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PubMed1992

High levels of "complexed" interleukin-6 in human blood.

The biochemical nature of endogenous interleukin-6 (IL-6) as it exists in human serum or plasma was investigated. Serum from a patient following bone marrow (BM) transplantation and fresh plasma samples from patients with epidermolysis bullosa or psoriasis, as well as from normal volunteers, were fractionated through G-200 columns and each of the eluted fractions assayed for IL (interleukin)-6 content using enzyme-linked immunosorbent assays (ELISAs) based on the monoclonal antibody (mAb) pairs IG61/5IL6 or 4IL6/5IL6 and in the B9 hybridoma growth factor bioassay. The IG61/5IL6 ELISA and the B9 assay detected IL-6 in BM serum almost exclusively of molecular mass approximately 20 kDa. In contrast, the 4IL6/5IL6 ELISA detected strong IL-6 immunoreactivity in complexes of size 100-150 and 400-500 kDa. IL-6 present in the 100-150- and 400-500-kDa complexes was purified by immunoaffinity chromatography through a 5IL6 mAb column. The 5IL6 mAb immunoaffinity column eluate of the respective pools from BM serum contained IL-6 at concentrations approaching 1 microgram/ml as characterized by Western blotting. Sufficient IL-6 and associated proteins were purified by 5IL6 mAb immunoaffinity column chromatography of the 100-150-kDa complex from 0.8 ml of BM serum to allow (i) verification of three of the polypeptides as IL-6 by amino-terminal sequencing (estimate of IL-6 in original serum sample: 5-10 micrograms/ml), (ii) identification by amino acid sequencing of the "associated" proteins as complement factor C3b (carboxyl-terminal of the alpha-chain), complement factor C4b (gamma-chain), C-reactive protein, and albumin, and (iii) detection of an "associated" polypeptide consistent with the soluble IL-6 receptor. Taken together, these data establish that IL-6 is present at unexpectedly high concentrations in human blood in novel biochemical complexes that include other plasma proteins, which in turn, can camouflage IL-6 immunoreactivity and bioactivity as measured in conventional assays.

Amino Acid Sequence↗
PubMed2005

BK-virus nephropathy and simultaneous C4d positive staining in renal allografts.

The role of antibodies in rejection of transplanted kidneys was the subject of debate at the last two Banff meetings and in medical journals. Diffuse C4d positive staining of peritubular capillaries (PTCs) was recognized as a marker of antibody-mediated rejection and this morphological feature was included in the updated Banff schema. At the same time polyomavirus infection of the renal allografts has been reported more frequently and is emerging as an important cause of renal allograft dysfunction and graft loss. At the present time, BK-virus nephropathy (BKN) represents the most common viral disease affecting renal allografts. BKN was identified in 6 patients in 12 biopsies and 2 graft nephrectomy specimens of 1115 biopsies between September 2000 and December 2003. Definite virus identification was done by immunohistochemistry. The reason for graft nephrectomies was graft failure due to BKN in a recipient after kidney-pancreas transplantation with good function of his pancreas graft and the necessity of continuing immunosuppression. Detection of C4d deposits was performed by immunofluorescence or by immunohistochemistry. In graftectomy samples C4d detection was performed by immunohistochemistry and retrospectively in all cases of BKN. Focal C4d positive PTCs and BKN were found simultaneously in 9 of 12 needle biopsies and in both graft nephrectomy samples. Detection of C4d by immunohistochemistry disclosed focal C4d positive staining in kidney tissue but diffuse in the sites where BK-virus inclusions in tubular epithelial cells were found. The complement system is part of the host defense response and is crucial to our natural ability to ward off infection. In cases of BKN, virus likely gains access to the bloodstream through injured tubular walls and via PTCs. Vascular endothelium in the PTCs represents a potential target antigen for alloresponse, and simultaneously possibly represents an imprint of complement activation or complement production in the places with BK-virus infection.

BK Virus↗
PubMed1991

A rare complement component C4 restriction fragment length polymorphism in two families with systemic lupus erythematosus.

C4 null alleles with or without C4A,21-OHA gene deletions are associated with systemic lupus erythematosus (SLE) in various populations. We describe a new, rare C4 restriction fragment length polymorphism (RFLP), a Taq I 3.5 kb fragment, in 2 patients with SLE and their families. This RFLP is not associated with one particular major histocompatibility complex (MHC) haplotype and has not been reported in patients with SLE, patients with congenital adrenal insufficiency, or in healthy individuals.

Adult↗
PubMed2004

[C4d: a pathogenetically relevant marker in kidney transplantation].

