IgG4-related pleural disease with aortitis and submandibular glands involvement successfully treated with corticosteroid: case-based review

Rheumatology International - IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition characterized by increased serum IgG4 level, infiltration of lymphocytes and IgG4-positive (IgG4+)...     

Current concept and diagnosis of IgG4-related disease in the hepato-bilio-pancreatic system

Recently, IgG4-related disease (IgG4-RD) has been recognized as a novel clinical entity with multiorgan involvement and unknown origin, associated with abundant infiltration of IgG4-positive cells. The Japanese research committee, supported by the Ministry of Health, Labor and Welfare of Japan, unified many synonyms for these conditions to the term “IgG4-RD” in 2009. The international symposium on IgG4-RD endorsed the comprehensive nomenclature as IgG4-RD, and proposed the individual nomenclatures for each organ system manifestations in 2011. Although the criteria for diagnosing IgG4-RD have not yet been established, proposals include the International Pathological Consensus (IPC) and the Comprehensive Diagnostic Criteria (CDC) for IgG4-RD for general use, and several organ-specific criteria for organ-specialized physicians, e.g., the International Consensus Diagnostic Criteria (ICDC) and the revised clinical diagnostic criteria in 2011 by the Japan Pancreas Society (JPS-2011) for type1 AIP; the Clinical Diagnostic Criteria 2012 for IgG4-sclerosing cholangitis (IgG4-SC-2012); the diagnostic criteria for IgG4-positive Mikulicz’s disease by the Japanese Society for Sjogren’s syndrome; and diagnostic criteria for IgG4-related kidney disease by the Japanese Society of Nephrology. In cases of probable or possible IgG4-RD diagnosed by the CDC, organ-specific diagnostic criteria should be concurrently used according to a diagnosis algorithm for IgG4-RD, with referral to a specialist.     

Recent Advances in the Concept and Pathogenesis of IgG4-Related Disease in the Hepato-Bilio-Pancreatic System

Recent studies have proposed nomenclatures of type 1 autoimmune pancreatitis (AIP) (IgG4-related pancreatitis), IgG4-related sclerosing cholangitis (IgG4-SC), IgG4-related cholecystitis, and IgG4-related hepatopathy as IgG4-related disease (IgG4-RD) in the hepato-bilio-pancreatic system. In IgG4-related hepatopathy, a novel concept of IgG4-related autoimmune hepatitis (AIH) with the same histopathological features as AIH has been proposed. Among organs involved in IgG4-RD, associations with pancreatic and biliary lesions are most frequently observed, supporting the novel concept of “biliary diseases with pancreatic counterparts.” Targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts. Based on genetic backgrounds, innate and acquired immunity, Th2-dominant immune status, regulatory T (Treg) or B cells, and complement activation via a classical pathway may be involved in the development of IgG4-RD. Although the role of IgG4 remains unclear in IgG4-RD, IgG4-production is upregulated by interleukin 10 from Treg cells and by B cell activating factor from monocytes/basophils with stimulation of toll-like receptors/nucleotide-binding oligomerization domain-like receptors. Based on these findings, we have proposed a hypothesis for the development of IgG4-RD in the hepato-bilio-pancreatic system. Further studies are necessary to clarify the pathogenic mechanism of IgG4-RD.     

