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PubMed2003

Membranoproliferative glomerulonephritis associated with hereditary deficiency of the 4th component of complement.

A 10-year-old female patient was found positive for urine protein and occult blood on Japanese school urinary screening. Examination of the blood was normal except low values of the complement system with CH50 13.5 U/ml, C3 45 mg/dl and C4 3 mg/dl. Renal biopsy demonstrated a focal membranoproliferative glomerulonephritis (MPGN). As for the activity of each component of the complement in the early stage of the disease, the C4 activity was markedly declined and the activity of classical pathway component was also decreased, but the activity of alternative pathway component was normal. On the HLA examination, the patient demonstrated a C4 double null haplotype (C4A2, Q0, BQ0 phenotype). A null C4 gene at both the C4A and C4B loci was found in her mother, aunt and grandfather on the mother's side and C4B null allele in her father and her grandmother on the mother's side. The development of the disease is found in 1 case and not in the other, although both have the genetic defect and the mechanism by which the complement is activated remains unknown. Thus, there appear to be many subjects to be studied as to the relationship between the defect of C4 gene and immune competence.

Child↗

PubMed1987

Host defense impairments that may lead to respiratory infections.

Host defense mechanisms spaced along the respiratory tree and in the alveolar spaces effectively remove or contend with micro-organisms that enter the airways, so serious lung infections occur rarely in healthy people. Special circumstances, such as virgin exposure to a virulent microbe or a large innoculum of a pathogen, can result in illness, but usually routine surveillance host defenses are protective and suffice to keep colonizing airway flora in check. When pneumonia develops or recurrent sinopulmonary infection exists, however, some element of the normal defense apparatus may have failed or is inadequate. This review highlights several components of the apparatus, that is immunoglobulins IgG and IgA and the interaction of alveolar macrophages and lymphocytes, and examines deficiencies in their function that may result in infection. Along the conducting airways, poor mucociliary clearance and/or deficiencies in certain IgG subclass antibodies or destruction of IgA may predispose to sinopulmonary infections; these may be a manifestation of a hereditary disease. In pneumonia the alveolar macrophage is positioned as the central cell which must respond in several directions. This scavenger phagocyte first intercepts the microbe and either can kill or contain it or must call in some other phagocytic cell or inflammatory mediator(s) for assistance. Opsonic antibodies (IgG) and other nonimmune opsonins (complement and surfactant or fibronectin fragments) facilitate phagocytosis, but an absence of antibody may permit infection to develop with encapsulated bacteria (pneumococcus). Insufficient bone marrow reserves of PMNs or a paucity of chemotactic factors to attract them into the alveoli is a situation that may permit gram-negative bacilli and fungal organisms to flourish. Inability of immune T-lymphocytes to energize macrophages, through soluble cellular mediators that provide cell-mediated immunity and activation, makes containment of certain intracellular microbes impossible for these phagocytes (Legionella or mycobacteria). Likewise, concomitant infection of macrophages with viruses (human immunodeficiency virus, and cytomegalovirus or herpes viruses) plus an excessive T-lymphocyte suppressor cell influence may make P. carinii and common bacterial and fungal organisms difficult to contain in the lungs of AIDS patients. Consideration about what the lung host deficiency might be can make therapy more specific through immunization to develop special antibodies, replacement of certain immunoglobulins (IgG subclasses), or selective administration of cell mediators (gamma-interferon or interleukins).

Antibody Formation↗

PubMed1977

Hereditary angio-oedema with mesangiocapillary glomerulonephritis.

A patient with hereditary angio-oedema (HAO) developed mesangiocapillary glomerulonephritis (MCGN) under observation. HAO is characterized by an inherited defect of complement-deficiency of C1 esterase. MCGN is often associated with another complement abnormality which leads to depression of serum C3 and there is some evidence that the complement abnormality precedes the nephritis. The coincidence of these two rare diseases in the present patient, and in one previously described, suggests that other complement abnormalities may predispose to the development of MCGN.

Angioedema↗

PubMed1987

Inherited deficiencies of complement components in man.

