Introduction:
A two-directional relationship is present between the neuroendocrine and immune systems of the body. Thyroid hormones elicit responses to immune cells like monocytes, macrophages, natural killer cells, and lymphocytes. These hormones affect reactions related to inflammatory processes such as chemotaxis, phagocytosis, reactive oxygen species generation, and the production of cytokines.
What Are Thyroid Hormones?
Thyroid hormones (THs) are essential in normal development and function. The thyroid produces thyroxine (T4) and triiodothyronine (T3) under thyrotropin-releasing hormone (TRH) and thyroid stimulating (TSH), which are effectors of the hypothalamic-pituitary-thyroid (HPT) axis. T4 gets converted to T3 (biologically active) in target tissues. Blood levels of THs give feedback (positive and negative) for the synthesis of TRH and TSH.
The action of THs is determined by circulating TH concentrations and its local action at tissue or cell-specific levels. Local action of THs depends on the following:
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TH transport into the target cell.
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TH metabolism into active or inactive hormones.
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TH binding to thyroid hormone receptors (THRs) mediates TH signaling by canonical or noncanonical modes of action.
These actions at tissue and cell levels vary in health and disease, resulting in variations of the effects of THs in an organism. The immune system is defensive when microorganisms act on the human body. Initially, innate immunity provides a fast, nonspecific response, whereas later, adaptive immunity slowly gives a specific response. Many immune cells are allotted for innate or adaptive immunity, responsible for pathogen recognition, elimination, and immunological memory. Increased immune responses are dangerous and hence should be tightly regulated.
Several types of immune cells can be allocated to the innate or the adaptive immune compartment, differentially facilitating pathogen recognition, elimination, and immunological memory. However, excessive immune responses can be seriously deleterious, and thus immunity needs to be tightly regulated. Twenty years ago, evidence was found for the production of TSH by immune cells. Initially, studies observed that leucocytes produced TSH when stimulation was done to staphylococcus enterotoxin A or on exposure to TRH. THs sometimes serve as negative regulators of hematopoietic TSH, similarly to the HPT axis.
Splenic dendritic cells (DCs) in the secondary lymphoid tissues show as a source of TSH. A study confirmed that most of the cells which produce TSH-producing cells are marginal zones surrounding T-cell areas and in germinal centers where DCs are enriched. The number of cells in the marginal zones of the spleen and lymph nodes increased with bacterial lipopolysaccharides (LPS), stating that TSH-producing cells of the immune system respond to antigenic stimuli resulting in increased production of TSH.
A study showed that bone marrow hematopoietic cells produced TSH when intracellular staining was done with CD45 (leucocyte-common antigen (LCA) CD11b. Intestinal epithelial cells and T cells are also found to produce TSH. Also, intestinal cells are found with TSH receptors.
What Is Non-thyroidal Illness Syndrome?
T4 and T3 levels decrease during severe illnesses like surgery or infections, though normal or reduced TSH levels exist. Decreased levels of T4 show disease severity and increased mortality. Hormonal changes are similar to central hypothyroidism but reverse as the patient recovers. Reverse T3 (rT3) in serum concentrations is elevated in critically ill patients, but this does not happen in central hypothyroidism. This condition is known as non-thyroidal illness syndrome (NTIS).
Autoimmunity can cause thyroid gland dysfunction resulting in primary hypothyroidism or hyperthyroidism.
What Is the Action of THs on Immune Cells?
Macrophages: When pathogens enter the body, cells that respond first are macrophages, present in tissues. Macrophages adapt to proinflammatory M1 or anti-inflammatory M2 phenotype. M1 macrophages work through phagocytosis and the generation of reactive oxygen species (ROS), whereas M2 macrophages repair tissue. Tissue-resident macrophages bring out their immune response via the secretion of cytokines (IL1β, IL6, and TNF).
Dendritic Cells: Dendritic cells (DCs) are found in lymphoid and non-lymphoid tissues and are involved in pathogen surveillance and adaptive immunity. There are two types of DCs. They are
- Classical DCs (cDCs): These antigen-producing cells (APC) initiate T cell responses with type 1 cDCs activating CD8+ T cells and type 2 activating CD4+ T helper cells.
- Plasmacytoid DCs (pDCs): Sources of type 1 interferons giving antiviral immunity.
- Neutrophils: Neutrophils are the first to come into a place of inflammation and clear pathogens through extracellular and intracellular killing. Intracellular killing is based on phagocytosis and ROS generation; extracellular killing is based on traps.
Monocytes: Monocytes go to the site of infection following neutrophils. They release pro-inflammatory cytokines and get differentiated into macrophages and DCs. THs increase the antibacterial immune response of monocyte-derived macrophage.
Natural Killer Cells: Natural killer (NK) cells are lymphocytes in the immune system. It readily kills the infected cells.
What Are the Local Actions of THs on Adaptive Immunity?
- Action on T cells: T lymphocytes are responsible for immune response in adaptive immunity. These are CD4+ and CD8+ T cells. CD8+ T cells act via apoptosis(cell death occurs due to a series of molecular steps in a cell) at the site of infection. In CD4+ T cells, differentiate into various T helper cells to bring out the immune response.
- Action on B cells: B lymphocytes secrete immunoglobulins(Ig). Based on the recognition of foreign antigens, these initiate B cells' activation.
What Is the Action of TSH on Immunity?
TSH itself also regulates the immune system. Immune cells show receptors of TSH (TSHR). Studies have shown that TSH promotes lymphocyte proliferation and activation, including NK, T, and B cells. Another finding from a study is that secretion of DCs increased, thereby increasing phagocytic activity and proinflammatory cytokines.
What Are the Unknowns of THs Actions on the Immune System?
Some unclear aspects of the actions of THs and immune systems are
- The components mediating TH action.
- Impact of THs on immune cell function.
- Tissue-specific TH availability in health and disease.
Future studies need to be conducted to clarify these unclear aspects of the actions of THs on the immune system.
Conclusion:
The immune system and how it responds to various aspects are still unclear. Many studies have been conducted to know about the actions of THs on the immune system. Further studies are required to learn more about the actions of THs on the immune system. Knowing better about the topic helps one understand the related diseases and helps diagnose the disease early.