儿童IgG4相关自身免疫性肝炎临床与病理特征分析*

目的 探讨儿童免疫球蛋白G4相关自身免疫性肝炎(IgG4-AIH)患者临床和肝组织病理学特征。方法 2014年6月～2019年6月我科收治的AIH儿童38例,符合2008年国际AIH小组(IAIHG)制定的简化诊断积分系统或1999年IAIHG制定的AIH诊断评分系统。根据肝组织IgG4阳性浆细胞浸润≥10个/高倍镜视野(HPF)诊断IgG4-AIH。采用ELISA法检测血清IgG和IgG4。常规行肝穿刺,采用免疫组织化学染色检测肝组织IgG4阳性浆细胞。结果 在38例AIH患者中,诊断IgG4-AIH患者4例,AIH患者34例;IgG4-AIH患者血清IgG和IgG4水平分别为22.6(13.2, 29.8)mg/dL和226.5(105.8,424.6)mg/dL,与AIH患者的18.9(10.4,25.3)mg/dL和209.4(96.1,401.6)mg/dL比,差异无统计学意义(P>0.05);IgG4-AIH组肝组织IgG4阳性浆细胞计数/HPF为40.2(25.4,55.7),显著高于AIH组患者;IgG4-AIH组肝组织IgG4阳性浆细胞计数与炎性反应活动分级(r=0.48)和肝纤维化分期(r=0.37)呈正相关(P<0.05);IgG4-AIH患者血清ALT恢复正常所需要的时间为(3.5±0.8)w,显著短于AIH组,血清AST恢复时间为(3.6±0.6)w,显著短于AIH组,血清碱性磷酸酶恢复时间为(4.0±1.1)w,显著短于AIH组,血清谷氨酰转肽酶恢复时间为(4.2±1.5)w,显著短于AIH组,血清IgG水平恢复正常的时间为(7.6±2.8)w,显著短于AIH组。结论 IgG4-AIH儿童具有AIH的基本特征,血清IgG4水平并不比AIH患者更高,但肝组织IgG4阳性浆细胞浸润显著多于AIH患者。另外,IgG4-AIH儿童对皮质激素治疗具有良好的应答反应,血清学指标的恢复时间也相对较短,这些特征有助于临床诊断。本组IgG4-AIH儿童例数太少,其结论有待于验证。     

IgG 1 subclass specificity for IgG rheumatoid factors in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the significance of IgG rheumatoid factors (IgG RF) in the pathogenesis of rheumatoid arthritis (RA), and to determine the specificity of IgG subclasses binding with IgG RF in RA (RA IgG RF) compared to IgG RF in normal subjects (NS IgG RF). METHODS: The reactivities of RA IgG RF and NS IgG RF for various IgG subclasses were studied by ELISA and inhibition assay, using purified IgG heavy chains of different IgG subclasses. RESULTS: In ELISA, the optical density (OD) value of the reaction of RA IgG RF with IgG 1 was significantly higher than with IgG 2, 3, or 4 (p < 0.01). Similarly, the OD value of the reaction of NS IgG RF with IgG 1 was significantly higher than with IgG 2 or 4 (p < 0.05). In the inhibition assay, the OD value of the reaction of RA IgG RF was decreased by IgG 1, 2, and 3 (p < 0.01), but not by IgG 4. The extent of inhibition by IgG 1 was significantly greater than that by IgG 2, 3, or 4 (p < 0.05). In contrast, the OD value of the reaction of NS IgG RF was not significantly inhibited by any of the IgG subclasses. CONCLUSION: RA IgG RF and NS IgG RF reacted most strongly with IgG 1. From the differences in reactivities between RA IgG RF and NS IgG RF in the inhibition assay, it can be inferred that RA IgG RF exhibits higher affinity for IgG than NS IgG RF.     

IgG4-related respiratory disease

Abstract

IgG4-related diseases (IgG4-RDs), such as autoimmune pancreatitis and IgG4-related Mikulicz disease, are often accompanied by intrathoracic lesions, which are called IgG4-related respiratory disease (IgG4-RRD). IgG4-RRD has few subjective symptoms, and is usually detected during workup of patients with extra-thoracic lesions of IgG4-RD. IgG4-RRD is characterized by various conditions, including masses, nodules, thickening, and infiltration at numerous sites in the thorax through lymphatic routes. Although elevated serum IgG4 concentrations and pathologic evidence of lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells are characteristic findings of IgG4-RD, other intrathoracic diseases, such as multicentric Castleman disease and malignancy, may present with similar findings. Developing diagnostic criteria for IgG4-RRD, including clinicoradiological and pathological characteristics, is necessary for its appropriate diagnosis.     

Predominance of IgG1 and IgG3 subclasses of autoantibodies to peptidylarginine deiminase 4 in rheumatoid arthritis

Analysis of IgG subclass distribution of antibodies may provide insights into the mechanisms driving antibody production. Here, we have first determined IgG subclass distribution of anti-recombinant peptidylarginine deiminase 4 (anti-hPADI4) antibodies in sera from patients with rheumatoid arthritis (RA). Sera from 103 RA patients were screened to IgG anti-PADI4 using recombinant antigens. For positive samples, the subclass distribution of IgG anti-hPADI4 was determined by means of establishing the equipotency of four HRP-labeled IgG subclass-specific monoclonal antibodies. The subclass profiles were compared among individuals with different disease status. Thirty-three out of 103 RA patients were determined as IgG anti-hPADI4-positive. As expressed by percentage levels to total IgG anti-hPADI4 activity, IgG1 and IgG3 were determined to be the predominant subclasses of anti-hPADI4. Furthermore, distinct subclass distribution patterns were observed in patients with different disease status. The IgG subclass distribution of anti-hPADI4 indicates that a leading T lymphocyte-regulated IgG1 and IgG3 responses may contribute to a better understanding of the role of anti-PADI4 in RA.     

