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PubMed1986

Major-histocompatibility-complex extended haplotypes in membranoproliferative glomerulonephritis.

Membranoproliferative glomerulonephritis is often associated with evidence of immune derangement, especially hypocomplementemia. We studied genetic markers for membranoproliferative glomerulonephritis within the major histocompatibility complex in 34 patients and their families and in 29 normal families. We examined the frequencies of extended haplotypes (combinations of alleles that tend to occur together) in patients and controls. The extended haplotype HLA-B8,DR3,SC01,GLO2(glyoxalase I 2) was observed in 9 of 68 disease-associated haplotypes (13 percent), but in only 3 of 205 controls (1 percent) (relative risk, 14.79; P less than 0.001). An extended haplotype similar except for a different glyoxalase allotype (B8,DR3,SC01,GLO1) did not occur with increased frequency, nor did any other extended haplotypes. Patients with the extended haplotype B8,DR3,SC01,GLO2 had a higher incidence of renal insufficiency than those without it (P less than 0.01). The data support the hypothesis that a specific extended haplotype of the major histocompatibility complex is associated with susceptibility to membranoproliferative glomerulonephritis, and that patients with glomerulonephritis who have this extended haplotype have a poorer prognosis for kidney survival than those without the haplotype.

Alleles↗
PubMed1975

On the mechanism of cytolysis by complement: evidence on insertion of C5b and C7 subunits of the C5b,6,7 complex into phospholipid bilayers of erythrocyte membranes.

The doughnut hypothesis of cytolysis by complement [Mayer, M. M. (1972) Proc. Nat. Acad. Sci. USA 69, 2954-2958] describes an annular structure made up of C5b-9 (complement factors C5b, C6, C7, C8, and C9) which becomes inserted in the lipid bilayer of the cell membrane, thus creating a hole. We now present initial explorations of this hypothesis. EAC1-6 and EAC1-7 (sheep erythrocytes carrying rabbit antibody and complement factors C1 through C6 or C1 through C7, respectively), prepared with either 125I-C3 or 125I-C5 were incubated with trypsin and the release of bound 125I was measured. In the case of 125I-C3, all of the radioactivity was released by trypsin from both intermediates. With 125I-C5, trypsin released all of the 125I from EAC1-6, but only 40-55% from EAC1-7. Possible reasons for resistance of the C5b subunit in EAC1-7 to tryptic digestion are discussed; in terms of the doughnut hypothesis it would be due to shielding by lipid molecules as a consequence of insertion into the lipid bilayer. In accord with this interpretation we have also found that C5b in EAC1-7, but not in EAC1-6, resists elution by 0.3 M NaC1. Similarly, we have found that 125I-C7 in EAC1-7 resists stripping by trypsin. Hence, we now propose the hypothesis that hydrophobic polypeptide chains from the C5b and the C7 subunits of C5b,6,7 complex become inserted in the phospholipid bilayer and that subsequent reactions with C8 and C9 open a channel across the membrane.

Animals↗
PubMed1998

Serine proteases in rodent hippocampus.

Brain serine proteases are implicated in developmental processes, synaptic plasticity, and in disorders including Alzheimer's disease. The spectrum of the major enzymes expressed in brain has not been established previously. We now present a systematic study of the serine proteases expressed in adult rat and mouse hippocampus. Using a combination of techniques including polymerase chain reaction amplification and Northern blotting we show that tissue-type plasminogen activator (t-PA) is the major species represented. Unexpectedly, the next most abundant species were RNK-Met-1, a lymphocyte protease not reported previously in brain, and two new family members, BSP1 (brain serine protease 1) and BSP2. We report full-length sequences of the two new proteases; homologies indicate that these are of tryptic specificity. Although BSP2 is expressed in several brain regions, BSP1 expression is strikingly restricted to hippocampus. Other enzymes represented, but at lower levels, included elastase IV, proteinase 3, complement C2, chymotrypsin B, chymotrypsin-like protein, and Hageman factor. Although thrombin and urokinase-type plasminogen activator were not detected in the primary screen, low level expression was confirmed using specific polymerase chain reaction primers. In contrast, and despite robust expression of t-PA, the usual t-PA substrate plasminogen was not expressed at detectable levels.

