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E C Franklin

Publications and source records attributed to E C Franklin.

At least 19 recordsLinked to original sources
PubMed1983

Identification of elastases associated with purified plasma membranes isolated from human monocytes and lymphocytes.

Studies were carried out to understand the pathogenesis of amyloid formation and to localize the elastase-like enzymes postulated to be associated with the surface of human peripheral blood monocytes and lymphocytes. These enzymes are known to degrade serum amyloid A and amyloid A proteins. Pure plasma membrane preparations were obtained by allowing cells to attach to polyacrylamide beads, followed by their disruption. The purity of the membranes was monitored by electron microscopy and enzyme determinations. The extracted membrane enzymes which have molecular weights of 56000 and 30000, respectively, were inhibited by DFP, MeO-Suc-Ala-Ala-Pro-Val-CH2Cl, Ac-Pro-Phe-Arg-CH2Cl . HCl, and elastinal but were not inhibited by EDTA or epsilon-amino caproic acid, thus exhibiting the properties of elastases. These enzymes cleave serum amyloid A to amyloid protein A. In some individuals, cleavage stops at this point, while in others a second step occurs, resulting in complete protein degradation. This activity was comparable whether monocyte or lymphocyte plasma membranes were employed. Since lymphocyte dependent cytotoxicity has also been attributed to surface proteases, it is likely that a spectrum of membrane associated enzymes mediate important physiologic function of these mononuclear leukocytes.

Cell Fractionation↗
PubMed1983

Characterization of amyloid deposits and P component from a patient with factor X deficiency reveals proteins derived from a lambda VI light chain.

Amyloid fibrils were isolated from a spleen obtained at surgery from a 58-year-old white man with primary amyloidosis presenting with factor X deficiency and responding dramatically to splenectomy. Gel filtration on Ultragel ACA 54 in 5 M guanidine 1 M acetic acid yielded components with molecular weights between 17,000 and 13,000. Two of them (17K and 15K) were studied in detail. Antigenic and amino acid sequence analysis showed that these proteins were related to lambda VI immunoglobulin light chain. The predominant protein subunits of the amyloid fibril of the deposits (17K) was processed at the carboxy terminus in the same section of the constant region as the only other lambda VI amyloid protein previously reported. Amino terminal sequence of the 15K protein revealed not only degradation at the C terminal, but also minor degradation at the amino terminal (three residues difference from the 17K species). P component was also isolated from the spleen and characterized. This represents the first antigenic and sequence analysis of tissue amyloid proteins and P component from a patient presenting with factor X deficiency and another example of amyloid proteins derived from the newly discovered amyloidogenic lambda VI light chain subgroup.

Amino Acids↗
PubMed1983

Primary structure of an amyloid prealbumin variant in familial polyneuropathy of Jewish origin.

The complete amino acid sequence of three related amyloid proteins (Mr 14,000, 10,000, and 5,000) derived from tissues of a Jewish patient who suffered from a variant of familial polyneuropathic amyloidosis was determined. The protein, which contains 127 residues, is identical to a human serum prealbumin subunit. Only one amino acid substitution, glycine for threonine, was detected at position 49, where enzymatic cleavage occurred, yielding Mr 5,000 and 10,000 fragments which represent the amino terminus (residues 1-48) and carboxyl terminus (residues 49-127) of the molecule, respectively. Thus, a prealbumin variant and its fragments constitute the amyloid fibrils in a heredofamilial amyloidosis syndrome of dominant inheritance.

Amino Acid Sequence↗
PubMed1983

Preferential association of kappa IIIb light chains with monoclonal human IgM kappa autoantibodies.

The predominance of the relatively uncommon V region subgroup isotype kappa III among the light chains of human monoclonal (IgM kappa) anti-IgG antibodies, (i.e., rheumatoid factors), was further documented through sequence analyses of ten such autoantibodies isolated from IgM-anti-IgG cold-insoluble immune complexes (mixed cryoglobulins). The amino-terminal sequence of all ten kappa-chains was characteristic for kappa III proteins and virtually identical to that of a prototype kappa III light chain. Similar sequence identity was found for kappa-chains isolated from three IgM kappa autoantibodies that formed cold-insoluble immune complexes with low-density lipoprotein (LDL). The thirteen light chains were found to be virtually identical in sequence for the first framework region (FR); ten of these proteins sequenced through the first complementarity-determining region (CDR) and into the second FR were markedly similar. The second CDR of five proteins was almost identical in sequence to that of the prototype kappa III-chain. Concordance was also demonstrated between the structural classification of the light chains as kappa III and their immunochemical classification as members of this V region subgroup. Serologic analyses of light chains isolated from seven IgM kappa autoantibodies (six anti-IgG, one anti-LDL) and of one intact IgM kappa anti-LDL antibody showed that each had antigenic determinants common to kappa II proteins. These light chains also expressed the antigenic determinant(s) of a V-region sub-subgroup of kappa III proteins designated kappa IIIb. Our studies confirm the preferential association of kappa III (and kappa IIIb) light chains with IgM kappa anti-IgG antibodies and demonstrate a similar association for IgM kappa anti-LDL antibodies. The finding that these and other types of IgM kappa autoantibodies, e.g., cold agglutinins, have remarkably similar light chains suggests an inherent restriction in the immune response to self-antigens.