The front line of research into immunoglobin G4-related disease - Do autoantibodies cause immunoglobin G4-related disease?

Abstract

IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. Although IgG4-RD is attracting strong attention as a new clinical entity, the pathogenesis of IgG4-RD and the roles of IgG4 are still unknown. Recently, self-antigens including Laminin 511 E8, Galectin-3 and Annexin A11, have been reported from one to the next as autoantigens which may be involved in the pathogenesis of IgG4-RD. In this review, we describe up-to-date information on the research of this emerging disease entity. Moreover, we discuss the pathogenesis of IgG4-RD by focusing on recent reports concerning autoantibodies.     

IgG4相关硬化性胆管炎的研究进展

免疫球蛋白G4相关硬化性胆管炎(immunoglob-ulin G4-related sclerosing cholangitis,IgG4-SC)是一种新近认识的以血清IgG4升高、慢性进行性阻塞性黄疸、弥漫性或局限性IgG4阳性浆细胞和淋巴细胞组织浸润、纤维化及闭塞性静脉炎为特征的慢性炎症性疾病,常并发自身免疫性胰腺炎(autoimmune pancreatitis,AIP),其临床、生化及影像学特征与原发性硬化性胆管炎(primary sclerosing cholangitis,PSC)或胆管癌(cholangiocarcinoma,CC)相似.类固醇激素是IgG4-SC的主要治疗手段,而肝移植是PSC唯一的有效治疗方法,CC则需外科手术治疗.因此,IgG4-SC与PSC或CC间的准确鉴别是目前面临的一个十分重要的课题.本文详尽地阐述了免疫球蛋白G4(immunoglobulin G4,IgG4)的特征和功能,IgG4-SC的诊断和治疗,IgG4-SC与AIP、PSC及CC之间关系等研究进展,为IgG4-SC的精确诊断和治疗提供了新的思路.     

Value of serum IgG4 in the diagnosis of IgG4-related disease and in differentiation from rheumatic diseases and other diseases

IgG4-related disease (IgG4-RD) is a novel disease entity that includes Mikulicz's disease, autoimmune pancreatitis (AIP), and many other conditions. It is characterized by elevated serum IgG4 levels and abundant IgG4-bearing plasmacyte infiltration of involved organs. We postulated that high levels of serum IgG4 would comprise a useful diagnostic tool, but little information is available about IgG4 in conditions other than IgG4-RD, including rheumatic diseases. Several reports have described cutoff values for serum IgG4 when diagnosing IgG4-RD, but these studies mostly used 135 mg/dL in AIP to differentiate from pancreatic cancer instead of rheumatic and other common diseases. There is no evidence for a cutoff serum IgG4 level of 135 mg/dL for rheumatic diseases and common diseases that are often complicated with rheumatic diseases. The aim of this work was to re-evaluate the usual cutoff serum IgG4 value in AIP (135 mg/dL) that is used to diagnose whole IgG4-RD in the setting of a rheumatic clinic by measuring serum IgG4 levels in IgG4-RD and various disorders. We therefore constructed ROC curves of serum IgG4 levels in 418 patients who attended Sapporo Medical University Hospital due to IgG4-RD and various rheumatic and common disorders. The optimal cut-off value of serum IgG4 for a diagnosis of IgG4-RD was 144 mg/dL, and the sensitivity and specificity were 95.10 and 90.76%, respectively. Levels of serum IgG4 were elevated in IgG4-RD, Churg-Strauss syndrome, multicentric Castleman's disease, eosinophilic disorders, and in some patients with rheumatoid arthritis, systemic sclerosis, chronic hepatitis, and liver cirrhosis. The usual cut-off value of 135 mg/dL in AIP is useful for diagnosing whole IgG4-RD, but high levels of serum IgG4 are sometimes observed in not only IgG4-RD but also other rheumatic and common diseases.     