Amino Acid Sequence↗
PubMed1976

Lysis of RNA tumor viruses by human serum: direct antibody-independent triggering of the classical complement pathway.

In earlier studies we found that human serum, but not serum from multiple other species, inactivated and lysed oncornaviruses from a number of diverse sources in the apparent absence of antibody. A detailed analysis of the role of the human complement (C) system in mediating this lytic process indicates that human C1q interacts directly, in the absence of immunoglobulin, with oncornaviruses. Binding of C1 via C1q in this manner leads to activation of C1r, C1s, and thus of the classical C pathway. Integrity of the classical pathway is an absolute requirement for lysis although activation of the alternative pathway considerably amplifies the amount of lysis obtained, possibly through involvement of the C3b-dependent feedback mechanism. Activation of C is accompanied by deposition of C components on the viral surface and lysis on completion of the C reaction sequence. Thus in this system, the C1q subunit of C1 subserves a specific recognition function normally associated with antibody. This ability of human serum to inactivate oncornaviruses may represent a natural defense mechanism operative in vivo which deters expression of intact oncornaviruses in human malignancies.

Cell Survival↗
PubMed1981

Mechanism of action of the C4 nephritic factor. Deregulation of the classical pathway of C3 convertase.

Three mechanisms that regulate the formation and function of the classical pathway C3 convertase (C4b2a) have been elucidated: (a) an intrinsic decay of the enzyme that is temperature dependent; (b) an extrinsic decay mediated by the effect of the serum protein C4b binding protein (C4-bp); and (c) inactivation of C4b by the proteolytic action of C4b/C3b inactivator (C4b/C3bINA), which cleaves that alpha' chain of C4b to yield C4d (alpha 2) and C4c (alpha 3, alpha 4, beta, and gamma chains). A fourth mechanism described here is based on the observation that the IgG fraction of the serum of certain patients with glomerulonephritis contains a protein termed C4 nephritic factor (NFc), which prevents the intrinsic decay of C4b2a. This protein, which prolongs the half-life of surface-bound C4b2a from 7.5 min to greater than 5 h, increases the use of C3 and C5. It also inhibits the decay produced by C4-bp by preventing the dissociation of C2a from the C4b2a complex. Additionally, the C2b/C3bINA alone, or in the presence of C4-bp, fails to cleave the alpha' chain of C4b in the surface-bound stabilized C4b2a complex. This protective property of NFc requires the presence of C2a, because C4b was not protected unless it was bound to C2a. Thus in the presence of NFc, the three natural controls of the function of the classical pathway convertase, intrinsic decay, extrinsic decay, and proteolytic cleavage, are bypassed.

Animals↗
PubMed1996

Diverse effects of tumor necrosis factor-alpha on three subclones from human myelomonocytic leukemia cell line ME-1 exhibiting different differentiation stages.

The effects of tumor necrosis factor-alpha (TNF-alpha) were examined in three subclone cells from human myelomonocytic leukemia cell line ME-1. These three subclone cells exhibit different differentiation stages of the myelomonocytic lineage. TNF-alpha exerted a growth-suppressive effect on the least mature subclone cells, ME-F2 cells. On the other hand, TNF-alpha induced the most mature ME-F1 cells and intermediate ME-F3 cells to differentiate along the monocytic pathway. TNF-alpha also enhanced interferon-gamma (IFN-gamma)-induced complement C2 production by ME-F1 and ME-F3 cells but did not affect production by differentiated ME-F1 and ME-F3 cells. These results suggest that the diversity of the effects of TNF on subclone cells from ME-1 depends on the stage of cell differentiation.

Cell Differentiation↗
PubMedDate not supplied

The complement system in host defense and inflammation.

