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PubMed2000

B cell-mediated infection of stimulated and unstimulated autologous T lymphocytes with HIV-1: role of complement.

In vivo, human immunodeficiency virus type 1 (HIV-1) is opsonized with complement fragments and virus-specific antibodies (Ab). Thus, HIV is able to interact with complement receptor (CR) - and Fc receptor (FcR) - positive cells such as B cells, follicular dendritic cells or macrophages. In this study we demonstrate that the interaction between B cells and HIV has an impact on autologous primary T cell infection in vitro. We confirmed the presence of complement-fragments and virus-specific Ab on serum-treated HIV using a virus-capture assay. In experiments with CR2-specific Ab we showed that the virus/B cell interaction was mainly dependent on CR2. In infection experiments immobilisation of HIV on stimulated tonsil B cells greatly enhanced the infection of interleukin (IL)-2-activated autologous tonsil T cells. Surprisingly, enhancement of T cell infection by B cell-HIV complexes was observed even in the absence of mitogenic stimuli such as PMA and was independent of the addition of exogenous IL-2. Taken together, these results indicate that primary B cells are able to efficiently transmit opsonised HIV to autologous primary T cells and induce a massive enhancement of infection. These in vitro experiments mimic the in vivo situation in the lymphoid tissue and suggest an alternative mechanism for the infection of primary T cells.

B-Lymphocytes↗
PubMed1982

Lichen planus in two immunodeficient hosts.

The exact pathogenic mechanism involved in lichen planus (LP) remains obscure. Two patients who have severe immunodeficiency diseases and who developed LP during the course of their illness are reported here. Both patients had hypogammaglobulinemia and disturbed immune function prior to the development of LP. Although such an association could be coincidental, the development of LP may be related to the underlying immune disturbances. Association of LP with several other disorders of the immune system has been previously observed. Other evidence for the possible involvement of an immunopathogenic mechanism in LP includes (1) deposition of immunoglobulin within the colloid bodies and at the dermoepidermal junction, (2) predominantly T cell dermal infiltrate in LP lesions, and (3) existence of clinical and histologic similarities between graft-versus-host disease and LP.

Agammaglobulinemia↗
PubMed1983

Inherited disorders of complement.

Isolated complement component deficiencies are uncommon. Deficiencies of all eleven components and two inhibitors of the classical pathway have been described. Complete absence of the components of the alternative pathway has not been described. The consequences of a single defect in complement are often predictable from an understanding of the biologic activities associated with activation of the complement system. Deficiency of C1 esterase inhibitor gives rise to the disease, hereditary angioedema; deficiency of the early components of the classical pathway are associated with lupus erythematosus; C3 and C3 inactivator deficiencies with pyogenic infections; C5 dysfunction with Leiner's disease; deficiencies of the terminal components with recurrent Neisseria bacteremia; and C9 deficiency with normal health. The complement system and its associated biologic activities are reviewed. The present knowledge of the inherited complement deficiencies and associated diseases, with particular emphasis on the dermatologic manifestations, genetics, and diagnosis, is summarized.

Angioedema↗
PubMed1990

Patterns of complement activation in idiopathic membranoproliferative glomerulonephritis, types I, II, and III.

