Relation of High Molecular Weight Proteins to the Serological Reactions in Rheumatoid Arthritis

Franklin, Edward C.; Kunkel, Henry G.; Müller‐Eberhard, Hans J.; Holman, Halsted R.

doi:10.1136/ard.16.3.315

Cited by 64 publications

(26 citation statements)

References 10 publications

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“…The second peak which was the active fraction represented 19S rheumatoid factor and the third peak in the upper portion of the tube consisted of material with an s rate between 6 and 12 (usually primarily approximately 7S). The latter was inactive in the various serological reactions and originated primarily from the lower molecular weight portion of the soluble 22S complex from the original serum (4,5). Combination of the fractions from the 19S peak (Tubes 4 through 7 in the experiment shown in Figure 4) furnished highly purified preparations of rheumatoid factor.…”

Section: Isolation From Specific Precipitatesmentioning

confidence: 99%

“…A number of observations (1,2) have demonstrated that the rheumatoid factor is a y-globulin with the solubility properties of a euglobulin. More recently, ultracentrifuge experiments (3,4) have indicated that the rheumatoid factor is a high molecular weight -y-globulin that exists in serum and plasma in the form of a complex. This complex can be visualized directly by means of the analytical ultracentrifuge in whole serum and in -y-globulin and euglobulin fractions and has a corrected sedimentation rate (s rate) of approximately 22S.…”

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confidence: 99%

“…This complex can be visualized directly by means of the analytical ultracentrifuge in whole serum and in -y-globulin and euglobulin fractions and has a corrected sedimentation rate (s rate) of approximately 22S. Previous studies (4,5) on the dissociation of the 22S complex by means of acid and urea have demonstrated that it is composed of two major constituents, one a 7S component and'the other 19S. The latter was found to be highly active by the serological reactions for rheumatoid factor.…”

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confidence: 99%

“…Considerable purification of the rheumatoid factor has been achieved by cellulose ion exchange chromatography (8,9), by elution from pneumococcus-antipneumococcus complexes (10), by elution from sensitized sheep cells (11), by ultrafiltration with membranes of graded porosity (12), and by preparative ultracentrifugation (4,13), but isolation in sufficient amounts to determine the complete physical and chemical properties of the rheumatoid factor has not been reported. The observations that rheumatoid factor precipitated directly with y-globulin (14) which had been aggregated by the procedures of isolation or heating at 630C.…”

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Studies on the Isolation and Characterization of the “Rheumatoid Factor”

Kunkel¹,

Franklin²,

Müller‐Eberhard³

1959

J. Clin. Invest.

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111

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Considerable evidence has been accumulated which indicates that a large proportion of the sera from patients with rheumatoid arthritis contains a factor which has the property of agglutinating particulate bodies such as red blood cells or latex particles when they are coated with -y-globulin or antibodies. Some of these reactions have been employed as diagnostic procedures and the factor or group of factors involved has been termed the "rheumatoid factor." A number of observations (1, 2) have demonstrated that the rheumatoid factor is a y-globulin with the solubility properties of a euglobulin. More recently, ultracentrifuge experiments (3, 4) have indicated that the rheumatoid factor is a high molecular weight -y-globulin that exists in serum and plasma in the form of a complex. This complex can be visualized directly by means of the analytical ultracentrifuge in whole serum and in -y-globulin and euglobulin fractions and has a corrected sedimentation rate (s rate) of approximately 22S. Previous studies (4, 5) on the dissociation of the 22S complex by means of acid and urea have demonstrated that it is composed of two major constituents, one a 7S component and'the other 19S. The latter was found to be highly active by the serological reactions for rheumatoid factor. The rheumatoid factor thus appeared to belong to the 19S class of y-globulins which is known to include certain antibodies as well as the Waldenstrom type macroglobulins (6, 7).Considerable purification of the rheumatoid factor has been achieved by cellulose ion exchange chromatography (8,9), by elution from pneumococcus-antipneumococcus complexes (10), by elution from sensitized sheep cells (11), by ultrafiltration with membranes of graded porosity (12), and by preparative ultracentrifugation (4, 13), but isolation in sufficient amounts to determine the complete physical and chemical properties of the rheumatoid factor has not been reported. The observations that rheumatoid factor precipitated directly with y-globulin (14) which had been aggregated by the procedures of isolation or heating at 630C. for 10 minutes (3, 13) offered a method of ready concentration from large volumes of serum. Furthermore the direct visualization of rheumatoid factor in the ultracentrifuge offered a means of observing purification particularly from certain unique sera where it represented a substantial portion of the total y-globulin.In the present study rheumatoid factor has been obtained in a high state

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Section: Isolation From Specific Precipitatesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Studies on the Isolation and Characterization of the “Rheumatoid Factor”

Kunkel¹,

Franklin²,

Müller‐Eberhard³

1959

J. Clin. Invest.

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111

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“…(Submitted for publication July 15, 1960; accepted August 18, 1960) Recent studies have demonstrated that the factors responsible for the various serological reactions currently employed for the diagnosis of rheumatoid arthritis represent macroglobulins which, in the isolated state, have a corrected sedimentation coefficient of approximately 19S (1)(2)(3)(4)(5). In serum and plasma, these proteins exist as complexes with low molecular weight y-globtulins and show a higher sedimentation rate, approximately 22S (6,7).…”

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Gamma Globulin Complexes in Rheumatoid Arthritis and Certain Other Conditions

