STUDY - Technical - New Dacian's Medicine
Pathological
Changes of Granulocytes and Monocytes (4)
Translation Draft
We ended up with "presentations" on mononuclear phagocytes.
We ended up with "presentations" on mononuclear phagocytes.
The system of mononuclear
phagocytes is defined as the continuous relationship of
monoblasts, promonocytes and monocytes with structurally varied
tissue macrophages, which form the reticuloendothelial system to
which we referred previously. Macrophages are long-lived
phagocytic cells that can perform many of the functions of
neutrophils. In addition, secretory cells are important which,
through their receptors and secretion products, participate in
many complex inflammatory and immunological processes, which are
not performed by neutrophils.
Monocytes leave circulation through diapedesis, slower than neutrophils, and have a half-life in the blood of 12-24 hours. After the blood monocytes reach the tissues, they differentiate into macrophages ("big eaters") with specialized functions after anatomical localization. Macrophages are especially abundant in the walls of the capillaries in the lungs, spleen, liver and bone marrow, their functions being to remove microorganisms and other harmful elements from the blood. Alveolar macrophages, Kupffer liver cells, splenic macrophages, peritumoral macrophages, bone marrow macrophages, lymphatic macrophages, microglial brain cells and dendritic macrophages all have specialized functions.
Secreted macrophages include lysozyme, neutral proteases, acidic hydrolases, arginases, numerous complement fractions, enzyme inhibitors (plasmin, alpha2 macroglobulin), binding proteins (transferin, fibronectin, transcobalamin II), numerous fractions of the complement, enzyme inhibitors (plasmin, alpha2 macroglobulin), binding proteins (transferin, fibronectin, transcobalamin II), numerous microcheoids and cytokines. Interleukin 1 has many important functions, including stimulation of the hypothalamus to initiate fever, mobilization of leukocytes in the bone marrow, as well as activation of lymphocytes and neutrophils. The alpha tumor necrosis factor (also called cashectin) is a pyrogen that performs many of the actions of IL-1 and plays an important role in the pathogenesis of gram-negative shock. It can stimulate the production of oxygenated water and other toxic oxygen radicals by macrophages and neutrophils. In addition, TNFalfa induces catabolic response to chronic inflammation, which contributes to massive weight loss (cachexia), associated with numerous chronic diseases.
Other secreted products of macrophages are reactive oxygen metabolites, bioactive lipids (arachidonic metabolites and platelet activating factors), chemokines, colony stimulation factors in the bone marrow and factors that stimulate fibroblasts and the proliferation of microvessels. Macrophages participate in the regulation of lymphocyte replication and the destruction of tumors, viruses and bacteria (Mycobacterium tuberculosis and Listeria monocytogenes). Macrophages are effector cells essential in the elimination of intracellular microorganisms.
Their ability to fuse and form giant cells that cluster into granulomas in response to some inflammatory factors is important in the elimination of intracellular bacteria and may be under the control of IFNgama. Macrophages play an important role in the immune response. They process and present lymphocyte antigens and secrete cytokines that modulate and direct the development and function of lymphocytes. Macrophages participate in the autoimmune phenomenon by removing immune complexes and other immunologically active substances from circulation. In addition, they play a role in wound healing, in the elimination of senescent cells and in the development of atheroma plaques.
In terms of disorders of the mononuclear phagocyte system, many alterations of neutrophils also extend to mononuclear phagocytes. Those drugs that inhibit the production of neutrophils in the bone marrow usually cause monocytopenia. Transitional monocytopenia also occurs after stress and administration of glucocorticoids. Monocytosis is associated with some infections, such as tuberculosis, brucellosis, subacute bacterial endocarditis, spotted fever, malaria and visceral leishmaniosis (kala azar).
Monocytosis is also found in malignant diseases, leukaemias, myeloproliferative syndromes, hemolytic anemias, chronic idiopathic neutropenia and granulomatous diseases such as sarcoidosis, regional enteritis and some vascular collagen diseases. All patients with LAD, HIE syndrome (Job), CHS and chronic granulomatous disease have defects in the mononuclear phagocyte system. Alteration of cytokine production by cytokines has been found in some patients with disseminated non-uberculous microbacterial infection who are not infected with human immunodeficiency virus (HIV).