Relationship between pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels in IgG4-related diseases

OBJECTIVE: We aimed to investigate the relationship between the number of involved organs or regions and serum immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) levels. METHODS: The number of pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels were examined by groups in 46 patients with IgG4‐related diseases at diagnosis prior to the initiation of steroid treatment: group A (one region involved, n = 7), group B (two regions involved, n = 11), group C (three regions involved, n = 12), group D (four regions involved, n = 9) and group E (five to seven regions involved, n = 7). RESULTS: Both serum IgG and IgG4 levels increased with the number of inflamed regions. Mean serum IgG levels were 15.11, 18.65, 20.92, 23.29 and 30.98 g/L while the mean IgG4 levels were 3.99, 4.70, 4.70, 9.86 and 16.49 g/L in group A, B, C, D and E, respectively. Regression analysis also suggested that IgG4 was positively correlated with the number of regions involved. Additionally, serum IgG4 was higher in patients with multiple lesions when accompanied by sclerosing sialadenitis. CONCLUSION: Patients having IgG4‐related disease with high serum IgG and IgG4 levels should be systematically examined for involved lesions.     

IgG4-related membranous nephropathy with high blood and low urine IgG4/IgG ratio: a case report and review of the literature

Membranous nephropathy (MN) is a rare manifestation of IgG4-related disease. Interestingly, the significance of IgG4 has also been documented in idiopathic MN (IMN). Previous studies reported that urine IgG4/IgG ratios were significantly higher in IMN compared with other kinds of nephropathy, indicating that impairment of charge selectivity barrier seemed to be an obvious characteristic of IMN. Although high blood concentration of IgG4 is very common in IgG4-related MN, no study about the urine IgG4 has been described before. Here, we present a 55-year-old male with IgG4-related MN. Complete remission of proteinuria was promptly achieved by glucocorticoid treatment without immunosuppressant. Consistent with previous reports, the serum antibody against M-type phospholipase A2 receptor was negative. Surprisingly, although the blood concentration of IgG4/IgG reached as high as 36 %, the urine concentration of IgG4/IgG was only 5 %. The calculated ratio of the renal clearance of IgG4 to IgG of this patient (0.15) was obviously lower than that of five patients with IMN (0.53～0.81). We speculated that this phenomenon might be a clue of the different pathogenesis between IgG4-related MN and IMN.     

Riedel's Thyroiditis with Increased IgG4 Plasma Cells: Evidence for an Underlying IgG4-Related Sclerosing Disease?

Background: Riedel's thyroiditis (RT) is a very rare chronic fibrosing disorder of unknown etiology that is often associated with multifocal fibrosclerosis (MFS). Immunoglobulin (Ig) G4-related sclerosing disease (IgG4-RSD), a new clinico-pathological entity also associated with MFS, is characterized by IgG4+ plasma cell infiltration and fibrosis in one or more organs. Although the association of RT and IgG4-RSD has been suggested, it has seldom been studied or reported. We report a classical case of RT with serological (IgG4 levels) and immunohistochemical (IgG and IgG4) assessment, in search of an underlying IgG4-RSD. Patient: The patient was a 57-year-old woman who underwent a subtotal thyroidectomy for a long-standing goiter with a rapidly enlarging isthmic nodule. Results: Histopathological examination of the surgical specimen revealed all of the morphological features of RT and IgG4-RSD, including partial fibrosis of the thyroid gland with destruction of the thyroid follicular architecture; obliterative phlebitis; and a mixed infiltrate composed of lymphocytes, eosinophils, and plasma cells. The fibro-inflammatory process extended beyond the thyroid capsule into the surrounding tissues. Immunohistochemical examination revealed approximately 70 IgG4+ plasma cells per high power field (HPF) with an IgG4/IgG ratio of 35%. Although serum levels of IgG4 were normal (20?mg/dL), total IgG levels were slightly elevated (1370?mg/dL). There was no evidence of involvement of other organs at the time of RT diagnosis. Conclusions: The morphological similarities between RT and IgG4-RSD suggest that these entities are closely related. Therefore, RT with increased IgG4+ plasma cells, with or without elevated IgG4 serum levels, may represent the first clinical manifestation of an underlying IgG4-RSD. However, due to the rarity of both conditions and the limited specificity and sensitivity of both IgG4 serum levels and IgG/IgG4 immunohistochemistry in the diagnosis of IgG4-RSD, further studies are needed to verify this hypothesis.     