Kunkel¹,

Müller‐Eberhard²,

Fudenberg³

et al. 1961

J. Clin. Invest.

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275

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Recent studies have demonstrated that the factors responsible for the various serological reactions currently employed for the diagnosis of rheumatoid arthritis represent macroglobulins which, in the isolated state, have a corrected sedimentation coefficient of approximately 19S (1-5). In serum and plasma, these proteins exist as complexes with low molecular weight y-globtulins and show a higher sedimentation rate, approximately 22S (6, 7). It has become clear that the rheumatoid factors have a specific affinity for ordinary y-globulin showing a behavior, particularly in certain of the serological tests, like that of anti-y-globulin antibodies. The possibility has been raised that the rheumatoid factor complex in serum represents an antigen-antibody complex.During the course of investigation of the rheumatoid factors and their complexes through ultracentrifugal analyses of sera showing high titer reactions in the latex fixation test and y-globulin precipitin test, another group of y-globulin complexes was encountered. These had sedimentation rates between 9 and 17S and were dissociated in urea and acid buffers in a manner similar to the previously observed dissociation of the rheumatoid factor complexes. Again the question arises as to whether these are antigen-antibody comlplexes or simple aggregates of y-globulin.Gamma globulin components in the 9 to 12S range have been observed in many preparations of normal Fr II y-globulin. The (15,16), although the sedimentation rate of the main abnormal protein was lower than the 18 to 20S range of the proteins described by Waldenstr6m. Macroglobulins of the latter class are a homogeneous group and are known to be stable proteins which do not dissociate in urea and acid and alkaline buffers (17). They have specific immunological properties and dissociate in the presence of agents breaking disulfide bonds (18).In the present study, sera from 11 different patients, 7 with classical rheumatoid arthritis, were found to contain multiple y-globulin complexes. These were readily detected in whole serum and plasma by direct ultracentrifugal analysis. They did not possess rheumatoid factor activity but were associated in the same sera with large amounts of rheumatoid factor. Investigation of the association and dissociation reactions of these complexes was carried out and certain of their properties de-fined. Evidence for and against the hypothesis that they represent antigen-antibody complexes of the y-globlulin-anti-y-glol)bulin type was sought. MATERIAL AND MIIETHODSSix of the 11 patients whose sera were specifically analyzed in this study were observed in the clinic and outpatient department of the Rockefeller Hospital. Three of the remainder represented patients in various New York 1-17

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The Rheumatoid Factors

Kunkel¹

1959

Arch Intern Med

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The term rheumatoid factors has been applied to a class of closely related proteins that are responsible for a variety of serological reactions currently employed for the diagnosis of rheumatoid arthritis. A marked intensification of interest in these factors has developed during the past two years, primarily because there is an intuitive feeling that they might represent a clue to the etiology of rheumatoid arthritis. Recent work, particularly with their isolation, has not diminished this interest, and it now appears that they probably represent antibodies, possibly autoantibodies. Also, the genetic distribution of these factors, and their occurrence in certain asymptomatic relatives of patients with rheumatoid arthritis, have offered a new and fundamental approach to the study of this disease.The evidence that these factors are involved in a direct causative manner in the joint lesions of rheumatoid arthritis is extremely scanty. Their occurrence in a wide variety of disorders other than rheumatoid arthritis, although at a lower incidence, argues against such a concept. Certain patients with liver disease, sarcoidosis, syphilis, parasitic disorders, and various other conditions associated with hyperglobulinemia, may contain rheumatoid fac¬ tors at an incidence of anywhere from 10% to 50%, depending on the sensitivity of the test employed.1,2'3 In rheumatoid arthritis, the incidence utilizing the same tests ranges from 60% to· 95%. Occasional patients with liver disease and sarcoidosis may show extremely high titers of rheuma¬ toid factor for prolonged periods without any signs of arthritis. Another argument that has been cited against any primary role for these factors is their absence in patients with agammaglobulinemia who have an associated arthritis resembling that of rheumatoid arthritis.4 However, a certain amount of indirect evidence has been ac¬ cumulated suggesting that the rheumatoid factors may contribute to some of the secondary manifestations of rheumatoid arthritis. The arteritis that is occasionally seen is associated with very high titers of rheumatoid factor.5 Hypersplenism and the manifestations of Felty's syndrome also ap¬ pear more frequently in patients with ex¬ tremely high titers.6 It has been suggested that in some of these situations the rheuma¬ toid factors, which exist as rather insoluble complexes in serum, may precipitate out in the body, with resultant secondary damage.Spontaneous precipitates from human serum have been noted which might be of signifi¬ cance, and might have an effect similar to certain known cryoglobulins. Serological Tests Serological Tests for the RheumatoidFactors.-A large number of different sero¬ logical tests are currently employed for diagnostic purposes. The sensitized sheep cell agglutination reaction is one of the oldest, but now appears to be one of the most specific.1·2 It lacks the sensitivity of some of the newer tests, and the incidence of positive results in rheumatoid arthritis patients usually ranges from 55% to 70%.The latex fixation and the bent...

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Relation of High Molecular Weight Proteins to the Serological Reactions in Rheumatoid Arthritis

Cited by 64 publications

References 10 publications

Studies on the Isolation and Characterization of the “Rheumatoid Factor”

Studies on the Isolation and Characterization of the “Rheumatoid Factor”

Gamma Globulin Complexes in Rheumatoid Arthritis and Certain Other Conditions

The Rheumatoid Factors

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