Autoimmune Polyglandular Syndrome Type 3 Complicated with IgG4-related Disease

Abstract

A 52-year-old Japanese woman developed type 1 diabetes mellitus (type 1 DM) at 41 years old. She became complicated with Hashimoto's disease and showed swelling of both submandibular glands, which was diagnosed as IgG4-related disease (IgG4-RD). This is a rare case of a Japanese patient with autoimmune polyglandular syndrome type 3A (APS-3A) coexisting with autoimmune thyroid disease (AITD) and type 1 DM complicated by IgG4-RD. Bilateral submandibular gland resection was successfully performed without steroid therapy. We discuss the possibility that the immunological pathogenic mechanisms of APS-3A and IgG4-RD are related.

Introduction

Type 1 diabetes mellitus (DM) is frequently associated with autoimmune diseases, such as autoimmune thyroid diseases (AITD) and idiopathic thrombocytopenic purpura (ITP) (1,2). Autoimmune polyglandular syndrome type 3 (APS-3) often occurs together with type 1 DM, AITD, and other autoimmune diseases (excluding Addison's disease) (3,4).

In 1961, Sarls et al. reported that chronic pancreatitis can be caused by self-immunization (5). In 1978, a case of Sjögren's syndrome with cellular infiltration of the salivary glands consisting of lymphocytes and plasma cells, hyperglobulinemia, and stenotic lesions of the common bile duct and main pancreatic duct was reported (6). In another case, primary sclerosing cholangitis was characterized by a firm, mass-like enlargement of the pancreas, diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, and obliterated phlebitis of the pancreatic veins (7). Hamano et al. detected high concentrations of serum IgG4 in patients with sclerosing pancreatitis and evidence of infiltration of lgG4-bearing plasma cells in both ureteral and pancreatic lesions in patients with both sclerosing pancreatitis and retroperitoneal fibrosis (8,9).

These are now thought to be conditions included in IgG4-related disease (IgG4-RD). The International Consensus Diagnostic Criteria were developed in 2011 for autoimmune pancreatitis (AIP), while the Japanese comprehensive diagnostic criteria were established for IgG4-RD (10,11). Okazaki et al. proposed an international consensus on the treatment of AIP at the International Consensus Symposium of the International Association of Pancreatology in 2016 (12). AIP is a disease with systemic symptoms, obstructive jaundice, and often concurrent glucose intolerance. The two types of AIP are type 1, which is common in Japan, and type 2, characterized by granulocytic epithelial lesions commonly observed in Europe and the United States (13,14). The characteristic features of type 1 AIP are increased serum IgG4 levels, lymphoplasmacytic sclerosing pancreatitis (abundant infiltration of IgG4-positive plasma cells and lymphocytes, storiform fibrosis, and obliterative phlebitis), extrapancreatic manifestations of IgG4-RD (e.g. sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis), and steroid responsiveness.

Recently, conditions such as AIP, Mikulicz's disease, and Riedel thyroiditis (RT) were grouped as IgG4-RD, which is characterized by elevated serum IgG4 levels, fibrosis, and plasma cell infiltration into tissues. IgG4-RD can be effectively treated with steroids (15).

Regarding the association between IgG4-RD and thyroid disease, Watanabe et al. reported that patients with IgG4-RD have elevated levels of anti-thyroid autoantibodies and are predisposed to hypothyroidism (16). Inflammatory lesions enriched with IgG4 have been observed in three inflammatory thyroid diseases: Hashimoto's disease, Graves' disease, and RT (17). These conditions are called IgG4-related thyroiditis (IgG4-RTD).

RT was first described by Bernhard Riedel in 1896 (18). In 2010, Dahlgren et al. proposed the following histologic diagnostic criteria for RT: 1) fibro-inflammatory process involving all or part of the thyroid gland; 2) presence of fibrous fibroinflammatory extension beyond the thyroid capsule into adjacent anatomic structures; 3) infiltration of inflammatory cells without giant cells, lymphoid follicles, oncocytes, or granulomas; 4) evidence of phlebitis obliterans; and 5) absence of neoplasm (10,19,20). This fibrosis may cause breathing problems, dysphagia, and hoarseness. Similar inflammatory lesions are often observed in multiple organs.

Hashimoto's disease has been considered a pathologically distinct disease characterized by the presence of goiter and serum anti-thyroid autoantibodies. The existence of a subtype of Hashimoto's disease has been described to show lymphoplasmacytic infiltration of the thyroid gland, fibrosis, increased IgG4-positive plasma cells, and high serum IgG4 levels (21-23).