Some viral infections alter the function of mononuclear phagocytes. For example, influenza virus infection is associated with an abnormal chemotactism of monocytes. Mononuclear phagocytes may be infected with HIV, and abnormal monocytactism and altered clearance of IgG-coated erythrocytes are also found in AIDS. These defects in the monocyte-macrophage system are likely to contribute to AIDS disorder and increased susceptibility to opportunistic infections due to intracellular microorganisms such as Pneumocystis carinii and M. avium complex.
T lymphocytes produce IFNgama, which induces the expression of the factor Fc and phagocytosis and stimulate the production of oxygenated water by mononuclear and neutrophil phagocytes. In some diseases, such as AIDS, the production of IFNgama may be deficient, while in other conditions, such as T-cell lymphoma, excessive release of IFNgama is suspected to cause phagocytization of erythrocytes by splenic macrophages. Specific defects of mononuclear phagocytes have been described in some autoimmune diseases. Clearance of radiomarked autologous erythrocytes covered by IgG, probably via the Fc receptor of splenic macrophages, is profoundly altered in patients with systemically active lupus erythematosus.
Patients with other autoimmune diseases characterized by the deposition of immune complexes in tissues, as happens in Sjogren's syndrome, mixed cryoglobulinemia, herpetiform dermatitis and chronic progressive multiple sclerosis, also have a defect in the function of the Fc receptor, illustrated by the clearance of erythrocytes coated with IgG. Clinically, normal subjects with genetic haplotypes commonly found in autoimmune diseases show an increase in the incidence of abnormality in the functional activity of the Fc receptor, suggesting that this defect predisposes individuals with this genetic profile to the disease of immune complexes.
Monocytopenia occurs in acute infections, stress and after administration of glucocorticoids. Monocytopenia also occurs in aplastic anaemia, hairy cell leukaemia and acute myeloid leukaemia, as a direct result of immunosuppressive and cytotoxic medication.
Eosinophils and neutrophils have morphology, many lysosome constituents, phagocytic capacity and similar oxidative metabolism. Eosinophils have a specific chemotactic receptor and respond to a specific chemokinone, eotaxin. However, there are major differences between the two cell types and little is known about the natural function of eosinophils. Eosinophils live much longer than neutrophils and, against these, tissue eosinophils can be recirculated.
During most infections eosinophils do not appear to have any important function. However, in invasive helminthic infection, such as hook worm infection, schistosomiasis, strongyloidosis, toxocariasis, trichinosis, filariasis, echinococosis and cysticercosis, eosinophils probably play a central role in the host's immune defense. Eosinophils are also associated with asthma, allergic skin reactions and other conditions of hypersensitivity.
The granules characteristic of eosinophils, colored in red (Wright coloration), contain a number of unique constituents. The distinguishing element of eosinophilic granule is its crystalline core, consisting of a protein rich in acornin (major basic protein), with histamine activity which is probably important in antiparasitic defense. Eosinophilic granules also contain a unique peroxidase, which catalyzes the oxidation of many substances to oxygenated water and can facilitate the destruction of microorganisms. Eosinophilic peroxidase, in the presence of oxygenated water and halid, initiates the secretion of mast cells in vitro, thus contributing to inflammation.
These substances in eosinophils are cationic proteins, some of which bind to heparin and reducing its anticoagulant activity. The cytoplasm of eosinophils contains Charcot-Leyden crystallized proteins, a bipyramidal hexagonal crystal, first described in leukaemias and then in the sputum of patients with asthma, which is a phospholipase and can act to reduce the toxicity of some lysophospholipids. Eosinophils also contain a strong neurotoxin. Patients with hypereosinophilic syndrome and eosinophilia in the cerebrospinal fluid have various neurological abnormalities.
Several factors stimulate the function of eosinophils in the immune defense of the host. For example, stimulants derived from T cells increase the ability of eosinophils to destroy parasites. The eosinophilic chemotactic factor derived from the mast cells of anaphylaxis (ECFa) increases the number of complement receptors of eosinophils and their ability to destroy parasites. In addition, the eosinophilic colony-stimulating factor (e.g. IL-5) produced by macrophages can not only increase the production of eosinophils in the bone marrow, but also activates eosinophils to destroy parasites.
