The immune system as a regulator of thyroid hormone activity

Abstract

It has been known for decades that the neuroendocrine system can both directly and indirectly influence the developmental and functional activity of the immune system. In contrast, far less is known about the extent to which the immune system collaborates in the regulation of endocrine activity. This is particularly true for immune-endocrine interactions of the hypothalamus-pituitary-thyroid axis. Although thyroid-stimulating hormone (TSH) can be produced by many types of extra-pituitary cells--including T cells, B cells, splenic dendritic cells, bone marrow hematopoietic cells, intestinal epithelial cells, and lymphocytes--the functional significance of those TSH pathways remains elusive and historically has been largely ignored from a research perspective. There is now, however, evidence linking cells of the immune system to the regulation of thyroid hormone activity in normal physiological conditions as well as during times of immunological stress. Although the mechanisms behind this are poorly understood, they appear to reflect a process of local intrathyroidal synthesis of TSH mediated by a population of bone marrow cells that traffic to the thyroid. This hitherto undescribed cell population has the potential to microregulate thyroid hormone secretion leading to critical alterations in metabolic activity independent of pituitary TSH output, and it has expansive implications for understanding mechanisms by which the immune system may act to modulate neuroendocrine function during times of host stress. In this article, the basic underpinnings of the hematopoietic-thyroid connection are described, and a model is presented in which the immune system participates in the regulation of thyroid hormone activity during acute infection.

Fig. 1

Small intestinal jejunum section from a day 4 reovirus serotype 3-infected mouse stained with biotinylated anti-TSHβ antibody 1B11 (10) and streptavidin fluorescein isothiocyanate. Note the predominance of TSH+ cells in the intestinal epithelium. Staining was rare in epithelial regions of non-infected mice or using isotype control antibody (data not shown).

Fig. 2

Model of immune regulation of thyroid hormone activity during acute infection. (A, top) During the early phase of infection (12-36 hrs) such as with enteric virus infection, e.g., rotavirus or reovirus (12) or systemic viral or bacterial infection, proinflammatory cytokines and/or bacterial-derived products stimulate the conversion of T₄ to T₃ in tanycytes of the third ventricle, causing suppression of TRH and TSH release and a decrease in T₃ and T₄ output. A general sense of malaise ensues due to curtailed metabolic activity, leading to energy conservation at a critical time of host physiological stress. (B, bottom) The immune system responds to the infectious process through the generation of innate and adaptive immune responses. As the infection is controlled, CD11b+ cells selectively mobilized in the bone marrow, peripheral lymphoid tissues, and possibly in the site of infection itself, traffic to the thyroid where they secrete TSH, prompting thyroid hormone release, which in turn leads to an elevation of metabolic activity. A critical feature of this model pertains to the readjustment in thyroid hormone activity by the immune system, since it is the immune system that would be most capable of determining the optimal time for this to occur in the context of the host’s response to infectious challenge.