I ncorporation of L-leucine-¹⁴C into proteins and immunoglobulins in vitro was determined in jejunal biopsy specimens from normal volunteers, patients with celiac sprue before and after introduction of gluten into the diet, patients with Whipple's disease in remission, and patients with immune deficiency states.Values for incorporation of L-leucine-¹⁴C into total and soluble protein by biopsies from five celiac sprue patients on a gluten-free diet were within, or slightly above, the 95% confidence limits for control data. One patient with celiac sprue and with normal intestinal histology had a normal value for incorporation into IgA; the other four patients with flat mucosas had elevated values. In Whipple's disease in remission, values for incorporation into total protein and IgA were within the control limits, whereas incorporation into soluble protein was increased. Patients with hypogammaglobulinemia or IgA deficiency had normal or elevated values for incorporation into total and soluble proteins; in these cases, however, no incorporation into IgA was detected.Biopsies from the four celiac sprue patients studied revealed that with introduction of gluten into the diet (a) incorporation into total protein, soluble protein, or both, increased; (b) incorporation into IgA increased in all patients, and in two instances the increase was greater than the increase in incorporation into total protein; and (c) incorporation into IgM increased in all patients. The changes during gluten administration usually occurred before changes in gastrointestinal absorptive function or in concentration of IgA in serum could be detected.These results indicate that gluten challenge stimulates increased local intestinal synthesis of immunoglobulins in patients with celiac sprue. The reaction occurs within days and it is possible that it plays a primary role in the pathogenesis of the disease.