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PubMed2004

Complement activation regulates the capacity of proximal tubular epithelial cell to stimulate alloreactive T cell response.

Tissue expression of C3 is an unexpected regulator of the alloimmune response in mouse kidney transplantation. It is unclear, however, whether a direct or an indirect action of complement on the host immune response is involved. Also unknown is which of the complement effector products, cleaved C3, cleaved C5, or C5b-9, is responsible. Proximal tubular epithelial cells (PTEC) not only constitute a major target of the alloimmune response but also produce substantial amounts of C3. This study investigated the property of mouse PTEC to stimulate alloreactive T cells in a complement-dependent manner. The proliferative and cytokine responses of primed alloreactive T cells were measured after exposure to donor-specific PTEC that had been pretreated with normal mouse serum, heat-inactivated mouse serum, or complement- deficient (C3, C5, or C6) mouse sera to differentially deposit complement components. PTEC were able to stimulate alloreactive T cells in an antigen-specific manner. Complement activation leading to the deposition of cleaved C3 on PTEC enhanced the alloreactive T cell response. This complement-mediated stimulation of the T cell response was dependent on C3 but not on C5 or C6. The primary influence of tissue-bound complement was on CD4(+) T cells. Moreover, the effect of complement on alloreactive T cells was B7 dependent, shown by inhibition studies with CTLA4-Ig. These results suggest that donor epithelium-bound C3 can upregulate the alloimmune response. It is postulated that surface-bound C3 interacts with complement receptors on alloreactive T cells or on antigen presenting cells to increase allo-immune stimulation.

Animals↗
PubMedDate not supplied

A rat model of pregnancy-induced sensitization to transplants.

Previous pregnancy is a known risk factor for alloantibody production and graft rejection in clinical transplantation. However, in previous rat models, immune responses to RT1.A antigens induced by allogeneic pregnancy resulted in prolonged survival of subsequent allografts. This study was designed to investigate the effects of a previous pregnancy on alloantibody response, complement activation, and allograft survival in a highly immunogenic rat strain combination. C6-sufficient and -deficient female PVG.1U (RT1.A(u)B(u)) rats were mated with allogeneic PVG.R8 (RT1.A(a)B(u)) males or control isogeneic PVG.1U (RT1.A(u)B(u)) males. Three weeks after parturition, experimental and control females received cardiac allografts from female PVG.R8 donors. A low dose of cyclosporine (CsA, 5 mg/kg on alternate days) was used for immunosuppression after transplantation. Allogeneic, but not control isogeneic, pregnancy elicited a weak, transient IgG alloantibody response that declined before transplantation. Experimental female recipients produced a rapid, vigorous IgM and IgG alloantibody response to the transplant despite CsA treatment. C6-sufficient recipients rejected their transplants at an accelerated rate (5 days, n = 6) compared with control animals (7 days, n = 5). In contrast, allografts to C6-deficient recipients functioned until sacrifice at 90 days in both the experimental group (n = 7) and control group (n = 4). Most experimental C6-deficient recipients continued to produce strong IgG alloantibodies for 90 days. Complement activation resulting from the alloantibody response was evidenced by the diffuse deposition of C3d on the vascular endothelium of the grafts. In summary, previous pregnancy leads to memory alloantibody responses that accelerate allograft rejection even with immunosuppression. Membrane attack complex is required for accelerated rejection induced by previous pregnancy.

Animals↗
PubMed1984

Macrophages release arachidonic acid, prostaglandin E2, and thromboxane in response to late complement components.

Rat peritoneal macrophages released arachidonic acid, prostaglandin E2, and thromboxane B2 when treated with normal rabbit or C6-deficient rabbit complement in vitro. Normal rabbit complement, however, was more efficient, which indicates that late complement components, in addition to the known effects of C3a and C3b, were responsible for an enhanced arachidonic acid turnover. Indeed, in the absence of the C3 cleavage products, the purified late complement components C5b6, C7, C8, and C9 stimulated the arachidonic acid, as well as the prostaglandin E2 and thromboxane B2 release. Incubation of C5b6, C7, C8, and C9 for 1 hr at 37 degrees C before addition to the macrophages abolished the stimulatory activity, being in complete agreement with the fact that a fluid phase-formed complex of C5-9 loses its membrane-binding capacity. Although the mechanism by which C5b-9-membrane interaction affects the arachidonic acid metabolism remains unclear, the data describe a new function of the late complement components.

Animals↗
PubMed1978

Activation of complement by radiographic contrast media: generation of chemotactic and anaphylatoxin activities.