Antibody-mediated allograft rejection should be discriminated from cell-mediated rejection processes since these two distinct pathogenic mechanisms are likely to require different therapeutic approaches. The complement split product C4 d (although biologically inactive by itself) turned out to be a reliable diagnostic marker of antibody-induced complement activation in kidney allografts. In contrast to other organs like heart and bowel, there is no indication that ischemia/reperfusion injury might induce the classical pathway of complement activation in the kidney. Endothelial C4 d deposits in peritubular capillaries of transplanted kidneys are therefore robust indicators of antibody-mediated alloreactivity with potentially unfavourable outcome. The high efficiency of therapeutic strategies aimed at removing alloantibodies from the recipient's circulation (i.e. immunoadsorption and plasmapheresis) in cases of C4d positive rejection further underscores the important pathogenic role of antibodies in renal allograft rejection and the diagnostic relevance of endothelial C4 d deposits. C4 d deposits can also occur de novo in late allograft biopsies. Their association with basement membrane injury in peritubular capillaries and glomeruli, which are the hallmarks of chronic rejection, indicates a contribution of humoral immune reactions to chronic rejection. Due to the clinical relevance of humoral rejection and due to the fact that the latest update of the Banff classification introduced the pathogenically based subdivision of acute rejection into a cell-mediated and an antibody-mediated variant every renal allograft biopsy should be stained for C4 d. It is important to be aware that humoral and cellular rejection often occur simultaneously and that C4d deposits alone are not an unequivocal proof of humoral rejection that immediately requires treatment.

Basement Membrane↗
PubMed1991

Characterization of a Trypanosoma cruzi C3 binding protein with functional and genetic similarities to the human complement regulatory protein, decay-accelerating factor.

Evasion of the complement system by microorganisms is an essential event in the establishment of infection. In the case of Trypanosoma cruzi, the causative agent of Chagas disease, resistance to complement-mediated lysis is a developmentally regulated characteristic. Infectious trypomastigotes are resistant to complement-mediated lysis in the absence of immune antibodies, whereas the insect forms (epimastigotes) are sensitive to lysis via the alternative complement pathway. We have purified a developmentally regulated, trypomastigote glycoprotein, gp160, and shown that it has complement regulatory activity. The T. cruzi gp160 restricts complement activation by binding the complement component C3b and inhibiting C3 convertase formation. The protein is anchored in the parasite membrane via a glycosyl phosphatidylinositol linkage, similar to the human complement regulatory protein, decay-accelerating factor. Using anti-gp160 antibodies we have isolated a bacteriophage lgt11 clone expressing a portion of the gp160 gene that shares significant DNA sequence homology with the human DAF gene. These results provide functional, biochemical, and genetic evidence that the T. cruzi gp160 is a member of the C3/C4 binding family of complement regulatory proteins, and that gp160 may provide the infectious trypomastigotes with a means of evading the destructive effects of complement.

Animals↗
PubMed1990

Conversion of the C4d.2 serologic allotype of murine complement component C4 to the C4d.1 allotype by site-specific mutagenesis.

C4d.1 and C4d.2 are serologically defined allotypes of murine complement component C4. Previous studies in Shreffler's laboratory have shown that the structural difference between the two allotypes lies within a single tryptic peptide of the C4 alpha-chain and that the sequences of this fragment from the two allotypes (determined from nucleic acid sequences of genomic clones) differ only by the substitution of arginine in C4d.2 for glutamine in C4d.1. Hence this single amino acid change apparently is responsible for the rather striking serological difference between the two allotypes. To test this conclusion, we have used site-specific mutagenesis to alter the sequence of a full-length C4 cDNA that was derived from a mouse strain expressing the C4d.2 allotype. We substituted a glutamine codon for the arginine codon at the specified site and expressed both mutant and parent recombinant C4 proteins by transient transfection of COS cells. We found that an alloantiserum specific for C4d.1 reacts with the mutant protein but not the parent whereas an alloantiserum specific for C4d.2 reacts with the parent protein, as expected, but not the mutant. These results confirm that a single amino acid difference specifies the C4d.1 and C4d.2 allotypes.

Alleles↗
PubMed1988

Structural basis for the C4d.1/C4d.2 serologic allotypes of murine complement component C4.

