IgG4-related disease
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IgG4-related disease Presented by Amornrat Prasertcharoensuk, MD. January12, 2018
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IgG4-related disease
- 1. IgG4 Related disease Amornrat Prasertcharoensuk , MD.
- 2. • Epidemiology • Historical context • Diagnostic criteria • Pathogenesis • Clinical presentation • Treatment Outline
- 3. • In Japan, there is an estimated prevalence of 100 cases per 1 million, and an annual incidence of 1 per 100,000 . • The population between 50 and 70 years of age are more susceptible in developing this disease, with men being affected more than women (2.8:1) • The annual incidence rate of AIP patients was estimated as 1.4 per 100,000 people in Japan in 2011 (Kanno et al. 2015). Epidemiology Sujani Yadlapati1 ,Elijah Verheyen2 ·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017
- 5. 23% of 113 patients 62% of 21patients 2%of 129 patients 12 out 0f 53 patients 80% of AIPpatients 9% in 33 cases of non infectious aortitis 4 of 10 patients with inflammatory aortic 23(15%)of 153 patients Sujani Yadlapati1 ,Elijah Verheyen2 ·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017
- 6. History of IgG4-related disease Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
- 7. Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
- 8. Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
- 9. J.G. Ghably et al. / Ann Allergy Asthma Immunol 114 (2015) 447-454
- 10. Clinical features Terumi Kamisawa, Yoh Zen, Shiv Pillai, John H Stone , thelancet,Vol 385 April 11, 2015 Dacryoadenitis Submandibular gland enlargement Submandibular gland enlargement Parotid disease, used to be called Mikulicz disease, the triad of parotid, lacrimal, and submandibular gland enlargement thickening of the bronchovascular bundle in the right lung as well as a posterior ground-glass infiltrate
- 11. Cory A. Perugino,1 Hamid Mattoo, ARTHRITIS & RHEUMATOLOGYVol. 69, No. 9, September
- 12. Organ involvement Arshia Duza Islam, Autoimmunity Reviews 14 (2015) 914–922
- 13. Unrelated conditions encompassing a wide range of organs shared two characteristics : 1. elevations in serum IgG4 concentrations . 2. a set of unique histopathological features . Hallmark of histopathological : lymphoplasmacytic inflitrate : storiform fibrosis : obliterative phlebitis IgG4 Related disease Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–
- 14. The storiform pattern of fibrosis depicted in this image from a patient with IgG4-RD showing dense fibrosis within which lymphocytes, plasma cells, and occasionally eosinophils are embeddedStoriform fibrosis: a histological pattern characterized by irregular, loosely arranged whorls on low-power light microscopy, akin to a straw blanket Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 15. c) Eosinophilic angiocentric fibrosis involving the orbital soft tissue. The concentric perivascular fibrosis is a characteristic feature of this variant of IgG4-RD. (d ) a diffuse and dense lymphoplasmacytic infiltrate with only rare residual air spaces (asterisk). Numerous lymphoid aggregates are present. Note the obliterative phlebitis (arrowheads), which is typical of IgG4-RD Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 16. highlights the B lymphAn immunoperoxidase stain for IgG4 (of the case shown in panel d ) shows a diffuse and marked increase in IgG4+ plasma cells, which is typical of IgG4-RD. ( f ) An elastin stain performed on an obliterated venous channel. ( g) An immunoperoxidase stain for CD3 shows that T cells are more diffusely distributed. (h) An immunoperoxidase stain for CD20 highlights the B lymphoid aggregates. Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 18. Diagnosis Criteria Definitive Diffuse or local swelling in single or multiple organs Serum IgG4 levels >134 mg/dL Histology (2 of 3) Lymphoplasmacytic inflitrate Fibrosis in storiform (whirled) pattern Obliterative phlebitis IgG4-positive plasma cell Ratio of IgG4 +/IgG + plasma cells < 40% and >10 IgG4 + plasma cells per HPF Probable Diffuse or local swelling in single or multiple organs Histology (2 of 3) Lymphoplasmacytic inflitrate Fibrosis in storiform (whirled) pattern Obliterative phlebitis IgG4-positive plasma cells Ratio of IgG4 +/IgG + plasma cells <40% and >10 IgG4 + plasma cells per HPF Possible Diffuse or local swelling in single or multiple organs Serum IgG4 levels >134 mg/dl or >Twofold upper limit of normal Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL,5 july 2017
