug-induced aspirin, colchicine, alcohol, glucocorticoids, ibuprofen and pyroxicam; b. acquired by neonatal status and hemodialysis; and c. inherited by the deficiency of leukocyte adhesion type 1 and 2), 2. function of deformability (which occurs only acquired through leukemia, neonatal status, diabetes mellitus and immature neutrophils), 3. chemokinesia-chemotactism function (a. drug-induced high doses of glucocorticoids, phenylbutazone, naproxen, indomethacin, interleukin 2 and weak effect induced by auranofin and colchicin); b. acquired (through thermal aggression, malignancy, malnutrition, periodontal disorders, neonatal status, systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus, sepsis, viral infection with influenza, herpes simplex, enteropathic acrodermatitis and AIDS; and c. inherited, in the case of Chediak-Higashi syndrome, deficiency of neutrophil-specific granules, recurrent hyper IgE infection syndrome, Down syndrome, alpha monoside deficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome) and 4. bactericidal activity function (a. drug-induced colchicine, cyclophosphamide and high doses of glucocorticoids; b. acquired in leukemia, aplastic anaemia, some neutropenia, tuftsin deficiency, thermal aggression, sepsis, neonatal status, diabetes, malnutrition and AIDS; and inherited c. in the case of Chediak-Higashi syndrome, neutral cell deficiency and chronic granulatous disorders).
Diseases caused by these are best treated as defects of adhesion, chemotactism and bactericidal activity. Characteristic elements of the most important inherited defects are represented by: 1. chronic granulomatous disease of childhood - 60% x-linked and 40% autosomal recessive (a. clinical manifestations: severe infections of the skin, ears and lungs, liver and bone with catalyzo-positive microorganisms such as Streptococcus Aureus, Burkholderia cepacia, Aspergillus sp., Chromobacterium violaceum, often hard-to-grow organisms, excessive inflammation with granulomas, frequent suppuration of the lymph nodes, granulomas may obstruct GI or GU tracts, gingivitis, thrush ulcers, seborrheic dermatitis; b. cellular and molecular defects: absence of respiratory burns due to one of the four subunits of NADPH oxidase in neutrophils, monocytes and eosinophils; c. diagnosis with NBT test, absence of superoxide and oxygenated water production by neutrophils; c. diagnosis with NBT test, absence of superoxide and oxygenated water by neutrophils , absence of chemoluminescence, migration/immunoblot test of NADPH oxidase components), 2. Chediak-Higashi syndrome - recessive autosomal (a. with clinical manifestations of recurrent pyogen infections, especially S. Aureus, many patients have a lymphoma-like disease in childhood, periodontal disease, partially oculocutaneous albinism, nystagmus, progressive peripheral neuropathy and mental retardation in some patients; b. cellular and molecular defects are represented by reduction of chemotism and famolyzosome fusion, increased respiratory burn, insufficient release from the marrow and abnormal skin tests; c. diagnosis with the help of giant primary granule neutrophils and other granular granular cells - Wright coloration); 3. deficiency of specific granules - probably autosomal recessive (a. with clinical manifestations represented by recurrent infections of the skin, ears and synopulmonary tract, delayed wound healing, low inflammation and hemorrhagic diathesis, b. cellular and molecular defects represented by abnormal chemotactism, disturbance of respiratory burns and destruction of bacteria, inability to regulate chemotactism and adhesion receptors according to stimulation and defect in the transcription of granular proteins, c. diagnosis by finding the absence of secondary/specific granules in neutrophils - Wright coloration, absence of granular content specific to neutrophils - i.e. lactoferin, absence of defence proteins and abnormalities of platelet granules); 4. deficiency of myeloperoxidase - recessive autosomal (a. with clinical manifestations represented by clinically normal appearance, with the exception of patients with an associated disease such as diabetes mellitus, then candidiasis or other fungal infections, b. cellular and molecular defects represented by the absence of myeloperoxidase due to pre and posttranslational defects, c. diagnosis by the absence of peroxidase in neutrophils); 5. deficiency of leukocytic - autosomal recessive adhesion (which is of two types: type 1 with clinical manifestations represented by delayed separation from the umbilical cord, sustained granulocysis, recurrent skin and mucous membrane infections, gingivitis and periodontal disease, b. cellular and molecular defects represented by the disturbance of adhesion, aggregation, migration, chemotactism and phagocytis of C3bi-coated particles by phagocytes, including insufficient/deficient production of CD18 subunit, common to