T cell regulation of polyclonal B cell responsiveness. III. Overt T helper and latent T suppressor activities from distinct subpopulations of unstimulated splenic T cells

Polyclonal activation of murine splenic B lymphocytes by lipopolysaccharide was found to be subject to regulation by helper and suppressor influences from T lymphocytes. In the normal adult spleen, only helper influences were exercised over polyclonal B cell activation; this influence is a property of Lyt-l(+)23(-) slowly sedimenting T cells. Suppressive influence evidently is latent, for it exists at such a low level (or the cells are so few in number) that its effects are difficult to detect. Suppressor T cell function may be evoked by culturing spleen cells at high ratios of T:B cells, by activating splenic T cells with concanavalin A, or by sonicating unstimulated splenic T cells to liberate a suppressive potential that is not expressed by these unstimulated cells when intact. The soluble fraction of resident splenic T cell sonicates exerts both helper and suppressor regulatory influences. The soluble helper activity is derived from Lyt-l(+)23(-) slowly sedimenting T cells, whereas suppressor activity is generated from a distinct subpopulation of Lyt-l(-)23(+) rapidly sedimenting T cells. The thymus contains cells capable only of helping but not of suppressing polyclonal activation of splenic B cells. Helper and suppressor activities contained in splenic T cell sonicates were separated by gel chromatography; the suppressive activity was found to elute with a molecular weight between 68,000 and 84,000 and the helper activity eluted with a molecular weight between 15,000 and 23,000. The data indicate that helper and suppressor activities are distinct molecular entities derived from distinct splenic T lymphocyte subpopulations. The possibility that these molecules are precursors to or components of antigen- specific or nonspecific helper and suppressor factors described in the literature is discussed

Effect of thyroglobulin autoantibodies on the metabolic clearance of serum thyroglobulin

Background: In order to establish whether thyroglobulin autoantibodies (TgAb) influence the metabolic clearance of thyroglobulin (Tg) in humans, serum Tg and TgAb were correlated shortly after radioiodine (131I) treatment. Methods: Samples were collected from 30 consecutive patients undergoing 131I activity for Graves' hyperthyroidism at the time of treatment and every 15 days thereafter, up to 90 days. Tg and TgAb were measured by immunometric assays (functional sensitivities: 0.1 ng/mL and 8 IU/mL). Results: Tg was detectable in all patients at day 0. Tg concentrations rose from a mean of 33.2 ng/mL [confidence interval (CI) 17.8–61.0 ng/mL] at day 0 to a mean of 214.6 ng/mL [CI 116.9–393.4 ng/mL] at day 30 and then steadily decreased, reaching the lowest concentration at day 90 (M = 10.9 ng/mL [CI 5.5–20.9 ng/mL]). Compared to their levels at day 0 (M = 23.6 IU/mL [CI 10.5–52.9 IU/mL]), TgAb remained stable through day 15 and then gradually increased up to a mean of 116.6 IU/mL [CI 51.9–262.2 IU/mL] at day 90. Patients were then split into two groups according to their TgAb status at day 0: undetectable (<8 IU/mL; 9 patients) or detectable (≥8 IU/mL; 21 patients) TgAb. Compared to the other cohort, patients with detectable TgAb showed significantly lower Tg concentrations at day 0 (M = 20.3 ng/mL [CI 10.1–40.2 ng/mL] vs. M = 101.8 ng/mL [CI 36.6–279.8 ng/mL]), similar at day 15, lower levels at day 30 (M = 146.5 ng/mL [CI 74.3–287.8 ng/mL] vs. M = 514.8 ng/mL [CI 187.8–1407.9 ng/mL]), at day 45 (M = 87.5 ng/mL [CI 43.1–176.6 ng/mL] vs. M = 337.9 ng/mL [CI 120.1–947.0 ng/mL]), at day 60 (M = 61.6 ng/mL [CI 31.0–121.4 ng/mL] vs. M = 255.8 ng/mL [CI 79.0–823.8 ng/mL]), and at day 75 (M = 24.5 ng/mL [CI 11.9–49.2 ng/mL] vs. M = 249.5 ng/mL [CI 63.5–971.1 ng/mL]), and similar levels at day 90. Patients with detectable TgAb showed a lower (M = 182.5 ng/mL [CI 92.0–361.0 ng/mL] vs. M = 514.8 ng/mL [CI 187.8–1407.9 ng/mL]) and an earlier (day 15 vs. day 30) peak of Tg. The mean Tg concentration was lower in patients with detectable TgAb than in those with undetectable TgAb (area under the curve: 17,340 ± 16,481 ng/mL vs. 36,883 ± 44,625 ng/mL; p = 0.02). Conclusions: TgAb influence the changes in Tg concentrations observed immediately after 131I treatment, inducing lower levels and an earlier peak of Tg. These observations indicate that TgAb significantly influence the metabolic clearance of Tg, supporting the concept that their interference in the measurement of Tg is mainly due to an in vivo effect

Pathophysiological lessons from rare associations of immunological disorders

Rare associations of immunological disorders can often tell more than mice and rats about the pathogenesis of immunologically mediated human kidney disease. Cases of glomerular disease with thyroiditis and Graves’ disease and of minimal change disease with lymphoepithelioma-like thymic carcinoma and lymphomatoid papulosis were recently reported in Pediatric Nephrology. These rare associations can contribute to the unraveling of the pathogenesis of membranous nephropathy (MN) and minimal change disease (MCD) and lead to the testing of novel research hypotheses. In MN, the target antigen may be thyroglobulin or another thyroid-released antigen that becomes planted in the glomerulus, but other scenarios can be envisaged, including epitope spreading, polyreactivity of pathogenic antibodies, and dysregulation of T regulatory cells, leading to the production of a variety of auto-antibodies with different specificities [immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX syndrome)]. The occurrence of MCD with hemopathies supports the role of T cells in the pathogenesis of proteinuria, although the characteristics of those T cells remain to be established and the glomerular permeability factor(s) identified