REVIEW URRENT C OPINION
IgG4 antibodies in autoimmune polyglandular disease and IgG4-related endocrinopathies: pathophysiology and clinical characteristics Bimota Nambam a, William E. Winter a,b, and Desmond A. Schatz a,b
Purpose of review This review discusses the IgG4-related disease spectrum (IgG4-RD), the autoimmune polyglandular syndromes (APS), the association of IgG4 with APS, and possible pathobiology. Recent findings IgG4-RD is a multiorgan autoimmune disorder characterized by fibrous inflammation, IgG4-positive plasma cell infiltration in affected tissues, and elevated serum concentrations of IgG4. IgG4-RD can affect any organ and has a heterogeneous presentation. Consensus criteria for diagnosis in specific organs have been established. The recognition and diagnosis of IgG4-RD are crucial because the disease responds favorably to immunosuppression (e.g., glucocorticoids, rituximab). The precise mechanisms leading to disease are unknown, but IgG4 antibodies may undergo a half antibody exchange, which renders them incapable of activating the complement pathway. Summary Despite significant advances in disease recognition and treatment strategies, the disorder remains poorly understood. The precise role of IgG4, whether it is protective or pathogenic, is still being debated. Keywords anticytokine antibodies, autoimmune polyglandular syndrome, IgG4-related disease
INTRODUCTION The autoimmune polyglandular syndromes (APSs) consist of a cluster of autoimmune diseases affecting endocrine and nonendocrine glands and organs. Loss of tolerance to self-antigens with the development of target autoimmunity is believed to underlie these disorders [1]. Based on organs affected, age of presentation, genetics, and inheritance patterns, two major types (APS-1 and APS-2) have been identified (Table 1) [2,3]; however, types 3 and 4 have also been described, but most experts consider types 3 and 4 to be variants of APS-2 [4,5]. Another polyendocrinopathy-associated autoimmune disorder is the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), caused by the dysfunction of FOXP3, a transcription factor characteristic of the regulatory T-cell lineage [6]. A more recently recognized multiorgan autoimmune disorder is IgG4-related disease (IgG4-RD), in which affected organs are characterized by fibrous inflammation, IgG4-positive plasma cell infiltration, and increased serum concentrations of IgG4 [7]. IgG4-RD can affect any organ [7–10,11 ,12 ], and &
&
some of these disorders, including thyroiditis and hypophysitis, are also seen in APS. Herein we provide an overview of the types of APS and specific disorders in relation to IgG4-RD.
AUTOIMMUNE POLYGLANDULAR SYNDROME-1 APS-1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), results from a mutation in the autoimmune
a
Department of Pediatrics, Division of Pediatric Endocrinology and Departments of Pathology, Immunology and Laboratory Medicine, Pediatrics, and Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA b
Correspondence to Desmond Schatz, MD, Professor and Associate Chairman of Pediatrics, Medical Director, Diabetes Center, University of Florida College of Medicine Box 100296 Gainesville, Florida 32610, USA. Tel: +1 352 273 9270; fax: +1 352 273 9361; e-mail: schatda@ peds.ufl.edu Curr Opin Pediatr 2014, 26:493–499 DOI:10.1097/MOP.0000000000000107
1040-8703 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pediatrics.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Endocrinology and metabolism
KEY POINTS IgG4 antibodies are unique compared with other subclasses of IgG; they undergo half antibody exchange and cannot activate the complement pathway. They are considered to be noninflammatory components of an immune reaction. Anticytokine antibodies (IFN-v) are highly specific for APS-1; anticytokine antibodies are mostly of the IgG1 and IgG4 subtypes. IgG4-RD is a multiorgan inflammatory disease with a heterogeneous presentation. A diagnosis of IgG4-RD should be made based on clinical and specific histopathological features. Glucocorticoids and rituximab are being used as firstline and second-line drugs, respectively, in IgG4-RD.
regulator gene (AIRE) on chromosome 21q22.3 [1,13,14]. The AIRE gene is involved in the expression of peripheral antigens in the thymus and deletion of self-reactive T cells. Mutations in the AIRE gene lead to the development of multiple organ-specific autoantibodies and autoimmunity (Table 2) [2,3,15]. APS-1 is diagnosed by the presence of two of the following three conditions: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and
adrenal insufficiency or the presence of adrenal autoantibodies. CMC usually presents in the first 3–5 years of life and any child with refractory CMC should be evaluated for concurrent endocrinopathies. Hypoparathyroidism often presents just before puberty followed by adrenal insufficiency. Hypocalcemia secondary to hypoparathyroidism may be masked in the presence of adrenal insufficiency because of volume contraction, and increased renal tubular reabsorption of calcium [16]. Sudden hypercalcemia in a hypoparathyroid patient may herald the onset of adrenal insufficiency [2]. Adrenal insufficiency is seen in more than two-thirds of APS-1 patients, but the diagnosis is often overlooked because the signs and symptoms are nonspecific (fatigue, weight loss, nausea, vomiting, abdominal pain). Hyperpigmentation sometimes can be seen, and is an important diagnostic feature when present. Besides the three cardinal pathological conditions, other concurrent disorders may be present in APS-1 patients (Table 1). Recent studies have reported the presence of high titers of neutralizing autoantibodies to type 1 interferon (IFN), mainly IFN-a and IFN-v, the latter of which appears to be highly specific for APS-1 [17,18]. The appearance of these antibodies precedes the development of organ-specific autoantibodies as well as early clinical manifestations, and these autoantibodies remain in the circulation for many years.