Isolated inherited deficiency states of almost every complement protein have been recognized. Almost all are autosomal recessive traits. Deficiency of the early-acting components C1, C4 and C2 is associated with increased risk of immune complex disease, particularly systemic lupus erythematosus. Patients with deficiency of C3, factor I or factor H have increased susceptibility to infection by pyogenic bacteria, whereas those with deficiencies of properdin, C5, C6, C7 or C8 are prone to systemic neisserial infection. Inherited deficiency of C1 inhibitor is transmitted as an autosomal dominant trait, is genetically heterogeneous, and is associated with attacks of angioedema and consumption of C4 and C2. There is evidence that a plasmin-modified fragment of C2 is responsible for the angioedema in this disorder. Administration of androgens tends to correct the biochemical abnormalities of hereditary angioedema and to prevent attacks.

Angioedema↗

PubMedDate not supplied

[Hereditary deficiency in complement C7 and platelet aggregation disorders associated with rheumatoid arthritis. One case (author's transl)].

In a patient suffering from rheumatoid arthritis thorough investigations led to the discovery of complete deficiency in the 7th component of the complement. A study of the patient's family tree confirmed the hereditary, codominant autosomal character of the deficiency, unrelated to the HLA system. The complement-dependent serum functions were investigated: the opsonizing and chemotactic activities were preserved, but bactericidal properties were lacking. Coagulation studies showed disorders in platelet aggregation in the presence of thrombin, and these were corrected by the addition of C7. The association of a dysimmune disease with C7 deficiency is probably not fortuitous; it might result from a common gene abnormality or, in some cases, from repeated infections.

Adolescent↗

PubMed2004

Biological effects of C1 inhibitor.

C1 inhibitor is a serine proteinase inhibitor (serpin) that regulates activation of both the complement and contact systems. Regulation of complement system activation takes place through inactivation of the classical pathway proteases, C1r and C1s, the lectin pathway protease, MASP2, and perhaps via inhibition of alternative pathway activation by reversible binding to C3b. Regulation of contact system activation takes place through inactivation of plasma kallikrein and coagulation factor XIIa. Deficiency of C1 inhibitor results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa. A variety of clinical, in vitro and animal experiments indicate that the mediator of increased vascular permeability in hereditary angioedema is bradykinin. Animal models suggest that in addition to its utility in therapy of hereditary angioedema, C1 inhibitor may prove useful in a variety of other diseases including septic shock, reperfusion injury, hyperacute transplant rejection, traumatic and hemorrhagic shock, and the increased vascular permeability associated with thermal injury, interleukin-2 therapy and cardiopulmonary bypass. The therapeutic effect in these disease models very likely results from a combination of complement system activation, contact system activation and perhaps from other activities of C1 inhibitor. These other activities include a direct interaction with endotoxin, which may help to prevent endotoxic shock and an interaction with selectin molecules on endothelial cells, which may serve both to concentrate C1 inhibitor at sites of inflammation and to inhibit the transmigration of leukocytes across the endothelium.

Angioedema↗

PubMed1982

Somatic cell hybridization studies on the genetic regulation and allelic mutations in metachromatic leukodystrophy.

Metachromatic leukodystrophy is a hereditary neurodegenerative disease associated with deficient arylsulfatase A activity. Clinical variants differ in onset times and severity of the disease but each breeds true within families. Somatic cell hybridization techniques were used to clarify the genetic relationship among these mutants. Hybrid clones isolated with a nonselective method from fusing fibroblasts of an infantile and a juvenile variant did not show complementation of arylsulfatase A activity. Hence, these clinical variants are allelic mutants. Previous somatic cell hybridization studies suggested that "arylsulfatase A-deficiency" is a dominant phenotype, in contrast to its apparent recessive mode of inheritance. To resolve this discrepancy, hybrid clones from fusing normal and arylsulfatase A-deficient fibroblasts were isolated nonselectively. They continued to express arylsulfatase A activity. Hence, even in vitro, "arylsulfatase A-deficiency" remains as a recessive phenotype.

Adult↗

PubMed2000

C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema.

