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PubMed1990

A BF subtype "Fb1" is a marker gene of some Mongoloid populations.

A factor B subtype, BF*Fb1, was first detected in Japanese by using isoelectric focusing or agarose gel electrophoresis in Tris/glycine/Veronal buffer. Our previous studies suggested that BF*Fb1 may be characteristic of some of Mongoloid populations. To investigate further distribution of BF*Fb1, samples randomly collected from Japanese in Yonaguni island of Japan and Cambodian were tested. BF*Fb1 was not observed in a Cambodian population whereas in a Japanese population of Yonaguni island, BF*Fb1 occurred at a frequency five times as high as those in main islands of Japan. In paternity cases, a Korean family with three offsprings was shown to transmit BF*Fb1 from the accused man to one of the offsprings. These data strongly indicate that BF*Fb1 is a marker gene for some of Mongoloid populations.

Alleles↗
PubMed1984

Structure and function of the anaphylatoxins.

Chemical and physical characterization of the anaphylatoxin molecules have provided a reasonably clear description of the architecture of these bioactive proteins. The primary structures of C3a, C4a, and C5a from man and from a number of animal species have been elucidated, and it is apparent that the three anaphylatoxins are genetically related. The anaphylatoxin protein chains very in length from 74 to 78 residues and no fewer than 30% of the residues are homologous when comparing C3a, C4a, and C5a within or between species. Synthetic peptide studies have been instrumental in identifying molecular features essential for the function of anaphylatoxins. Information gleaned from the structure-function studies with synthetic analogue peptides of the anaphylatoxins define putative "active sites" in these effector molecules. Linear sequences at the carboxy-terminus of C3a and C4a fulfill all of the criteria of an "active site," in that synthetic peptides of an identical sequence can mimic the biologic actions of the natural factors. In the case of human C3a, a crystallographic analysis has been performed and a three-dimensional structure was elucidated at the 3.2 A level. The crystalline structure of C3a provides valuable new information regarding the alpha helical regions and identifies the arrangement of intra-chain disulfide linkages. Taken together, the structural data now accumulated for anaphylatoxins permit molecular modelling of these proteins, designates favored conformational arrangements of the native structures, and specifically localizes the effector sites. Furthermore, elements at the essential active site have been defined with such precision that models are proposed detailing the exact nature of ligand interactions between anaphylatoxins and specific cellular receptors. Biologic characterization of the anaphylatoxins continues at a rapid pace and each advance provides a clearer view of the role of these humoral mediators in host defense. A variety of responses to anaphylatoxins are known to occur at the cellular level and are mediated in a hormone-like fashion. Diversity of action for these factors at the tissue level is readily explained by the numerous cell types stimulated by the anaphylatoxins. Cellular responses to the anaphylatoxins are perhaps the most easily defined and studied; however, tissue and systemic effects more accurately reflect the physiologic role of anaphylatoxins. Considerable progress has been made in understanding the mechanisms whereby anaphylatoxins mediate two major tissue effects, namely enhancement of vascular permeability and induction of smooth muscle contraction.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1983

Synthesis of complement by macrophages and modulation of their functions through complement activation.

During the last decade considerable progress has been made to characterize intimate functional links between macrophages, a major cellular component of immunoinflammatory responses, and the complement system representing the major humoral mediator of inflammation. Macrophages of various species and tissue sites have been shown to synthesize and release most of the complement components providing these cells with their own "pericellular" complement system. Circumstantial evidence for the assembly of both classical and alternative pathway convertases has been adduced. An intricate network of feedback loops involving endogenous and extrinsic factors operates to adjust complement production to acute requirements, for example augmenting production in the face of accelerated turnover at sites of inflammation, and returning it to baseline levels once the inflammatory stimulus has subsided, in order to maintain a fine-tuned balance. The molecular mechanisms underlying regulation of complement synthesis by macrophages are beginning to be elucidated by use of gene technology. On the other hand, complement activation products exert a number of effects on macrophages via specific surface receptors causing internalization of offending agents, microbes, and immune complexes, promotion of intracellular killing, controlling migration behavior, inducing release of potent biologic substances such as lysosomal enzymes, arachidonic acid metabolites, and interleukin 1. In these interactions, two important humoral mediator systems of inflammation, the complement system and the arachidonic acid cascade, are functionally linked at the level of the macrophage. Stimulation of the release of immunomodulating compounds from macrophages invoke a role for complement in immune regulation. This multifaceted interplay is of particular importance considering the mobility of macrophages that allows them to gain almost unrestricted access to sites of ongoing immunoinflammatory responses. The time seems to have come to abandon the petrified thinking in socalled systems as, for instance, humoral versus cellular, specific versus unspecific, and to proceed to interlocking functions guided by physiology proper.

Anaphylatoxins↗
PubMed1993

Multifactorial study of inflammatory myopathies. Report of 29 cases.

