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Anti-Antibody Activity of a Monoclonal Macroglobulin (Waldenstroim's Macroglobulinemia/Igm/Flagellin/Antigen-Antibody Complexes)

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Anti-Antibody Activity of a Monoclonal Macroglobulin (Waldenstroim's Macroglobulinemia/Igm/Flagellin/Antigen-Antibody Complexes) Proc. Nat. Acad. Sci. USA Vol. 68, No. 11, pp. 2846-2851, November 1971 Anti-Antibody Activity of a Monoclonal Macroglobulin (Waldenstroim's macroglobulinemia/IgM/flagellin/antigen-antibody complexes) NOEL L. WARNER,* MALCOLM R. MACKENZIEI AND H. HUGH FUDENBERG The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and the Division of Hematology and Immunology, University of California, Medical Center, San Francisco, Calif. 94122 Communicated by Sir Macfarlane Burnet, August 2, 1971 ABSTRACT A monoclonal macroglobulin from a MATERIALS AND METHODS patient with Waldenstrom macroglobulinemia has been shown to have antiglobulin activity of a new type, namely, Waldenstrbm Macroglobulins (IgM). IgM proteins from that of a true anti-antibody. The protein reacts with sera of patients with macroglobulinemia were isolated; human, primate, and rabbit IgM and IgG,-only when the monomer subunits, heavy and light chains were produced as target immunoglobulin is complexed to an antigen. The implications of the general findings of antiglobulin described (20). activity of monoclonal proteins is discussed in relation to Fragmentation of Immunoglobulins. Papain digestion of the possible etiology of the disease. IgMBrd was performed as per the method of Deutsch et al. Monoclonal immunoglobulins derived from malignant- (21). Adequacy of the separation of fragments was tested by lymphoid or plasma-cytoid cells have been firmly established electrophoresis versus antisera to ps and K chains, in rabbits. to be analogous to their nonmalignant counterparts in Assay for Anti-Antibody Activity. The basic assay system is possessing both constant and variable regions of the immuno- a modification of the Herzenberg and Warner technique (22) globulin polypeptide chains (1-3). Various antibody activities for precipitation of mouse immunoglobulins with antiallotype have been reported for these proteins, including an anti- sera. The assay involves the use of a liquid precipitation globulin specificity like that of the rheumatoid factor (4-7), system with an lu2I-labeled antigen combined with a specific and binding to lipoproteins (8), cold agglutinins (9, 10), antibody in different dilutions, such that soluble complexes nucleic acid derivatives (11), streptolysin (12), phosphoryl are formed, which do not sediment under the conditions used. cholinet, §, some bacterial antigens (13), and several haptens, The complexes can, however, be precipitated by the addition such as dinitrophenol (14-17). of a second antibody directed against the antibody involved In the consideration of the specific case of monoclonal in the soluble complex. Briefly, 125I-labeled proteins were proteins (macroglobulins) produced from Waldenstr6m-type prepared by the method of Greenwood et al. (23), with tumors, it appears that a rather high incidence of antiglobulin Chloramine T as oxidant. Labeled antigens were diluted in specificities have been observed. In previous reports of this 3% bovine-serum albumin (BSA) in 0.05 MI Tris buffer type, the Waldenstr6m macroglobulin was shown to bind to (pH 7.5); about 3- to 10-ng samples were placed in 6 X 50 mm native autologous IgG globulin (6, 18) and in a few cases, to tubes in a volume of 50 jul. Antisera were similarly diluted in also crossreact with the dinitrophenol hapten (19). As this BSA-buffer, and an appropriate dilution determined by high association of antiglobulin activity with Waldenstr6m prior titration, was then added to the tubes, also in a volume proteins may not be through mere chance, but rather reflects of 50 Al. Samples of macroglobulin or myeloma sera, or purified some basic autoimmune process in the etiology of the disease, proteins to be tested for anti-antibody activity, were then it is of considerable importance to examine for other types of added to the tubes in 10 Al volumes, again diluted in BSA- possible antiglobulin specificity in Waldenstr6m proteins. buffer. After mixing, the tubes were incubated at 370C for This report documents the first example of a Waldenstrom 2 hr, chilled at 4°C for 2-18 hr, and then centrifuged at macroglobulin with the antiglobulin specificity of a true 10,000 rpm for 10 min; 50 ;&l samples of supernatant were anti-antibody, namely, the reaction with gammaglobulin then removed for radioactivity counting. only when the gammaglobulin is itself complexed to another antigen. Antigen-Antibody Assays Used. (i) Transferrin (kindly provided by Dr. A. C. Wang); rabbit antitransferrin. (ii) Chicken IgG (isolated by starch block electrophoresis and Abbreviation: BSA, bovine-serum albumin; Dnp, dinitrophenyl. Sephadex gel filtration of adult chicken serum) and a poly- * Address for reprints: Dr. N. L. Warner, The Walter and Eliza valent rabbit antiserum to chicken IgG. (iii) Monomer Hall Institute of Medical Research, R.M.H. Post