- 19. PATHOGENESIS
- 20. Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
- 21. Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–
- 22. J.G. Ghably et al. / Ann Allergy Asthma Immunol 114 (2015) 447-
- 23. Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
- 24. Cory A. Perugino,1 Hamid Mattoo, ARTHRITIS & RHEUMATOLOGY Vol. 69, No. 9, September 2017
- 25. Cory A. Perugino,1 Hamid Mattoo, ARTHRITIS & RHEUMATOLOGY Vol. 69, No. 9, September 2017
- 27. Mitsuhiro Akiyama et al., the British Society for Rheumatology, 24 March 2017
- 28. Mitsuhiro Akiyama et al., the British Society for Rheumatology, 24 March 2017
- 29. Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–
- 30. Mitsuhiro Akiyama et al., the British Society for Rheumatology, 24 March 2017
- 31. • small subset –japan study in AIP • human leukocyte antigen (HLA) serotypes DRB1*0405 and DQB1*0401 have been shown to increase susceptibility of IgG4-RD in Japanese populations . • There exist additional non-HLA genes in which single-nucleotide polymorphisms (SNPs) are implicated in increased disease susceptibility and recurrence. Genetic Sujani Yadlapati1 ,Elijah Verheyen2 ·,Petros Efthimiou , Rheumatology INTERNATIONAL,2017
- 33. • The enlargement of the lacrimal and salivary glands (IgG4-related dacryoadenitis and sialadenitis [IgG4-DS]) in this condition was found to be elastic, painless, and persistent (occurring for >3 months) • In contrast, in Sjogren’s syndrome , the enlargement of the parotid gland is predominant. • Complicating diagnosis IgG4 RD also frequently test positive for anti- SSA and/or anti SSB autoantibody . Organ involvement in the head and neck region Salivary glands Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
- 34. Lacrimal gland and orbit •22.5% of cases of orbital lymphoproliferative disorders . •involvement include the lacrimal glands, extraocular muscles, and orbital nerves (IgG4-related dacryoadenitis ) • neuroimaging studies difficult to evaluate whether the lesion is benign or malignant only via imaging, histopathological examination is essential , Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
- 35. Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
- 36. • IgG4-related thyroiditis reportedly includes Riedel’s thyroiditis (RT) ,Hashimoto’s thyroiditis (HT) and IgG4- related thyroiditis. • RT is now firmly considered as an IgG4-RD variant, and has long been known to be associated with systemic fibrosclerosing diseases, many of which are now included within the spectrum of IgG4-RD. • HT shows a partial overlap with IgG4-related thyroiditis . HT higher anti-thyroglobulin levels, anti-thyroid peroxisomal levels, and antibody titers; and diffuse low echogenicity on ultrasonography Thyroid Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
- 37. A – Bilateral enlargement of the parotid and submandibular glands Mikulicz’s disease. B- lacrimal gland disease C- Proptosis and exotropia orbital pseudotumor associated with IgG4-RD Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 38. (d) Coronal computed tomographic image of the patient shown in panel c. In addition to his orbitalpseudotumor, he had left maxillary sinusitis (evidentin this image) and proteinuria caused by tubulointerstitial nephritis. For these reasons, he wassuspected to have granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) formany months. (e) IgG4-related thyroid disease, formerly termed Riedel’s thyroiditis. The thyroid gland has a hard, woody feel Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 39. • IgG4-related hypophysitis of the anterior pituitary , Magnetic resona (MRI) findings show sellar enlargement and thickening of the pituitary stalk • IgG4-RD is one of the most common causes of hypertrophic pachymeningitis (HP), mass effect, nerve compression, or vascular compromise • A recent survey study in Japan showed that among 159 patients with HP, antineutrophil cytoplasmic antibody (ANCA)-related HP was the most frequent form (34%), followed by IgG4-related HP (9%) Pituitary gland and dura mater Kenichi Takano , Auris Nasus Larynx 44 (2017) 7–17