Table 1. APS-1 and APS-2 [2,3] APS-1
APS-2
Incidence
IgG4 antibodies in autoimmune polyglandular disease and IgG4-related endocrinopathies: pathophysiology and clinical characteristics Bimota Nambam a, William E. Winter a,b, and Desmond A. Schatz a,b
Purpose of review This review discusses the IgG4-related disease spectrum (IgG4-RD), the autoimmune polyglandular syndromes (APS), the association of IgG4 with APS, and possible pathobiology. Recent findings IgG4-RD is a multiorgan autoimmune disorder characterized by fibrous inflammation, IgG4-positive plasma cell infiltration in affected tissues, and elevated serum concentrations of IgG4. IgG4-RD can affect any organ and has a heterogeneous presentation. Consensus criteria for diagnosis in specific organs have been established. The recognition and diagnosis of IgG4-RD are crucial because the disease responds favorably to immunosuppression (e.g., glucocorticoids, rituximab). The precise mechanisms leading to disease are unknown, but IgG4 antibodies may undergo a half antibody exchange, which renders them incapable of activating the complement pathway. Summary Despite significant advances in disease recognition and treatment strategies, the disorder remains poorly understood. The precise role of IgG4, whether it is protective or pathogenic, is still being debated. Keywords anticytokine antibodies, autoimmune polyglandular syndrome, IgG4-related disease
INTRODUCTION The autoimmune polyglandular syndromes (APSs) consist of a cluster of autoimmune diseases affecting endocrine and nonendocrine glands and organs. Loss of tolerance to self-antigens with the development of target autoimmunity is believed to underlie these disorders [1]. Based on organs affected, age of presentation, genetics, and inheritance patterns, two major types (APS-1 and APS-2) have been identified (Table 1) [2,3]; however, types 3 and 4 have also been described, but most experts consider types 3 and 4 to be variants of APS-2 [4,5]. Another polyendocrinopathy-associated autoimmune disorder is the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), caused by the dysfunction of FOXP3, a transcription factor characteristic of the regulatory T-cell lineage [6]. A more recently recognized multiorgan autoimmune disorder is IgG4-related disease (IgG4-RD), in which affected organs are characterized by fibrous inflammation, IgG4-positive plasma cell infiltration, and increased serum concentrations of IgG4 [7]. IgG4-RD can affect any organ [7–10,11 ,12 ], and &
&
some of these disorders, including thyroiditis and hypophysitis, are also seen in APS. Herein we provide an overview of the types of APS and specific disorders in relation to IgG4-RD.
AUTOIMMUNE POLYGLANDULAR SYNDROME-1 APS-1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), results from a mutation in the autoimmune
a
Department of Pediatrics, Division of Pediatric Endocrinology and Departments of Pathology, Immunology and Laboratory Medicine, Pediatrics, and Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA b
Correspondence to Desmond Schatz, MD, Professor and Associate Chairman of Pediatrics, Medical Director, Diabetes Center, University of Florida College of Medicine Box 100296 Gainesville, Florida 32610, USA. Tel: +1 352 273 9270; fax: +1 352 273 9361; e-mail: schatda@ peds.ufl.edu Curr Opin Pediatr 2014, 26:493–499 DOI:10.1097/MOP.0000000000000107
1040-8703 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pediatrics.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Endocrinology and metabolism
KEY POINTS IgG4 antibodies are unique compared with other subclasses of IgG; they undergo half antibody exchange and cannot activate the complement pathway. They are considered to be noninflammatory components of an immune reaction. Anticytokine antibodies (IFN-v) are highly specific for APS-1; anticytokine antibodies are mostly of the IgG1 and IgG4 subtypes. IgG4-RD is a multiorgan inflammatory disease with a heterogeneous presentation. A diagnosis of IgG4-RD should be made based on clinical and specific histopathological features. Glucocorticoids and rituximab are being used as firstline and second-line drugs, respectively, in IgG4-RD.
regulator gene (AIRE) on chromosome 21q22.3 [1,13,14]. The AIRE gene is involved in the expression of peripheral antigens in the thymus and deletion of self-reactive T cells. Mutations in the AIRE gene lead to the development of multiple organ-specific autoantibodies and autoimmunity (Table 2) [2,3,15]. APS-1 is diagnosed by the presence of two of the following three conditions: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and
adrenal insufficiency or the presence of adrenal autoantibodies. CMC usually presents in the first 3–5 years of life and any child with refractory CMC should be evaluated for concurrent endocrinopathies. Hypoparathyroidism often presents just before puberty followed by adrenal insufficiency. Hypocalcemia secondary to hypoparathyroidism may be masked in the presence of adrenal insufficiency because of volume contraction, and increased renal tubular reabsorption of calcium [16]. Sudden hypercalcemia in a hypoparathyroid patient may herald the onset of adrenal insufficiency [2]. Adrenal insufficiency is seen in more than two-thirds of APS-1 patients, but the diagnosis is often overlooked because the signs and symptoms are nonspecific (fatigue, weight loss, nausea, vomiting, abdominal pain). Hyperpigmentation sometimes can be seen, and is an important diagnostic feature when present. Besides the three cardinal pathological conditions, other concurrent disorders may be present in APS-1 patients (Table 1). Recent studies have reported the presence of high titers of neutralizing autoantibodies to type 1 interferon (IFN), mainly IFN-a and IFN-v, the latter of which appears to be highly specific for APS-1 [17,18]. The appearance of these antibodies precedes the development of organ-specific autoantibodies as well as early clinical manifestations, and these autoantibodies remain in the circulation for many years.
Table 1. APS-1 and APS-2 [2,3] APS-1
APS-2
Incidence
