Interviews with John Cambier, PhD, and Angela Leung, MD, MSc
The function of beta cells remains the driving force behind the development and management of diabetes. Since islet antigen-reactive B lymphocytes are known to contribute to the development of autoimmune disease, it appears there may be an explanation for thyroid disease, as well.1 Interestingly, in healthy individuals, B cells that have high antigen receptor affinity are polyreactive possibly due to the addition of an N-region, which may explain its broader function in autoimmunity.2
As such, environmental forces such infection or trauma may trigger an autoimmune reaction in individuals with a genetic predisposition (ie, presence of HLA alleles), by disrupting B-cell anergy, which may present as diabetes, but less expected, in thyroid diseases too.1
There seems to be a connect to and role of the beta cell dysfunction in autoimmune thyroid disease, according to John Cambier, PhD, distinguished professor and chair of immunology and microbiology at the University of Colorado School of Medicine, during his plenary presentation, Understanding How Breaches in Immune Tolerance Lead to Autoimmune Thyroid Disease,2 at the American Thyroid Association 87th annual meeting in Vancouver, British Columbia, Canada.
Breaches in immune system tolerance appear to lead to autoimmune thyroid disease (AITD), and understanding this process more completely may eventually help recognize the disease earlier and also create a target for therapeutic interventions,1 said Dr. Cambier.
While the research is ongoing, the findings to date may help clinicians, both endocrinologists and primary care practitioners, provide an explanation to patients with Hashimoto's thyroiditis and Graves' Disease that their conditions began well before they had any symptoms or might have been able to change their disease course, due to these breaches in immune tolerance,1 Dr. Cambier told EndocrineWeb.
B-Cell Influence on Autoimmunity
In this presentation, Dr. Cambier reviewed the team’s research efforts, focusing on the role of B cells in the development of autoimmune thyroid disease (AITD). Observed differences have become apparent between healthy individuals and those with AITD or diabetes.1
"In healthy humans, insulin autoreactive B cells are found in blood but appear silenced by a mechanism called anergy, so they don't cause trouble, specifically autoimmunity," he said, "Essentially, the studies are defining B cells as a target for therapeutic intervention in autoimmune thyroid disease."
About 70% of the millions of B cells made each day in the body are autoreactive.
"These cells must be silenced in some way to prevent autoimmunity for occurring," Dr. Cambier said, and this silencing is a delicate process, as achieving this function will need to be accomplished without affecting individuals who are not autoreactive.1
In effect, these B cells appear to demonstrate an absence of the expected response that instead become activated in some first-degree relatives of people with diabetes and in every case of new-onset diabetes, he said. These B cells then appear to proceed to the pancreatic islets, where they seem to interact with T cells in such a way as to initiate disease.1
"A similar reaction appears to be happening in autoimmune thyroid disease," said Dr. Cambier, "Thyroid antigen (thyroglobulin and thyroid peroxidase) reactive B cells are found in the blood of healthy humans, but in new-onset AITD, patients appear to have lost the anergy and become activated," he said.
In future studies, Dr. Cambier intends to examine whether the B cells become localized in the thyroid gland, and if so, what their role is or what function do they present.1
There is good reason to pursue this line of research. Graves' disease, the most common cause of hyperthyroidism in the U.S., affects 7 to 8 times more women than men, according to the American Thyroid Association.3 Hashimoto's thyroiditis, the most common cause of hypothyroidism in the United States, most often affects middle-aged women, but can occur at any age, and also in men and children.4
Dr. Cambier is hopeful that disease etiology of autoimmune thyroid disease may become clearer as this research on the role in and function of B cells in the thyroid glands of patients with AITD and their first-degree relatives carries forward.
Clinical trials of B-cell targeted therapies may begin in a year or so, according to Dr. Cambier.
"We are putting a lot of effort into B cell-targeted therapies that do not deplete the B cell, and will, therefore, lessen any risks,'' he told EndocrineWeb, "These [methodologies] involve the use of antibodies at the B cell antigen receptor that will act as 'reverse agonists,' inducing an anergic-like state."
The update is ''a provocative look at the interesting crossroads between immunology and thyroidology," said Angela M. Leung, MD, MSc, assistant professor of medicine at the University of California at Los Angeles David Geffen School of Medicine, who moderated the session in which Dr. Cambier presented.
Dr. Cambier's idea of targeting B cells to alter thyroid autoimmunity is ''a novel translational perspective with potential impact on a wide range of thyroid disorders," she told EndocrineWeb.
Neither Dr. Leung nor Dr. Cambier reports any financial disclosures.