We made a comparative clinical, immunopathological and therapeutic evaluation in 17 patients with polymyositis (PM) and 12 patients with dermatomyositis (DM), followed up at our Neuromuscular Center. DM can be distinguished by its clinical appearance and pathological changes. Current evidence suggests that it results from vasculopathy. For studying these inflammatory myopathies we used multifactorial diagnostic criteria, evaluating the therapeutic response by means of a composite clinical and functional score in a longitudinal study. In muscle biopsy specimens we characterized with monoclonal antibodies T lymphocyte subpopulations (CD4, CD8), macrophages, IgG, IgM, C1q, C3, C4 complement fractions, MHC-I, MHC-II. In PM the cell-mediated immunity was more pronounced and in some cases both MHC-I and MHC-II molecules were found on the surface or within muscle fibers. Our patients were treated with steroids; in resistant cases azathioprine, cyclophosphamide, plasmapheresis, high-dose intravenous immunoglobulins (ivIgG) and total body irradiation were added to the therapeutic schedule.

Adolescent↗
PubMed1989

C4A gene deletion and HLA associations in black Americans with systemic lupus erythematosus.

In North America and European Caucasoids with systemic lupus erythematosus (SLE) there is an increased frequency of a C4A, CYP21A gene deletion, largely associated with the HLA-B8,DR3,C4A*QO extended haplotype. There have been no consistent HLA associations reported for SLE in blacks, although an increased frequency of serologically determined C4A null alleles has been reported in two studies. We studied 79 black American SLE patients and 68 black controls by restriction fragment length polymorphism analysis to determine if a C4A gene deletion was a genetic risk factor for SLE. Moreover, the nature of the deletion and any HLA phenotypic associations were sought. Nineteen of 79 (24%) patients compared to 5 of 68 (7.4%) controls had a phenotypic C4A,CYP21A gene deletion (P = .005; RR = 4). A homozygous deletion in four patients gave a genotypic frequency of 23/158 (14.5%) SLE patients vs 5/136 (3.7%) controls (P = .001; RR = 4.5). The deletion was associated with HLA-DR2 (P = .03) and HLA-DR3 (P = .03). Moreover, all subjects with the deletion had HLA-DR2 or DR3 (P = 7.7 x 10(-6). HLA-B44 was also associated with the deletion (P = .02), and eight of the nine HLA-B44 positives also carried HLA-DR2. HLA-B8 approached significance (P = .08) and was always accompanied by HLA-DR3. Finally, this black population demonstrated a unique C4B gene size polymorphism with 80% C4B "short" as compared to the 40% C4B "short" frequency reported in whites. We conclude that a large C4A,CYP21A gene deletion, particularly associated with the HLA-B44, -DR2, and -DR3 alleles, is the strongest genetic risk factor thus far identified for SLE susceptibility in black Americans. Furthermore, the unique preponderance of the C4B "short" gene form may be a factor in the actual formation of the deletion.

Black People↗
PubMed1989

Complement activation and neutrophil dysfunction in burned patients with sepsis--a study of two cases.

The changes in complement components and neutrophil functions were investigated in two cases of flame burn patients who died of multiple organ failure following septic shock. In the period of bacteremia, complement activation was observed in the plasma of both patients, using an immunoblotting method demonstrating C3a-related antigens. Coincidently, reduced neutrophil function and a decrease in the superoxide and leukotriene producing capacity, were also observed. An in vitro study showed that the capacity to produce superoxide and leukotriene became reduced in normal neutrophils after exposure to complement activated serum. These observations suggested that complement activation, probably brought about by massive bacterial infection, induced the impairment of neutrophil functions and resulted in a further breakdown of the host defence system, thereby leading to sepsis.

Adult↗
PubMed1991

Plasma protein and apolipoprotein synthesis by human yolk sac carcinoma cells in vitro.

Three human yolk sac carcinoma cell lines were characterized for the expression of several markers. Each of the cell lines expressed alpha-fetoprotein, without detectable levels of chorionic gonadotropin, and the level of alpha-fetoprotein expression increased dramatically when the cultures were held without passage for extended periods. The secretion of a number of plasma proteins was documented by metabolic labeling, immunoprecipitation, and gel analysis. The major plasma proteins detected were alpha-1-antitrypsin, alpha-fetoprotein, transthyretin, beta-2 microglobulin, and plasminogen, with lower levels of transferrin and complement C4 released. Apolipoproteins B, E, and A1 were secreted in high levels as well and were found in the form of lipoprotein particles. Time course experiments on the synthesis of apolipoproteins E and A1 indicated that, as with alpha-fetoprotein, the level of synthesis increased substantially when the cultures were held without passage. The results indicate that these yolk sac carcinoma cells display a protein expression profile similar to that observed for the human yolk sac, and the possibility that the cells may have the potential to differentiate is discussed.

Apolipoproteins↗
PubMed1978

A case of Menetrier's disease associated with protein-losing gastropathy and abnormal serum complement profile.