- 40. (a) Magnetic resonance imaging study demonstrating a large mass in the left maxillary sinus that enhances with gadolinium. (b) Magnetic resonance imaging study of the brain showing enlargement and enhancement of the pituitary gland and its stalk Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 41. • Lung : inflammatory pseudotumor, central airway disease, localized or diffuse interstitial pneumonia, and pleuritis . • radiologic manifestations, which include: (a) solid nodular lesions, sometimes with spiculations; (b) round-shaped, ground-glass opacities; (c) alveolar interstitial disease, with honeycombing, bronchiectasis, and diffuse ground-glass opacities; and (d ) thickening of the bronchovascular bundle. • Pleura and pericardium :severe, nodular thickening of the visceral or parietal pleura with diffuse sclerosing inflammation, sometimes associated with pleural effusion CHEST Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 42. (c) bronchovascular bundle lesion in IgG4-RD involving the lung. IgG4-RD has a predilection for the bronchovascular bundle regions within this organ. hard, pearly nodules adjacent to the large airways. (d ) Histopathology of IgG4-RD involving the bronchovascular bundle within the lung Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 43. (E) Computed tomographic angiogram demonstrating a dissection of the aortic arch. Examination of the resected aorta revealed IgG4-related aortitis. (F) Lymphoplasmacytic aortitis. Shown is a section of the resected aorta stained with hematoxylin and eosin and visualized at 25× magnification. Black arrowheads indicate lymphoid aggregates in the adventitia. Yellow arrowheads indicate plasma cell infiltrates in the media. The dashed line indicates the intima–media boundary Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 44. • Pancreas. type 1 (IgG4- related) AIP include mild abdominal pain; weight loss; and acute, obstructive jaundice (known as painless jaundice). • The sensitivity of igG4 levels in diagnosis AIP range from 50-92%. • Required imaging(MRCP,ERCP,CT,MRI) and histopathology for diagnostic . • diffusely enlarged pancreas, the so-called “sausage-shaped pancreas,” or with a focal mass, have a hypodense rim. • The pancreatic duct is characterized by caliber irregularities, followed by a length of narrowing without distal dilation . ABDOMEN Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47 Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017
- 45. • Biliary tract. IgG4-related sclerosing cholangitis considered to have primary sclerosing cholangitis and who respond well to glucocorticoids. • IgG4- SC is characterized on ERCP, MRCP, CT, and/or endoscopic ultrasound (US) with concentric mural thickening and segmental or long ductal narrowing and possible pre stenotic dilation with delayed contrast enhancing uptake • Type 1 Isolated distal stenosis of the common hepatic duct. Type 2 Diffuse stenosis. Type 3 Hilar and distal common hepatic duct stenosis. Type 4 Isolated hilar common hepatic duct stenosis ABDOMEN Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47 Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017
- 46. (g)Type 1 (IgG4-related) autoimmune pancreatitis. Computed tomography scan of the abdomen revealing diffuse pancreatic enlargement, with loss of normal lobularity. (h) Retroperitoneal fibrosis Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47
- 47. Kidney Annu. Rev. Pathol. Mech. Dis. 2014. 9:315–47 Common :tubulointerstitial nephritis and membranous glomerulonephritis (negative for phospholipase –A2 receptor ) Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL,5 july 2017 Delay steroid – result severe fibrosis and atrophy of kidneys
- 48. IgG4-related lymphadenopathy Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL, 2017 • modestly enlarged non-tender nodes, absence of constitutional symptoms, and distinct histology fndings on biopsy Five characteristic patterns are seen on histology, all of which feature an abundance of IgG4 positive cells with eosinophilic infltration : Type 1 Multi-centric Castleman disease-like. Type 2 Follicular hyperplasia. Type 3 Interfollicular expansion. Type 4 Progressive transformation of germinal centerlike. Type 5 Nodal infammatory pseudotumor-like
