Endocrine Immunology

W. Savino, F. Guaraldi, W., Savino, F., Guaraldi, Federica Guaraldi, Giovanni Corona, Federica, Guaraldi, Giovanni, Corona

• Publisher: S. Karger
• Year: 2017
• Print ISBN: 9783318060133
• eBook ISBN: 9783318060140
• Topic: Medicine
• Subtopic: Immunology

In the last decades, several in vitro and in vivo studies have revealed the existence of a very complex network between the neuroendocrine and immune system. Important molecular mechanisms underlying these interactions, in both physiological and pathological conditions, have also been described. Indeed, hormones play a pivotal role in the development and functional regulation of the immune system – both innate and acquired responses. Immune system cells present specific hormone receptors and themselves produce some hormones, thus influencing hormone secretion. More recently, the modulation of hormone secretion has been attempted for treating associated autoimmune disorders, further supporting the strong interplay between the endocrine and immune system. Distinguished experts, who have published extensively in their fields, have contributed comprehensive chapters to this volume. The focus is on the various aspects of endocrine-neuro-immune connections, providing an updated panorama - from basics to clinical applications - of current knowledge and still debated issues.

Savino W, Guaraldi F (eds): Endocrine Immunology.
Front Horm Res. Basel, Karger, 2017, vol 48, pp 76-83 (DOI: 10.1159/000452907)

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A Novel Clinical Entity of Autoimmune Endocrinopathy: Anti-PIT-1 Antibody Syndrome

Genzo Iguchi · Hironori Bando · Yutaka Takahashi

Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

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Abstract

Pituitary-specific transcription factor 1 (PIT-1; POU domain, class 1, transcription factor 1 (POU1F1)) is an essential transcription factor for the differentiation of somatotrophs, lactotrophs, and thyrotrophs, and for the expression of growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). Mutations in PIT-1 cause congenital defects in GH and PRL secretion and severe TSH insufficiency. Anti-PIT-1 antibody syndrome, firstly reported in 2011, is characterized by acquired GH, PRL, and TSH deficiencies without PIT-1 mutation and is associated with the presence of the circulating antibody against PIT-1 protein as a marker. Various autoantibodies are detected with multiple endocrine organopathies in this syndrome; therefore, it meets the criteria of autoimmune polyglandular syndrome. Mechanistically, cytotoxic T lymphocytes specifically reacting with PIT-1 protein play an important role in the development of this syndrome.

© 2017 S. Karger AG, Basel

Background

In 2011, Yamamoto et al. [1] reported 3 unique cases of acquired combined pituitary hormone deficiency (CPHD). The clinical characteristics of these patients are described briefly below.

Patient 1: a 44-year-old man presented with facial, finger, and arm edema without any abnormalities during his growth and pubertal development. Endocrinological examinations revealed extremely low levels of serum thyroid-stimulating hormone (TSH) and free T4 (FT4); basal levels of serum growth hormone (GH) and prolactin (PRL) were not detectable. In provocation tests, blunted responses of GH, PRL, and TSH, and normal responses of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and adrenocorticotropic hormone (ACTH) were observed. Gastric tissue biopsy revealed autoimmune gastritis. Autoantibodies against microsomes, thyroglobulin, and parietal cells were detected in the serum.

Patient 2: a 75-year-old man had slowly progressive insulin-dependent diabetes mellitus and low levels of serum TSH and FT4, indicating central hypothyroidism. He also had undetectable basal levels of serum GH and PRL, and autoantibodies against microsomes, glutamic acid decarboxylase (GAD), and parietal cells.

Patient 3: a 78-year-old man with acquired central hypothyroidism had pituitary deficiency similar to patients 1 and 2. Autoantibodies against thyroid peroxidase (TPO) were detected in the serum.

Intriguingly, the endocrinological examination of these adult patients revealed GH-, PRL-, and TSH-specific deficiencies, similar to congenital CPHD in children, which is caused by PIT-1 mutation. However, the condition is not congenital, and the patients exhibited no PIT-1 mutations. Moreover, the patients’ sera specifically recognized PIT-1 protein, indicating the existence of an antibody against PIT-1.

Immunohistochemical analysis of the pituitary in patient 2 revealed the absence of GH-, PRL-, and TSH-positive cells and PIT-1-positive cells, despite the presence of ACTH-, LH-, and FSH-positive cells. Histological analysis showed inflammatory infiltrate and disrupted tissue structure in the gastric mucosa, pancreas, adrenal gland, liver, and thyroid. In addition, ELISpot assay demonstrated PIT-1-reactive cytotoxic T lymphocytes (CTLs) and CD8+ lymphocytes infiltrate, suggesting that CTLs play a pivotal role in the pathogenesis [2], and that the anti-PIT-1 antibody is not the cause but a marker of anti-PIT-1 antibody syndrome.

This novel clinical entity termed ‘anti-PIT-1 antibody syndrome’ was defined by (1) acquired CPHD characterized by specific GH, PRL, and TSH deficiencies; (2) the presence of circulating anti-PIT-1 antibodies; and (3) various autoimmune endocrinopathies including insulitis, thyroiditis, and adrenalitis that are generally observed in autoimmune polyglandular syndrome (APS) [3].