Iodinated radiographic contrast media such as methylglucamine diatrizoate and sodium ioglycamate activate serum complement in vitro. This was shown by a dose-, time-, and temperature-dependent decrease of total hemolytic complement activity in normal human serum, consumption of C4 and C6 activity, conversion of C3 to C3b, and generation of C5-derived chemotactic and smooth muscle contracting activity. Complement activation was achieved even in sera depleted of immunoglobulin and properdin, which may indicate that contrast media induce complement activation by mechanisms different from the classical or alternative pathway.

Anaphylatoxins↗
PubMed1976

Absence of the sixth component of complement in a patient with repeated episodes of meningococcal meningitis.

A previously healthy 6-year-old boy who presented with meningococcal meningitis responded favorably to ampicillin, but suffered two and possibly three repeat attacks in the ensuing month. No abnormality of the otolarynx, skin, or neuroskeleton was found. The infecting strain, Neisseria meningitidis, Group Y, Type IV, was sensitive to the therapeutic agents used, and antibiotic levels were adequate. Serum bactericidal antibody titers against autologous meningococci were high. Serum complement hemolytic bactericidal activities, however, were entirely lacking, and this was attributable to a complete deficiency of C6. Measurements of the remaining complement components, C-dependent chemotaxis and opsonization, neutrophil function, specific immunity, and the coagulation system, were normal. The parents had half-normal C6 levels. Recurrence of meningitis in this patient supports the concept that complement plays a role in resistance to certain microorganisms and emphasizes the need for complete evaluation of the complement system in individuals with unexplained repeated infections.

Child↗
PubMed1979

Familial herpes simplex infection associated with activation of the complement system.

A patient with severe recurrent herpes infection was evaluated for immunologic analysis including a profile of complement components. The peripheral blood lymphocytes from the patient responded by proliferation to herpes simplex antigen but failed to produce leukocyte migration inhibition factor. Herpes simplex antibody titers increased during active infection. Total hemolytic complement (TCH50), the third (C3), fifth (C5), sixth (C6) and seventh (C7) components of complement, and factor B were dramatically reduced; the first (C1), second (C2) and fourth (C4) components of complement were within normal limits. In family members with a history of recurrent herpes simplex, one or more of the later complement components (C5, C6 or C7) was reduced. This study demonstrates the activation of complement in these serums via the alternative pathway.

Adult↗
PubMed1979

Delayed rejection of cardiac xenografts in C6-deficient rabbits.

Puppy hearts were engrafted to C6-deficient rabbits, and also to complement-sufficient animals in order to determine the influence of the sixth component of complement on xenograft rejection. Delayed rejection was observed in the puppy hearts engrafted to the C6-deficient animals indicating that complement sufficiency of C6 is required for hyperacute xenograft rejection.

Animals↗
PubMed1997

The role of CD11b/CD18 mediated neutrophil adhesion in complement deficient xenograft recipients.

Hyperacute rejection (HAR) of discordant xenografts is dependent on local complement activation. The formation of a functional complex of the complement components C5b-9 (membrane attack complex, MAC) causes endothelial injury and activation leading to coagulation and inflammation. In PVG rats which selectively lack the C6 component of complement, the MAC complex is not formed, whereas early split products of the complement cascade are produced normally. We reported previously that HAR is averted in C6 deficient xenograft recipients, and that subsequent accelerated acute rejection (AAR) can be delayed by inhibition of CD11b/CD18 (Mac-1) dependent neutrophil adhesion using leumedin, a member of a novel class of anti-inflammatory agents. Here we report the in vivo effects of a dose-response study using 2 new members of another class of Mac-1 directed agents designated nactins. Discordant cardiac xenografts from Hartley guinea pigs were heterotopically grafted into PVG(C6-) and PVG(C6+) rats. Experimental animals were divided into 3 groups receiving leumedin (group 1) or nactin (groups 2 and 3). Control animals received intravenous saline solution only. All C6(+) rats rejected their grafts hyperacutely within 10 to 15 min, irrespective of mode or dosage of treatment. C6 deficient controls rejected grafts within 17.7 +/- 3.5 h (n = 10). Treatment with leumedin/nactin prolonged graft survival up to 61.0 +/- 4.7 h (n = 4-6), with dose dependent differences in effectiveness among the 3 compounds tested. Histology showed that treatment was associated with less edema, hemorrhage, and neutrophil infiltrate at 2, 6, and 12 h. The marked decrease in hemorrhage seen in nactin-treated animals may reflect an interaction of Mac-1 with blood coagulation factors. Our data confirm that the neutrophil adhesion pathway is involved in AAR, especially when complement mediated injury due to MAC is restricted.

Acute Disease↗
PubMed1977

Haemolytic assays in agarose plates for components of the classical complement pathway: interference by the alternative pathway.