- 50. Diagnosis Criteria Definitive Diffuse or local swelling in single or multiple organs Serum IgG4 levels >134 mg/dL Histology (2 of 3) Lymphoplasmacytic inflitrate Fibrosis in storiform (whirled) pattern Obliterative phlebitis IgG4-positive plasma cell Ratio of IgG4 +/IgG + plasma cells < 40% and >10 IgG4 + plasma cells per HPF Probable Diffuse or local swelling in single or multiple organs Histology (2 of 3) Lymphoplasmacytic inflitrate Fibrosis in storiform (whirled) pattern Obliterative phlebitis IgG4-positive plasma cells Ratio of IgG4 +/IgG + plasma cells <40% and >10 IgG4 + plasma cells per HPF Possible Diffuse or local swelling in single or multiple organs Serum IgG4 levels >134 mg/dl or >Twofold upper limit of normal Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL,5 july 2017
- 51. P. Brito-Zeron et al. / Best Practice & Research Clinical Rheumatology 30 (2016) 261
- 52. P. Brito-Zeron et al. / Best Practice & Research Clinical Rheumatology 30 (2016) 261 - 278
- 53. P. Brito-Zeron et al. / Best Practice & Research Clinical Rheumatology 30 (2016) 2
- 54. Sujani Yadlapati1,Elijah Verheyen2·,Petros Efthimiou , Rheumatology INTERNATIONAL,5 july 2017
- 55. Zhang et al, Medicine ,Volume 94, Number 2, January 2015
- 56. Zhang et al, Medicine ,Volume 94, Number 2, January 2015
- 58. • elevated serum IgG4 levels (to greater than 135 mg/dl) were reported in 84 % (1586/1883) of patients with IgG4-RD, and the mean serum IgG4 level was 769 mg/dl (Stone et al. 2015). • elevation of serum IgG4 levels is not restricted to IgG4-RD and is also seen in other conditions such as autoimmune disease, allergic conditions, carcinoma, and Castleman’s disease. • elevated serum IgG4 levels by themselves have a low specificity (60 %) and a low positive predictive value (34 %) for the diagnosis of IgG4-RD (Carruthers et al. 2015a). IgG4RD cannot be diagnosed solely on the basis of serum IgG4 levels Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
- 59. Cutoff value of infiltrated IgG4-positive plasma cells is more than 10 cells per HPF, but the cutoff value varies according to the specific tissue. Measurement of the IgG4-positive cell/total IgG-positive cell ratio, in which a minimum ratio of 40 % is usually used, may also be useful, especially in cases in which fibrosis is predominant. Although findings of storiform fibrosis and obliterative phlebitis enhance diagnostic specificity, clinicopathological correlation is always essential (Deshpande et al. 2012) Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
- 60. L. Vasaitis / European Journal of Internal Medicine 27 (2016) 1–
- 61. TREATMENT
- 62. STEROID Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
- 63. J.G. Ghably et al. / Ann Allergy Asthma Immunol 114 (2015) 447-45
- 64. EMERGING TREATMENT MODELS IN RHEUMATOLOGY , ARTHRITIS & RHEUMATOLOGY Vol. 69, No. 9, September 2017
- 66. ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 7, July 2015,
- 67. ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 7, July 20
- 69. PROGNOSIS 115 patients with either AIP or IgG4-SC were evaluated, with 50% of patients experiencing relapse, and 11% of patients developing malignancy. (Hugget et al.) Indeed, the risk is signifcantly elevated for compared to the general population (odds ratio = 2.25, P = 0.02) Cancers among 15 out of 108 patients with IgG4-related AIP (14%), with a relative risk of 4.9 (Shiokawa et al) increased risk of non-Hodgkin’s lymphoma (NHL) for patients with IgG4-RD, with a standardized incidence rate as high as 16 (Takahasi et al ) Kazuichi Okazaki , Current Topics in Microbiology and Immunology (2017) 401: 1–17
Editor's Notes
- Spectrum of complex fibro – inflammatory disorder – under diagnosed dut to unfamiliarity by clinical Primary clinical feature entails a tumor like presentation couple with tissue – destructive lesions
- Encompasses a sprectrum of complex immune –mediated fibro-inflammatory disease – Disease entity result of plasma –cell mediated overproduction of the igG4 subclass of immunoglobulin igG Outstanding igG 60-70% og igG
- Type 1 lymphoplasmacytic scelerosing pancreatitis IDCP – idiopathic duct – centric chronic pancreatitis Primary scelosing cholangitis