Complement profiles on 22 hypocomplementemic patients with membranoproliferative glomerulonephritis (MPGN) type I, on 11 with MPGN II, and on 16 with MPGN III, gave evidence that the nephritic factor of the amplification loop (NFa) is responsible for the hypocomplementemia in MPGN II and the nephritic factor of the terminal pathway (NFt) for the hypocomplementemia in MPGN III. In contrast, in MPGN I, there was evidence for three complement-activating modalities, NFa, NFt, and immune complexes. As a result, four different patterns of complement activation were seen. NFa, found in MPGN II, produces a complement profile characterized mainly by C3 depression. In addition, four of seven (57%) severely hypocomplementemic MPGN II patients (C3 less than 30 mg/dL) had slightly depressed levels of factor B, and one of seven (14%) of properdin, but in all the C5 concentration was normal. In contrast, all eight severely hypocomplementemic patients with MPGN II had depressed C5 and properdin levels, and six of eight (75%) depressed levels of C6, C7, and/or C9. Of eight MPGN III patients with moderate hypocomplementemia, 50% had depressed C5 and properdin levels and the remainder, depressed C3 only. This spectrum of profiles is most likely produced by varying concentrations of NFt. In MPGN I, nine of 23 (39%) had a profile indicating only classical pathway activation; seven of 23 (39%), a pattern compatible with NFt alone; four of 23 (9%), evidence for both classical pathway activation and NFt; and three of 23 (13%), a pattern compatible with NFa. The unique multifactorial origin of the hypocomplementemia in MPGN I, often giving evidence of classical pathway activation, together with previously reported differences in glomerular morphology and clinical features at onset, makes it distinct from MPGN III. Depressed C8 levels were found to some extent in all hypocomplementemic states. The levels were uncommonly depressed in patients with NFa, most markedly depressed with NFt, and moderately reduced with classical pathway activation. The cause is not known. Diagnostically, profiles showing classical pathway activation and low levels of C6, C7, and/or C9 are specific for MPGN I. Those showing only classical activation are likewise diagnostic of MPGN I if systemic lupus erythematosus (SLE) and chronic bacteremia are ruled out.

Complement Activation↗
PubMed1999

C1qB and clusterin mRNA increase in association with neurodegeneration in sporadic amyotrophic lateral sclerosis.

We analyzed postmortem tissues of sporadic amyotrophic lateral sclerosis (SALS) for mRNA levels of two inflammatory proteins, complement C1qB and clusterin (apoJ). By Northern blot hybridization, SALS was associated with increased mRNA for C1qB and clusterin in the motor cortex (Brodmann area A4), but not in superior temporal cortex (A17), relative to neurologically normal controls. By in situ hybridization, SALS spinal cords showed increased C1qB and clusterin mRNA in areas undergoing neurodegeneration. This evidence implicates inflammatory mechanisms during neurodegenerative processes in SALS.

Adolescent↗
PubMed1985

Acute glomerulonephritis in children. An evolutive morphologic and immunologic study of the glomerular inflammation.

This study deals with 80 children showing a clinically typical acute nephritic syndrome with proteinuria and/or hematuria, edema, and hypertension. Their ages ranged between 2 years 5 months and 16 years; 36 cases were female. In 73 cases a streptococcal infection was demonstrated; the remaining 7 cases did not show morphologic differences with the former. No previous renal disease nor familial history of nephropathies were elicited. In every case a renal biopsy was obtained in the first 60 days of clinical disease; in 46 cases a second renal biopsy was obtained sometime between 6 and 45 months since the beginning of the disease. In 3 cases the renal tissue was considered to be normal by light microscopy, immunofluorescence and electron microscopy in both the first and second biopsies. These 3 patients were not considered as cases of morphologic acute glomerulonephritis in spite of showing a typical clinical picture and they are not included in the evaluation of the glomerular inflammatory evolution. In all the remaining 77 cases C3 granular and segmentary intramembranous and mesangial dense deposits were found in the first biopsy. The second biopsy showed morphologic and immunologic normalization in 27% of the cases, slight lesions in 56% and an increase in severity in 17% of the cases.

Acute Disease↗
PubMed2003

Activation of the complement cascade by Bordetella pertussis.

Bordetella pertussis must survive the defenses of the human respiratory tract including the complement system. The BrkA (Bordetella resistance to killing) protein prevents killing by the antibody-dependent classical pathway. In this study, the ability of B. pertussis to activate the human complement cascade by other pathways was examined. B. pertussis was not killed in serum depleted of C2, however serum depleted for factor B killed B. pertussis as efficiently as intact serum, suggesting complement activation occurred exclusively by the classical pathway. B. pertussis was not killed by serum depleted of antibody, suggesting the bacteria fail to activate the antibody-independent branches of the classical pathway, including the mannose binding lectin pathway. Mutants lacking the terminal trisaccharide of lipopolysaccharide retained the complement-resistant phenotype, suggesting this structure does not influence activation of complement.