Adult↗
PubMed1982

Familial renal amyloidosis: case reports and genetic studies.

Rapidly progressive biopsy-proved renal amyloidosis developed in three brothers, aged 49, 52, and 55, or Irish-American origin. None had evidence of a plasma cell dyscrasia, a monoclonal serum or urine protein, or any underlying chronic disease. Immunoperoxidase staining of one pulmonary and one renal biopsy specimen was negative for Amyloid A (AA), Amyloid L (AL), and prealbumin. To investigate factors that might play a role in the disease, the subjects and 21 relatives were typed for antigens of the A, B, C, and DR loci and the linked marker genes for factor B and glyoxalase. The ability of macrophages to degrade serum amyloid A (SAA) [1] was examined. One brother yielded an intermediate AA-like produce similar to what is seen in most patients with AA or AL amyloidosis and 40 percent of normal subjects. The other two degraded SAA completely to small peptides. Analysis of the families revealed first that the disease was not linked to the major histocompatibility complex. We were unable to demonstrate a genetic relationship between processing of SAA by peripheral mononuclear cells and the human leukocyte antigen locus. Finally, the pattern of SAA degradation was not associated with the development of the disease.

Adult↗
PubMed1982

Amyloidosis associated with renal cell carcinoma of the AA type.

Amyloid fibrils were found at postmortem examination in a 70 year old woman with generalized amyloidosis associated with renal carcinoma (hypernephroma). Clinically, her amyloid disease presented as nephrotic syndrome. It was demonstrated by electrophoretic and amino acid sequence analysis studies that the amyloid fibrils contained AA protein identical to that found in amyloidosis associated with chronic inflammatory and infectious diseases as well as in the genetic form of familial Mediterranean fever.

Adenocarcinoma↗
PubMed1982

gamma Heavy chain disease in man: cDNA sequence supports partial gene deletion model.

Human gamma heavy chain disease (HCD) is characterized by the presence in serum of a short monoclonal Ig gamma chain unattached to light chains. Although most HCD proteins have internal deletions, in some the defect is NH2-terminal. The OMM gamma 3 HCD serum protein is of the latter type, having undergone an extensive NH2-terminal deletion with a sequence starting within the hinge. A cell line synthesizing the OMM protein has enabled us to study the biogenesis of the abnormal molecule. In vitro translation of isolated mRNA yields a protein containing a hydrophobic NH2-terminal leader sequence. In the intact cell, the precursor molecule is processed normally to yield a protein with an NH2-terminal sequence homologous to the beginning of the variable (V) region. The nucleotide sequence of cDNA prepared from the OMM mRNA encodes a 19-amino acid leader followed by the first 15 residues of the V region. An extensive internal deletion encompasses the remainder of the V and the entire CH1 domain. Immediately following the short V region, there is information in the cDNA for the entire normal hinge. The primary synthetic product is thus an internally deleted molecule that undergoes postsynthetic degradation to yield the NH2-terminally deleted serum protein. The structure of the OMM mRNA suggests that the protein abnormality results from a partial gene deletion rather than defective splicing.

Amino Acid Sequence↗
PubMed1982

Staphylococcal protein A and human IgG subclasses and allotypes.

Staphylococcal protein A binds molecules belonging to the IgG1, IgG2, and IgG4 subclasses. IgG3 proteins generally do not bind, except for those coded by the two gamma 3 alleles, which are G3m(u-): G3m(b0,b3,b5,s,v). G3m(u) is located in the CH2 domain. The difference between G3m(u-) and G3m(u+) IgG3 proteins correlates with the sequence at position 339 in the CH2 domain--Ala and Thr respectively. There is another structural difference in the CH3 domain which correlates with protein A binding and non-binding: all IgG proteins that bind protein A have His at position 435, whereas those that do not, have Arg at that position.

Alleles↗
PubMed1982

Bence Jones proteins and light chains of immunoglobulins. Preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda).

An antiserum prepared against a lambda-Bence Jones protein from a patient (SUT) who had multiple myeloma and amyloidosis had specificity for lambda-light chains of the chemically defined variable (V) region lambda-chain subgroup lambda VI. Sequence analyses of protein SUT and of five other lambda-light chains recognized immunologically as of the V lambda VI subgroup revealed that all six proteins had the N-terminal sequence characteristic for prototype lambda VI proteins. The isotypic nature of the V lambda VI subgroup was demonstrated immunochemically: lambda VI molecules were detected among light chains isolated from the IgG proteins of each of 12 normal individuals and lambda VI antigenic determinants were also detectable on the intact IgG proteins. The frequency of lambda VI molecules among lambda-type light chains is estimated to be approximately 5% based on the finding that 5 of 91 lambda Bence Jones proteins were of the V lambda VI subgroup. Proteins of the V lambda VI subgroup, in contrast to those of the other five chemically-classified lambda chain subgroup, appear to be preferentially associated with the amyloid process as evidenced by the fact that all six lambda VI proteins were obtained from patients with amyloidosis AL and, in addition, 5 of 42 lambda-type monoclonal immunoglobulins from patients with primary or myeloma-associated amyloidosis were classified by immunodiffusion analyses as having lambda VI-type light chains.

