High levels of circulating triiodothyronine induce plasma cell differentiation

Abstract

The effects of hyperthyroidism on B-cell physiology are still poorly known. In this study, we evaluated the influence of high-circulating levels of 3,5,3 0 -triiodothyronine (T 3 ) on bone marrow, blood, and spleen B-cell subsets, more specifically on B-cell differentiation into plasma cells, in C57BL/6 mice receiving daily injections of T 3 for 14 days. As analyzed by flow cytometry, T 3 -treated mice exhibited increased frequencies of pre-B and immature B-cells and decreased percentages of mature B-cells in the bone marrow, accompanied by an increased frequency of blood B-cells, splenic newly formed B-cells, and total CD19C B-cells. T 3 administration also promoted an increase in the size and cellularity of the spleen as well as in the white pulp areas of the organ, as evidenced by histological analyses. In addition, a decreased frequency of splenic B220 C cells correlating with an increased percentage of CD138 C plasma cells was observed in the spleen and bone marrow of T 3 -treated mice. Using enzyme-linked immunospot assay, an increased number of splenic immunoglobulinsecreting B-cells from T 3 -treated mice was detected ex vivo. Similar results were observed in mice immunized with hen egg lysozyme and aluminum adjuvant alone or together with treatment with T 3 . In conclusion, we provide evidence that high-circulating levels of T 3 stimulate plasmacytogenesis favoring an increase in plasma cells in the bone marrow, a longlived plasma cell survival niche. These findings indicate that a stimulatory effect on plasma cell differentiation could occur in untreated patients with Graves' disease.

Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

“…Consistent with previous studies, EtOH treatment of these mice produced significant increases in molecular markers of Kupffer cell and stellate cell activation, matrix remodeling, and fibrosis relative to PF PPAR-␣Ϫ/Ϫ mice, and serum ALT values indicative of hepatocellular necrosis were elevated threefold over EtOH WT mice. In addition, an increased hepatic population of CD3ϩ T cells and increased CD138 mRNA, an indicator of B cell differentiation into immunoglobulin-secreting plasma cells (8), in mice lacking PPAR-␣ and exposed to EtOH are consistent with an increased autoimmune response. These indications of increased progression of liver pathology in EtOH PPAR-␣Ϫ/Ϫ mice were accompanied by significant increases in lipid peroxidation and 4-HNE adducts and thus might also be mediated via the toxic effects of lipid peroxidation products.…”

“…Expression of B220 mRNA was suppressed relative to PF in EtOH-treated WT and dKO mice (P Ͻ 0.05). Interestingly, expression of CD138 mRNA, a marker of B cell differentiation into immunoglobulin-secreting plasma cells (8), was increased in PF PPAR-␣Ϫ/Ϫ mice and dKO mice from the PF groups compared with either PF WT or GSTA4Ϫ/Ϫ mice (P Ͻ 0.05) and increased by chronic EtOH treatment in all mouse genotypes relative to their PF groups (P Ͻ 0.05). Molecular markers of Kupffer cell activation and chemokine and cytokine production were also examined.…”

Environmental Enrichment Induces Pericyte and IgA-Dependent Wound Repair and Lifespan Extension in a Colon Tumor Model

“…In addition to activation of these NHRs, common inhibitors of the GC pathway including breakpoint cluster region (BCR), 11-beta-dehydrogenase isozyme 2 (HSD11β2), and gamma secretase complex are inhibited (Figure 3A; Table S3B), an activity that would further increase GC signaling. Interestingly, a subset of NHRs also involved in wound repair (Rieger et al, 2015) are activated by EE in the colons of Tcf4 Het/+ Apc Min/+ mice (Figure 3A; Tables S3B and S3D) including; peroxisome proliferator-activated receptor (PPARα; NR1C1; Figure 2A; (Michalik and Wahli, 2006)), thyroid hormone receptor (THRA; NR1A1; (Bloise et al, 2014; Contreras-Jurado et al, 2014)), oxysterol receptors (Liver X receptor; LXR; NR1H2, NR1H3, NR1H4; (Beyer et al, 2015)) retinoic acid receptors (RARA and RXRA; (Hunt et al, 1969; Rieger et al, 2015)) as well as the nuclear receptor coactivator (NCOA1) involved in co-activation of GR, RXR, THRA and PPAR nuclear hormone receptors (Walsh et al, 2012). This finding suggests that NHRs commonly involved in the wound repair process may play a role in improving the lifespan of EE Tcf4 Het/+ Apc Min/+ male animals.…”

“…In EE colons, several different NHR signaling pathways are activated, suggesting that each may play a role in the tumor wound repair response. For example in EE tumor bearing animals, GC and MC signaling may play a role in reduced inflammation and revascularization (Ullian, 1999), while the reactivation of thyroid hormone signaling may effect both re-epithelialization and B cell recruitment and migration to the tumor periphery (Bloise et al, 2014; Contreras-Jurado et al, 2014). In our study, we have further characterized thyroid hormone signaling within the stromal and tumor cell compartments in EE tumor bearing mice, and found activation of both hormone metabolism and the hormone receptor.…”

Antithyroid Drug Therapy in Patients with Graves’ Disease

“…Finally, ATD therapy may have immunosuppressive effects, either indirectly or directly. Some experts have proposed that the hyperthyroid state itself can perpetuate a dysregulated immune system, for example via induction of plasma cell differentiation [ 7 ] or affection of one or more among the many other mechanisms whereby thyroid hormones participate in immune system homeostasis [ 8 ]. In this construct, by making and keeping patients euthyroid, the immune system's normal tolerance to "self" is gradually restored [ 9 ].…”