It has been observed that when serum C6 is measured by the haemolytic radial diffusion technique a heat labile factor limits the size of the haemolytic rings. This reduction is haemolysis has been shown to be due to alternative pathway activation of C6 in the agarose plate; and that the heat labile factor is Factor B of the alternative pathway. This phenomenon is of practical importance when assaying for C6; however, it does not explain the observations of a C6 inactivator reported by Nelson & Biro (1968).

Antigen-Antibody Complex↗
PubMed1973

A new complement-mediated cytolytic mechanism--the C1-bypass activation pathway.

A new cytolytic pathway is described whereby cells sensitized with cytotoxic antibody can be specifically lysed in the complete absence of intact, classical complement pathway function. Evaluation of this model with sera deficient in the 4th (C4), 2nd (C2), and 6th (C6) components of complement has revealed that this new lytic mechanism, termed the C1-bypass activation pathway, is initiated by the antibody-mediated activation of C1. Utilizing components of the previously described alternate complement pathway, this pathway bypasses C4 and C2 to activate the third to ninth components of complement (C3-9) with induction of membrane damage.

Animals↗
PubMed1990

Role of the terminal complement pathway in accelerated autologous anti-glomerular basement membrane nephritis.

The terminal complement pathway (C5b to C9) has been demonstrated to have an important role in the mediation of glomerular immune injury in various models of experimental glomerulonephritis. In the present studies, the role of the terminal complement pathway in the accelerated autologous phase of anti-glomerular basement membrane (GBM) nephritis in the rabbit was investigated. Normocomplementemic rabbits and rabbits deficient in C6 (C6D) who are therefore unable to form the terminal complement pathway were immunized with sheep immunoglobulin G (IgG) before being injected with a subnephrotoxic dose of the gamma 2 fraction of sheep anti-rabbit GBM. C6D animals had a delay in the onset of the glomerular injury, as manifested by proteinuria. At 72 hours, controls had a greater degree of proteinuria (15.2 +/- 8.8 mg protein/mg creatinine vs. 2.6 +/- 2.1, P = 0.197), but at 120 hours there were no differences in proteinuria between C6D and control animals (11.1 +/- 3.6 mg protein/mg creatinine vs. 12.2 +/- 6.2, P = 0.89). Light microscopy demonstrated more severe glomerular injury in C6D animals with marked cellular proliferation and large areas of glomerular necrosis. Interestingly, C6D animals had significantly higher levels of sheep IgG remaining in their glomeruli at 120 hours (0.95 +/- 0.12 micrograms sheep IgG/1 x 10(4) glomeruli, N = 11, vs. 0.57 +/- 0.07, N = 11, P = 0.014) and 72 hours (1.22 +/- 0.25 micrograms, N = 3, vs. 0.60 +/- 0.15, N = 3, P = 0.104) compared with 24 hours when there was no difference (1.25 +/- 0.22 micrograms, N = 7, vs. 1.08 +/- 0.14, N = 7, P = 0.53). C6D rabbits had a greater rise in serum creatinine at 120 hours (2.3 +/- 0.5 mg/dl vs. 1.3 +/- 6.4, P = 0.132). We conclude that in C6D animals, the persistence of glomerular immune deposits is responsible for more severe renal injury and renal failure.

Animals↗
PubMed2004

Functional insights from the structure of the multifunctional C345C domain of C5 of complement.

The complement protein C5 initiates assembly of the membrane attack complex. This remarkable process results in lysis of target cells and is fundamental to mammalian defense against infection. The 150-amino acid residue domain at the C terminus of C5 (C5-C345C) is pivotal to C5 function. It interacts with enzymes that convert C5 to C5b, the first step in the assembly of the membrane attack complex; it also binds to the membrane attack complex components C6 and C7 with high affinity. Here a recombinant version of this C5-C345C domain is shown to adopt the oligosaccharide/oligonucleotide binding fold, with two helices packed against a five-stranded beta-barrel. The structure is compared with those from the netrin-like module family that have a similar fold. Residues critical to the interaction with C5-convertase cluster on a mobile, hydrophobic inter-strand loop that protrudes from the open face of the beta-barrel. The opposite, helix-dominated face of C5-C345C carries a pair of exposed hydrophobic side chains adjacent to a striking negatively charged patch, consistent with affinity for positively charged factor I modules in C6 and C7. Modeling of homologous domains from complement proteins C3 and C4, which do not participate in membrane attack complex assembly, suggests that this provisionally identified C6/C7-interacting face is indeed specific to C5.

Amino Acid Sequence↗
PubMed2005

Terminal complement components mediate release of von Willebrand factor and adhesion of platelets in arteries of allografts.