Eosinophilia is the presence of more than 500 eosinophils per microlitres of blood and is commonly found in many situations, not only in parasitic infections. Significant tissue eosinophilia may occur without blood eosinophilia. Perhaps the most common cause of eosinophilia is the allergic reaction to drugs, such as iodate products, aspirin, sulfonamides, nitrofurantoin, penicillins and cephalosporins. Allergic conditions of hay fever, asthma, eczema, serum disease, allergic vasculitis and pemfigus are characteristically associated with eosinophilia.
Eosinophilia also occurs in vascular collagen diseases (e.g. rheumatoid arthritis, eosinophilic fasceitis, allergic angeitis and node periarthritis) and malignant diseases (e.g. Hodgkin's disease, fungal mycosis, chronic myeloid leukemia and cancer of the lungs, stomach, pancreas, ovaries and uterus), as well as in rare diseases such as Job syndrome and BGC (the mechanism of eosinophilia in these conditions being unknown). Eosinophilia is characteristically found in helminthic inflammations. Therapeutic administration of CYtokines IL-2 and GM-CSF frequently causes transient eosinophilia. The most dramatic hypereosinophilic syndromes are Loeffler syndrome, Loeffler endocarditis, eosinophilic leukaemia and idiopathic hypereosinophilic syndrome (with levels of 50,000-100,000 eosinophils per microlitre).
Idiopathic hypereosinophilic syndrome comprises a heterogeneous group of disorders, the common feature of which is prolonged hypereosinophilia of unknown cause, and associated organ dysfunction, which can affect the heart, central nervous system, kidneys, lungs, gastrointestinal tract and skin. Bone marrow is affected in all patients, but the most severe complications are those involving the heart and central nervous system. Eosinophils are discovered in affected tissues and are believed to cause local deposition of toxic eosinophilic proteins, such as the major eosinophilic cationic and basic protein.
In the heart, pathological changes lead to thrombosis, which can cause endocardial fibrosis and restrictive endocarditopathy. Similar pathological changes contribute to tissue damage from other organs.
Although the mechanism of hypereosinophilia is not known, glucocorticoid administration has been observed to usually induce remission. In patients who do not respond to glucocorticoids, a hydroxyurea-type cytotoxic agent has been successfully used to reduce the peripheral blood level of eosinophils and greatly improve prognosis. Alpha interferon is also effective in some patients, including those who do not respond to hydroxyurea. Aggressive medical and surgical therapeutic approaches are used in patients with cardiovascular complications.
Monocytes leave circulation through diapedesis, slower than neutrophils, and have a half-life in the blood of 12-24 hours. After the blood monocytes reach the tissues, they differentiate into macrophages ("big eaters") with specialized functions after anatomical localization. Macrophages are especially abundant in the walls of the capillaries in the lungs, spleen, liver and bone marrow, their functions being to remove microorganisms and other harmful elements from the blood. Alveolar macrophages, Kupffer liver cells, splenic macrophages, peritumoral macrophages, bone marrow macrophages, lymphatic macrophages, microglial brain cells and dendritic macrophages all have specialized functions.
Secreted macrophages include lysozyme, neutral proteases, acidic hydrolases, arginases, numerous complement fractions, enzyme inhibitors (plasmin, alpha2 macroglobulin), binding proteins (transferin, fibronectin, transcobalamin II), numerous fractions of the complement, enzyme inhibitors (plasmin, alpha2 macroglobulin), binding proteins (transferin, fibronectin, transcobalamin II), numerous microcheoids and cytokines. Interleukin 1 has many important functions, including stimulation of the hypothalamus to initiate fever, mobilization of leukocytes in the bone marrow, as well as activation of lymphocytes and neutrophils. The alpha tumor necrosis factor (also called cashectin) is a pyrogen that performs many of the actions of IL-1 and plays an important role in the pathogenesis of gram-negative shock. It can stimulate the production of oxygenated water and other toxic oxygen radicals by macrophages and neutrophils. In addition, TNFalfa induces catabolic response to chronic inflammation, which contributes to massive weight loss (cachexia), associated with numerous chronic diseases.
