Katlyn Mayer’s Advanced Biochemistry Blog

Cellular and Genetic Basis of the Disease

Cellular and Genetic Basis of the Disease

Hashimoto’s Disease is characterized by many protein, gene, and cellular abnormalities. The most well-known gene disruption in Hashimoto’s Disease is the abnormalities associated in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). While it is not a mutation that causes the irregularities, rather its down-regulation. A study conducted in 2003 found that those suffering from Hashimoto’s Disease exhibited mutations in the Human Leukocyte Antigen (HLA) in conjunction with the CTLA-4 down-regulation. The HLA protein has long been implicated in many autoimmune diseases such as type 1 diabetes and Celiac Disease. The connection found between these two genes is important for establishing who might suffer from Hashimoto’s or other autoimmune diseases later on.

A cell biology explanation for a possible cause of Hashimoto’s Thyroiditis involves the concept of apoptosis— cellular “suicide.” While one of the causes of thyroid cell destruction is known to be antibodies against thyroid perxodiase and thyroglobulin, another way in which the cells die is through apoptosis. Autoimmune disease are known to be particularly tough against the natural tissues of the body. Antibodies are an external factor that causes the death of healthy thyroid tissue, but apoptosis is an internal pathway that also causes the death of hyealthy thyroid tissue. Using immunohistochemistry and realtime PCR, researchers were able to identify the faulty genes and proteins that are implicated in this pathway include mutated Fas, decreased expression of Bcl-2 (a mitochondrial protein), as well as a marked increase in the expression of death agonists to death antagonists. Because mitochondrial DNA is passed down from mother to child, this apoptosis theory of disease mechanism offers a plausible explanation as to how the disease is caused by genetic factors.This finding is important as providers should be on the lookout for these gene ratios in addition to the presence of the Hashimoto’s antibodies in the blood in patients suffering from symptoms of hypothyroidism in order to rule out Hashimoto’s. 

Selenocysteine contains a selenium atom instead of a sulfur atom. It is sometimes referred to as the “21st amino acid.”

Another study implicated the SEPS1 gene as a possible genetic marker for Hashimoto’s Thyroiditis. This group studied the Han Chinese population of Hashimoto’s patients– the same population studied in 1985 in the paralysis studies discussed in the Background and History section of my theme pages. The study notes that the variations have already been noted in European population. SEPS1, also known as SELS (selenoprotein S) is a human protein which contains a selenocysteine residue at its active site. The protein is known to regulate cytokine production which is crucial for the inflammatory response in the immune system. Several single nucleotide polymorphisms (SNPs) are implicated in causing mutations to SEPS1 which can lead to uncontrolled inflammation– particularly of the thyroid tissue. This contributes to the autoimmune nature of Hashimoto’s Thyroiditis.

4 comments

  1. Hi Katlyn, thank you for the very interesting read on the genetics behind Hashimoto’s thyroiditis. You broke everything down very clearly and made it approachable. I have a few questions for you. What do you mean by the mutations in CTLA-4 cause down-regulation, but not irregularities? Does this mean that mutations are in promoter or enhancer regions of the gene and, thus, down-regulate expression of a normal CTLA-4 protein? Also, since it appears that HT is correlated to increased inflammatory response in the body, has it been linked to other conditions which are also a result of increased inflammation, such as asthma or rheumatoid arthritis? Keep up the good work! Your website is very well done!

    1. Hi Matt! Thank you for your comment. As it turns out, the polymorphisms are in the promoter region. This causes the down regulation in expression of the protein without actually changing the protein itself. The literature shows a pattern of patients with other autoimmune diseases such as type I diabetes and celiac disease getting diagnosed with HT later on, but there is not much information on people with HT getting diagnosed with other autoimmune diseases.

  2. Hi Katy!

    I just finished reviewing your theme pages, and you did a great job! I really enjoyed learning about Hashimoto’s. I have a close friend with the disease and she suffers from all of the symptoms that you mentioned, and now I can tell her a little bit about why.

    My first comment/question came up when I read the background/history page. You mention that high iodine intake and selenium deficiency are dietary factors that can contribute to hypothyroidism. My question is: do you have any idea what type of diet (on a food level – not a “high in selenium diet” level) clinicians recommend to those who suffer from Hashimoto’s? Like I said on your spotlight blog, it does seem really beneficial to take a holistic approach to our health and treat our bodies right based on our particular needs. I think all those smaller efforts can, at a minimum, help to prevent disease aggravation, so I was wondering if you explored that at all.

    I was also interested in the section about Hashitoxic Periodic Paralysis in which you mention symptoms like tremors and a sensation of paralysis. So, these sound like neurological symptoms, and I was wondering if you knew anything about how hypothyroidism affects the nervous system? I do not know much about thyroid hormones and their effects, but this paralysis business sounds pretty different from the other symptoms like weight loss, water retention, etc.

    Meanwhile, I am slightly confused about the disease mechanism. So, the body produces thyroid antibodies that are destroying the gland and preventing release of TSH which is needed for many reasons… hopefully that’s right. Specifically, these antibodies fight against thyroid peroxidase, for example, which is partially responsible for producing thyroid hormone? My actual question is, this means that thyroid peroxidase has no role in converting levothyroxine to the T3 active form, right? If I am right, it’s sort of interesting that whatever converts it to the T3 form isn’t also effected by the thyroid antibodies. Hopefully my understanding isn’t too off.

    Thank you for such an interesting read, Katy!

  3. Hi Gianna! Thank you for your comments! I’m happy to answer your questions about Hashimoto’s Thyroiditis!

    There is not one specific diet that physicians recommend for Hashimoto’s, but the general consensus seems to be avoiding large amounts of table salt with added iodine. For people suffering from other autoimmune diseases on top of Hashimoto’s which is a very common phenomenon, special diets that go along with that autoimmune disease (gluten free for celiacs, low carb for diabetes, etc.), seem to help alleviate some of the symptoms associated with Hashimoto’s Disease.

    To answer your second question, the endocrine system works closely with the nervous system. The endocrine system is responsible for releasing hormones that cause local and systemic effects while neurotransmitters are what cause effects in the nervous system. The endocrine system can exert similar effects to the nervous system because both are using chemical messengers to exert their effects.

    Thyroid peroxidase is the enzyme that is targeted by the antibodies in HT. Thyroid peroxidase is required to add iodine to thyroglobulin which is the protein responsible for converting the T4 to T3 as well as the reverse reaction, T3 to T4.

    I hope I answered your questions!

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