R. Dean Wochner

The role of the kidney in the catabolism of Bence Jones proteins, intact IgG molecules, and isolated L chains, Fab and Fc fragments of IgG, was studied. The proteins were purified, radioiodinated, and their survival times measured in nephrectomized, ureter-severed, and control mice. Active endogenous catabolism was the major factor in overall Bence Jones metabolism since excretion as proteinuria accounted for less than 25% of the total metabolism. The survival times of lambda- and kappa-type human Bence Jones proteins and the Bence Jones protein produced by mice with MPC-2 plasma cell tumor were exceedingly short in both unoperated and ureter-severed mice, with 50% of the injected protein catabolized in from 0.8-1.6 hr. In contrast, the survival of Bence Jones protein was markedly prolonged in nephrectomized animals, with 50% of the injected dose catabolized in from 9 to 17 hr. This ten-fold decrease in catabolic rate indicates that the kidneys are the major site of breakdown of Bence Jones proteins. Similar studies with other proteins indicated that the kidneys are also the major site for catabolism of isolated L chains but not of intact IgG molecules. The Fc immunoglobulin fragment was not catabolized and the Fab fragment only partially catabolized by the kidney. When ureter-severed animals were allowed to develop advanced uremia before being studied, the survival of Bence Jones protein was greatly prolonged, indicating that the catabolic process is impaired in the presence of uremia. The nature of this renal catabolism remains unknown. These observations suggest that the Bence Jones proteins and L chains observed in the urine of patients may reflect only a small fraction of such molecules synthesized by these patients. Furthermore, they provide an explanation for the prolongation of Bence Jones protein survival and the development of Bence Jones proteinemia observed in subjects with multiple myeloma and impaired renal function.

Intestinal lymphangiectasia is a disease characterized by dilated intestinal lymphatics, protein-losing enteropathy, hypoalbuminemia, and edema. The immunologic status of 18 patients with intestinal lymphangiectasia was studied. Concentrations of IgG, IgA, and IgM were measured by immune precipitation and metabolism of these three immunoglobulins was studied using purified radioiodinated proteins. The serum concentration and total body pool of each immunoglobin were greatly reduced. The fraction of the intravascular protein pool catabolized per day was increased to 34% for IgG, 59% for IgA, and 66% for IgM; these are in contrast with control values of 7%, 28%, and 17%, respectively. Synthetic rates of the immunoglobulins were normal or slightly increased. Primary circulating antibody response was tested in five patients with Vi and tularemia antigens. Titers elicited in patients with the Vi antigen were significantly lower than those seen in a control group, whereas no difference was seen between patient and control responses to the tularemia antigen. Lymphocytopenia was noted in patients with intestinal lymphangiectasia. The mean circulating lymphocyte count was 710 +/- 340/mm(3) in contrast to 2500 +/- 600/mm(3) in controls. Cellular hypersensitivity was studied with skin tests and skin grafts. 91% of normal individuals reacted to at least one of the four skin test antigens: purified protein derivative, mumps, Trichophyton, and Candida albicans; in contrast, only 17% of patients with intestinal lymphangiectasia had a positive reaction. Each of three patients tested with dinitrochlorobenzene had a negative reaction. Finally, all four patients who received skin homografts have retained these grafts for at least 12 months. The immunological disorders in patients with intestinal lymphangiectasia appear to result from loss of immunoglobulins and lymphocytes into the gastrointestinal tract secondary to disorders of lymphatic channels. Lymphocyte depletion then leads to skin anergy and impaired homograft rejection.

lins) are antibody containing molecules which are present normally in all animal species that have been appropriately examined. In man, the 'y,-macroglobulins constitute about 7 % of the total gamma globulin group and 1 to 2 % of all serum protein. They differ from the more abundant 6.6 S y-globulins in being larger (mol wt about 1,000,000), in being unable to pass the placental barrier, and in having distinctive antigenic charac-teristics (1, 2). Antibodies such as the isohemag-glutinins, typhoid 0 antibodies, and cold aggluti-nins are predominantly in the y,-macroglobulin group. Infants respond principally with macro-globulin antibodies (3-5), and in adult animals and man the response to many (perhaps all) anti-gens normally passes through an early stage in which antibody activity is entirely limited to the 'yi-macroglobulins (6-9). The amount of gamma macroglobulin (and macroglobulin antibody) in the serum depends on the rate and duration of macroglobulin synthe-sis and on the rate of y1-macroglobulin removal and catabolism. Previous studies in animals (9, 10) and man (11-14) have indicated that y1-macroglobulins are catabolized more rapidly than 6.6 S y-globulins. Half-times of 2 to 3 days have been reported for normal human gamma macroglobulin (11), and half-times of 6.5 to 13 days have been found with macroglobulins obtained from patients with Wal-denstrom's macroglobulinemia (12, 13). In some of these studies (11), the methods used for iso-lating the 71-macroglobulin may have altered the protein and thus shortened the apparent survival. In other studies (12) where radioactive labeled amino acids were used in vivo, the apparent sur-vival may have been spuriously prolonged due to persistent radioactivity in the precursor amino * Submitted for publication October 25, 1963; accepted

EXCESSIVE loss of plasma proteins into the gastrointestinal tract, which may be a major factor in the pathogenesis of hypoproteinemia and edema, has been demonstrated to occur in association with a number of well defined disorders of the gastrointestinal tract such as giant hypertrophy of the gastric rugae,1 regional enteritis,2 sprue,3 Whipple's intestinal lipodystrophy,4 ulcerative colitis2 and gastrointestinal cancer.5 The study of patients with protein-losing gastroenteropathy has also led to the elucidation of a number of syndromes that were previously unrecognized as causes of hypercatabolic hypoproteinemia. These include intestinal lymphangiectasia6 7 8 and gastrointestinal protein loss associated with constrictive pericarditis9 or agammaglobulinemia. . . .

Myotonic dystrophy is a hereditary progressive muscular abnormality with dominant transmittance that was first proposed as a separate entity by Batten and Gibb (1) and by Steinert (2) in 1909. The muscular abnormality that is the dominant feature of the disease is characterized by weakness, wasting, and myotonia, especially of the facial, neck, and distal musculature. Other abnormalities frequently associated with the disease include frontal alopecia, cataracts, gonadal atrophy, low basal metabolic rate with normal thyroid function, impaired glucose tolerance, and electrocardiographic abnormalities.