The C4d.1 antigenic specificity was first defined serologically in 1959 as an H-2-associated cellular alloantigen first designated "G," later H-2.7. It was subsequently shown to be an allotype of component C4 of the C system, with the antigenic determinant carried on the C4d proteolytic fragment of the alpha-chain, thus the designation C4d.1. Alloantisera defining an antithetical Ag, C4d.2, were also prepared. Previous studies in our laboratory showed that the structural difference between the two specificities resides in a single tryptic peptide of C4d. As an efficient approach to definition of the amino acid difference(s) involved, genomic clones covering the C4d regions from two H-2 haplotypes of the C4d.1 type have been prepared and sequenced, and compared with two sequences already available for C4d.2-type molecules. The results indicate that the rather striking serologic difference between C4d.1 and C4d.2 is attributable to the single amino acid substitution of arginine in C4d.2 for glutamine in C4d.1. The substituted residue is in a highly hydrophilic region of the C4 molecule, at a position homologous to one that contributes to the Chido/Rodgers serologic difference of human C4 molecules. This substitution also determines a new Pst I site in C4d.1 strains. A HindIII restriction fragment length polymorphism between C4d.1 and C4d.2 has also been observed.

Amino Acid Sequence↗
PubMed1989

HLA and complement C4 antigens in polyarticular onset seronegative juvenile chronic arthritis: association of early onset with HLA-DRw8.

HLA-A,B,C,DR and DQ antigens were tested in 53 British Caucasian patients with polyarticular onset seronegative juvenile chronic arthritis (JCA); C4 allotypes were also tested in 46. A strong association with HLA-DRw8 was found (RR = 6.1, Fp = 7.6 x 10(-5)), with increased -B5(51) and C4A QO, and decreased -DR7 frequencies. DRw8 incidence correlated with an onset under 5 years, 9 of 12 DRw8+ cases being in this subgroup (Fp = less than 0.06), whereas B5 and C4A QO were prevalent in late onset (greater than or equal to 5 years). Erosions after 5 years associated with HLA-DRw6, and their absence with -Cw1 and -DR5. Genetic susceptibility factors and a further subdivision by onset age are thus demonstrated in this disease. Comparative data suggest that the genetic basis of susceptibility to early onset disease is similar to that of pauciarticular JCA.

Adolescent↗
PubMed1986

Monoclonal antibodies to human vitamin K-dependent protein S.

Monoclonal antibodies to human protein S have been prepared using established hybridoma technology. One antibody was isolated that binds protein S only when Ca2+ is present; others bind antigen equally well in the presence or absence of EDTA. Other antibodies display a diminished affinity for protein S in the presence of EDTA. Purified immunoglobulins from cell lines displaying Ca2+ dependence were immobilized and used to purify protein S from fractions obtained by barium precipitation of citrated plasma, ammonium sulfate fractionation, and chromatography on diethylaminoethanol (DEAE)-Sephadex and dextran sulfate agarose. Essentially homogeneous protein S was isolated from the barium-citrate-adsorbed, 35% ammonium-sulfate-soluble proteins using a totally Ca2+-dependent antibody and EDTA elution. Protein S and several substances of higher mol wt were bound directly from plasma by a partially Ca2+-dependent antibody and were eluted partially with EDTA and NaCl and finally with NaSCN. The largest and most abundant of the high mol wt materials is likely protein S-complement C4b-binding protein complex. The immunoaffinity-isolated protein S was found to be indistinguishable from conventionally isolated protein S in terms of activity, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) mobility, and by high-performance liquid chromatography (HPLC). These studies establish reagents that can probe the structure of protein S and isolate protein S in its free and complexed forms.

Antibodies, Monoclonal↗
PubMed1988

Genetic mapping of the 21-hydroxylase locus: estimation of small recombination frequencies.

The locus for 21-hydroxylase (CA21HB) has been mapped to the interval between the HLA-B and HLA-DR loci on chromosome 6. Several methods of estimating genetic distance were used to determine whether CA21HB is closer to HLA-B or HLA-DR based on data collected on 157 families ascertained through a proband with the classical form of 21-hydroxylase deficiency (CA12Hd). The results were inconclusive but serve to highlight the limitations of present methods of estimating genetic distance when recombination frequencies are of the order of .005.

Chromosome Mapping↗
PubMed1987

Autoantibodies and immunogenetics in 30 patients with systemic sclerosis and their families.

Clinical and serological evidence of connective tissue disease was found in a high proportion of 132 family members of 30 patients with systemic sclerosis. In 20 probands with the milder CREST form of the disease, 10 had HLA-DR5 and 12 had null alleles at the C4 loci. None of 11 probands with more severe systemic sclerosis had HLA-DR5; all 11 had null alleles at the C4 loci. All but two of the probands had either HLA-DR5 or a C4 null allele, and this was also the case for the majority of the relatives with autoantibodies. Genetic markers of the major histocompatibility complex, including HLA-DR5 and C4 null alleles, appear to be closely associated with markers of disease in these probands and their families.

Antibodies, Antinuclear↗