leukocytic integrins, c. diagnosis specified by the reduction of surface expression of integrins containing CD18, using monoclonal anti-LXA-1, Mac-1 or CR3 antibodies, p150.95 and type 2 with a. clinical manifestations represented by severe mental retardation, small stature, Bombay -hh blood phenotype, recurrent infections and granuocytosis , b. cellular and molecular defects represented by the disturbance of the running of phagocytes along the endothelium and c. diagnosis specified by the reduction of expression on the surface of the phagocyte of Sialyl-Lewis, using monoclonal antiCD15s antibodies) and 5. recurrent infection syndrome - Hyper IgE - recessive autosomal/ Job syndrome (with a. clinical manifestations represented by eczemaor dermatitis, "cold" skin abscesses, recurrent pneumonia with S. aureus with bronchopleural fits and cysts, medium eosinophilia, mucocutaneous candidiasis, atopia, coarse facies, restrictive lung disease and scoliosis, b. cellular and molecular defects represented by reduction of chemotactism in some patients, reduction of activity of suppressor T lymphocytes and c. diagnosis by clinical elements, serum IgE greater than 2,000 IU/ ml, serum level of anti-S. aureus increased, serum and salivary level of IgA-S.
Two types of leukocytic adhesion (AD) deficiency have been described, both of which are autosomal recessively transmitted and causing neutrophils to be unable to leave circulation to reach the site of infection, leading to constant leukocytosis and increased susceptibility to infection. Patients with LAD1 have mutations in CD18, the common component of the integrates OF AFA-1, Mac-1 and p150.95, which leads to a defect in the close adhesion between neutrophils and endothelium. The heterodmer formed by CD18/ CD11b (Mac-1) is also a receiver for opsonin derived from complement C3bi (CR3).
The CD18 gene is located on the distal chromosome 21q. Variable expression of the defect determines the severity of the clinical picture. The complete lack of expression of leukocyte adhesion proteins by inactive neutrophils causes the severe phenotype in which inflammatory cytokines do not increase the expression of leukocyte adhesion proteins on neutrophils or activated B or T cells. Functional abnormalities are predictable because of the role these molecules play in normal leukocyte function. Neutrophiles (and monocytes) of patients with LAD 1 adhere poorly to endothelial cells and protein-covered areas and have deficiencies in migration, aggregation and chemotactism.
Patients with this syndrome have recurrent bacterial and fungal infections of the skin, oral and genital mucosa, respiratory and intestinal tracts, persistent leukocytosis (15,000 - 20,000 neutrophils/ microlitre) because the cells do not border and, in severe cases, a history of delayed separation from the umbilical cord. Infections, especially skin infections, tend to become necrotic, with progressively widening edges, delayed healing and developing keloid scars. The most common bacterium is Staphylococcus aureus and gram-negative intestinal bacteria. LAD 2 is determined by an abnormality of SLe (CD15s), the ligand of neutrophils that interact with endothelial cell selections.
Abnormal chemotactism of neutrophils and monocytes occurs in recurrent infection with hyperimmunoglobulin E (HIE) or Job syndrome. The molecular basis of this syndrome is unknown, but some cases appear to be transmitted autosomally dominantly. Patients with this syndrome have coarse facies, bone abnormalities, including external frontal hyperostosis, hyperteleism, cyphoscoliosis, osteoporosis and eczema. They develop recurrent synopulmonary and skin infections that tend to be much less inflamed than would correspond to the severity of the infection, called "cold abscesses".
A high degree of suspicion is necessary to diagnose infections in these patients that may seem normal, despite the extension of the disease. For many years cold abscesses were considered the result of the disorder of chemotactism, with too few phagocytes arriving too late, probably secondary to a lymphocytic factor that inhibits chemotactism. However, it is not clear whether the defect of chemotastism is variable, and the fundamental explanation of the alteration of the defence is complex and incomplete deciphered.
The most common defect of neutrophils is myeloperoxidase deficiency, has is transmitted autosomal recessively and can have an incidence of around 1 in 2,000 people. Isolated myeloperoxidase deficiency is not associated with clinically manifested compromised defense, as other defensive systems, such as oxygenated water generation, are accelerated. The bactericidal activity of neutrophils is delayed, but not absent. However, if another defect in the host's immune system, such as decompensated diabetes, accompanies peroxidase deficiency, then the host's antimicrobial defence may be significantly compromised.
