**3. Pathogenesis of IgG4-RD**

Pathogenesis of IgG4-RD is not fully understood. It seems that many factors contribute to disease development, including allergic, autoimmune and genetic factors [12].

The observed positive response to drugs blocking B-lymphocyte activity and monoclonal increase of IgG4 concentration suggested a significant role of B lymphocytes in the initiation and maintenance of the disease process [13]. However, current research indicates inappropriate activation of T lymphocytes causing autoimmune defect.

The first publications indicated an increase of Th2 cytokine production in patients with IgG4-RD [14, 15]. However, it turned out that this effect is seen only in patients with IgG4-RD and concomitant allergic symptoms [16]. It was shown that in response to Th2-dependent cytokines, such as interleukin 4, 5, 10, and 13, as well as transforming growth factor beta (TGF-β), the eosinophil number and concentration of IgG4 and IgE increase and fibrosis progresses [17]. Eosinophilia, similarly to allergy, may occur in 1/3 of patients with IgG4-RD. However, the correlation between the increased number of eosinophils and clinical symptoms of allergy was not confirmed. Similarly, allergic symptoms did not correlate in patients with IgG4-RD with increased IgE concentration [18]. Allergic symptoms included allergic rhinitis, nasal polyps, bronchial asthma and atopic dermatitis [19]. Further studies showed that a key role in the pathomechanism of IgG4-RD play T follicular helper cells (Tfh) and regulatory T cells (Treg). Their role is particularly seen in relation with class switching of B cells and induction of aberrant lymphoid follicle formation in tissue. However, II-21 and II-4 related to Tfh play a great role in the formation of germinal centers, differentiation of B lymphocytes, induction of plasmoblasts and the phenomenon of class switching leading to the production of igG4 [20, 21]. This is in the Tfh germinal centers of lymph nodes that II-4 is produced and long-lasting memory lymphocytes responsible for disease recurrences proliferate [22, 23].

**75**

*IgG4-Related Disease and the Spectrum of Mimics in Rheumatology*

of participation of annexin A11 in the pathogenesis of AIP [30].

gene polymorphism and a molecule for type Fc-3 receptor on B cells [39].

In the course of IgG4-RD, infiltrations composed mainly of IgG4 are formed, and characteristic fibrosis of affected organs is seen. These lesions usually form pseudotumors, which may occur in every organ. Most commonly observed locations of IgG4-RD are shown in **Table 2**. Single clinical cases of disease occurrence in the brain and cerebrospinal meninges, as well as intestines, causing ileus, have also been reported [40, 41]. IgG4-RD may affect one organ or occur in a generalized form. It seems that some locations may be more common for a particular sex. For example, lesions in the pancreas are more common in men, while sialadenitis

**4. Clinical manifestations of IgG4-RD**

The analyses of immunophenotyping of Thf subclasses showed that in IgG4-RD, cytokines type Th2 (IL-4, IL-5, IL-13) are produced by cells not expressing CXCR3 and CCR6 [24]. The number of Th2 cells is increased in IgG4 and correlates with increased IgG4 concentration in serum and IL4, the number of plasmocytes and the number of affected organs [21, 25]. However, in AIP, an increased number of CD4+ and CD25+ Treg was observed [21, 25]. In the most recent reports, attention has been paid to cytotoxic lymphocytes CD4+ (CTLs) [26–29] as well as the possibility