BACKGROUND: Both humoral and cellular immune responses can cause arterial injury in organ transplants, but the manifestations of these different inflammatory mechanisms have not been dissected fully. The present study was designed to define the effects of the terminal complement components on arterial injury in vivo. METHODS: The authors have developed congenic rat strains with a C6 deficiency. The absence of C6 terminates the cascade of complement after C5 cleavage and prevents the assembly of the membrane attack complex. Hearts were transplanted from PVG.1A (RT1) rats to major histocompatibility complex-incompatible C6-deficient (C6-) or C6-sufficient (C6+) PVG.1U (RT1) rats. RESULTS: PVG.1A (C6-) cardiac grafts were rejected acutely (6-7 days) by untreated PVG.1U (C6+) recipients but survived significantly longer in PVG.1U (C6-) recipients (8 to >30 days). Arteries of cardiac allografts in C6+ recipients demonstrated extensive endothelial injury evidenced by release of von Willebrand factor (vWF) and accompanied by platelet aggregation. In contrast, vWF was retained in Weibel-Palade storage granules of arterial endothelial cells in cardiac allografts that were rejected by C6- recipients. In the absence of C6, intimal alterations were limited to lifting of endothelial cells from supporting stroma by infiltrating mononuclear cells, duplicating the clinical lesion described as endotheliitis or intimal arteritis. Delaying graft rejection with a short course of cyclosporine did not decrease vWF release and platelet aggregation in PVG.1U (C6+) recipients. CONCLUSIONS: Mononuclear cell infiltration of the arterial intima occurs in the absence of C6, but C6 deficiency limits the release of vWF from arterial endothelial cells.

Animals↗
PubMed1989

Hereditary factors in Takayasu disease. III. Polymorphism of human complements.

Genetic polymorphisms in C2, C4, C6, C7 and BF alleles of human complement were studied in 80 Japanese patients with Takayasu disease, and compared with those of 433 normal Japanese. Statistically significant high frequencies of C4A2 (chi 2: 27.2; p less than 0.01) and C4BQ0 allotype (chi 2: 8.7; p less than 0.01) were found in patients with Takayasu disease. Furthermore, all patients carrying C4A2 were found to be associated with C4BQ0. In addition, patients with HLA Bw52 were strongly associated with C4A2BQ0. In 5 patients homozygous C4BQ0 was found. These data suggest that some genetic factor(s) may contribute to the pathophysiological condition of Takayasu disease, which is strongly associated with the complotype of HLA Bw52-C4A2BQ0.

Adult↗
PubMed1977

C6: synthesis by the liver in vivo.

The allotype of the sixth component of complement was determined in a patient before and after liver transplantation. The C6 phenotype changed from A before transplantation to B (the donor phenotype) within 10 days of the transplant and remained wholly of the donor phenotype at 17 wk. This demonstrates that the liver is the exclusive or predominant site of C6 synthesis in vivo in man.

Blood Transfusion↗
PubMed1976

Immunoglobulins and complement in pleural effusions associated with bronchogenic carcinoma.

Levels of IgG, IgA, IgM, the total haemolytic complement (CH50), and the individual components C1q, C3, C4, C6, and C7 were measured in 29 pleural effusions. Of these, 18 were associated with carcinoma of the bronchus and 11 were non-malignant effusions including empyemas. The level of IgG was significantly lower in the malignant group when compared with non-malignant effusions. The usefulness of measurements of IgG with respect to malignant effusions associated with carcinoma of the bronchus requires an expanded study to show whether it has any real diagnostic value. There were no significant differences in other immunoglobulins, the CH50, and individual complement components between the two groups. The identification of total haemolytic activity in the majority of effusions in both groups indicates that all nine components of the classical pathway of complement, including macromolecules such as C1, can be present in pleural fluids.

Carcinoma, Bronchogenic↗
PubMed1990

Membrane attack complex of complement in Henoch-Schönlein purpura skin and nephritis.

The present study using direct immunofluorescence with monoclonal antibodies to C5b-9 complex-related antigens was undertaken to determine whether complement activation in Henoch-Schönlein purpura (HSP) causes assembly of the membrane attack complex of complement (MAC) in skin and nephritis lesions. The deposition of C5, C6, C7, C8, C9, and C5b-9 neoantigens was noted in the vascular walls of papillary dermis and/or subpapillary dermal plexus of the vessels in 11 out of 15 patients with HSP. Their presence in vessel walls indicates complement activation which leads to terminal complement activation. There were small deposits of S protein at the same sites in three of the 11 skin specimens. Thus, the majority of C5b-9 demonstrated in HSP skin was the cytolytically active C5b-9 complex, MAC. Granular deposits of C5b-9 related antigens without S protein were also found in the capillary walls and mesangium of the glomeruli of two out of four specimens from patients with HSP nephritis; in the other two S protein was colocalized with the deposition of C5b-9. The results of the present study indicate that complement activation leading to generation of MAC may possibly be involved in the pathogenesis of vascular injury in a significantly large number of skin lesions and of HSP nephritis.

Antibodies, Monoclonal↗