An acquired form of myeloperoxidase deficiency occurs in monocytic leukemia and acute myeloblastic leukaemia. Chediak-Higashi syndrome (SCH) is a rare autosomal recessive disease. Neutrophiles and other cells containing lysosomes of patients with SCH typically have large granules. Patients with SCH have numerous infections due to a multitude of infectious agents. In SCH, neutrophils and monocytes have altered chemotactism and abnormal rates of microbial destruction due to the slowing fusion of lysosome granules with phagocytics. The "natural killer" function is also altered.
Chronic granulomatous disease (BGC) is a group of disorders of monocyte and granulocytic oxidative metabolism. Although BGC is rare, occurring once in 250,000 individuals, according to current estimates, it constitutes an important model of oxidative metabolism altered in neutrophils. Most often, BGC is transmitted x-linked recessively, although in about 40% of patients the disease is transmitted autosomal recessively. In all patients with BGC, mutations of four genes corresponding to four proteins are included in the plasma membrane that interfere with oxygenated water generation processes occur. The leukocytes of patients with BGC thus have a severely diminished oxygenated water production.
The genes involved in each of these defects were cloned and sequentialized, and their location on the chromosome identified. Patients with BGC typically have infections with catalyzo-positive microorganisms (organisms that destroy their own oxygenated water production). When patients with BGC become infected, they experience extensive inflammatory reactions and suppurations of the lymph nodes, despite proper treatment with antibiotics. Foot-and-mouth ulcers and chronic inflammation of the nostrils are usually present.
Granulomas are common and may clog the gastrointestinal or genitourinary tracts. Excessive inflammatory reactions probably reflect abnormal chronicization of inflammation, by being unable to degrade chemotactic factors and antigens that cause persistent neutrophil accumulation. Alteration of the destruction of intracellular microorganisms by macrophages may lead to persistence of cellularly mediated immunity of granulomas.
I will continue by addressing the functional anomalies of neutrophils (as announced). The types of inherited and acquired abnormalities of phagocyte function (grouped after its impairment) are represented by: 1. adhesion-aggregation function (a. drug-induced aspirin, colchicine, alcohol, glucocorticoids, ibuprofen and pyroxicam; b. acquired by neonatal status and hemodialysis; and c. inherited by the deficiency of leukocyte adhesion type 1 and 2), 2. function of deformability (which occurs only acquired through leukemia, neonatal status, diabetes mellitus and immature neutrophils), 3. chemokinesia-chemotactism function (a. drug-induced high doses of glucocorticoids, phenylbutazone, naproxen, indomethacin, interleukin 2 and weak effect induced by auranofin and colchicin); b. acquired (through thermal aggression, malignancy, malnutrition, periodontal disorders, neonatal status, systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus, sepsis, viral infection with influenza, herpes simplex, enteropathic acrodermatitis and AIDS; and c. inherited, in the case of Chediak-Higashi syndrome, deficiency of neutrophil-specific granules, recurrent hyper IgE infection syndrome, Down syndrome, alpha monoside deficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome) and 4. bactericidal activity function (a. drug-induced colchicine, cyclophosphamide and high doses of glucocorticoids; b. acquired in leukemia, aplastic anaemia, some neutropenia, tuftsin deficiency, thermal aggression, sepsis, neonatal status, diabetes, malnutrition and AIDS; and inherited c. in the case of Chediak-Higashi syndrome, neutral cell deficiency and chronic granulatous disorders).