In patients with IgG4-RTD and Hashimoto's disease, fibrosis is localized to the thyroid tissue, anti-thyroid autoantibodies have high titers, and the thyroid function is decreased. In contrast, RT is characterized by inflammation and fibrosis that extend beyond the thyroid tissue. Occasionally, IgG4-RD is complicated with APS-3. However, the relationship between APS-3 and IgG4-RD is unclear.

We herein report a rare case of APS-3 complicated with IgG4-RD in a Japanese woman.

Case Report

A 52-year-old Japanese woman developed type 1 DM at 41 years old. Her anti-glutamic acid decarboxylase and anti-insulin antibodies were positive. She was treated with multiple daily insulin therapy for 11 years. At 50 years old, she was clinically suspected of having ITP due to a low platelet count, which was closely monitored. Two years later, she exhibited swelling of both submandibular glands. Color Doppler ultrasonography of the bilateral submandibular glands showed nodular hypoechoic areas with mild high vascularity (Fig. 1A). IgG4-RD was suspected because her serum IgG4 levels were elevated to over 400 mg/dL. She declined to receive steroid therapy and was therefore admitted to our hospital for glycemic control before bilateral mandibular gland resection.

Figure 1.

Ultrasonography findings of the bilateral submandibular glands. The upper row is the right submandibular gland, and the lower row is the left submandibular gland. Color Doppler imaging shows several lobulated hypoechoic masses with mildly high vascularity (A). Computed tomography (CT) shows normal findings in the thoracic region and no pulmonary nodule or mediastinal tumor (B). CT shows no significant swelling of the pancreas, pancreatic duct dilation, or retroperitoneal tumor (C).

She had no purpura or bleeding spots. The patient's height was 153.7 cm, and her weight was 60.6 kg (body mass index 25.7 kg/m²) on admission. Blood and urine examinations (Table 1) revealed the following: platelet count, 50,000/mm³; fasting plasma glucose, 164 mg/dL; and hemoglobin A1c, 10.5%. Although her thyroid function was normal, anti-thyroid peroxidase antibody was positive, and ultrasonography revealed characteristic findings of Hashimoto's disease. However, the results of chest and abdominal computed tomography did not show evidence of a diffuse, enlarged sausage-shaped pancreas or a capsule-like rim around the pancreas and did not indicate a mediastinal or retroperitoneal tumor (Fig. 1B, C). After intensive treatment with insulin, bilateral submandibular gland resection was successfully performed.

Table 1.

Results of the Blood and Urine Examinations.

WBC (/mm3)		6,030		LDL-C (mg/dL)		108.8
Neut (%)		47.0		HDL-C (mg/dL)		70.7
RBC (×104/mm3)		535		TG (mg/dL)		119
Hb (g/dL)		14.9		CRP (mg/dL)		0.05
PLT (×104/mm3)		5.0		IgG (mg/dL)		1,840
TP (g/dL)		7.6		IgG4 (mg/dL)		405
Alb (g/dL)		4.2		IgM (mg/dL)		119
T-BIL (mg/dL)		0.6		IgA (mg/dL)		157
AST (U/L)		36		TSH (IU/mL)		2.13
ALT (U/L)		16		F-T3 (pg/mL)		2.59
LDH (U/L)		187		F-T4 (ng/dL)		1.17
ALP (U/L)		230		TG-Ab (U/mL) (<28)†		<10
γ-GTP (U/L)		19		TPO-Ab (U/mL) (<16)†		70
AMY (U/L)		51		FPG (mg/dL)		164
p-AMY (U/L)		23		HbA1c (%)		10.5
BUN (mg/dL)		13		CPR (ng/mL)		0.01
Cr (mg/dL)		0.47		GAD-Ab (U/mL) (<1.5)† (RIA)		4.5
eGFR (mL/min/1.73 m2)		105.4		SS-A Ab (U/mL) (<10)†		<7.0
Na (mEq/L)		140		SS-B Ab (U/mL) (<10)†		<7.0
K (mEq/L)		3.6		U-Glu		(4+)
CL (mEq/L)		103		U-Ket		(-)
CK (U/L)		47		U-Pro		(-)
T-CHO (mg/dL)		210		U-ACR (mg/g Cr)		8.0
Glucagon test
Time (min)		0		5		10
Glucose (mg/dL)		262		281		303
CPR (ng/mL)		0.01		0.01		0.01