Other secreted products of macrophages are reactive oxygen metabolites, bioactive lipids (arachidonic metabolites and platelet activating factors), chemokines, colony stimulation factors in the bone marrow and factors that stimulate fibroblasts and the proliferation of microvessels. Macrophages participate in the regulation of lymphocyte replication and the destruction of tumors, viruses and bacteria (Mycobacterium tuberculosis and Listeria monocytogenes). Macrophages are effector cells essential in the elimination of intracellular microorganisms.
Their ability to fuse and form giant cells that cluster into granulomas in response to some inflammatory factors is important in the elimination of intracellular bacteria and may be under the control of IFNgama. Macrophages play an important role in the immune response. They process and present lymphocyte antigens and secrete cytokines that modulate and direct the development and function of lymphocytes. Macrophages participate in the autoimmune phenomenon by removing immune complexes and other immunologically active substances from circulation. In addition, they play a role in wound healing, in the elimination of senescent cells and in the development of atheroma plaques.
In terms of disorders of the mononuclear phagocyte system, many alterations of neutrophils also extend to mononuclear phagocytes. Those drugs that inhibit the production of neutrophils in the bone marrow usually cause monocytopenia. Transitional monocytopenia also occurs after stress and administration of glucocorticoids. Monocytosis is associated with some infections, such as tuberculosis, brucellosis, subacute bacterial endocarditis, spotted fever, malaria and visceral leishmaniosis (kala azar).
Monocytosis is also found in malignant diseases, leukaemias, myeloproliferative syndromes, hemolytic anemias, chronic idiopathic neutropenia and granulomatous diseases such as sarcoidosis, regional enteritis and some vascular collagen diseases. All patients with LAD, HIE syndrome (Job), CHS and chronic granulomatous disease have defects in the mononuclear phagocyte system. Alteration of cytokine production by cytokines has been found in some patients with disseminated non-uberculous microbacterial infection who are not infected with human immunodeficiency virus (HIV).
Some viral infections alter the function of mononuclear phagocytes. For example, influenza virus infection is associated with an abnormal chemotactism of monocytes. Mononuclear phagocytes may be infected with HIV, and abnormal monocytactism and altered clearance of IgG-coated erythrocytes are also found in AIDS. These defects in the monocyte-macrophage system are likely to contribute to AIDS disorder and increased susceptibility to opportunistic infections due to intracellular microorganisms such as Pneumocystis carinii and M. avium complex.
T lymphocytes produce IFNgama, which induces the expression of the factor Fc and phagocytosis and stimulate the production of oxygenated water by mononuclear and neutrophil phagocytes. In some diseases, such as AIDS, the production of IFNgama may be deficient, while in other conditions, such as T-cell lymphoma, excessive release of IFNgama is suspected to cause phagocytization of erythrocytes by splenic macrophages. Specific defects of mononuclear phagocytes have been described in some autoimmune diseases. Clearance of radiomarked autologous erythrocytes covered by IgG, probably via the Fc receptor of splenic macrophages, is profoundly altered in patients with systemically active lupus erythematosus.
Patients with other autoimmune diseases characterized by the deposition of immune complexes in tissues, as happens in Sjogren's syndrome, mixed cryoglobulinemia, herpetiform dermatitis and chronic progressive multiple sclerosis, also have a defect in the function of the Fc receptor, illustrated by the clearance of erythrocytes coated with IgG. Clinically, normal subjects with genetic haplotypes commonly found in autoimmune diseases show an increase in the incidence of abnormality in the functional activity of the Fc receptor, suggesting that this defect predisposes individuals with this genetic profile to the disease of immune complexes.
Monocytopenia occurs in acute infections, stress and after administration of glucocorticoids. Monocytopenia also occurs in aplastic anaemia, hairy cell leukaemia and acute myeloid leukaemia, as a direct result of immunosuppressive and cytotoxic medication.
Eosinophils and neutrophils have morphology, many lysosome constituents, phagocytic capacity and similar oxidative metabolism. Eosinophils have a specific chemotactic receptor and respond to a specific chemokinone, eotaxin. However, there are major differences between the two cell types and little is known about the natural function of eosinophils. Eosinophils live much longer than neutrophils and, against these, tissue eosinophils can be recirculated.
During most infections eosinophils do not appear to have any important function. However, in invasive helminthic infection, such as hook worm infection, schistosomiasis, strongyloidosis, toxocariasis, trichinosis, filariasis, echinococosis and cysticercosis, eosinophils probably play a central role in the host's immune defense. Eosinophils are also associated with asthma, allergic skin reactions and other conditions of hypersensitivity.