Diseases caused by these are best treated as defects of adhesion, chemotactism and bactericidal activity. Characteristic elements of the most important inherited defects are represented by: 1. chronic granulomatous disease of childhood - 60% x-linked and 40% autosomal recessive (a. clinical manifestations: severe infections of the skin, ears and lungs, liver and bone with catalyzo-positive microorganisms such as Streptococcus Aureus, Burkholderia cepacia, Aspergillus sp., Chromobacterium violaceum, often hard-to-grow organisms, excessive inflammation with granulomas, frequent suppuration of the lymph nodes, granulomas may obstruct GI or GU tracts, gingivitis, thrush ulcers, seborrheic dermatitis; b. cellular and molecular defects: absence of respiratory burns due to one of the four subunits of NADPH oxidase in neutrophils, monocytes and eosinophils; c. diagnosis with NBT test, absence of superoxide and oxygenated water production by neutrophils; c. diagnosis with NBT test, absence of superoxide and oxygenated water by neutrophils , absence of chemoluminescence, migration/immunoblot test of NADPH oxidase components), 2. Chediak-Higashi syndrome - recessive autosomal (a. with clinical manifestations of recurrent pyogen infections, especially S. Aureus, many patients have a lymphoma-like disease in childhood, periodontal disease, partially oculocutaneous albinism, nystagmus, progressive peripheral neuropathy and mental retardation in some patients; b. cellular and molecular defects are represented by reduction of chemotism and famolyzosome fusion, increased respiratory burn, insufficient release from the marrow and abnormal skin tests; c. diagnosis with the help of giant primary granule neutrophils and other granular granular cells - Wright coloration); 3. deficiency of specific granules - probably autosomal recessive (a. with clinical manifestations represented by recurrent infections of the skin, ears and synopulmonary tract, delayed wound healing, low inflammation and hemorrhagic diathesis, b. cellular and molecular defects represented by abnormal chemotactism, disturbance of respiratory burns and destruction of bacteria, inability to regulate chemotactism and adhesion receptors according to stimulation and defect in the transcription of granular proteins, c. diagnosis by finding the absence of secondary/specific granules in neutrophils - Wright coloration, absence of granular content specific to neutrophils - i.e. lactoferin, absence of defence proteins and abnormalities of platelet granules); 4. deficiency of myeloperoxidase - recessive autosomal (a. with clinical manifestations represented by clinically normal appearance, with the exception of patients with an associated disease such as diabetes mellitus, then candidiasis or other fungal infections, b. cellular and molecular defects represented by the absence of myeloperoxidase due to pre and posttranslational defects, c. diagnosis by the absence of peroxidase in neutrophils); 5. deficiency of leukocytic - autosomal recessive adhesion (which is of two types: type 1 with clinical manifestations represented by delayed separation from the umbilical cord, sustained granulocysis, recurrent skin and mucous membrane infections, gingivitis and periodontal disease, b. cellular and molecular defects represented by the disturbance of adhesion, aggregation, migration, chemotactism and phagocytis of C3bi-coated particles by phagocytes, including insufficient/deficient production of CD18 subunit, common to leukocytic integrins, c. diagnosis specified by the reduction of surface expression of integrins containing CD18, using monoclonal anti-LXA-1, Mac-1 or CR3 antibodies, p150.95 and type 2 with a. clinical manifestations represented by severe mental retardation, small stature, Bombay -hh blood phenotype, recurrent infections and granuocytosis , b. cellular and molecular defects represented by the disturbance of the running of phagocytes along the endothelium and c. diagnosis specified by the reduction of expression on the surface of the phagocyte of Sialyl-Lewis, using monoclonal antiCD15s antibodies) and 5. recurrent infection syndrome - Hyper IgE - recessive autosomal/ Job syndrome (with a. clinical manifestations represented by eczemaor dermatitis, "cold" skin abscesses, recurrent pneumonia with S. aureus with bronchopleural fits and cysts, medium eosinophilia, mucocutaneous candidiasis, atopia, coarse facies, restrictive lung disease and scoliosis, b. cellular and molecular defects represented by reduction of chemotactism in some patients, reduction of activity of suppressor T lymphocytes and c. diagnosis by clinical elements, serum IgE greater than 2,000 IU/ ml, serum level of anti-S. aureus increased, serum and salivary level of IgA-S.
Two types of leukocytic adhesion (AD) deficiency have been described, both of which are autosomal recessively transmitted and causing neutrophils to be unable to leave circulation to reach the site of infection, leading to constant leukocytosis and increased susceptibility to infection. Patients with LAD1 have mutations in CD18, the common component of the integrates OF AFA-1, Mac-1 and p150.95, which leads to a defect in the close adhesion between neutrophils and endothelium. The heterodmer formed by CD18/ CD11b (Mac-1) is also a receiver for opsonin derived from complement C3bi (CR3).