Bordetella pertussis↗
PubMed2000

Pathogenesis of heroin-associated glomerulonephritis. Correlation between the inflammatory activity and renal deposits of immunoglobulin and complement?

Renal specimens from 19 autopsies of persons known to be intravenous heroin-addicts and with severe lympho-monocytic glomerulonephritis were investigated to correlate the inflammatory activity and deposits of immunoglobulin and complement. In all sections, there were 10 or more LCA-positive cells/glomerulum, counted in 20 glomerula but only up to 3 LCA-positive cells in a control-group of 10 autopsied persons without drug addiction and any renal diseases. In some cases diffuse granular deposits of immunoglobulin were found together with deposits of Clq. Although these changes cannot be demonstrated in all cases, deposits of Clq point to an activation of the classical way of the complement binding system in heroin-associated glomerulonephritis. The underlying process, activation of the complement binding system by heroin/morphin itself and adulterants or by hepatitis B and C infection, which are frequent in heroin-addicts, is still unclear.

Adolescent↗
PubMed1983

Schistosoma mansoni: complement activation in human and rodent sera by living parasites of various developmental stages.

Living Schistosoma mansoni of various developmental stages were studied with respect to their ability to activate the complement system in sera of humans, mice and rats. Immunofluorescence assays demonstrated that binding of human C3 occurred on fresh schistosomula as well as on schistosomula prepared from mouse lymph-nodes or lungs and on adult schistosomes. However, rodent C3 was deposited only on fresh schistosomula. Deposition of human C3 on the worms' surface required activation of the complement system. The alternative pathway was shown to be involved in deposition of human C3 on schistosomes of all ages, whereas activation of the classical pathway was demonstrable only with fresh schistosomula. Immunoelectrophoretic studies demonstrated a dose-dependent cleavage of human C3 and conversion of factor B by living adult schistosomes. The results demonstrate that the ability of living schistosomes to activate complement in vitro is dependent not only on their development stage but also on the species of the serum.

Animals↗
PubMed1989

Identification of a trypanocidal factor against Trypanosoma equiperdum in normal human serum.

Normal human serum (HS) contains trypanolytic activity and agglutinins to Trypanosoma equiperdum, while such activities are not found in sera from a range of animals susceptible to infection. HS given to T. equiperdum-infected mice caused a rapid decrease in the number of circulating trypanosomes and protection from lethal infection. Trypanolytic activity of human serum was found to be associated, after DEAE chromatography and Sephadex G-200 gel filtration, with the fraction containing 19S antibodies. Immunofluorescence assays confirmed a binding of human IgM and C1q complement component onto the surface of T. equiperdum. Anti-T. equiperdum activity of HS was specifically directed to T. equiperdum surface components and not to some mouse serum components adsorbed on parasites during the growth in the host, because HS adsorbed in vivo in CD-1 mice retained full protective and agglutinating properties. Trypanocidal activity appears in human serum about the 7th month after birth and persists until late in life. On the contrary, human purified high-density lipoprotein had no significant in vitro or in vivo trypanocidal activity. In conclusion, strong natural anti-T. equiperdum activity in human serum was mainly mediated by natural antibodies of the IgM class. The presence of natural IgM active against T. equiperdum in HS could represent one of the natural mechanisms of resistance of refractory hosts against trypanosome infections. This phenomenon provides further evidence that host specificity of trypanosomes may be partly conditioned by the presence of natural antibodies.

Agglutination Tests↗
PubMed1985

Possible involvement of terminal complement complex in active Heymann nephritis.