The granules characteristic of eosinophils, colored in red (Wright coloration), contain a number of unique constituents. The distinguishing element of eosinophilic granule is its crystalline core, consisting of a protein rich in acornin (major basic protein), with histamine activity which is probably important in antiparasitic defense. Eosinophilic granules also contain a unique peroxidase, which catalyzes the oxidation of many substances to oxygenated water and can facilitate the destruction of microorganisms. Eosinophilic peroxidase, in the presence of oxygenated water and halid, initiates the secretion of mast cells in vitro, thus contributing to inflammation.
These substances in eosinophils are cationic proteins, some of which bind to heparin and reducing its anticoagulant activity. The cytoplasm of eosinophils contains Charcot-Leyden crystallized proteins, a bipyramidal hexagonal crystal, first described in leukaemias and then in the sputum of patients with asthma, which is a phospholipase and can act to reduce the toxicity of some lysophospholipids. Eosinophils also contain a strong neurotoxin. Patients with hypereosinophilic syndrome and eosinophilia in the cerebrospinal fluid have various neurological abnormalities.
Several factors stimulate the function of eosinophils in the immune defense of the host. For example, stimulants derived from T cells increase the ability of eosinophils to destroy parasites. The eosinophilic chemotactic factor derived from the mast cells of anaphylaxis (ECFa) increases the number of complement receptors of eosinophils and their ability to destroy parasites. In addition, the eosinophilic colony-stimulating factor (e.g. IL-5) produced by macrophages can not only increase the production of eosinophils in the bone marrow, but also activates eosinophils to destroy parasites.
Eosinophilia is the presence of more than 500 eosinophils per microlitres of blood and is commonly found in many situations, not only in parasitic infections. Significant tissue eosinophilia may occur without blood eosinophilia. Perhaps the most common cause of eosinophilia is the allergic reaction to drugs, such as iodate products, aspirin, sulfonamides, nitrofurantoin, penicillins and cephalosporins. Allergic conditions of hay fever, asthma, eczema, serum disease, allergic vasculitis and pemfigus are characteristically associated with eosinophilia.
Eosinophilia also occurs in vascular collagen diseases (e.g. rheumatoid arthritis, eosinophilic fasceitis, allergic angeitis and node periarthritis) and malignant diseases (e.g. Hodgkin's disease, fungal mycosis, chronic myeloid leukemia and cancer of the lungs, stomach, pancreas, ovaries and uterus), as well as in rare diseases such as Job syndrome and BGC (the mechanism of eosinophilia in these conditions being unknown). Eosinophilia is characteristically found in helminthic inflammations. Therapeutic administration of CYtokines IL-2 and GM-CSF frequently causes transient eosinophilia. The most dramatic hypereosinophilic syndromes are Loeffler syndrome, Loeffler endocarditis, eosinophilic leukaemia and idiopathic hypereosinophilic syndrome (with levels of 50,000-100,000 eosinophils per microlitre).
Idiopathic hypereosinophilic syndrome comprises a heterogeneous group of disorders, the common feature of which is prolonged hypereosinophilia of unknown cause, and associated organ dysfunction, which can affect the heart, central nervous system, kidneys, lungs, gastrointestinal tract and skin. Bone marrow is affected in all patients, but the most severe complications are those involving the heart and central nervous system. Eosinophils are discovered in affected tissues and are believed to cause local deposition of toxic eosinophilic proteins, such as the major eosinophilic cationic and basic protein.
In the heart, pathological changes lead to thrombosis, which can cause endocardial fibrosis and restrictive endocarditopathy. Similar pathological changes contribute to tissue damage from other organs.
Although the mechanism of hypereosinophilia is not known, glucocorticoid administration has been observed to usually induce remission. In patients who do not respond to glucocorticoids, a hydroxyurea-type cytotoxic agent has been successfully used to reduce the peripheral blood level of eosinophils and greatly improve prognosis. Alpha interferon is also effective in some patients, including those who do not respond to hydroxyurea. Aggressive medical and surgical therapeutic approaches are used in patients with cardiovascular complications.