Association between autoimmune pancreatitis and systemic autoimmune diseases

AIM: To investigate the association between autoimmune pancreatitis (AIP) and systemic autoimmune diseases (SAIDs) by measurement of serum immunoglobulin G4 (IgG4).METHODS: The serum level of IgG4 was measured in 61 patients with SAIDs of different types who had not yet participated in glucocorticosteroid treatment. Patients with an elevated IgG4 level were examined by abdominal ultrasonography (US) and, in some cases, by computer tomography (CT).RESULTS: Elevated serum IgG4 levels (919 ± 996 mg/L) were detected in 17 (28%) of the 61 SAID patients. 10 patients had Sjögren’s syndrome (SS) (IgG4: 590 ± 232 mg/L), 2 of them in association with Hashimoto’s thyroiditis, and 7 patients (IgG4: 1388 ± 985.5 mg/L) had systemic lupus erythematosus (SLE). The IgG4 level in the SLE patients and that in patients with SS were not significantly different from that in AIP patients (783 ± 522 mg/L). Abdominal US and CT did not reveal any characteristic features of AIP among the SAID patients with an elevated IgG4 level.CONCLUSION: The serum IgG4 level may be elevated in SAIDs without the presence of AIP. The determination of serum IgG4 does not seem to be suitable for the differentiation between IgG4-related diseases and SAIDs.     

IgG-subclass antibody responses and the natural history of hepatic cystic echinococcosis in asymptomatic patients

Given that cystic echinococcosis (CE) is a serious clinical problem in endemic countries, there is still relatively little information available on the natural history of the human disease. The aim of the present study was to correlate serological status with pathology, in ultrasound-characterised, asymptomatic cases of human CE. Serum concentrations of IgG reacting with antigen B from cyst fluid and of similarly specific IgG1, IgG2, IgG3 and IgG4 were determined by ELISA and further investigated by immunoblotting. CE cases with simple cysts (Type I), or cysts with clear laminations and daughter cysts (Types II and III) exhibited elevated IgG4 seropositivity, whereas concentrations of specific IgG1 and IgG4 declined in CE cases characterised by cyst infiltration or calcifications (Types IV and V). The responses of each specific IgG subclass were used, in association with an ultrasound classification, to try to develop an immunoserological natural-history profile of CE in asymptomatic patients. Specific IgG4 antibody responses were particularly associated with the evolutive phase of CE (Types I, II and III), whereas the IgG1, IgG2 and IgG3 responses tended to be associated with the involutive phase (Types IV and V). These results indicated that an IgG4 antibody response was associated with (or was a marker for) cystic development, growth and disease progression, whereas the IgG1, IgG2 and IgG3 responses occurred predominantly when cysts became infiltrated or were destroyed by the host. The findings support the view that evolutive and subsequent involutive phases occur in untreated CE.     

Current approach to the diagnosis of IgG4-related disease – Combination of comprehensive diagnostic and organ-specific criteria

IgG4-related disease (IgG4-RD) is a fascinating clinical entity proposed by Japanese investigators, and includes a wide variety of diseases, formerly diagnosed as Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis, retroperitoneal fibrosis, etc. Although all clinicians in every field of medicine may encounter this new disease, a unifying diagnostic criterion has not been established. In 2011, the Japanese IgG4 team, organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan, published comprehensive diagnostic criteria for IgG4-RD. Several problems with these criteria have arisen in clinical practice, however, including the difficulty obtaining biopsy samples from some patients, and the sensitivity and the specificity of techniques used to measure serum IgG4 concentrations. Although serum IgG4 concentration is an important clinical marker for IgG4-RD, its diagnostic utility in differentiating IgG4-RD from other diseases, called IgG4-RD mimickers, remains unclear. This review describes the current optimal approach for the diagnosis of IgG4-RD, based on both comprehensive and organ-specific diagnostic criteria, in patients with diseases such as IgG4-related pancreatitis (AIP), sclerosing cholangitis, and renal, lung and orbital diseases.     

Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011

Background

IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells. Although IgG4-RD is not rare and is clinically important, its clinical diagnostic criteria have not been established. Comprehensive diagnostic criteria for IgG4-RD, including the involvement of various organs, are intended for the practical use of general physicians and nonspecialists.