We investigated whether the appearance of various complement components in renal deposits of immune complexes correlated with the development of proteinuria in rats with active Heymann nephritis. Sequential kidney biopsy specimens and serum samples were obtained from Lewis rats immunized with Fx1A in complete Freund's adjuvant. Circulating antibodies against purified auto-antigen renal tubular epithelial glycoprotein, as measured by ELISA, were found in the circulation together with a diffuse granular deposition of IgG1, IgG2a, and IgG2b in the glomeruli within 2 weeks after immunization. Biopsy specimens taken 4 weeks after immunization showed diffuse deposition of C4 and C3, which indicated that activation of complement by the classical pathway had occurred. The detection of the C5b-9 complex of complement in glomerular deposits coincided with the development of abnormal proteinuria indicating that the glomerular damage in this autoimmune disease may be caused by complement-mediated lesions in the glomerular capillary walls.

Animals↗
PubMed2003

High expression of complement components in omental adipose tissue in obese men.

OBJECTIVE: Accumulation of visceral fat is recognized as a predictor of obesity-related metabolic disturbances. Factors that are predominantly expressed in this depot could mediate the link between visceral obesity and associated diseases. RESEARCH METHODS AND PROCEDURES: Paired subcutaneous and omental adipose tissue biopsies were obtained from 10 obese men. Gene expression was analyzed by DNA microarrays in triplicate and by real-time polymerase chain reaction. Serum C3 and C4 were analyzed by radial immunodiffusion assays in 91 subjects representing a cross section of the general population. Body composition was measured by computerized tomography. RESULTS: Complement components C2, C3, C4, C7, and Factor B had higher expression in omental compared with subcutaneous adipose tissue ( approximately 2-, 4-, 17-, 10-, and 7-fold, respectively). In addition, adipsin, which belongs to the alternative pathway, and the classical pathway components C1QB, C1R, and C1S were expressed in both depots. Analysis of tissue distribution showed high expression of C2, C3, and C4 in omental adipose tissue, and only liver had higher expression of these genes. Serum C3 levels correlated with both visceral and subcutaneous adipose tissue in both men (r = 0.65 and p < 0.001 and r = 0.52 and p < 0.001, respectively) and women (r = 0.34 and p = 0.023 and r = 0.49 and p < 0.001, respectively), whereas C4 levels correlated with only visceral fat in men (r = 0.36, p = 0.015) and with both depots in women (visceral: r = 0.58, p < 0.001; and subcutaneous: r = 0.51, p < 0.001). DISCUSSION: Recent studies show that the metabolic syndrome is associated with chronically elevated levels of several immune markers, some of which may have metabolic effects. The high expression of complement genes in intra-abdominal adipose tissue might suggest that the complement system is involved in the development of visceral adiposity and/or contributes to the metabolic complications associated with increased visceral fat mass.

Adipose Tissue↗
PubMed2001

Complement binding is an early feature of necrotic and a rather late event during apoptotic cell death.

The phagocytosis of dying cells is an integral feature of apoptosis and necrosis. There are many receptors involved in recognition of dying cells, however, the molecular mechanisms of the scavenging process remain elusive. The activation by necrotic cells of complement is well established, however, the importance of complement in the scavenging process of apoptotic cells was just recently described. Here we report that the complement components C3 and C4 immediately bound to necrotic cells. The binding of complement was much higher for lymphocytes compared to granulocytes. In case of apoptotic cell death complement binding was a rather late event, which in lymphocytes was preceded by secondary necrosis. Taken together complement binding is an immediate early feature of necrosis and a rather late event during apoptotic cell death. We conclude that complement may serve as an opsonin for fragments of apoptotic cells that have escaped regular scavenging mechanisms.

Apoptosis↗
PubMed2001

Mannose-binding lectin gene: polymorphisms in Japanese patients with systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome.