- Regarding tissue diagnosis, there are three main histopathological features of IgG4-RD: (1) dense lymphoplasmacytic infltrate; (2) fbrosis, arranged at least focally in a storiform pattern; (3) obliterative phlebitis [59]. 1. Dense lymphoplasmacytic infltrate Small lymphocytes difusely intermingled with plasma cells. Germinal centers may or may not be present. The lymphocytic infltrate is composed predominantly of T cells with fewer aggregates of B cells. Plasma cells may be predominant. In addition, eosinophils and macrophages can be seen in setting of angiocentric fbrosis. 2. Storiform-type fbrosis pattern Spindle cells (either fbroblasts or myofbroblasts) radiating from a center and buried within lymphoplasmacytic infltrate. 3. Obliterative phlebitis Venous channels damaged by a dense lymphoplasmacytic infltrate
- IgG4 is a T helper type 2 (Th2)-dependent immunoglobulin and has low affinity for its target antigen. Th2 cytokines such as interleukin (IL)-4 and IL-10 direct naïve human B cell immunoglobulin isotype switching to IgG4 and IgE production (Meiler et al. 2008). As shown in Fig. 1, at least six subsets of CD4+ Th cells have been identified to date: Th0, Th1, Th2, Th17, regulatory T (Treg), and follicular helper T (Tfh) cells, which are generally considered to maintain homeostasis of the immune system. Interestingly, various diseases may be induced by the impaired regulation of these cells (King et al. 2008). Recent studies suggested that Fig. 1 CD4+ T helper subsets lineage. Abbreviations Th, T helper; Treg, regulatory T; Tfh, follicular helper T; CTL, cytotoxic T cell 76 M. Moriyama and S. Nakamura particular Th subsets might be involved in the initiation of IgG4-RD (van der Neut et al. 2007; Rispens et al. 2009). This review will summarize the results of recent studies seeking to understand the role of Th cell subsets in IgG4-RD. 2 Th1/Th2 Balance Th1 cells produce IL-2, interferon (IFN)-c, and tumor necrosis factor (TNF)-a, which induce the inflammatory responses responsible for cellular immunity. In contrast, Th2 cells produce IL-4, IL-5, and IL-13, which provide help for humoral immunity. Th2 responses can also counteract Th1-mediated microbicidal action. Many allergic and autoimmune disorders are associated with polarization of the Th1/Th2 balance (Kennedy et al. 1992; Rapoport et al. 1993). IL-4 causes immunoglobulin isotype switching to IgG4 and IgE production (Punnonen et al. 1993). IgG4-RD patients also frequently develop allergic disease, including bronchial asthma, allergic rhinitis, and atopic dermatitis, with severe eosinophilia and elevation of serum IgE levels (Zen et al. 2007). Thus, many studies of this disease suggest that Th2 polarization contributes to the pathogenesis of IgG4-RD (Zen et al. 2007; Tanaka et al. 2012; Nakashima et al. 2010; Maehara et al. 2012b; Miyake et al. 2008). We also previously reported that peripheral CD4+ Th cells from patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS), so-called Mikulicz’s disease, revealed deviation of the Th1/Th2 balance toward Th2 (Miyake et al. 2008). Furthermore, the expression profile of cytokines in salivary glands from patients with IgG4-DS suggested that Th2 immune reactions might play a key role in IgG4 production (Tanaka et al. 2012). However, the mechanism of Th2 immune activation in IgG4-RD remains to be clarified. In a recent study, we focused on IL-33 as a recently identified cytokine that directly stimulates ST2, the IL-33 receptor, expressed by Th2 cells, eosinophils, and mast cells, to induce production of IL-4, IL-5, and IL-13 (Schmitz et al. 2005). IL-33 is mainly expressed by epithelial cells but also by a wide variety of cell types, including dendritic cells, macrophages, fibroblasts, mast cells, and osteoblasts. Our current data demonstrate that the expression of IL-33 in salivary glands from IgG4-DS patients is significantly higher than that in patients with chronic sialadenitis and healthy controls. Interestingly, the expression of IL-33 in salivary glands was detected around ectopic GCs only in IgG4-DS patients. To confirm the identity of IL-33-producing cells around ectopic GCs, we analyzed the coexpression of immune cell markers and IL-33. The localization of IL-33 was consistent with that of CD163-positive M2 macrophages. In addition, mRNA expression of IL-33 was positively correlated with that of Th2 cytokines only in IgG4-DS patients (manuscript in preparation). These results suggest that the main IL-33 producing cells in IgG4-DS might be M2 macrophages and that they are deeply involved in activation of Th2 immune respons
