Immunoendocrinology: When (neuro)endocrinology and immunology meet
It is with great pleasure to introduce Professor Antonelli as the Guest Editor for this special issue of Reviews in Endocrine & Metabolic Disorders. Prof. Antonelli is board certified in Internal Medicine, Endocrinology, and Oncology, and the Director of the Immuno-Endocrine Section of Internal Medicine, Head of the Laboratory of Primary Human Cells and Associate Professor in the Department of Clinical and Experimental Medicine at the University of Pisa, Italy. For this guest issue, Prof. Antonelli assembled a panel of international expert contributors to discuss current aspects of immunoendocrinology.
There is increasing awareness of the intricate and intertwined relationship between the endocrine and immune system. In part, this is caused by an explosion of various immunotherapies including cellular immunotherapy (for instance, sipuleucel-T (Provenge), tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta)), antibody-based therapy (i.e. rituximab (Rituxan, Mabthera), atezolizumab (Tecentriq), avelumab (Bavencio), ofatumumab (Arzerra), alemtuzumab (Campath-1H), durvalumab (Imfinzi), ipilimumab (Yervoy), tremelimumab, pembrolizumab, nivolumab (Opdivo)), cytokine therapy (i.e. interferon, interleukin-2), combination immunotherapy, and others. Among antibody based immunotherapies are the checkpoint inhibitor antibodies with ipilimumab being the first antibody approved by the Federal Food and Drug Administration (FDA). More and more immune-related adverse events of immune checkpoint inhibitor treatment are being unraveled and algorithms for acute management of endocrine complications have been proposed [1, 2, 3, 4, 5, 6, 7, 8].
My first encounter with immunology occurred while studying at the Friedrich-Alexander University of Erlangen-Nuremberg in the 1980s and rotating through the Department of Medicine headed by Professor Joachim R. Kalden, who in 1970 reported on the effect of hypophysectomy on the immune system in male Sprague-Dawley strain rats . Many fellow immunologists and rheumatologists trained under Prof. JR Kalden have risen to the top of the field [10, 11, 12]. My next immunological encounters, including the occurrence of bullous pemphigoid after treatment with furosemide, happened during residency training at the Ohio State University Medical Center  followed by the National Institutes of Health (NIH) which had the largest impact on my education in immunology and its intersection with endocrinology . At the NIH I met many immunology and other experts, including Profs. George Chrousos, Ronald Wilder, Esther Sternberg, Ilias Elenkov, Philip Gold, Julio Licinio, and Thomas Fleisher [15, 16, 17]. After departing the NIH and spending a few years in Germany, I had the pleasure to collaborate with visceral and thoracic surgeon expert Prof. Ott and we published a study showing that converting liver transplant recipients from cyclosporine A therapy to steroid-saving tacrolimus monotherapy caused a decline in mean serum cholesterol and high density cholesterol levels but an increase in low density cholesterol serum concentrations, apparently without beneficial effect on the atherogenic lipid profile .
After joining the University of Mississippi Medical Center in 2006, I had the honor to be invited by Profs. Julius Cruse and Robert Lewis in the Department of Immunopathology, both being Editors of the Atlas of Immunology (ISBN 9781439802687) and Historical Atlas of Immunology (ISBN-13: 978–1,842,142,172 and ISBN-10: 1842142178), to provide lectures outlining the intersection between immunology and endocrinology: https://www.researchgate.net/publication/270161648_Autoimmune_Syndromes_Endocrine_Autoimmunity_Potpourri).
Profs. Cruse, Lewis, and I always had very informative and entertaining discussions until recently, when Prof. Cruse sadly passed away [19, 20, 21, 22]. Based on these intellectual interactions with these two wonderful colleagues I learned more about immunoendocrinology and in 2013, I had the honor to present a lecture at the Southern States Chapter of the American College of Endocrinologists (https://www.researchgate.net/publication/329124524_When_Neuroendocrinology_and_Immunology_Meet_Practical_Considerations), illustrating how the immune system controls endocrine organs and function and reviewing how sex steroids control neuro-inflammatory processes in the brain. As usual, caring for patients often makes me think about why people have certain afflictions. Acknowledging that Mississippi is one of the US states with the highest percentage of obese individuals, it is conceivable that persistent organic pollutants impact the immune system. Persistent organic pollutants have high lipid solubility and bioaccumulate in fatty tissues of not only animals but also humans (https://en.wikipedia.org/wiki/Persistent_organic_pollutant). Furthermore, contamination of groundwater and drinking (tap) water with micropollutants and pharmaceuticals, including antibiotics, can impact health of animals and humans and their (intestinal) microbiome [23, 24, 25, 26, 27].