C1-esterase inhibitor (C1-Inh) therapy was introduced in clinical medicine about 25 years ago as a replacement therapy for patients with hereditary angioedema caused by a deficiency of C1-Inh. There is now accumulating evidence, obtained from studies in animals and observations in patients, that administration of C1-Inh may have a beneficial effect as well in other clinical conditions such as sepsis, cytokine-induced vascular leak syndrome, acute myocardial infarction, or other diseases. Activation of the complement system, the contact activation system, and the coagulation system has been observed in these diseases. A typical feature of the contact and complement system is that on activation they give rise to vasoactive peptides such as bradykinin or the anaphylatoxins, which in part explains the proinflammatory effects of either system. C1-Inh, belonging to the superfamily of serine proteinase inhibitors (serpins), is a major inhibitor of the classical complement pathway, the contact activation system, and the intrinsic pathway of coagulation, respectively. It is, therefore, endowed with anti-inflammatory properties. However, inactivation of C1-Inh occurs locally in inflamed tissues by proteolytic enzymes (e.g., elastase) released from activated neutrophils or bacteria thereby leading to increased local activation of the various host defense systems. Here we will give an overview on the biochemistry and biology of C1-Inh. We will discuss studies addressing therapeutic administration of C1-Inh in experimental and clinical conditions. Finally, we will provide an explanation for the therapeutic benefit of C1-Inh in so many different diseases.

Animals↗

PubMed1986

Coumarin induced acral skin necrosis associated with hereditary protein C deficiency.

Hemorrhagic skin necrosis of the toes was observed in a patient with heterozygous protein C deficiency (protein C:Ag 32% and protein C activity 30%) on the 4th day of coumarin treatment overlapping with effective intravenous anticoagulation with heparin. Family studies revealed protein C deficiency in two sisters of the proposita without a history of thromboembolic disease. Immunologic studies in the proposita at the time of coumarin necrosis revealed slight depression of complement factor C4 and the presence of immune complexes. The present case and review of the literature show that the pathogenetic mechanism leading to coumarin necrosis in patients with protein C deficiency seems not yet to be fully understood.

Adult↗

PubMed2001

A case of hereditary angioedema associated with idiopathic hypoparathyroidism.

Hereditary angioedema is a rare autosomal dominant disease characterized by the edema of subcutaneous tissues, respiratory tract and bowel. It is caused by the deficiency of C1 esterase inhibitor. Hereditary angioedema may be associated with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroiditis and glomerulonephritis. We report a 34-year-old male patient with hereditary angioedema who developed idiopathic hypoparathyroidism. Autoimmunity seems to be an important basis of this association and it might be caused by the immune dysfunction due to decreased level of complements; nevertheless, a casual association could not be excluded. To our knowledge, this is the first report of hereditary angioedema in association with idiopathic hypoparathyroidism in the medical literature.

Adult↗

PubMed1993

[Congenital C1-esterase inhibitor deficiency. A study of 4 Algerian families].

We present the results of a preliminary study (the first of this kind in Algeria) in which 4 families presenting with congenital deficiency of the C1-esterase inhibitor (C1-INH) responsible for hereditary angioneurotic oedema were biologically explored. The complement fractions C1-INH, C4 and C3d were assayed in 38 subjects of the 4 families. Extending this biological evaluation to all members of theses families enabled us to identify all asymptomatic subjects (46 percent in our series). In 2 patients the congenital disease was associated with systemic lupus erythematosus. Some clinico-biological discordances are reported and discussed in the light of data from the literature.

Adolescent↗

PubMed1968

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

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.

Adult↗

PubMed2000

Therapeutic inhibition of the complement system. Y2K update.