The role of plasmoblasts and IgG4 itself is still not known in the pathomechanism of IgG4-RD. It is thought that they are more of disease markers than factors of disease development [5, 22]. Among IgG, there are 4 subclasses in humans (IgG1- IgG4). Normally, IgG4 constitute about 2–3% of all IgG, and their serum concentration is 35–51 mg/dL on average. Higher serum concentration of IgG4 was observed in men and in the elderly [31]. IgG4 and IgE are usually produced as a result of chronic exposure to antigens [32] or after allergy immunotherapy [33]. IgG4 is not able to form immunocomplexes which could stimulate antigen-presenting cells and enhance immunological response. Moreover, it does not initiate the classic pathway of complement activation [34]. The IgG4 antibodies bind weakly to complement C1q and Fcy receptors. As a consequence, they are not involved in antibodydependent cell-mediated cytotoxicity [35]. Additionally, IgG4 antibodies are dynamic molecules—altering their properties by spontaneous exchange of one of the two Fab fragments between individual immunoglobulin molecules. This process involves dissociation of immunoglobulin G4 heavy-chain dimers and a subsequent bonding of each IgG4 half-molecule with a different IgG4 half-molecule. This half-molecule exchange yields bi-specific antibodies able to bind with two different antigens, but monovalent for each of them. These properties of IgG4 molecules are the reason why IgG4 antibodies do not bind to the complement directly, do not initiate the classic pathway of complement activation, or why they are poor Fc receptor activators. This reduced IgG4 effector function has been responsible for these antibodies being considered anti-inflammatory [31]. IgG4 are believed to constitute a veritable antigen "garbage disposal" system, which can attenuate inflammation or protect against type I hypersensitivity by inhibiting IgE activity, as well as prevent type II and III hypersensitivity by blocking immune complex formation [36, 37]. Genetic studies seem to confirm some genetic background of IgG4-RD. Until present, differences in the expression of different genes have been found in salivary glands of patients with Sjӧgren syndrome and in patients with IgG4-RD, compared to healthy population. Only in a group of patients with IgG4-RD, overexpression of genes related to cell proliferation, organization of extracellular matrix and tissue fibrosis was confirmed [38]. Also, the relationship was found between AIP and class II antigen of the major histocompatibility complex HLA-DRB1\*0405-DQB1\*0401 and nuclear factor κB

*DOI: http://dx.doi.org/10.5772/intechopen.83368*

#### *IgG4-Related Disease and the Spectrum of Mimics in Rheumatology DOI: http://dx.doi.org/10.5772/intechopen.83368*

*Chronic Autoimmune Epithelitis - Sjogren's Syndrome and Other Autoimmune Diseases...*

disease depending on the location of the lesions (**Table 1**) [4].

**2. Epidemiology**

**3. Pathogenesis of IgG4-RD**

factors [12].

autoimmune defect.

cian may have contact with IgG4-RD, independent of his/her speciality.

observed in 4–20% of patients, depending on a publication [9–11].

In 2011, classification criteria were presented with a spectrum of diseases described so far in medicine that may correspond to IgG4-RD. The first relationship between autoimmune pancreatitis and increased serum IgG4 was observed in 2001 and it is one of the most common manifestations of IgG4-RD-type 1 of autoimmune pancreatitis [3]. Currently, there is a tendency to introduce the name IgG4-RD

Due to possible location of pathologic lesions in most of the organs, every physi-

The disease develops mostly in men, middle-aged or older. The ratio of disease incidence in men vs. women is between 1:0.77 and 4:1 [5, 6]. The disease incidence is not fully known and it seems that it varies significantly for different parts of the world. The highest number of IgG4-RD cases has been reported so far for Asia. In Japan, based on the register of patients with IgG4-RD, the disease incidence was determined to be 0.28–1.08 in 100,000 people [7]. Despite the fact that the disease is not often seen in children, there were more than a dozen such cases reported in the world [8]. In the case of an affected aorta, lesions in the course of IgG4-RD were

Pathogenesis of IgG4-RD is not fully understood. It seems that many factors contribute to disease development, including allergic, autoimmune and genetic

The observed positive response to drugs blocking B-lymphocyte activity and monoclonal increase of IgG4 concentration suggested a significant role of B lymphocytes in the initiation and maintenance of the disease process [13]. However, current research indicates inappropriate activation of T lymphocytes causing