†Normal range. Alb: albumin, ALP: alkaline phosphatase, ALT: alanine transaminase, AMY: amylase, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CK: creatine kinase, CL: chloride, CPR: C-peptide immunoreactivity, Cr: creatinine, CRP: C-reactive protein, eGFR: estimated glomerular filtration rate, FPG: fasting plasma glucose, F-T3: free triiodothyronine, F-T4: free thyroxine, GAD-Ab: glutamic acid decarboxylase antibody, HbA1c: hemoglobin A1c, HDL-C: high-density lipoprotein cholesterol, IgA: immunoglobulin A, IgG: immunoglobulin G, IgG4: immunoglobulin G4, IgM: immunoglobulin M, K: potassium, LDH: lactate dehydrogenase, LDL-C: low-density lipoprotein cholesterol, Na: sodium, Neut: neutrophils, p-AMY: pancreatic amylase, PLT: platelet, RBC: red blood cell, RIA: radioimmunoassay, SS-A Ab: Sjögren’s syndrome-A antibody, SS-B Ab: Sjögren’s syndrome-B antibody, T-CHO: total cholesterol, TG: triglyceride, TG-Ab: thyroglobulin antibody, T-BIL: total bilirubin, TP: total protein, TPO-Ab: thyroid peroxidase antibody, TSH: thyroid-stimulating hormone, U-ACR: urine albumin-to-creatinine ratio, U-Glu: urine glucose, U-Ket: urine ketone, U-Pro: urine protein, WBC: white blood cell, γ-GTP: γ-glutamyl transpeptidase

The pathological findings included storiform fibrosis, plasma cell infiltration into the glands, and an elevated ratio of IgG4-positive cells to IgG-positive cells of more than 40% (Fig. 2A, B, C). These findings met the 2020 revised comprehensive diagnostic criteria for IgG4-RD. Her condition has been stable without steroid therapy for two years.

Figure 2.

Photomicrographs of submandibular gland resection. Storiform fibrosis: spindle-shaped cells, inflammatory cells, and fine collagen fibers forming a flowing arrangement on Hematoxylin and Eosin staining (A). IgG immunostaining revealed numerous IgG-positive plasma cells (arrow; magnification, ×400) (B). IgG4 immunostaining revealed numerous IgG4-positive plasma cells (arrow; magnification, ×400) (C).

Discussion

The prevalence of IgG4-RD complicated with ITP is high (24-32). Murase et al. reported that IgG4 anti-platelet antibodies recognized a common specific antigen expressed in the pancreas and platelets (27), and Helicobacter pylori infection may cause AIP (27,33,34). Morimoto et al. described a patient with membranoproliferative glomerulonephritis-like glomerular disease, ITP, and AIP (28). ITP is a systemic extrapancreatic lesion associated with AIP. Therefore, IgG4-RD, especially AIP, is often complicated by ITP. IgG4-RD has also been reported in conjunction with APS-3, but some studies have focused on the complications of AIP and type 1 DM (also associated with Hashimoto's disease) (35,36), while others have discussed the complications of sclerosing cholangitis and type 1 DM (also associated with Hashimoto's disease) (37).

In Japan, three cases of simultaneous AIP and type 1 DM have been reported (35,38,39). Taniguchi et al. identified two possible links between AIP and type 1 DM: common factors in the pathogenesis of both diseases and local disturbance of immunobalance associated with AIP triggering the immune mechanism of type 1 DM in patients with susceptible major histocompatibility complex protein human leukocyte antigen (HLA) (35).

Furthermore, Ennazk et al. suggested that cell-mediated autoimmunity could explain the occurrence of AIP and type 1 DM and that individuals carrying HLA DRB1*04:05-DQB1*04:01 are most at risk of complications of AIP and type 1 DM (36,39).

In contrast, islet-specific autoantibodies, including anti-islet cell antibodies, anti-insulin autoantibodies, anti-insulinoma-associated antigen-2 antibodies, and anti-zinc transporter 8 antibodies, are biomarkers for type 1 DM. HLA is crucial for humans. Autoantigens from β-cells are presented to antigen-presenting cells, and HLA activates CD4-positive T cells (40,41). The activated T cells then destroy β-cells, while regulatory T cells (Tregs) modulate this process.

APS was classified into types 1, 2, 3, and 4 by Neufeld et al. in 1980 (1). APS-3 includes AITD and other autoimmune endocrine diseases, such as type 1 DM, pernicious anemia, vitiligo, and systemic lupus erythematosus without adrenal insufficiency. Our patient was diagnosed with APS-3 due to the presence of type 1 DM and Hashimoto's disease, and she was further diagnosed with IgG4-RD. APS-3 is further classified into types A to D (Table 2) (3,4). Our case fits the criteria for APS-3A. APS-3 is a multifactorial disease involving multiple genetic and environmental factors. The HLA-class II haplotype DRB1*09:01-DQA1*03:02-DQB1*03:03 is one of the major genetic predispositions for APS-3 in Japanese patients (42). Our patient's HLA class II haplotype was DRB1*09:01-DQA1*03:02-DQB1*03:03, matching the common haplotype of Japanese patients.

