Centennial of the Description of Hashimoto's Thyroiditis: Two Thought-Provoking Events

A mong the medical historical events commemorated in 2012, a notable one was the centennial of the description of Hashimoto's thyroiditis (HT), today the most common form of autoimmune thyroid disease (AITD). Though there have been four published articles in the last 2 years celebrating the centennial (1 –4), this commentary concerns the meetings that took place in spring on the island of Kos, Greece, and in winter 2012 in Fukuoka, Japan.

One hundred years ago, in 1912, Hakaru Hashimoto, a young Japanese doctor investigating the pathological relationships of the various types of goiter at Kyushu Imperial University in Fukuoka, reported on four women with a clinical-pathologic entity characterized by goiter, lymphocytic infiltration, parenchymal atrophy, and fibrosis. He published his observations in the German journal Archiv für Klinische Chirurgie, and then moved to the University of Göttingen in Germany for further studies in the pathologic sciences (5). Following Hashimoto's first description, the terms Hashimoto and Hashimoto disease began to appear during the 1930s in the titles of papers (6,7). Approximately 20 years later, the landmark publications by Witebsky and Rose (8,9) described the production of antithyroglobulin antibodies in rabbits as well as changes in the thyroid gland following active immunization with rabbit thyroid extracts. Subsequently, Roitt and Doniach (10) reported on the presence of antithyroglobulin antibodies in the sera of patients with “struma lymphomatosa.” Then in 1962, Doniach and Roitt, basing their conclusions on discoveries and reports about its genetic origin, proposed renaming the disease after Hakaru Hashimoto, who first recognized this entity (11). The description of HT proved to be a cornerstone achievement not only in the history of thyroidology but for medicine at large, since it created a platform that enabled pathology and immunology to merge more closely. Further, it had numerous implications for endocrinology and especially thyroidology because of the importance of autoimmune disorders in our field. Moreover, this historical discovery, followed by constant new breakthroughs and advancements, were extraordinarily timely given that the prevalence of HT during the past century has escalated to the point that it is at present the most frequent autoimmune disease.

The decades-long endeavor to decipher the autoimmune nature of HT, supported by established knowledge that many other environmental factors besides iodine excess may trigger the disease, has propelled HT to an exceptionally high level of interdisciplinary research. To varying degrees, autoimmune genetics, nutrigenetics, and epigenetics contribute to the unraveling of the disease's pathogenesis, expression, continuance, and progression. Thus, genetic linkage between AITD and HLA was demonstrated; specifically, serological HLA-DR3 was discovered to be implicated in the disease, an association reported first in mice (12). This association was, however, found to be common to both HT and Graves' disease (13,14). Following this, several other loci associated with AITD, both immune-regulatory (CD40, CD25, CTLA-4, and PTNP22) and thyroid-specific genes (those for thyroglobulin and TSH-receptor), could be identified and confirmed (15,16). Recently, another fundamental contribution to the scientific research described a single nucleotide polymorphism (SNP) in which the substitution of alanine or glutamine with arginine at position 74 in the HLA-DR peptide-binding pocket confers susceptibility exclusively to HT (17). Lately, fine mapping of the AITD locus on chromosome 10q showed replicated association of the AITD phenotype with SNP rs6479778, which is located within the ARID5B gene, reported to be associated with rheumatoid arthritis and Graves' disease in Japanese patients (18). In the meantime, the long-sought autoimmune-suppressive T-cell population was demonstrated to be delineated as CD25 expressing CD4⁺ and was specifically identified as constituting naturally occurring regulatory T (Treg) cells (19). In 2003, the discovery was made that the transcription factor Foxp3 is expressed by natural CD25⁺CD4⁺ Treg cells (20). Mutations of Foxp3 lead to impairment of Treg cell development and, via immune dysregulation, to the immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, which manifests as type 1 diabetes mellitus and thyroiditis, among other disorders (21). However, the journey is still not at its end even several decades after the identification of the disease, and as Leslie J. De Groot stated in 2012 at the International Symposium in Fukuoka, “…we still know very little about initiating events, or early immunologic responses, or in fact whether the disease actually starts in the thyroid.”

The centennial of the identification of Hashimoto's disease was celebrated in May 2012 in the framework of the Educational Course of the European Thyroid Association held on the island of Kos, home of Hippocrates, and still more prominently in Fukuoka in early December 2012 at the International Symposium which was organized by the Institute for Advanced Study (Princeton, NJ), the Department of Surgery and Oncology, Kyushu University (Fukuoka, Japan), and the Division of Endocrinology and Metabolism, Kurume University. The celebrations honored the dedication of a pioneer in modern-day immunology and thyroidology. Both meetings were impressively combined with moving social events, such as the ceremony re-enacting the Hippocratic oath at the Asclepeion of Kos and a very comprehensive exhibition depicting multiple aspects of the life of Hakaru Hashimoto at the meeting in Fukuoka. The symposium was truly superb thanks to the participation of leading scientists from around the world, as well as a large and motivated audience. In the midst of an exceptionally inspirational atmosphere, further enhanced by numerous demonstrations of traditional Japanese hospitality, the conference brought us together and deepened our interpersonal and scientific exchanges.

Meditation on the momentous discovery of HT opens up reflection on the role of intuition and dedicated application within the entire field of medical research. In the case of the brilliant young Japanese doctor, it was his observational acuity and penetrating insight, sustained by relentless hard work, that enabled him to definitely identify the signs of the disease. These qualities, which are so often required in medical research, constitute an admirable and highly inspiring example for doctors and serve as a radiant reminder to both young and older members of the medical profession to persevere regardless of all difficulties in their endeavors and research. Dr. Hakaru Hashimoto was an unusually restless spirit whose boundless curiosity propelled him far ahead of his time. Moreover, his decision to travel abroad to complete his education at the University of Göttingen was a pioneering step in his day, a move that is nowadays very common.

The HT centennial meeting in Fukuoka will remain an unforgettable event for its overall excellence, the distinction of its attendees, and the warmth and conviviality of its social activities. Moreover, the thought-provoking significance of the Fukuoka commemorative meeting can arouse within us deliberation upon the whole matter of scientific enterprise and the part played by both an individual's striving, but also his or her “sixth sense” within this discipline. Further unknown aspects of HT will without doubt be elucidated in the years to come, certainly much earlier than the celebration of its second centennial. However, the meeting in Fukuoka, Hakaru Hashimoto's place of work, was like an echo sounding down the corridors of time, honoring a spectacular advance in medical knowledge, while simultaneously renewing alliances and friendships and further strengthening our collaboration to achieve our goal for ever better treatment of our patients.