Such an environmental impact can lead to molecular mimicry. In predisposed individuals, a microbial antigen would then trigger autoimmunity because of structural similarity to an autoantigen of the host [28, 29, 30, 31, 32, 33, 34, 35, 36]. Being born and growing up in such an obesogenic and polluted environment may be more challenging for changing the deleterious course on health than coming into such an environment from outside as an adult, although both situations will alter the gut microbiome [37, 38, 39, 40, 41]. The question arises when the time has come to act on limiting endocrine disrupting chemicals (https://www.researchgate.net/publication/292335196_Endocrine_Disruptors_is_it_time_to_act and https://www.researchgate.net/publication/270161477_Endocrine_Aspects_in_Obesity_What_the_Non-Endocrinologist_Should_Know/download). The FDA has published pamphlets on how to dispose of unused medicines and the risks associated with the environmental release of pharmaceuticals on the United States FDA “flush list” .
As a simple rule, in my opinion, one should read about the ancient Greek philosophers and their concept of the four elements, earth, fire, water, and air, and put that into contemporary context in hopes of identifying what people need to do to preserve life on the planet Earth (https://en.wikipedia.org/wiki/Classical_element).
The complex interaction between environmental, hormonal, immune, and genetic factors has been coined as a “mosaic of autoimmunity” . The autoimmune/inflammatory syndrome is induced by adjuvants including aluminum and silicone. Medical conditions of this syndrome are vaccination-induced autoimmunity, silicone implants-induced autoimmunity, Gulf War syndrome, macrophagic myofasciitis with chronic fatigue syndrome, and the sick building syndrome [44, 45, 46].
The presence of autoantibodies alone is not sufficient to define a disease as autoimmune. According to Whitebsky there also should be a demonstration of lymphocytic infiltration in the target organs, identification and characterization of auto-antigens, and induction of the disease in animal models with the injection of auto-antigens and passive transfer by serum or lymphocytes . Interestingly, (only) approximately 30% of patients with stiff person syndrome develop diabetes mellitus, although auto-antibodies directed to the 65-kDa isoform of glutamic acid decarboxylase (GAD) are present . In the TrialNet pathway to prevention study, 994 relatives with normal glucose tolerance and being positive for a single “diabetes” autoantibody, were followed prospectively and tested for antibodies against islet cells, zinc transporter 8, insulin, insulinoma associated antigen 2, and GAD. After a median follow-up of 2 years, 141 relatives were found to have at least one additional autoantibody . When comparing identical twins and full siblings in the TrialNet pathway to prevention study including 17,226 subjects, the risk of type 1 diabetes at 3 years was high (>69%) for identical twins who were positive for initially multiple and single “diabetes” auto-antibodies and for non-identical twins with multiple “diabetes” autoantibodies. For initially “diabetes” autoantibody negative identical twins, the risk of developing type 1 diabetes was 1.5% .
Similarly, euthyroid individuals may have very high titers of antithyroid peroxidase antibodies . Analyzing more than 16,000 individuals in the National Health and Nutrition Examination Survey (NHANES) revealed a prevalence of approximately 10% of people with anti-thyroglobulin antibodies and approximately 11% of subjects with antithyroperoxidase antibodies. Positivity for both antithyroidal antibodies increased the odds ratio of developing hypothyroidism from 6.9 (anti-thyroperoxidase antibody alone) to 23.5. The presence of anti-thyroglobulin antibody alone was not a risk factor of hypothyroidism. Interestingly, no anti-thyroid antibodies were detected in 31% of men and in 11% of women who had unequivocal elevations (> 10 mIU per liter) of thyroid stimulating hormone/TSH [https://www.thyroidmanager.org, 52, 53]. 1184 Western Australian subjects were followed for 13 years while checking serum concentrations of thyroid stimulating hormone (TSH) and antibodies directed to thyroid peroxidase and thyroglobulin. In 112 subjects, overt hypothyroidism developed. In women with positive antithyroidal antibodies, 55% became hypothyroid when the initial TSH was between 2.5 and 4.0 mU per Liter .