Amino Acid Sequence↗
PubMed1982

The modification of human immunoglobulin binding to staphylococcal protein A using diethylpyrocarbonate.

Human IgG subclasses 1, 2, and 4, as well as proteins of the IgG3 subclass that are allotype G3m (s+t+), bind avidly to staphylococcal protein A by means of their Fc portion. Proteins of the IgG3 subclass that are allotype G3m (s-t-) do not bind. The importance of a histidine residue at position 435 has been implicated from comparison of amino acid sequences of immunoglobulins that bind with those that do not bind to staphylococcal protein A, as well as from crystallographic data. Modification of histidines at a low concentration of diethylpyrocarbonate successfully and reversibly alters the binding of immunoglobulins to staphylococcal protein A with only minimal change in the antigenic properties. This method provides strong evidence for the critical importance of histidine in the binding of immunoglobulins to staphylococcal protein A.

Diethyl Pyrocarbonate↗
PubMed1982

Structural studies on an IgM-lambda pyroglobulin.

An IgM-lambda pyroglobulin from a patient with Waldenström's syndrome was studied. Heavy and light chains were separated and their N-terminal amino acid sequence determined. The heavy chain was unblocked and belonged to the VHIII subclass, and the light chain belonged to the lambda I subclass. Factors influencing pyroprecipitability were examined through experiments designed to study some of the physical and chemical properties of an IgM-lambda pyroglobulin. Pyroprecipitability was affected by pH, ionic strength, urea, and reducing agents, suggesting an involvement of noncovalent electrostatic interactions. It was also demonstrated through recombinant experiments that it is necessary to have covalently joined homologous heavy and light chains in pentameric form for pyroprecipitation to occur. Since neither heavy nor light chains had any unique structural features, the reasons for this property remain obscure but may reflect the result of conformational factors.

Amino Acid Sequence↗
PubMed1982

Idiopathic AL-kiv amyloidosis presenting as giant hepatomegaly.

The 11/2-yr course of idiopathic systemic amyloidosis in a 63-yr-old woman was characterized by inanition, subcutaneous ecchymoses and giant hepatomegaly, the liver weighing 8.5 kg at autopsy. Skeletal survey and bone marrow aspirate were normal. The major components of isolated amyloid fibrils were 16,000- and 23,000-dalton proteins. The 16,000-dalton component was shown by amino acid sequencing to be a fragment of the kappa (k)iv light chain, the first such case. These clinicochemical correlations suggest that isolated massive hepatomegaly may prove to be a hallmark of idiopathic amyloid light chain-related protein k amyloidosis.

Adult↗
PubMed1981

A variant of prealbumin from amyloid fibrils in familial polyneuropathy of Jewish origin.

Amyloid fibrils were isolated from spleen and thyroid obtained at autopsy from one patient (S.K.O.) of Jewish origin with familial amyloidotic polyneuropathy. Gel filtration on Sephadex G100 after solubilization in 5 M guanidine HCl yielded three major components with 14,000, 9,000, and 5,000 mol wt, respectively. The two larger components shared antigenic determinants with human prealbumin. Amino acid analysis and amino terminal sequence studies revealed the 14,000-mol wt protein to be an intact prealbumin subunit. The 9,000-mol wt fragment obtained in highest yield encompassed the region from position 49-127 and the 5,000 mol wt fraction encompassed the amino terminal of prealbumin (position 1-48). An amino acid substitution (Gly/Thr) was detected at position 49, where enzymatic cleavage occurred. Thus, several prealbumin-derived fragments, predominantly the carboxyl end, constitute the amyloid fibrils in a heredofamilial amyloidosis syndrome of dominant inheritance.

Adult↗
PubMed1981

The effect of combination therapy (steroids, immunosuppressives, and plasmapheresis) on 5 mixed cryoglobulinemia patients with renal, neurologic, and vascular involvement.

A prospective clinical study evaluated the effects of combined chemotherapy, steroids and plasmapheresis on 5 patients with mixed cryoglobulinemia with renal or neurologic and vasculitic manifestations. Treatment included prednisone (1mg/kg/day), chlorambucil (white blood cell count at greater than 3,000/mm3), and plasmapheresis (1 to 3 liters/week). There was healing of cutaneous ulcers (3/3), improvement in renal function (4/4), and diminution of purpura (2/2), but little improvement in peripheral neuropathy. Complications included leukopenia, perineal ulcers, and osteomyelitis.

Aged↗
PubMed1981

Amyloidosis.

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Amyloid↗