Eosinophilia-myalgia
syndrome is a multisystemic disease with severe skin,
haematological and visceral manifestations, which frequently
evolves chronically and can sometimes be
fatal. The syndrome is characterized by eosinophilia (greater than 1.00 eosinophils per microlitre) and debilitating general myalgia, with no recognizable cause. Eosinophilic fasceitis, pneumonitis, myocarditis and neuropathy, culminating in insufficiency, respiratory failure and encephalopathy, have been described.
The association of this disease with the ingestion of products containing L-Tryptophan from a single source has led to the identification and characterization of the presumptive etiological agents that have contaminated these preparations. Although the accumulation of eosinophils, lymphocytes, macrophages and fibroblasts in the affected tissues suggests that these cells play an important role in the pathogenesis of eosinophilia-myalgia syndrome, the precise mechanism by which they act is not established. Several studies have shown the activation of eosinophils and the storage of toxic proteins derived from eosinophils in the affected tissues.
The activation of fibroblas and increased expression of genes encoding molecules of different types of connective tissue have been demonstrated. Furthermore, IL-5 and beta growth and transformation factor were involved as potential mediators. Treatment consisted of the prohibition of products containing L-Tryptophan and the administration of glucorticoids. Most patients recovered entirely, remained stable, or experienced slow recovery, but for some patients (up to 5%) disease can be fatal. This condition emphasizes the importance of chemical and environmental factors in the development of systemic disorders characterized by chronic inflammation and fibrosis.
Eosinopenia occurs in stresses, such as acute bacterial infection and after administration of glucocorticoids. The mechanism of acute eosinopenia in acute bacterial infection is unknown, but is independent of endogenous glucocorticoids, since it occurs under conditions of complete adrenalectomy. No adverse effectof eosinopenia is known.
I will complete this post with the presentation of some elements about diagnostics and laboratory evaluation. Initial studies of the entire haemoleukogram and different cell types, as well as bone marrow examination, are followed by the assessment of bone marrow reserves (steroid challenge test), circulating cell margin peak (epinephrine challenge test) and cell margin capacity (endotoxin challenge test).
In vivo assessment of inflammation is possible with the Rebuck skin test or the in vivo blister test, which measures the ability of leukocytes and inflammation mediators to accumulate locally in the skin. In vivo, IgG-coated erythrocytes clearance provides a useful way to monitor the mononuclear phagocyte system. In vitro, aggregation tests, adhesion, chemotactism, phagocytosis, degranulation and antibacterial activity (for Staphylococcus aureus) of phagocytes help to specify cellular or humoral lesions, which can be further characterized at the molecular level. The impairment of oxidative metabolism is investigated using the nitroblue tetrazolium (MBT) staining test, which is based on the ability of oxidative metabolism products to reduce soluble, yellow MBT to black-blue forman, an insoluble compound that precipite intracellularly and can be observed under a microscope.
Other aspects of neutrophylic oxidative metabolism are defined by studies of the production of superoxide and oxygenated water. The most important aspect of patient evaluation is that patients with leukopenia or leukocytic dysfunction frequently have delayed inflammatory responses. Therefore, clinical manifestations may be minimal, despite generalized infection, and common infections should always be suspected. Early signs of infection require prompt crop identification of the responsible microorganism and the use of antibiotics and surgical drainage of abscesses. Prolonged antibiotic therapy is often required.
Daily transfusion with leukocyte preparations (enriched in neutrophils) is controversial. In patients with BGC, daily antibiotic therapy (trimetoprim-sulfamethoxazole) decreases the frequency of serious infections. Surgical treatment is necessary for complete drainage of liver, lung and bone abscesses. Short corticosteroid belts have had extremely beneficial effects in the treatment of BGC granulomas. For example, obstruction of the gastrointestinal or genitourinary tract in BGC may be reduced using short corticosteroid cures, followed by long-term treatment with nonsteroidal anti-inflammatory drugs. Human recombinant IFNgama, which nonspecifically stimulates phagocytic cell function, reduces both the frequency of infections in patients with BGC by 79% and the severity of infections (number of hospital days for infection). This effect of IFNgama is added to the prophylactic effect of antibiotics.