Guest Editor Prof. Antonelli whose roots of endocrinology and immunology go back into the 1980's and I myself have met at one of the annual Endocrine Society meetings via introduction by Prof. Salvatore Benvenga who has also worked at the NIH in Bethesda, MD, in the past [55, 56, 57, 58, 59, 60, 61]. This guest issue begins with a review on the immune cell-adipocyte crosstalk as an important regulator not only of adipose tissue function, but also of systemic metabolism and homeostasis . The group around Professor Chavakis has made major contributions on inflammasome pathways . The second article will then focus on the role of microbiota in maintaining nutritional, metabolic, and immunologic homeostasis with an emphasis on thyroid autoimmunity . Next will be a review of the increasing prevalence of chronic lymphocytic thyroiditis in papillary microcarcinoma. Hashimoto’ s thyroiditis coexists in approximately one third of patients with papillary thyroid microcarcinoma . At my present clinical practice location, I see many patients with autoimmune skin disorders referred by dermatologists. In particular, women with alopecia areata and/or totalis suffer from this appearance. Unfortunately, no universal therapy exists, although successful hair regrowth after certain immunotherapies, with ustekinumab, has been reported [65, 66, 67]. A retrospective study showed that 12 of 70 patients (17%) with alopecia totalis had complete hair regrowth but 30 patients with alopecia universalis (65%) remained in an alopecic state without improvement long term . The epidemiology, clinical manifestations, and pathogenesis of the main autoimmune skin disorders such as alopecia, vitiligo, pemphigus, bullous pemphigoid, and their association with thyroid disease will be reviewed by Dr. Baldini and colleagues , followed by a review on thyroid disorders induced by checkpoint inhibitors such as monoclonal antibodies directed to cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death receptor-1 (anti-PD-1), and programmed death-ligand 1 (anti-PD-L1) . Checkpoint inhibitor therapy, especially with anti-CTLA-4, is also associated with hypophysitis . Dr. Gubbi and colleagues from the NIH review the topic primary hypophysitis and other autoimmune disorders of the sellar and suprasellar regions with an emphasis on lymphocytic hypophysitis .
Myoinositol is involved in intracellular thyroid-stimulating hormone signaling, has immunomodulatory effects, and may be effective in protecting thyroid cells from reactive oxygen species such as hydrogen peroxide and pro-inflammatory cytokines which will be reviewed by the group around Prof. Antonelli [71, 72].
Immunomodulatory effects can also be observed in/with many other substances and medications. The role of the peptide hormone somatostatin has been recently reviewed in an issue on neuroendocrine neoplasms, including its impact on the immune system . Somatostatin receptor subtype 1 and subtype 2 are both expressed on fibroblast-like synovial cells and somatostatin analog therapy may be effective in treating patients with rheumatoid arthritis . Of 175 patients with sarcoidosis, all but one patient showed uptake when undergoing somatostatin receptor scintigraphy. In 6% of these patients, exclusive extrapulmonary disease was identified .
Besides their well established role in reducing cardiovascular risk, statins also exert immunomodulatory effects. This topic including statins, metformin, pro-protein-convertase-subtilisin-kexin type-9 (PCSK9) inhibitors, angiotensin converting enzyme inhibitors and sex hormones will be reviewed by me with colleagues Dr. Hehmke and Prof. Krabbe, who have extensive experience with immunodiagnostics methods utilized at the Institute of Diabetes “Gerhardt Katsch” in Karlsburg, Germany . Statins are known to be associated with myopathy and many patients with muscle complaints have these complaints in the absence of prior statin use . Myalgia is reported in approximately 9% of patients on atorvastatin and in approximately 5% of placebo patients when using self-reported symptoms and there have not been validated scales to diagnose statin-associated myalgia . Interestingly, discontinuation of statin therapy for 2 weeks caused improvement in musculoskeletal symptoms in 75% of patients with statin-associated muscle side effects. After stopping initial statin therapy, 92% of patients are able to tolerate a second statin. A skeletal muscle biopsy is recommended for persistent tenderness and myalgia with moderate to severe elevations of creatine kinase. Major autoimmune myopathies include dermatomyositis, polymyositis, myositis associated with antisynthetase syndrome, inclusion body myositis, and immune-mediated necrotizing myopathy. Typically, glucocorticoisteroids are considered first-line therapy, although intravenous immunoglobulin has also been used, especially in patients with immune-mediated necrotizing myopathy related to statin use . The detection of anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase antibodies with prior or current statin use can assist in diagnosis and management, as timely treatment with immunosuppressive agents can increase the likelihood of a favorable outcome . In an Australian population-based case-control study, using the South Australian Myositis Database, of all histologically confirmed cases of idiopathic inflammatory myositis and controls from the North West Adelaide Health Study, statin exposure at the time of diagnosing idiopathic inflammatory myositis occurred in 31% of patients and in 22% of matched controls .
This issue will be concluded by 2 articles related to infection with hepatitis C virus, one article by Dr. Colaci and colleagues, reviewing endocrine disorders in such patients and the final article, a systematic review and meta-analysis, by Prof. Antonelli and colleagues focusing on the development of diabetes mellitus [80, 81].
As I conclude my term as the Editor-in-Chief of this journal, I wish to say farewell and thank the readership, guest editors, associate editors, Editorial Board, and the current and past Springer staff, especially Laura Walsh, Elizabeth Dziubela, Mitchelle Joseph, Rosario Gramatica, and John Rafael Patricio, for their support which has helped the journal maintain its excellent Impact Factor.
Compliance with ethical standards
Conflict of interest
Profs. Koch and Antonelli declare no direct conflict with this article.
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