The CD18 gene is located on the distal chromosome 21q. Variable expression of the defect determines the severity of the clinical picture. The complete lack of expression of leukocyte adhesion proteins by inactive neutrophils causes the severe phenotype in which inflammatory cytokines do not increase the expression of leukocyte adhesion proteins on neutrophils or activated B or T cells. Functional abnormalities are predictable because of the role these molecules play in normal leukocyte function. Neutrophiles (and monocytes) of patients with LAD 1 adhere poorly to endothelial cells and protein-covered areas and have deficiencies in migration, aggregation and chemotactism.
Patients with this syndrome have recurrent bacterial and fungal infections of the skin, oral and genital mucosa, respiratory and intestinal tracts, persistent leukocytosis (15,000 - 20,000 neutrophils/ microlitre) because the cells do not border and, in severe cases, a history of delayed separation from the umbilical cord. Infections, especially skin infections, tend to become necrotic, with progressively widening edges, delayed healing and developing keloid scars. The most common bacterium is Staphylococcus aureus and gram-negative intestinal bacteria. LAD 2 is determined by an abnormality of SLe (CD15s), the ligand of neutrophils that interact with endothelial cell selections.
Abnormal chemotactism of neutrophils and monocytes occurs in recurrent infection with hyperimmunoglobulin E (HIE) or Job syndrome. The molecular basis of this syndrome is unknown, but some cases appear to be transmitted autosomally dominantly. Patients with this syndrome have coarse facies, bone abnormalities, including external frontal hyperostosis, hyperteleism, cyphoscoliosis, osteoporosis and eczema. They develop recurrent synopulmonary and skin infections that tend to be much less inflamed than would correspond to the severity of the infection, called "cold abscesses".
A high degree of suspicion is necessary to diagnose infections in these patients that may seem normal, despite the extension of the disease. For many years cold abscesses were considered the result of the disorder of chemotactism, with too few phagocytes arriving too late, probably secondary to a lymphocytic factor that inhibits chemotactism. However, it is not clear whether the defect of chemotastism is variable, and the fundamental explanation of the alteration of the defence is complex and incomplete deciphered.
The most common defect of neutrophils is myeloperoxidase deficiency, has is transmitted autosomal recessively and can have an incidence of around 1 in 2,000 people. Isolated myeloperoxidase deficiency is not associated with clinically manifested compromised defense, as other defensive systems, such as oxygenated water generation, are accelerated. The bactericidal activity of neutrophils is delayed, but not absent. However, if another defect in the host's immune system, such as decompensated diabetes, accompanies peroxidase deficiency, then the host's antimicrobial defence may be significantly compromised.
An acquired form of myeloperoxidase deficiency occurs in monocytic leukemia and acute myeloblastic leukaemia. Chediak-Higashi syndrome (SCH) is a rare autosomal recessive disease. Neutrophiles and other cells containing lysosomes of patients with SCH typically have large granules. Patients with SCH have numerous infections due to a multitude of infectious agents. In SCH, neutrophils and monocytes have altered chemotactism and abnormal rates of microbial destruction due to the slowing fusion of lysosome granules with phagocytics. The "natural killer" function is also altered.
Chronic granulomatous disease (BGC) is a group of disorders of monocyte and granulocytic oxidative metabolism. Although BGC is rare, occurring once in 250,000 individuals, according to current estimates, it constitutes an important model of oxidative metabolism altered in neutrophils. Most often, BGC is transmitted x-linked recessively, although in about 40% of patients the disease is transmitted autosomal recessively. In all patients with BGC, mutations of four genes corresponding to four proteins are included in the plasma membrane that interfere with oxygenated water generation processes occur. The leukocytes of patients with BGC thus have a severely diminished oxygenated water production.
The genes involved in each of these defects were cloned and sequentialized, and their location on the chromosome identified. Patients with BGC typically have infections with catalyzo-positive microorganisms (organisms that destroy their own oxygenated water production). When patients with BGC become infected, they experience extensive inflammatory reactions and suppurations of the lymph nodes, despite proper treatment with antibiotics. Foot-and-mouth ulcers and chronic inflammation of the nostrils are usually present.
Granulomas are common and may clog the gastrointestinal or genitourinary tracts. Excessive inflammatory reactions probably reflect abnormal chronicization of inflammation, by being unable to degrade chemotactic factors and antigens that cause persistent neutrophil accumulation. Alteration of the destruction of intracellular microorganisms by macrophages may lead to persistence of cellularly mediated immunity of granulomas.
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