In this discussion I have reviewed the major role of complement in host defense and inflammation. In addition, I have discussed dificiency states. Although these are rare, their clinical signs and symptoms can be predicted, at least in part, on the basis of our current understanding of the biological activities of complement and the various pathways of complement activation. This is not to say that complement plays no role in a wide variety of other illnesses. However, when complement plays a role in an illness, often this is not because it is functioning in an aberrant fashion. The usual situation is that complement is being activated and is serving its normal function in causing inflammation and damage to tissues under abnormal circumstances. Thus, for example, circulating antigen complexes may be deposited in the kidney, activate complement, and mediate tissue inflammation. In this case, complement is functioning normally but is being activated under abnormal circumstances. The same type of analysis can be made for many diseases of many different organ systems. At present, we have no drugs that are effective in humans in controlling the activation of complement and complement-mediated inflammation. We have not yet even established whether local variations in the activity of complement may affect the course of a clinical infection, but there is certainly strongly suggestive evidence to support this idea. It should be clear that under certain circumstances complement may well be a major factor in controlling the course of an infection. The near future should bring a vast expansion in our understanding of how complement contributes to specific clinical illnesses and to the defense of the host against specific microorganisms.

Angioedema↗
PubMedDate not supplied

The role of complement in the host's defense against Streptococcus pneumoniae.

In recent years there has been a growing realization that the complement systems plays an important role in the host's defense against infection and that it plays an especially critical role in both natural and acquired immunity to Streptococcus pneumoniae. The terminal components of the complement system, C3-C9, are responsible for most protective functions of the complement system. However, in order to subserve their protective functions, C3-C9 must first be activated. In vitro studies have shown that pneumococci are able to activate the terminal components of complement, C3-C9, by at least two different mechanisms, the classical and alternative pathways. Regardless of the pathway of their activation, C3-C9 produce anaphylatoxic, chemotactic, and opsonic activities in serum, each of which has the potential to play an important protective role in pneumococcal infections. Studies with experimental animals and the experience gained from study of complement deficiencies in humans have each fulfilled the promise of the in vitro studies by demonstrating that the complement system plays a biologically significant role in vivo in the host's defense against S. pneumoniae.

Animals↗
PubMed1979

Complement-enhanced immunity to infection with Neisseria gonorrhoeae in mice.

Subcutaneous chambers were implanted in mice, injected with Neisseria gonorrhoeae, and supplemented with complement as a model for studying the immunogenicity and strain diversity of N. gonorrhoeae. Immunotypic resistance to N. gonorrhoeae in immunized mice was significantly (P less than 0.01) increased by injection of exogenous guinea pig complement into the host before challenge with gonococci. By using this model to test gonococcal isolates from various geographical areas, two highly immunogenic but immunotypically different gonococcal strains were identified. The piliated cells of these strains induced both complement-enhanced immunity and a degree of exogenous complement-independent immunity. The immunity in mice not treated with complement developed more slowly, was less effective, and waned earlier than that which was complement-dependent. Pretreatment with complement, although highly effective in preventing infection in immunized mice, was much less beneficial in terminating already established infections, even though bactericidal antibodies were present at the time of complement treatment. The mouse chamber model in which both complement-mediated and complement-independent mechanisms of protection can be evaluated may provide an additional tool for elucidating the immunology of gonococcal or other microbial infections.

Animals↗
PubMed1980

Identification of the activator system for antibody to Toxoplasma as the classical complement pathway.

In view of the many recent advances in our understanding of the composition and function of the complement system, it was decided to apply this newer knowledge to an investigation of the heat-labile activator required for the action of antibody to Toxoplasma gondii in the neutralization and dye tests. With use of antibody-coated toxoplasma trophozoites in a diluent of 0.2% gelatin in 0.85% NaCl and alkaline methylene blue as indicator, various component-deficient sera were added to activate the antibody on the protozoan membranes. It was determined that the classical complement system is required for antibody activity and that the properdin system plays no role in the reaction. Human sera genetically deficient in C5, C6, C7, and C8 were shown to be inactive as activators of antibody to Toxoplasma. The addition of specific missing components immediately restored full activity to the deficient sera.

Animals↗