The capacity of human phagocytes to generate superoxide anion (O2-), a free radical of oxygen, and a possible role for this radical or its derivatives in the killing of phagocytized bacteria were explored using leukocytes from normal individuals and patients with chronic granulomatous disease (CGD). Superoxide dismutase, which removes O2-, consistently inhibited phagocytosis-associated nitroblue tetrazolium (NBT) reduction indicating the involvement of O2- in this process. Similarly, superoxide dismutase inhibited the luminescence that occurs with phagocytosis, implicating O2- in this phenomenon, perhaps through its spontaneous dismutation into singlet oxygen. Subcellular fractions from homogenates of both normal and CGD leukocytes generated O2- effectively in the presence of NADH as substrate. However, O2- generation by intact cells during phagocytosis was markedly diminished in nine patients with CGD. Leukocytes from mothers determined to be carriers of X-linked recessive CGD by intermediate phagocytic reduction of NBT elaborated O2- to an intermediate extent, further demonstrating the interrelationship between NBT reduction and O2- generation in phagocytizing cells. Activity of superoxide dismutase, the enzyme responsible for protecting the cell from the damaging effects of O2-, was approximately equal in homogenates of normal and CGD granulocytes. Polyacrylamide electrophoresis separated this activity into a minor band that appeared to be the manganese-containing superoxide dismutase associated with mitochondria and a more concentrated, cyanide-sensitive, cytosol form of the enzyme with electrophoretic mobility that corresponded to that of erythrocyte cuprozinc superoxide dismutase. Superoxide dismutase inhibited the phagocytic killing of Escherichia coli, Staphylococcus aureus, and Streptococcus viridans. A similar inhibitory effect was noted with catalase which removes hydrogen peroxide. Neither enzyme inhibited the ingestion of bacteria. Peroxide and O2- are believed to interact to generate the potent oxidant, hydroxyl radical (.OH). A requirement for .OH in the phagocytic bactericidal event might explain the apparent requirement for both O2- and H2O2 for such activity. In agreement with this possibility, benzoate and mannitol, scavengers of .OH, inhibited phagocytic bactericidal activity. Generation of singlet oxygen from O2- and .OH also might explain these findings. It would seem clear from these and other studies that the granulo cyte elaborates O2- as a concomitant of the respiratory burst that occurs with phagocytosis. To what extent the energy inherent in O2- is translated into microbialdeath through O2- itself, hydrogen peroxide, .OH, singlet oxygen, or some other agent remains to be clearly defined.

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The role of superoxide anion generation in phagocytic bactericidal activity. Studies with normal and chronic granulomatous disease leukocytes.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(97)09137-X.pdf

Plasma bradykinin in angio-oedema

Copyright © 2008 Massachusetts Medical Society. A 19-year-old woman presents to the emergency department with light-headedness, severe abdominal pain, and intractable nausea and vomiting that began 12 hours earlier. The patient reports previous episodes of abdominal pain and swelling of her hands and feet that have been attributed possibly to food allergies, which have recently become more frequent. There is no associated urticaria. Her only medication is an oral contraceptive that was started 3 months earlier. She notes a history of similar episodes in her father. She is afebrile, with a blood pressure of 75/40 mm Hg, a pulse of 120 beats per minute, and diffuse abdominal tenderness with guarding and rebound tenderness. How should her case be evaluated and treated?

Clinical practice. Hereditary angioedema.

C1 inhibitor deficiency (hereditary angioedema [HAE]) is a rare disorder for which there is a lack of consensus concerning diagnosis, therapy, and management, particularly in Canada. European initiatives have driven the approach to managing HAE with 3 C1-INH Deficiency Workshops held every 2 years in Hungary starting in 1999, with the third Workshop having recently been held in May 2003. The European Contact Board has established a European HAE Registry that will hopefully advance our knowledge of this disorder. The Canadian Hereditary Angioedema Society/Societe d'Angioedeme Hereditaire du Canada organized a Canadian International Consensus Conference held in Toronto, Ontario, Canada, on October 24 to 26, 2003, to foster consensus between major European and North American HAE treatment centers. Papers were presented by investigators from Europe and North America, and this consensus algorithm approach was discussed. There is a paucity of double-blind placebo-controlled trials in the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Enclosed is the consensus algorithm approach recommended for the diagnosis, therapy, and management of HAE and agreed to by the authors of this article. This document is only a consensus algorithm approach and requires validation. As such, participants agreed to make this a living 2003 algorithm (ie, a work in progress) and agreed to review its content at future international HAE meetings. The consensus, however, has strength in that it was arrived at by the meeting of patient-care providers along with patient group representatives and individual patients reviewing information available to date and reaching agreement on how to approach the diagnosis, therapy, and management of HAE circa 2003. Hopefully evidence to support approaches to the management of HAE will approach the level of meta-analysis of randomized controlled trials in the near future.