Rigorous oral hygiene reduces, but does not eliminate, discomfort of gingivitis, periodontal disease and thrush ulcers (oral chlorhexidine washes and brushing of teeth with sodium bicarbonate-oxygenated water paste helps many patients). Ketoconazole has had extremely beneficial effects on mucocutaneous candidiasis in patients with Job syndrome. Treatment to restore myelopoiesis in patients with neutropenia due to insufficient production included the use of androgens, glucocorticoids, lithium and immunosuppressive therapy. Recombinant G-CSF has been successfully used in the treatment of some forms of neutropenia due to suppressed production, especially in that caused by neoplasm chemotherapy.
Patients with chronic neutropenia whose bone marrow reserve is good should not receive prophylactic antibiotherapy. Patients with a constant or cyclic neutrophil level or 500 cells per microlitre may benefit from prophylactic antibiotherapy and G-CSF during periods of neutropenia. Trimethoprim-sulfamethoxazole (160/800mg) administered twice a day is currently used to prevent infections, although there are indications that it predisposes to fungal infections. No more common fungal infections have been found in BGC patients treated with this antibiotic.
Oral quinolones such as norfloxacin and cyclofloxacin may be used as alternatives. The proven efficacy of trimetoprim-sulfamethoxazole in preventing P. carinipneumonia pneumonia in patients with severe, persistent neutropenia due to cytotoxic chemotherapy encourages the use of this type of prophylaxis. These patients and those with phagocytic cell dysfunction should avoid prolonged exposure to aerosols, dust or decomposing matter (protective layer, dung), which are frequently rich in aspergillus spores or other fungi. Restricting social activities or contacts does not have much influence on the risk of infection.
Treatment of congenital defects of phagocytes is theoretically possible through bone marrow transplantation. However, the complications of bone marrow transplantation are serious, and patients with phagocyte defects, medically properly cared for, can live many years without contacting a lethal infection. The identification of specific genetic defects in patients with LAD 1 and BGC allowed the correction, in vitro, of B lymphocytes by gene transfer. Genetic correction was performed on the peripheral blood progenitor cells of patients with BGC. This therapeutic approach has been successful in vitro, leading to the functional restoration of NADPH oxidase. Various experiments have been carried out, which means that genetic therapy of BGC and other genetic diseases can be used in the future.
fatal. The syndrome is characterized by eosinophilia (greater than 1.00 eosinophils per microlitre) and debilitating general myalgia, with no recognizable cause. Eosinophilic fasceitis, pneumonitis, myocarditis and neuropathy, culminating in insufficiency, respiratory failure and encephalopathy, have been described.
The association of this disease with the ingestion of products containing L-Tryptophan from a single source has led to the identification and characterization of the presumptive etiological agents that have contaminated these preparations. Although the accumulation of eosinophils, lymphocytes, macrophages and fibroblasts in the affected tissues suggests that these cells play an important role in the pathogenesis of eosinophilia-myalgia syndrome, the precise mechanism by which they act is not established. Several studies have shown the activation of eosinophils and the storage of toxic proteins derived from eosinophils in the affected tissues.
The activation of fibroblas and increased expression of genes encoding molecules of different types of connective tissue have been demonstrated. Furthermore, IL-5 and beta growth and transformation factor were involved as potential mediators. Treatment consisted of the prohibition of products containing L-Tryptophan and the administration of glucorticoids. Most patients recovered entirely, remained stable, or experienced slow recovery, but for some patients (up to 5%) disease can be fatal. This condition emphasizes the importance of chemical and environmental factors in the development of systemic disorders characterized by chronic inflammation and fibrosis.
Eosinopenia occurs in stresses, such as acute bacterial infection and after administration of glucocorticoids. The mechanism of acute eosinopenia in acute bacterial infection is unknown, but is independent of endogenous glucocorticoids, since it occurs under conditions of complete adrenalectomy. No adverse effectof eosinopenia is known.
I will complete this post with the presentation of some elements about diagnostics and laboratory evaluation. Initial studies of the entire haemoleukogram and different cell types, as well as bone marrow examination, are followed by the assessment of bone marrow reserves (steroid challenge test), circulating cell margin peak (epinephrine challenge test) and cell margin capacity (endotoxin challenge test).
