One of the most promising avenues of approach to the relationship between specificity and amino acid sequence of antibodies utilizes the products of malignant lymphoid cells. T h e patient with multiple mye-loma characteristically produces large amounts of a protein similar to normal yG- or normal γΑ-immunoglobulin, but much more homogeneous (Fahey, 1962). Many lines of evidence suggest that isolated myeloma pro-tein is homogeneous with respect to amino acid composition and se-quence. In a similar disease, Waldenstrom's macroglobulinemia, large amounts of a homogeneous γΜ-immunoglobulin (macroglobulin) are synthesized.
As already indicated, the Bence Jones proteins excreted in the urine are homogeneous light chain monomers or dimers derived from myeloma protein or macroglobulin. Homogeneity is of course a prerequisite for meaningful studies of amino acid sequence and attempts to determine the complete sequence of individual Bence Jones proteins are currently in progress in the laboratories of L. C. Craig and F. W. Putnam.
A basic premise of this approach is that the myeloma or Bence Jones protein is a typical, single representative of the heterogeneous γ-globulin population and is not really "abnormal/' Presumably, it represents the product of a clone of malignant lymphoid cells derived from a single precursor. In contrast, many clones contribute to the synthesis of normal immunoglobulins of a given class and even to antibody of one specificity derived from a single animal. There is little if any evidence in contra-diction to this view and many kinds of experimental data support it. If this theory is correct, studies of amino acid sequence in such "parapro-teins" will yield information regarding the extent of variability of se-quences among antibodies and should lead to the identification of the variable and invariant regions of the polypeptide chains.
One limitation is that, so far, antibody activity has not been demon-strated in a myeloma protein. This might reflect the difficulty of finding the antigen associated with such a protein. Alternatively, it is conceivable that many or even most γ-globulin molecules are synthesized without any instruction from an antigen and that specificity is an accident of associa-tion of a particular pair of light and heavy chains; i.e., many
immuno-60 ALFRED NISONOFF AND FRANKLIN P. INMAN
globulin molecules do not have a corresponding antigen. In any event, the study of myeloma and Bence Jones proteins may yield, for the first time, precise information as to the degree of heterogeneity of γ-globulins and may result in localization of the active regions of the light and heavy chains.
ACKNOWLEDGMENTS
This work was supported by grants from the National Institute of Allergy and In-fectious Diseases (AI-06281) and the National Science Foundation (GB-1563). Dr.
Nisonoff is a recipient of a Research Career Award of the National Institutes of Health.
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