- rum IgE levels [5,6]. In contrast to patients with autoimmune diseases supported by T helper 1 (Th1) or Th17-mediated immunity and production of inflammatory cytokines interleukin-2 (IL-2), interferon gamma, and tumor necrosis factor alpha, the patients with IgG4-RD have mainly upregulated responses of Th2 (cytokines IL-4, IL-5, IL-13, and IL-21) and regulatory T (Treg) cells (IL-10 and transforming growth factor beta 1 (TGF-β1)) [7]. Th2 induces an allergic immune response with eosinophilia and increased serum IgE [8,9]. Activated mast cells, strongly positive for IgE, promote the differentiation of naïve T cells to Treg cells [10]. IL-10 also known as anti-inflammatory cytokine promotes the differentiation of B cells to plasma cells and subsequent production of IgG4. IL-4 activates macrophages to produce high levels of IL-10. IL-21 produced by Th2 and T follicular helper cells is important in the formation of germinal centers
- Cartoon depicting components of the immune response that could lead to altered eosinophil, IgE, total IgG, IgG4, and immunoregulatory cytokine levels culminating in the observed pathologic effects of fibrosis (fibrosclerotic disease) and multiorgan dysfunction. TH2 cells (IL-4 and IL-13) activate B cells to class switch to IgE and IgG4, with factors such as TGF-b, vitamin D, and IL-10 inducing an IgG4 response. The presence of IL-10, IL-12, and IL-21 seem to push the response more toward IgG4 than toward IgE, suggesting much of the observed pathology represents the type of cytokine cocktail elaborated during the aberrant immune response in these individuals with IgG4-related disease. Recent studies by Furukawa et al63 also have demonstrated a role for macrophage-derived IL-10 and CCL 18 in tissue fibrosis in IgG4-related dacryoadenitis and sialadenitis. Other organ-specific factors also can influence the evolution of unique or specific pathologic features. CCL 18, chemokine ligand-18; IL, interleukin; TGF b, transforming growth factor-b; TH2, T-helper cell type 2; T-reg, T-regulatory cell.
- Figure 3. T cell–B cell collaboration, mediated by interleukin-4 (IL-4) and IL-21, is at the center of driving the differentiation of activated B cells into antibody-secreting cells. During this interaction, multiple processes occur including class-switch recombination (CSR) and somatic hypermutation (SHM), resulting in affinity maturation. T cell–dependent plasmablasts circulate for a short period of time before a small fraction of them home to the bone marrow, where they differentiate into long-lived plasma cells. The initial decline in serum IgG4 levels following treatment is attributed to the loss of T cell–independent plasmablasts in the tissue and T cell–dependent plasmablasts in the blood. In the case of CD20-targeted therapy, the loss of plasmablasts occurs secondary to destroying their activated parent B cells. The slow and gradual decline in serum IgG4 levels is attributable to the slow reduction in long-lived plasma cells residing in the bone marrow. Tfh cell 5 follicular helper T cell.
- Unique characteristics of immunoglobulin 4 (IgG4) antibodies. (a) IgG4: a noninflammatory antibody. Fab arm exchange, inability to fix complement, poor binding to activating FcγRI, and the capacity to engage the inhibitory FcγR (FcγRIIB) are unique features of IgG4 that make it a noninflammatory immunoglobulin. The heavy chains of IgG4 can switch between inter- and intrachain disulfide bonded configurations. Intrachain disulfide bonded IgG4 is composed of noncovalently associated hemi-IgG4 molecules, which can be exchanged in vitro, under reducing conditions, or in vivo, potentially aided by FcRn recycling. This process, termed Fab arm exchange, can give rise to bispecific IgG4 antibodies. (b) Theoretical immune complexes that can be formed by bispecific IgG4 antibodies. The nature of the immune complexes formed in vivo in IgG4-related disease is unknown. There are two possibilities: (i ) Fab arm exchange of antigenspecific IgG4 with antibodies of irrelevant specificity may result in functionally monovalent antibodies. Such antibodies would give rise to small, nonprecipitating immune complexes. (ii ) Fab arm exchange between IgG4 antibodies that react with different epitopes on the same antigen would result in functionally bivalent antibodies, and may result in the formation of large immune complexes. Such immune complexes may be inefficiently cleared due to lack of complement binding and may account for the IgG4 deposits seen in some cases of IgG4-related disease. --gG4 is the