Activation of complement is an essential part of the mechanism of pathogenesis of a large number of human diseases; its inhibition by pharmacological means is likely to suppress disease processes in complement mediated diseases. From this point of view low molecular weight synthetic inhibitors of complement are being developed and high molecular weight natural inhibitors of human origin present in plasma or embedded in cell membrane are being purified or produced in their recombinant forms. This review is concerned with high molecular weight inhibitors, some of which are already in clinical use but may be efficacious in many other diseases in which they have not yet been tried. C1-esterase inhibitor (C1-INH) concentrate prepared from human plasma is being successfully used for the treatment of hereditary angioneurotic edema. Recently, C1-INH has been found to be consumed in severe inflammation and has been shown to exert beneficial effects in several inflammatory conditions such as human sepsis, post-operative myocardial dysfunction due to reperfusion injury, severe capillary leakage syndrome after bone marrow transplantation, reperfusion injury after lung transplantation, burn, and cytotoxicity caused by IL-2 therapy in cancer. Factor I has been used for the treatment of factor I deficiency. Recombinant soluble forms of membrane cofactor protein (MCP), and decay accelerating factor (DAF) have not yet been tried in humans but have been shown to be effective in immune complex mediate inflammation in animals. Organs of pigs transgenic for one or more of human membrane regulators of complement namely membrane cofactor protein (MCP), decay accelerating factor (DAF) or CD59, are being produced for transplantation into humans. They have been shown to be resistant to hyperacute rejection in non-human primates; acute vascular rejection is still a problem in their clinical use. It is hoped that these observations together with future developments will make xeno-transplantation in clinical practice a reality. Several recombinant variants of complement receptor 1 (CR1) have been produced. The most effective of these appears to be sCR1-SLe x, sCR1 part of which inhibits complement and carbohydrate Sle x moiety inhibits selectin mediated interactions of neutrophils and lymphocytes with endothelium. Although clinical trials of sCR1 in humans is eagerly awaited, several of the recombinant versions of sCR1 have been shown to suppress ischemia/reperfusion injury, thermal trauma, and immune complex mediated inflammation. They have also been shown to be effective in experimental models of systemic sclerosis, arthritis, myasthenia gravis, Guillain Barré syndrome and glomerulonephritis. Intravenous immunoglobulin, three of the most prominent properties of which are neutralization of autoantibody activity, suppression of autoantibody production and inhibition of complement activity, is being used in several diseases. These include autoimmune thrombocyopenic purpura, Kawasaki disease and several neurological diseases such as myasthenia gravis and Guillain Barre syndrome. In many uncontrolled small scale studies intravenous immunoglobulin has been shown to be effective in many immunological including dermatological diseases; controlled clinical trials in a large number of patients with these diseases is needed to establish the efficacy. It is hoped that in future therapeutic inhibition of complement will be one of the major approaches to combat many human diseases.

Animals↗

PubMed1989

[2 families with meningococcal infection and a hereditary disorder of the 5th component of the complement system].

Within a period of six months, a 20-year-old female with a homozygous deficiency of the C5 component of complement developed meningococcal meningitis twice (different serogroups). Additional C5 deficiencies were not found in relatives. Homozygous deficiency of C5 was also present in another family in which a 16-year-old female and an 18-year-old sister suffered from meningococcal meningitis. Some characteristics of meningococcal disease in patients with C5 deficiency differed from meningococcal disease in patients with a normal complement system: meningitis occurred at a relatively advanced age, was associated with serogroups W-135, B and X and recurred in two of three patients.

Adolescent↗

PubMed2002

Mechanisms of C1-inhibitor deficiency.

C1 inhibitor (C1-Inh) is a protease inhibitor of the serpin family. It interacts and forms complexes with several serine proteases although not all these interactions were proved to be relevant in vivo. Based on studies in deficient patients, C1-Inh appears pivotal in regulating the activation of complement classical pathway and of contact system. The best recognized consequence of defective C1-Inh function is predisposition to episodes of self-limited, increased vascular permeability (angioedema) that is restricted to three specific sites, which include the subcutaneous space, the gut and the upper airway. Candidate mediator of angioedema is bradykinin, a potent vasoactive peptide, released upon contact system activation. Mutations in C1-Inh structural gene are the most common cause of C1-Inh deficiency and lead to hereditary angioedema. Recurrent angioedema are also seen in the acquired defect of C1-Inh that is due to autoantibodies against this protein or to an associated disease causing accelerated catabolism of C1-Inh. Apart from the profound deficiency of C1-Inh characteristic of angioedema, it has been suggested that, in specific pathologic settings, C1-Inh levels in the low normal range could still represent a significant functional deficiency. Such conditions, as extensively investigated in sepsis, are of great relevance because they open the possibility of using C1-Inh as therapeutic agent in several different diseases.