Mannose-binding lectin (MBL) is a key element of the innate immunity, with a structure similar to complement C1q. Serum MBL levels are greatly affected by the polymorphisms of the MBL gene. In particular, codon 54 mutation of the MBL gene results in a significant reduction of serum MBL. To determine whether polymorphism of the MBL gene is associated with occurrence of systemic lupus erythematosus (SLE), rheumatoid arthritis and Sjögren's syndrome in the Japanese population, we analyzed the MBL gene polymophisms of these patients and controls, by polymerase chain reaction-restriction fragment length polymorphism methods. We found that patients studied had a significantly higher frequency of having homozygous codon 54 mutation compared to controls. In particular, patients with SLE or Sjögren's syndrome showed higher probabilities of being homozygous for this mutation. Among subjects with the same genotype, SLE patients tended to have higher serum MBL concentration than controls. Analysis of the promotor region suggested that SLE patients heterozygous for the codon 54 mutation have a higher probability of having a low producing haplotype for the gene without the codon 54 mutation. We conclude that persons homozygous for codon 54 mutation of the MBL gene may be prone to occurrence of autoimmune disorders including SLE, in the Japanese. MBL may have protective effects on occurrence and progression of SLE.

Arthritis, Rheumatoid↗
PubMed1989

C3 binds covalently to the C gamma 3 domain of IgG immune aggregates during complement activation by the alternative pathway.

Ovalbumin-antiovalbumin IgG immune aggregates were incubated with normal human serum in the presence of iodo[1-14C]acetamide, in conditions in which only the alternative pathway of complement was activated. The [14C]C3b-IgG covalent complexes formed were digested with pepsin, and analysed by SDS/polyacrylamide-gel electrophoresis and fluorography. Covalent complexes of [14C]C3-Fd and [14C]C3-pFc' were visualized, demonstrating that, during complement activation by the alternative pathway, C3 is covalently incorporated into the C gamma 3 domain of IgG, as well as into the Fd region. The C gamma 2 domain becomes protected from pepsin action by the bound C3b. All the covalent linkages between C3 and the IgG were sensitive to hydroxylamine. When [14C]C3-pFc' covalent complexes were treated with 1 M-NH2OH and loaded onto a Bio-Gel P-4 column, a radioactive peak of 3 kDa was obtained. The material released from [14C]C3-pFc' and [14C]C3-F(ab')2 complexes after treatment with 1 M-NH2OH was mixed and analysed in the Bio-Gel P-4 column. A similar radioactive peak of 3 kDa was obtained. When this peak, either from [14C]C3-pFc' alone or from the mixture of [14C]C3-F(ab')2 and [14C]C3-pFc', was fractionated by h.p.l.c., virtually the same radioactive peptide profile was obtained, indicating that very similar C3 peptides remained covalently bound to both regions (Fab and C gamma 3) of the antibody molecule. It is suggested that C3 bound to the C gamma 3 domain of IgG may interfere with the Fc-Fc interactions of immune aggregates and thus may be involved in several biological properties displayed by these complement-activating aggregates.

Antigen-Antibody Complex↗
PubMed1997

Inhibition of human complement by beta-glycyrrhetinic acid.

Licorice, the root extract of Glycyrrhiza glabra I., is used as a medicine for various diseases. Anti-inflammatory as well as anti-allergic activities have been attributed to one of its main constituents, glycyrrhizin. These activities are mainly ascribed to the action of the aglycone, beta-glycyrrhetinic acid. beta-Glycyrrhetinic acid has a steroid-like structure and is believed to have immunomodulatory properties. To determine whether interference with complement functions may contribute to the immunomodulatory activity of beta-glycyrrhetinic acid, its effects on the classical and alternative activation pathways of human complement were investigated. We found that beta-glycyrrhetinic acid is a potent inhibitor of the classical complement pathway (IC50 = 35 microM), whereas no inhibitory activity was observed towards the alternative pathway (IC50 > 2500 microM). The anticomplementary activity of beta-glycyrrhetinic acid was dependent on its conformation, since the alpha-form was not active. It was also established that naturally occurring steroids, e.g. hydrocortisone and cortisone, did not inhibit human complement activity under similar conditions. Detailed mechanistic studies revealed that beta-glycyrrhetinic acid acts at the level of complement component C2.

Administration, Topical↗