least common of the four subclasses of IgG and accounts for 3–6% of total IgG in normal serum. IgG4 exhibits negligible binding to FcγII and FcγIII receptors and C1q protein complex, and is unable to activate the classical complement pathway. Although the IgG1 response is considered to precede the IgG4 response, the switch is driven by the repeated and prolonged exposure to the antigen [22]. Structural differences of the core IgG4 hinge allow the heavy chains to separate and recombine randomly forming antibodies with two different antigen-binding sites. The bispecific IgG4 molecules are unable to crosslink antigen and lose the ability to form immune complexes. In addition, IgG4 can bind the Fc portion of other IgG antibodies and may contribute to the molecule's anti-inflammatory effect [23,24]. Moreover, IgG4 may function as a blocking or neutralizing antibody, protecting the body from severe allergic reactions in response to food or environmental allergens
- Chronic stimulation by unknown antigens activates APCs, and they induce the differentiation of Tfh2 cells. FDCs (or Tfh2 cell accumulation themselves) secrete CXCL13, which induces Tfh2 cells and B cell accumulation through interaction with CXCR5, resulting in the formation of ectopic germinal centres in affected tissues. Tfh2 cells induce the differentiation of naı¨ve B cells into plasmablasts and plasma cells, and IgG4 class-switching through cell-to-cell contact with the elaboration of IL-4 and IL-21. IgG4 itself and the cytokines from Tfh1 cells, cytotoxic CD4+ T cells and Treg cells may contribute to tissue damage and fibrosis. Tfh2: T follicular helper 2 cells; Tfh1: T follicular helper 1 cells; APC: antigenpresenting cell; FDC: follicular dendritic cell; SHM: somatic hypermutation; CXCL13: CXC chemokine ligand 13; Bcl-6: B cell lymphoma-6; PD-1: programmed death-1; AID: activation-induced cytidine deaminase; CD40L: CD40 ligand Mitsuhiro Akiyama et al.
- MRCP – magnetic resonance cholangiopancreatography ERCP – endoscopic retrograde cholangiopancreatography
- MRCP – magnetic resonance cholangiopancreatography ERCP – endoscopic retrograde cholangiopancreatography
- .1. “Watch-and-wait” strategy In asymptomatic patients or those with limited disease, e.g., with only involvement of lymph nodes or salivary glands, “watch-andwait” strategy can be applied [101]. Follow-up of these patients is important by assessing organ dysfunction clinically and/or by imaging. 7.2. Specific treatment In symptomatic patients glucocorticoids and B-cell depletion for induction of remission are used. In some cases, surgical interventions are needed, and in severe cases, urgently
- Suggested regimens include a 4-week course of 40–80 mg of prednisone every day Clinical remissions are described diferently from studyto-study because parameters of treatment response correlate imperfectly with one another. To generalize these fndings, the IgG4-RD responder index (IgG4-RDI) was developed for more accurate characterization of disease activity and response [56]. Baseline levels of serum IgG4, IgE, and circulating eosinophils have been described as alternative markers for disease relapse in IgG4-RD Systemic glucocorticoids, which are well known to induce nonselective apoptosis of lymphocytes, are the first-line approach for the most patients with symptomatic IgG4-RD. Most patients (86–99%) [3,4,38] respond well to glucocorticoids within 2–4 weeks. Two main steroid regimens, based on type 1 AIP and cholangitis treatment, have been employed for the management of IgG4-RD, even for other organ manifestations. A Japanese approach suggests an initial dose 0.5–0.6 mg/kg/day or fixed-dose of prednisone 30–40 mg/day for 2–4 weeks and then tapering by 5–10 mg every 1–2 weeks to low maintenance dose of prednisone 2.5–5 mg/day, which is continued from 6 months up to 3 years [3,4,102]. Another approach established at the Mayo Clinic [103,104] is an initial treatment with prednisone 40 mg/day for 4 weeks and then tapering by 5 mg/week during a 7-week taper period until the patient is off prednisone by the end of 11 weeks. In clinical practice, higher prednisone doses may be needed to induce remission and to prevent major organ damage. Although glucocorticoids usually induce the remission in most cases, 25–50% of patients relapse on low maintenance dose or after discontinuation of glucocorticoids [3,103]