Methods

Two IgG4-RD study groups, the Umehara and Okazaki teams, were organized by the Ministry of Health, Labor and Welfare Japan. As IgG4-RD comprises a wide variety of diseases, these groups consist of physicians and researchers in various disciplines, including rheumatology, hematology, gastroenterology, nephrology, pulmonology, ophthalmology, odontology, pathology, statistics, and basic and molecular immunology throughout Japan, with 66 and 56 members of the Umehara and Okazaki teams, respectively. Collaborations of the two study groups involved detailed analyses of clinical symptoms, laboratory results, and biopsy specimens of patients with IgG4-RD, resulting in the establishment of comprehensive diagnostic criteria for IgG4-RD.

Results

Although many patients with IgG4-RD have lesions in several organs, either synchronously or metachronously, and the pathological features of each organ differ, consensus has been reached on two diagnostic criteria for IgG4RD: (1) serum IgG4 concentration >135?mg/dl, and (2) >40% of IgG+ plasma cells being IgG4+ and >10?cells/high powered field of biopsy sample. Although the comprehensive diagnostic criteria are not sufficiently sensitive for the diagnosis of type 1 IgG4-related autoimmune pancreatitis (IgG4-related AIP), they are adequately sensitive for IgG4-related Mikulicz??s disease (MD) and kidney disease (KD). In addition, the comprehensive diagnostic criteria, combined with organ-specific diagnostic criteria, have increased the sensitivity of diagnosis to 100% for IgG4-related MD, KD, and AIP.

Conclusion

Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists.     

Biomarkers in autoimmune pancreatitis and immunoglobulin G4-related disease

Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.     

Elevated IgG4 levels in patients demonstrating sarcoidosis-like radiologic findings

One of the radiologic patterns associated with IgG4-related systemic disease was similar to that of pulmonary sarcoidosis. We analyzed whether suspected pulmonary sarcoidosis might include unrecognized IgG4-related systemic disease. The enrolled patients had bilateral hilar lymphadenopathy and/or lung nodules on chest computed tomography, used to diagnose the patients who could either be compatible with or suggested as having pulmonary sarcoidosis. The IgG4 levels were retrospectively measured. Bronchoalveolar lavage (BAL) was analyzed for the presence of IgG subclasses, and specimens were stained by an antibody to IgG4. We compared these data in the suspected sarcoidosis patients, with or without elevated serum IgG4, with the laboratory data and bronchoscopy results in patients with definite sarcoidosis. All enrolled patients were followed for over 5 years. The patients were classified as 49 definite and 44 suspected sarcoidosis patients. Eight patients, including 6 suspected sarcoidosis patients, had elevated abnormal levels of serum IgG4. The suspected sarcoidosis patients had significantly lower percentages of lymphocytes and IgG in the BAL. One suspected sarcoidosis patient had positive IgG4 staining in a lung specimen. The elevated serum IgG4 patients among the patients with suspected sarcoidosis showed significantly higher levels of BAL IgG4, IgG4/IgG, and IgG4/IgG3 compared with the levels of the normal serum IgG4 patients. The follow-up study revealed that 1 patient with elevated serum IgG4 was complicated with other organ failure caused by IgG4-related systemic disease, and Castleman disease was diagnosed in 2 patients. IgG4-related systemic disease was, therefore, identified among the patients with elevated serum IgG4.     

Toll-like receptor activation in basophils contributes to the development of IgG4-related disease

Background

IgG4-related disease (IRD) is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells into the affected organs. Although T helper type 2 (Th2) cytokines are implicated in enhanced IgG4 responses, molecular mechanisms accounting for the development of IgG4 antibody responses are poorly defined. Since basophils function as antigen-presenting cells for Th2 responses, we tried to clarify the role of basophils in the development of IgG4 responses in this study.

Methods

IgG4 and cytokine responses to various nucleotide-binding oligomerization domain-like receptor and Toll-like receptor (TLR) ligands were examined by using basophils isolated from healthy controls and from patients with IgG4-related disease.

Results

Activation of TLRs in basophils from healthy controls induced IgG4 production by B cells, which effect was associated with enhanced production of B cell activating factor (BAFF) and IL-13. In addition, activation of TLRs in basophils from patients with IRD induced a large amount of IgG4 by B cells from healthy controls. This enhancement of IgG4 production was again associated with BAFF and IL-13.

Conclusions

These data suggest that innate immune responses mediated through TLRs may play a role in the development of IgG4-related disease, in part by production of BAFF from basophils.