Table 2.

Characteristics of Autoimmune Polyglandular Syndrome Type 3.

Subtype	3A	3B	3C	3D
Autoimmune thyroid disease (Hashimoto’s thyroiditis, endocrine exophthalmos, Grave’s disease, etc.)
	Endocrine disease	Gastrointestinal apparatus	Skin/ hemopoietic system/ nervous system	Collagen disease/ vasculitis
	Asymptomatic thyroiditis	Chronic atrophic gastritis	Vitiligo	Systemic lupus erythematosus
	Idiopathic myxedema	Pernicious anemia	Alopecia	Discoid lupus erythematosus
	Type 1 diabetes mellitus	Celiac disease	Thrombocytopenia	Mixed connective tissue disease
	Hirata’s disease	Chronic inflammatory bowel disease	Autoimmune hemolytic anemia	Rheumatoid arthritis
	Premature ovarian failure	Autoimmune hepatitis	Myasthenia gravis	Reactive arthritis
	Neurohypo-physitis	Primary biliary cirrhosis	Stiff-man syndrome	Scleroderma
	Lymphocytic hypophysitis		Multiple sclerosis	Sjögren’s syndrome
			Anti-phospholipid syndrome	Vasculitis

Characteristics are modified from Büyükçelik, 2014 and Betterle, 2003.

Many factors contribute to the pathology of APS-3. Cytotoxic T lymphocyte-related antigen (CTLA4), forkhead box P3 (FOXP3), and various cytokine genes contribute to susceptibility to APS-3 (43,44). Tregs play an important role in maintaining immune tolerance in healthy individuals, and the nuclear transcription factor FOXP3 is important for controlling the immune function by Tregs. A decreased inhibitory function by Tregs may be involved in the onset of type 1 DM, despite the lack of changes in the number of Tregs (45). Furthermore, immune responses to infections, food, and environmental allergens in IgG4-RD result in the activation of CD4-positive cytotoxic T lymphocytes, mediating inflammation and fibrosis. T helper 2 (TH2) cells; Tregs; TH2 cytokines such as interleukin (IL)-4, -5, -13; Treg cytokines such as IL-10 and transforming growth factor (TGF) β, IL-21 produced from TH2 cells, and follicular helper T cells contribute to B-cell and plasma cell proliferation, activation, upregulation of IgG4-class switch, and ectopic germinal center formation (46). However, further studies are needed to clarify the pathological significance and mechanism of APS-3 and IgG4-RD.

T-cell immune disorders are involved in the pathogenic mechanism in both APS-3 and IgG4-RD, and autoimmune diseases develop due to the disruption of the TH1/TH2 balance and immune response regulation from Treg to cytotoxic T-cell dominance.

In Japan, DM caused by type 1 AIP has attracted attention as a complication of IgG4-RD and DM (47). Approximately 66.5% of patients with AIP who were treated in 2002 had DM. Among them, 51.6% developed DM concurrently with the onset of AIP, and 33.3% had DM before the onset of AIP (48). DM in AIP is caused by both an impaired blood flow to the endocrine gland (islets of Langerhans) due to fibrosis of the pancreatic exocrine gland and damage to the islets of Langerhans due to inflammatory spillover (49), which is different from the usual mechanism of type 1 DM. In other words, the combination of IgG4-RD with extrapancreatic lesions and type 1 DM may be due to other mechanisms.

In our case, color Doppler sonography of the bilateral submandibular glands showed no obvious high vascularity, but hypoechoic nodules were noted, and a pathological examination revealed findings characteristic of IgG4-RD, allowing the diagnosis of IgG4-DS. IgG4-DS is often associated with lesions in other organs, including the pancreas, retroperitoneum, kidney, lungs, aorta, prostate, and thyroid (50). In IgG4-DS, as in IgG4-RD in other organs, the cytokine profile of TH2 cells is predominant, and Treg infiltration is involved in the pathogenesis.

We treated a patient with rare pathologies involving a combination of APS-3A and IgG4-RD without steroid therapy. The development of APS-3 and IgG4-RD may be related; however, the precise nature of this relationship merits further investigation.

The authors state that they have no Conflict of Interest (COI).