The origins of autoimmune thyroid disease should be appropriately viewed from the context of immunological dysregulation, set forth by a myriad number of genetic and epigenetic factors. This view should seek to investigate the metabolic significances of thyroid physiology, with its highly oxidative environment, as well as its propensities towards heightened danger signaling and innate immunological response mechanisms. Mechanisms involving innate immune signaling such as the complement immune response, the inflammasome, TLRs (toll like receptors), PRRs (pattern recognition receptors), viral, retroviral, xenobiotic, pathogenic and other antigenic influences should be considered primary drivers of autoimmune thyroid disease susceptibility.
The recognition that the innate immune system plays a significant role in autoimmune thyroid disease leads to a deeper understanding of how danger signaling coordinates with the antibody system. From the clinical perspective, the presence of rising thyroid antibodies is characteristic of autoimmunity, yet it is the innate immune system which can be seen as the primary alarm system that is responding to the threat of danger.
The Innate Immune System & Thyroid Tissue
The innate immune system is considered an ancient cellular process, predating the adaptive immune system in terms of the evolutionary timeline. The study of the innate immune system in disease is of great interest because this system is the initial defense response following the hours of acute infection, which will greatly influence the subsequent immunological processes to follow. Additionally, innate immunological mechanisms are at the core of the autoimmune process, due to the complex set of processes, which promote TH1-mediated immunity and response to antigenic factors.
The complement immune system, a 3-tiered series of protein cascading reactions, plays a critical role in pathogenic identification and neutralization. Deficiencies, excesses and variations of complement protein mechanisms are strongly linked to a number of autoimmune conditions, and are often influenced by genetic predispositions.
The complement immune system is comprised of 3 pathways: the Lectin pathway, the Alternative pathway and the Classical pathway. Using the lectin pathway, upon pathogenic identification and binding, complement proteins C4 and C2 are split off into C4a, C4b, C2a and C2b by MBL-1 and MBL-2 (mannose binding lectin). Lectin activation participates in the formation of C3 convertases, which are critical for the subsequent opsonization of targeted pathogens. The Classical complement pathway recognizes and works in concert with IgG and IgM antibodies during antigenic recognition.
A study from 2003 investigating the role of complement activation in autoimmune Hashimoto’s and Grave’s disease, found that thyroid cells over-express complement C4, as well as all of the downstream products of C4. The study found that C4 is capable of binding directly with the TPO protein (thyroid peroxidase). This is significant because it highlights the activation of the innate immune defenses occurring within thyroid tissues (1). Because complement C4 can directly bind to TPO, it calls into question how thyroid antibodies are actually formed.
It’s key to remember that the thyroid gland is an oxidation-rich environment, which will normally generate numerous reactive oxygen species and pro-oxidants. The release of the complement immune cascade is sensitive to changes in this highly oxidizing environment, and will be up-regulated under heightened ROS conditions.
Autoantibodies against complement proteins C1q have been described in lupus, as well as in Hashimoto’s and Grave’s disease (6). C1q, C1r and C1s are critical activators of the Classical complement pathway. Autoantibodies against C1q would not only potentially handicap the Classical pathway, but also create havoc with the Lectin complement pathway, due to the fact that both pathways share Complements C4 and C2, and the split C4a, C4b, C2a and C2b proteins.
Thyroid & The Inflammasome
The inflammasome is a multi-protein, intracellular complex that plays a key role as part of the innate immune defense. The Inflammasome is activated when PRRs (pattern recognition receptors) and TLR’s (toll-like receptors) are engaged. These receptors are found on cell surfaces as well as inside of cells. These receptors are activated by a number of stimuli, namely PAMPs (pathogen associated molecular patterns) and DAMPs (damage associated molecular patterns). PAMPs are derived from various pathogenic fragments (such as viruses, bacteria, fungi) and DAMPs are typically derived from the body’s own broken down and damaged tissues (such as degraded fragments of hyaluronic acid, mitochondria and intracellular misfolded proteins). PRRs can also be activated by a number of toxins, such as aluminum, mercury, cadmium, asbestos and silica. The activation of the inflammasome leads to the recruitment of pro-inflammatory cytokines IL-1ß, IFN gamma, TH18 and NF kappa beta. The over-expression of the inflammasome has been studied as a key mechanism in the development of autoimmune disease (3, 4).
Importantly, autoimmune thyroid cells feature an elevated expression of the TLR’s (toll like receptors) (2). Viral infections will directly engage the inflammasome and their receptors, and numerous viral infections are associated with Hashimoto’s and Grave’s disease. Some of the most common include: EBV (epstein barr virus), enteroviruses such as Coxsackie, CMV (cytomegalovirus), parovirus, mumps, HSV-1, HHV-6, as well as exogenous RNA retroviruses such as HTLV-1 and HIV (5).
Retroviral Infection In Hashimotos & Grave’s Disease
Retroviruses are a type of virus known as RNA viruses. A significant percentage of the human genome is comprised of endogenous retroviruses, such as HERV-K and HERV-W. These endogenous retroviruses are largely silenced. However they can be reactivated under certain circumstances, and actually play important roles in embryological development. Mechanisms of danger signaling leads to their reverse transcription and subsequent formation of PAMPs, and the engagement of the innate immune system. It has been recognized that the reverse transcription of endogenous retroviruses plays an important part in host defense against incoming pathogens and viruses. It has even been proposed that fewer numbers of endogenous retroviruses in certain genomic regions is etiological in the development of autoimmune diseases (9).