PIT-1 Is Essential for the Differentiation of 3 Pituitary Cell Types

PIT-1 is a member of the POU homeodomain family of transcription factors, which are specifically expressed in the pituitary gland and are important for the normal development of its anterior portion [4, 5]. PIT-1 maps to human chromosome 3p11.2. It is required for the differentiation of somatotrophs, lactotrophs, and thyrotrophs, and regulates the expression of GH, PRL, and TSH in the anterior pituitary [6]. Snell (dw/dw) and Jackson (dw/dwJ) dwarf mice with mutations in PIT-1 show specific deficits in GH, PRL, and TSH [7]. Recently, it has been reported that the binding of PIT-1-occupied enhancers to a nuclear matrin-3-rich network is a key event in the effective activation of PIT-1 regulated gene transcription [8]. Tatsumi et al. [9] firstly reported a case of cretinism with CPHD, together with low levels of TSH, GH, and PRL caused by a homozygous nonsense mutation in PIT-1. Thereafter, many autosomal recessive mutations and a dominant negative mutation were reported in association with this condition [10, 11].

Autoantibodies in Hypophysitis and the Anti-PIT-1 Antibody

Several autoantibodies are reported in patients with autoimmune hypophysitis, namely, GH1 or GH2 [12], α-enolase [13], pituitary gland-specific factors 1a and 2 [14], secretogranin-2 [15], and GH and proopiomelanocortin [16]. The specificity of these pituitary antibodies is not high, as they have been found in various pituitary diseases, such as Sheehan’s syndrome [17], Cushing’s disease [18], and pituitary adenomas [19], suggesting that the antibody is produced as a result of inflammation or disruption of the pituitary tissue. Moreover, the involvement of these antigens in the pathophysiology of hypophysitis has not been fully clarified. Recently, several reports have strongly suggested the close relationship of antibodies with the pathogenesis of disease, for example, anti-pituitary antibodies against hypogonadotropic hypogonadism, ACTH deficiency, GH deficiency, and isolated PRL deficiency [20-23]. In anti-PIT-1 antibody syndrome, the presence of an antibody against PIT-1 protein indicates autoimmunity to PIT-1-expressing cells. Given that PIT-1 is an essential and specific transcription factor for GH-, PRL-, and TSH-producing pituitary cells, autoimmunity to PIT-1 might play a causal role in the development of this syndrome.

Pathogenesis of Anti-PIT-1 Antibody Syndrome

Although autoimmunity to PIT-1 has been suggested to play a role in the pathogenesis of anti-PIT-1 antibody syndrome, whether the anti-PIT-1 antibody is a marker or cause of this condition is unknown. Further examinations to elucidate the involvement of antibody- or cell-mediated immunity in anti-PIT-1 antibody syndrome have been performed [2]. Patient serum did not inhibit the proliferation of GH3 cells, which express endogenous PIT-1 protein and secrete GH and PRL. Moreover, there was no anti-secretory effect or complement-dependent cytotoxic activity in the patient serum, indicating that the antibody does not play a pathogenic role in the development of the disease. However, the ELISpot assay revealed the presence of CTLs that specifically reacted to the recombinant PIT-1 protein in the patient’s peripheral lymphocytes. Immunohistochemical analysis showed CD8+ cell infiltration, a characteristic of CTLs in the pituitary gland, adrenal gland, stomach, thyroid gland, liver, and pancreas of the patient, suggesting that CTLs play an essential role in the pathogenesis of anti-PIT-1 antibody syndrome [2]. CTLs generally act against viruses by targeting infected cells or eliminating tumor cells by recognizing tumor antigens presented with HLA class I molecules. It is also known that they play an essential role in the development of several autoimmune diseases [24], for example, alopecia areata [25], multiple sclerosis [26], and type 1 diabetes mellitus [27]. In type 1 diabetes mellitus, CTL clones in the peripheral blood show the same antigen specificity as that of CTLs infiltrating the pancreas [28].

Although some of the pathogenic mechanisms of anti-PIT-1 antibody syndrome have been resolved, certain aspects are still unclear. In particular, it is puzzling why specific autoimmunity to PIT-1 occurs in these patients. One possibility is molecular mimicry: infection by an exogenous pathogen that contains epitopes similar to PIT-1 protein may cause cross-reactivity in the immune reaction.

APS and Anti-PIT-1 Antibody Syndrome

In patients with anti-PIT-1 antibody syndrome, histological analyses have revealed various autoimmune endocrinopathies, including insulitis, thyroiditis, and adrenalitis [1]. The endocrinological findings in patient 1 suggested the presence of subclinical primary adrenal insufficiency. In patient 2, primary hypogonadism was observed, and autoimmune adrenalitis was histologically confirmed. Autoimmune gastritis with a disappearance of parietal cells was observed in patients 1 and 2. Various autoantibodies, such as those against microsomes, thyroglobulins, TPO, GAD, and parietal cells were detected. Alopecia and cerebellar ataxia were also observed in the...

Table of contents

• Cover Page
• Front Matter
• Immune-Neuro-Endocrine Reflexes, Circuits, and Networks: Physiologic and Evolutionary Implications
• Inflammation and Thymus Ageing
• Intrahypophyseal Immune-Endocrine Interactions: Endocrine Integration of the Inflammatory Inputs
• Pituitary Autoimmunity
• Prolactin: An Immunomodulator in Health and Disease
• A Novel Clinical Entity of Autoimmune Endocrinopathy: Anti-PIT-1 Antibody Syndrome
• Leptin, Neuroinflammation and Obesity
• Thyroid Autoimmunity and Cancer
• Role of Cortistatin in the Stressed Immune System
• Steroids and Autoimmunity
• Endocrine Autoimmunity in Down’s Syndrome
• The Somatotrope Growth Hormone-Releasing Hormone/Growth Hormone/Insulin-Like Growth Factor-1 Axis in Immunoregulation and Immunosenescence
• Endocrine Immunology of Chagas Disease
• Author Index
• Subject Index
• Back Cover Page