A 44-year-old man with Menetrier's disease associated with protein-losing gastropathy and with abnormal serum complement profile is reported. He was treated by an antifibrinolytic compound tranexamic acid (trans-AMCHA) since he was found to have elevated fibrinolytic activity in the biopsied gastric mucosa. The therapy brought his serum protein from 3.8 g/dl to 5.6g/dl, however could not reduce his mucosal disorder. Substitution of a placebo for trans-AMCHA resulted in marked depression of his serum protein to 3.7 g/dl. It was concluded that trans-AMCHA was effective in raising his serum protein to a certain extent but failed to block the vicious circle of "mucosal disorder", "increased tissue fibrinolysis" and "hypoproteinemia" (Kondo, M. et al. Gastroenterology 70, 1045, 1976). Abnormal serum complement profile seen in this patient was found to be due to cold activation of the classical complement pathway (Kondo, M. et al. J. Immunol. 117, 486, 1976). Although no correlation between the phenomenon and Menetrier's disease has been clarified yet, the appearance of wheezing as in asthma when exposed to cold suggested that cold activation of complement occurred in vivo and resulted in increasing of the vascular permeability in the lungs.

Adult↗
PubMed2003

The effect of locally synthesised complement on acute renal allograft rejection.

The complement system of components and receptors is one of the earliest forms of defence. Excessive or inappropriate activation can result in tissue damage, classically illustrated in immune-mediated nephritis. In addition, complement forms a bridge between innate and adaptive immunity, helping to prepare and focus T and B lymphocyte responses. More recent research in renal allograft models has shown that complement-inhibited and complement-deficient animals have reduced inflammatory injury and lowered antidonor immune responses. Furthermore, it is known that the transplanted kidney is a significant site of local synthesis of C3, although until recently the relative contribution of locally produced C3 to transplant injury was unknown. Current evidence indicates that defective local synthesis of C3 both reduces tissue injury and lowers the antidonor T cell response, substantially increasing graft survival. Among various possible explanations to account for these findings, the data favours a direct effect of complement on alloreactive T cell stimulation. Study of complement gene regulation by common immunosuppressive agents suggests that they do not influence local complement synthesis. Alternative approaches are therefore required to control the local effect of complement in the extravascular tissue compartment of the graft.

Acute Disease↗
PubMed2003

Diagnosis and treatment of antibody-mediated kidney allograft rejection.

Evidence of a significant pathogenetic role of donor-reactive antibodies (DRA) in kidney allograft rejection is accumulating. At least, partially owing to the recent discovery of the complement split product C4d as a valuable rejection marker, antibody-mediated rejection (AMR) has regained increasing attention. We review here the value of various diagnostic criteria, including immunohistochemistry (C4d staining), histomorphology and posttransplant serology, for the diagnosis of AMR. Furthermore, the mechanisms underlying alloantibody/complement-mediated allograft injury are discussed in detail. Finally, a thorough discussion of recently proposed "anti-humoral" therapeutic strategies is provided.

Acute Disease↗
PubMed2001

Pharmacokinetics of viral antibodies after administration of intravenous immunoglobulin in patients with chronic lymphocytic leukaemia or multiple myeloma.

OBJECTIVE: Intravenous immunoglobulin (IVIG) preparations are derived from human pooled plasma and should fulfil high standards of purity and viral safety. Introduction of additional purification steps, however, may result in modulation of the biological properties of immunoglobulins. Since cleavage of the Fab-fragment leads to a significant decrease in half-life, the latter provides information about the integrity of the immunoglobulin G (IgG) molecules. Therefore, a pharmacokinetic study of a novel preparation is required to determine safety and disposition in the target population. METHODS: Twenty-seven patients with chronic lymphocytic leukaemia (CLL) and 12 with multiple myeloma received intravenous infusions of IVIG containing antibodies against hepatitis B virus (anti-HBs; n= 15; 8960 IU), cytomegalovirus (anti-CMV; n = 9; 14,250 U) or varizella-zoster-virus (anti-VZV; n = 15; 6000 IU), respectively. Serum concentrations of viral antibodies were determined for 71 days during and after infusion. RESULTS: Maximum serum concentrations of anti-HBs, anti-CMV and anti-VZV were observed at about 4 h (median) after start of the infusion. Total body clearances came to 0.14 +/- 0.08 ml/min (anti-HBs), 0.10 +/- 0.02 ml/ min (anti-CMV) and 0.14 +/- 0.07 ml/min (anti-VZV). The terminal elimination half-lives were determined to be 25.34 +/- 8.34 days (anti-HBs), 24.66 7.28 days (anti-CMV) and 31.79 +/- 12.47 days (anti-VZV). Clinical chemistry parameters including C3- and C4-complement serum concentrations revealed no pathological changes, seroconversion for hepatitis B and C and HIV did not occur. CONCLUSIONS: The pharmacokinetic parameters of the IgG antibodies calculated after administration of the novel IVIG preparations to patients with CLL and multiple myeloma are in close agreement with data obtained from healthy volunteers and with values of native IgG, suggesting that the production process did not impair clinically relevant characteristics of the viral antibodies.

Antibodies, Viral↗