Exogenous retroviruses have been studied since the early 1970’s, as potential players in cancer. HIV is the most commonly known exogenous retrovirus. HTLV-1 is a retrovirus associated with T-cell lymphoma, leukemia, and a variety of myelopathies.
A considerable number of studies have been published, analyzing a variety of populations with concurrent autoimmune thyroid and HTLV-1 (5). Retroviral infections will engage the innate immune system through PRR’s of the inflammasome, as well as through Classical pathway C1 complexes (7). Curiously, NLRP3 inflammasome polymorphisms are associated with protection against HTLV-1, highlighting the role of genetic diversity in retroviral defenses and susceptibilities (8).
The Inflammasome Is Coordinated By The Mitochondria
Emerging research in the field of cell biological danger signaling reveals that the mitochondria are critical coordinators of inflammasome assembly (24). The interactions between mitochondria, mitochondrial DNA and the innate immune system have been observed for some time (25). These critical interactions place the primary-energy-producing factories of our cells in a front row center position as modulators of immune response mechanisms.
Mitochondria of thyroid cells are highly biologically active. In order to generate thyroxine (T4), thyroid cells produce H2O2 (hydrogen peroxide). Thyroid cells are also major producers of reactive oxygen species, including the superoxide anion. It is significant to consider that mitochondria of any cell type will generate reactive oxygen species as a byproduct of oxidative phosphorylation. During states of inflammatory cell danger signaling, mitochondrial energy production is decreased and oxygen builds up inside of cells as a means to generate more ROS (26). The perceived threat of infection will create a metabolic shift to occur within a cell, leading to a change of metabolism away from assembly and constructive processes, towards defense mechanisms, in order to protect against the threat of danger (chemical, pathogenic, or other).
From the clinical perspective in autoimmune thyroid disease, thyroid mitochondrial function should become a core focus, as well as the main instigators of danger signaling activation.
Modulation of the Innate Immune Response
A number of therapeutic mechanisms have been studied which have shown to modulate the innate immune responses in a variety of ways. Clinically speaking, the antigenic factors that are engaging the innate immune system should be identified appropriately. Faulty, exaggerated or deficient aspects of the innate immune response will alter host immunity and increase chances for autoimmune disease.
With respect to therapeutics, it should be understood that the innate immune response is a critical part of host defense. The desire to suppress or heighten innate immunity can lead to further, counter-regulatory imbalances. In the context of autoimmune thyroid, the modulation of the innate immune system should proceed foundational nutritional interventions, if necessary.
With respect to autoimmune thyroid, this often involves: viral and pathogenic influences, chemical and heavy metal toxicity, dietary immune reactions (such as gluten, sugar, alcohol, dairy).
AMPK is a critical protein kinase that when activated has shown to down-regulate the inflammasome (15). AMPK can be increased through a number of mechanisms. Some of the most notable include:
- Caloric restriction (10)
- Berberine (11) – A versatile plant alkaloid with glucose-modulating properties, as well as anti-fungal and anti-microbial effects. Berberine acts to modulate glucose via AMPK activation.
- Bitter melon (12) – A versatile bitter gourd with AMPK-enhancing effects, notable for lowering glucose and possibly modulating adiponectin. Bitter melon also possesses anti-viral properties, and has historically been used in Asia to reduce infectious agents.
- Lipoic acid (13) – A potent disulfide antioxidant and NrF2 promoter. Nrf2 has also been shown to regulate the Inflammasome (16).
Other Inflammasome Modulators
- The ketone ß-hydroxybutyrate has shown to reduce inflammasome activity (14). This is of interest given that this ketone body can be increased through ketogenic, carbohydrate-restricted diets. ß-hydroxybutyrate is also available supplementally, as well as through endogenous production in the liver from medium chain triglycerides.
- Cannabis, CBD & endocannabinoid activation inhibits TLR (toll like receptors), and in general is a potent anti-inflammatory (22). CBD has emerged as a significant natural compound against autoimmune disease, and its inhibitory effects on inflammasome activation is one of the most notable.
- The Chinese herb astragalus root has shown to inhibit the Inflammasome NOD receptors (19). Not everyone with autoimmune disease responds favorably to astragalus, however. The reasons for this have been debated for years. However, for those who do respond well to astragalus, it is considered one of the most significant herbal medicines in Traditional Chinese Medicine.
- Resveratrol inhibits the Inflammasome and stabilizes mitochondrial integrity, and augments an important cell clean up process known as autophagy (20).
- Baicalin, aka Chinese Skullcap (Scutilleria Baicalensis) inhibits TLR4 (toll like receptor 4) in mice (23). Clinically speaking, Chinese skullcap is a potent botanical agent, with notable anti-inflammatory, anti-viral, and GABA-A receptor-promoting effects.
- Complement immune activity can be activated by 1,3 ß glucans (17). These are a class of immunomodulating polysaccharides from medicinal mushroom complexes. Interestingly, fungal derived beta glucans (from candida albicans) is a known activator of the inflammasome.
- Polysaccharides from astragalus root are activators of complement (18).
- Arabinogalactan is a biopolymer that is considered to be an “anti-complement” compound, yet it increases the consumption of C4 and C3, including an increase splitting of these into their fragmented forms. New studies need to be conducted to provide more evidence as to this compounds effects (21).
Future research is necessary to better understand the relationships between the innate immune system, thyroid mitochondrial function, danger signaling, and the potential role of numerous natural products and botanicals to modulate important pathways involved in autoimmune thyroid disease.