Angioedema↗

PubMed1985

Angioedema.

Angioedema is characterized by a well-demarcated swelling on the skin, oropharyngolaryngeal tissue, or the gastrointestinal wall. Underlying mechanisms may include IgE-mediated reactions, complement activation, inhibition of the cyclo-oxygenase pathway of arachidonic acid metabolism, direct release of mediators from mast cells, and activation of the kinin-forming system. Foods, drugs, inhalants, insect bites, blood transfusion, collagen vascular disease, infections, physical factors, neoplasms, and hereditary factors can cause angioedema through one or more of these mechanisms. Chronic angioedema lasts more than 6 weeks or recurs during this period. Acute angioedema is a self-limited disorder and resolves spontaneously, or with simple therapy, in several days; the patient rarely requires a complete work-up. Chronic angioedema may necessitate a detailed history, physical examination, and limited clinical or laboratory tests to exclude serious underlying illnesses. The H1 antihistamines are used for the treatment of both acute and chronic angioedema. An H2 antihistamine, a second H1 antihistamine, or rarely even a low dose of corticosteroid may be added to the regimen if H1 antihistamine alone fails to control chronic angioedema. Hereditary angioedema is an autosomal dominant disease that is caused by C1INH deficiency. In patients with this disorder, swelling of the lip, pharynx, and extremities may follow trauma to soft tissue. Other clinical manifestations include abdominal pain, nausea, vomiting, and suffocation because of laryngeal swelling. Diagnosis can be confirmed by the finding of low levels of C4 and C2 and the absence of nonfunction of C1INH. Androgens reverse the biochemical defects.

Angioedema↗

PubMed1983

[Hereditary complement defects].

The complement system is one of the most important and best analyzed biological amplification systems in humans. Hereditary deficiency states of one of the components may lead to various autoimmune disorders, recurrent bacterial infections or recurrent cutaneous edema in non-atopic subjects. This review makes an attempt to describe clinics and pathophysiology of the component deficiencies known to date. A procedure for laboratory evaluation of patients with suspected complement deficiency is described.

Autoimmune Diseases↗

PubMed1976

Diagnostic procedures in immunodermatology.

Most immunologic diseases are caused by the derailment of the humoral or cellular pathways of the immunologic defense system. This derailment results from numerous factors such as the inability of the patient to remove the pathogen; the consumption, defect, or deficiency in any component of these pathways, and the overproduction of any of the components. To diagnose these immunologic disorders one has to detect the pathogen and the reactions caused by it and to determine the cause of its nonclearance. The immunofluorescence techniques has been invaluable in detecting both the antigen that causes the disease and the reactions initiated by the antigen, such as the production of antibodies and the activation of the complement system. The immunoperoxidase technique has also been used for these purposes in certain instances. For detecting the circulating immune complexes which occur as intermediates in the chain of reactions initiated by the antigen, various physiochemical and biologic techniques have been used. However, none of these tests seems to be totally reliable for determining whether circulating immune complexes are present. The consumption of complement was detected by hemolytic estimations and radial immunodiffusion or rocket electrphoresis. These techniques were also useful in detecting the hereditary deficiencies in immunoglobulins and components of classical and alternative pathways of complement activation. Since these techniques cannot be used to estimate IgE, the radioallergosorbent test was used to measure such levels in the atopic patients. Cellular hypersensitivity was detected with skin tests together with methods which assess the ability of lymphocytes to produce mediators in response to antigen. Many of these mediator assays, however, are not suitable for this purpose. A satisfactory substitute appears to be to determine the factor in antigen-stimulated, lymphocyte culture supernatants which activates macrophages to take up radiolabeled colloidal gold or radiolabeled glucosamine. In contact allergic dermatitis, an increase in the IgD-bearing lymphocytes and granulocytes has also been correlated with cellular hypersensitivity. Lymphocytes and polymorphonuclear leukocytes coated with antibodies mainly directed against nuclear antigens of the basal layer cells of the noninvolved epidermis have invariably been encountered in psoriasis. The use of these findings for diagnostic purposes and for understanding the mechanisms of certain diseases is being explored.

Animals↗