In vivo assessment of inflammation is possible with the Rebuck skin test or the in vivo blister test, which measures the ability of leukocytes and inflammation mediators to accumulate locally in the skin. In vivo, IgG-coated erythrocytes clearance provides a useful way to monitor the mononuclear phagocyte system. In vitro, aggregation tests, adhesion, chemotactism, phagocytosis, degranulation and antibacterial activity (for Staphylococcus aureus) of phagocytes help to specify cellular or humoral lesions, which can be further characterized at the molecular level. The impairment of oxidative metabolism is investigated using the nitroblue tetrazolium (MBT) staining test, which is based on the ability of oxidative metabolism products to reduce soluble, yellow MBT to black-blue forman, an insoluble compound that precipite intracellularly and can be observed under a microscope.
Other aspects of neutrophylic oxidative metabolism are defined by studies of the production of superoxide and oxygenated water. The most important aspect of patient evaluation is that patients with leukopenia or leukocytic dysfunction frequently have delayed inflammatory responses. Therefore, clinical manifestations may be minimal, despite generalized infection, and common infections should always be suspected. Early signs of infection require prompt crop identification of the responsible microorganism and the use of antibiotics and surgical drainage of abscesses. Prolonged antibiotic therapy is often required.
Daily transfusion with leukocyte preparations (enriched in neutrophils) is controversial. In patients with BGC, daily antibiotic therapy (trimetoprim-sulfamethoxazole) decreases the frequency of serious infections. Surgical treatment is necessary for complete drainage of liver, lung and bone abscesses. Short corticosteroid belts have had extremely beneficial effects in the treatment of BGC granulomas. For example, obstruction of the gastrointestinal or genitourinary tract in BGC may be reduced using short corticosteroid cures, followed by long-term treatment with nonsteroidal anti-inflammatory drugs. Human recombinant IFNgama, which nonspecifically stimulates phagocytic cell function, reduces both the frequency of infections in patients with BGC by 79% and the severity of infections (number of hospital days for infection). This effect of IFNgama is added to the prophylactic effect of antibiotics.
Rigorous oral hygiene reduces, but does not eliminate, discomfort of gingivitis, periodontal disease and thrush ulcers (oral chlorhexidine washes and brushing of teeth with sodium bicarbonate-oxygenated water paste helps many patients). Ketoconazole has had extremely beneficial effects on mucocutaneous candidiasis in patients with Job syndrome. Treatment to restore myelopoiesis in patients with neutropenia due to insufficient production included the use of androgens, glucocorticoids, lithium and immunosuppressive therapy. Recombinant G-CSF has been successfully used in the treatment of some forms of neutropenia due to suppressed production, especially in that caused by neoplasm chemotherapy.
Patients with chronic neutropenia whose bone marrow reserve is good should not receive prophylactic antibiotherapy. Patients with a constant or cyclic neutrophil level or 500 cells per microlitre may benefit from prophylactic antibiotherapy and G-CSF during periods of neutropenia. Trimethoprim-sulfamethoxazole (160/800mg) administered twice a day is currently used to prevent infections, although there are indications that it predisposes to fungal infections. No more common fungal infections have been found in BGC patients treated with this antibiotic.
Oral quinolones such as norfloxacin and cyclofloxacin may be used as alternatives. The proven efficacy of trimetoprim-sulfamethoxazole in preventing P. carinipneumonia pneumonia in patients with severe, persistent neutropenia due to cytotoxic chemotherapy encourages the use of this type of prophylaxis. These patients and those with phagocytic cell dysfunction should avoid prolonged exposure to aerosols, dust or decomposing matter (protective layer, dung), which are frequently rich in aspergillus spores or other fungi. Restricting social activities or contacts does not have much influence on the risk of infection.
Treatment of congenital defects of phagocytes is theoretically possible through bone marrow transplantation. However, the complications of bone marrow transplantation are serious, and patients with phagocyte defects, medically properly cared for, can live many years without contacting a lethal infection. The identification of specific genetic defects in patients with LAD 1 and BGC allowed the correction, in vitro, of B lymphocytes by gene transfer. Genetic correction was performed on the peripheral blood progenitor cells of patients with BGC. This therapeutic approach has been successful in vitro, leading to the functional restoration of NADPH oxidase. Various experiments have been carried out, which means that genetic therapy of BGC and other genetic diseases can be used in the future.
Weekend of the best and
understanding, love and gratitude!
Dorin, Merticaru