Office, Park- preparation of flagellin of Salmonella adelaide strain 1338, ville, Victoria, Australia, 3050. Mr. John with various antisera t Present address: Department of Internal Medicine, School of kindly provided by Pye, Medicine, University of California, Davis, Calif. to flagellin of S. adelaide, prepared in either rabbit, mouse, t Leon, -M. A., and N. M. Young, Fed. Proc., 29, 437 Abstr. rat, or man. Several antisera to S. adelaide were fractionated (1970). by Sephadex G-200 gel filtration, to give an IgM and IgG § Potter, M., R. Lieberman, L. Wood, and D. S. McKean, Fed. antiflagellin fraction. These antiflagellin sera were kindly Proc., 29, 437 Abstr. (1970). provided by Drs. Richard Wistar and Ian Mackay. (iv) 2846 Downloaded by guest on September 24, 2021 Proc. Nat. Acad. Sci. USA 68 (1971) Anti-Antibody Activity of IgM 2847 TABLE 1. Precipitation of antigen-antibody complex by TABLE 2. Precipitation of antigen-antibody Waldenstrim macroglobulins complexes by IgMBrd Amount Percent Percent precipitation of antigen*- Protein (ug) precipitation* Amount antibody complex Nil 5 Protein (mg) I II III Normal human IgM 2.5 5 1gMBrd 6.0 68 Nil 1 5 1 1.5 65 1gMBrd 3.0 16 48 49 41 different 0. 8 12 40 37 Waldenstr6m IgM 0.2 19 18 proteins 1.5-6.0 5 JgMBi 8.2' 3 .5 3 4.1 1 5 3 *Of BC-IgGl myeloma protein with its anti-idiotype anti- * Antigen was labeled with 1251. serum. I. Transferrin-rabbit antiserum to transferrin. II. Chicken gammaglobulin-rabbit antiserum to chicken gammaglobulin. Human IgG3 myeloma protein Vi, with a rhesus monkey III. Flagellin of S. adelaide strain 1338-rabbit antiserum to antiserum to another IgG3 myeloma protein. (v) Human flagellin. IgG1 myeloma protein BC, with an anti-idiotype serum prepared in a rabbit that was immunised with BC protein and then absorbed with normal human IgG. (ti) Human 16 ,Ag of each of two other IgM proteins gave no enhanced IgG1 myeloma protein BC, with a goat antiserum to human precipitation. Fresh normal rabbit serum in a final concen- IgG, and (vii) Mouse IgG2a myeloma protein GPC-7, with tration of 2.5% also gave significant precipitation of the a mouse antiallotype serum (C57 anti-NZB [New Zealand labeled antigen-antibody complex, but did so in all four Black ]) . assays, in distinction to IgMBrd achieving this in only two cases. RESULTS To further test species specificity, four other antigen- Precipitation of a Soluble Antigen-Antibody Complex by antibody combinations were used, involving rabbit, monkey, lValdenstrim Macroglobulins. 42 purified Waldenstr6m macro- mouse, and goat antisera (Table 4). Normal rabbit serum globulins were tested for their ability to precipitate a soluble gave significant enhanced precipitation in all cases, whereas antigen-antibody complex involving '251-labeled IgG1 my- IgMBrd failed to react with mouse antibody, did not react eloma protein BC with its anti-idiotype serum. Whereas no with the goat antibody, but did give marked enhanced pre- precipitation was observed with any of the 41 macroglobulins, cipitation with both rabbit and monkey antibody. Control nor with normal human IgM, by the use of between 1.5-6.0 IgMBj failed to react in any assay. ug of protein, Waldenstrom protein BRD gave 65% precipi- Isospecificity of Ig4Brd. IgM was shown in the previous tation with 1.5 Ag (Table 1). assays to react against a human antiflagellin antiserum, This protein (IgMBrd) and one of the other inactive Walden- therefore demonstrating its isospecificity. To fuither examine strfm proteins (IgMBi), were then similarly tested in three this, primary and secondary human antisera to flagellin other antigen-antibody assay systems, all involving rabbit were fractionated into IgM- and IgG-containing fractions. antibody, but with entirely different antigens and their appropriate antisera. Again, IgMBrd gave significant pre- cipitation in all three assays (Table 2), with as little as 0.2 TABLE 3. Species specificity of IgMBrd against antigen- ug of protein. The different degrees of precipitation of the antibody complexes with flagellin 1338 antigen labeled antigen in the three assays is only a reflection of the amount of its specific antiserum used. In all cases, IgMBd Percent of 12I-labeled flagellin- was tested for its ability to precipitate the labeled antigen antibody complex precipitated without the presence of the appropriate antiserum, and in all Protein Amount Rabbit* Humant Ratt Mouse§ cases no precipitate was observed. Control IgMBi gave no 0 significant precipitation in any of the assay systems. Nil 0 8 9 By the latex-particle agglutination test with human Normal rabbit gammaglobulin-coated particles, purified IgMBrd at a con- serum 2. a5 ,l 35 16 23 22 centration of 12.0 mg/ml gave positive agglutination to a IgMBrd 12.0 jug 56 54 2 7 dilution of '/80. 3.0 /ug 48 50 2 7 Species Specificity of IgMIIBrd Anti-Antibody. Flagellin O. 8jug 37 39 2 7 IgMBi 16.0 jug 0 8 1 monomer 1338 was labeled with 1251 and used with antisera IgMK 16. 0 ug 1 0 to flagellin, prepared in the rabbit, rat, man, or mouse. When these sera were used at a dilution such that less than 10% * Hyperimmune rabbit antiserum to flagelliD.
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