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2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema

Hereditary angioedema is manifested by attacks of swelling of the extremities, face, trunk, airway, or abdominal viscera, occurring spontaneously or secondary to trauma. It is inherited as an autosomal dominant trait and is due to deficient activity of the inhibitor of the activated first component of complement. The clinical diagnosis can be confirmed by the findings of low levels of C4 or C1 esterase inhibitor activity, or both. Therapy may be divided into three phases: long-term prophylaxis of attacks, short-term prophylaxis of attacks, and treatment of acute attacks. Long-term prophylaxis may be achieved with antifibrinolytic agents and androgens. Short-term prophylaxis with these agents and plasma transfusions has been successful. Specific therapy for acute attacks is not available, but good supportive care, together with a knowledge of the course of the disease, can prevent asphyxiation from airway obstruction. Before the advent of therapy, mortality was reported as high as 30%.

Hereditary angioedema: the clinical syndrome and its management.

A B S T R A C T Normal human serum contains 18 ±5 mg/100 ml of Cl esterase inhibitor (alpha-2 neuraminoglycoprotein) as estimated by immunochemical means. Of 118 patients with hereditary angioneurotic edema, the sera of 80, from 42 kindred, contained a mean concentration of 3.15 mg/100 ml or 17.5% of normal. The mean serum concentration in 35 patients in 7 other kindred was 20 mg/100 ml or 111% of normal, and 3 patients in another kindred contained over 80 mg/100 ml or greater than 400% of normal. The nonfunctional inhibitors in patients' sera of these eight kindred were identical with normal Cl esterase inhibitor by Ouchterlony analysis, but they were different from normal and from each other with respect to their electrophoretic mobility, their capacity to bind Cl esterase, and their ability to inhibit esterolysis of N-acetyl-tyrosine-ethylester.

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Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema

The role of serum factors in the phagocytosis of pneumococci was studied employing a spectrophotometric assay which measures reduced nitro blue tetrazolium (NBT) dye. Dye reduction occurs within the phagocyte shortly after bacterial ingestion as measured by the phagocytic index technique and by the uptake of (125)I-pneumococci. Bacteria prepared with gammaG antibody were not phagocytosed unless a small volume of fresh normal serum was added. Using fresh sera deficient in single complement components, it was demonstrated that the first four components are necessary for optimal bacterial phagocytosis. When highly purified complement components were added to the antibody-coated pneumococci, enhancement of phagocytosis was achieved only with the sequential addition of C1, C4, C2, and C3. Evidence has been presented that human C3 bound to an immune complex exhibits peptidase activity and that this activity is essential for phagocytosis. A heat-labile, dialyzable serum cofactor which enhances C3 peptidase activity enhanced the phagocytosis of pneumococci prepared with purified complement components. A second phagocytosis-promoting cofactor, which is not a complement component, was found to be a heat-labile, 5-6S, beta pseudoglobulin. This protein may stabilize C3 peptidase activity or inhibit enzymatic inactivation of C3.

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The enhancement of bacterial phagocytosis by serum the role of complement components and two cofactors

/pdf/hereditary-deficiency-of-the-second-component-of-complement-43isjnyr7n.pdf

Hereditary Deficiency of the Second Component of Complement (C'2) in Man*

A kindred has been investigated in which seven individuals were found to have half-normal serum concentrations of the third component of complement (C′3). This partial deficiency was transmitted as an autosomal dominant trait. Affected individuals were entirely healthy. Hemolytic complement titers were slightly reduced but immune adherence titers and reagent titrations of the classical complement components were normal.

Examination for C′3 allotypes revealed that all affected individuals had patterns resembling those of homozygotes. Analysis of the inheritance of C′3 structural genes disclosed that the most likely mechanism for partial C′3 deficiency in this family was nonexpression of one allele.

/pdf/inherited-deficiency-of-the-third-component-of-human-3p2mc31zun.pdf

Inherited deficiency of the third component of human complement (C′3)

When purified human C′1 esterase is injected intradermally in man, increased vascular permeability results. This effect is not blocked by soybean trypsin inhibitor and is not abolished by pretreatment with the antihistamine, pyribenzamine, or by compound 48/80. Thus, the effect is not due to the release of endogenous histamine. The decreased permeability response of individuals with a specific hereditary deficiency of C′2 is evidence for the complement-dependent nature of this reaction. The apparently normal response to intradermal C′1 esterase developed by individuals with an acquired specific deficiency of C′3 suggests that the vasoactive substance may be derived from one of the early reacting complement components. Characteristic attacks of angioedema have been provoked by the intradermal injection of human C′1 esterase in two individuals with hereditary angioneurotic edema. Patients with hereditary angioneurotic edema are unresponsive to intradermal injections of C′1 esterase immediately after attacks.

/pdf/effect-of-c-1-esterase-on-vascular-permeability-in-man-369yhuhuu0.pdf

Effect of C′1 esterase on vascular permeability in man: studies in normal and complement-deficient individuals and in patients with hereditary angioneurotic edema

Martin R. Klemperer

Papers

Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema

The enhancement of bacterial phagocytosis by serum the role of complement components and two cofactors

Hereditary Deficiency of the Second Component of Complement (C'2) in Man*

Inherited deficiency of the third component of human complement (C′3)

Effect of C′1 esterase on vascular permeability in man: studies in normal and complement-deficient individuals and in patients with hereditary angioneurotic edema