The first publications indicated an increase of Th2 cytokine production in patients with IgG4-RD [14, 15]. However, it turned out that this effect is seen only in patients with IgG4-RD and concomitant allergic symptoms [16]. It was shown that in response to Th2-dependent cytokines, such as interleukin 4, 5, 10, and 13, as well as transforming growth factor beta (TGF-β), the eosinophil number and concentration of IgG4 and IgE increase and fibrosis progresses [17]. Eosinophilia, similarly to allergy, may occur in 1/3 of patients with IgG4-RD. However, the correlation between the increased number of eosinophils and clinical symptoms of allergy was not confirmed. Similarly, allergic symptoms did not correlate in patients with IgG4-RD with increased IgE concentration [18]. Allergic symptoms included allergic rhinitis, nasal polyps, bronchial asthma and atopic dermatitis [19]. Further studies showed that a key role in the pathomechanism of IgG4-RD play T follicular helper cells (Tfh) and regulatory T cells (Treg). Their role is particularly seen in relation with class switching of B cells and induction of aberrant lymphoid follicle formation in tissue. However, II-21 and II-4 related to Tfh play a great role in the formation of germinal centers, differentiation of B lymphocytes, induction of plasmoblasts and the phenomenon of class switching leading to the production of igG4 [20, 21]. This is in the Tfh germinal centers of lymph nodes that II-4 is produced and long-lasting memory lymphocytes responsible for disease recurrences

**74**

proliferate [22, 23].

The analyses of immunophenotyping of Thf subclasses showed that in IgG4-RD, cytokines type Th2 (IL-4, IL-5, IL-13) are produced by cells not expressing CXCR3 and CCR6 [24]. The number of Th2 cells is increased in IgG4 and correlates with increased IgG4 concentration in serum and IL4, the number of plasmocytes and the number of affected organs [21, 25]. However, in AIP, an increased number of CD4+ and CD25+ Treg was observed [21, 25]. In the most recent reports, attention has been paid to cytotoxic lymphocytes CD4+ (CTLs) [26–29] as well as the possibility of participation of annexin A11 in the pathogenesis of AIP [30].

The role of plasmoblasts and IgG4 itself is still not known in the pathomechanism of IgG4-RD. It is thought that they are more of disease markers than factors of disease development [5, 22]. Among IgG, there are 4 subclasses in humans (IgG1- IgG4). Normally, IgG4 constitute about 2–3% of all IgG, and their serum concentration is 35–51 mg/dL on average. Higher serum concentration of IgG4 was observed in men and in the elderly [31]. IgG4 and IgE are usually produced as a result of chronic exposure to antigens [32] or after allergy immunotherapy [33]. IgG4 is not able to form immunocomplexes which could stimulate antigen-presenting cells and enhance immunological response. Moreover, it does not initiate the classic pathway of complement activation [34]. The IgG4 antibodies bind weakly to complement C1q and Fcy receptors. As a consequence, they are not involved in antibodydependent cell-mediated cytotoxicity [35]. Additionally, IgG4 antibodies are dynamic molecules—altering their properties by spontaneous exchange of one of the two Fab fragments between individual immunoglobulin molecules. This process involves dissociation of immunoglobulin G4 heavy-chain dimers and a subsequent bonding of each IgG4 half-molecule with a different IgG4 half-molecule. This half-molecule exchange yields bi-specific antibodies able to bind with two different antigens, but monovalent for each of them. These properties of IgG4 molecules are the reason why IgG4 antibodies do not bind to the complement directly, do not initiate the classic pathway of complement activation, or why they are poor Fc receptor activators. This reduced IgG4 effector function has been responsible for these antibodies being considered anti-inflammatory [31]. IgG4 are believed to constitute a veritable antigen "garbage disposal" system, which can attenuate inflammation or protect against type I hypersensitivity by inhibiting IgE activity, as well as prevent type II and III hypersensitivity by blocking immune complex formation [36, 37].

Genetic studies seem to confirm some genetic background of IgG4-RD. Until present, differences in the expression of different genes have been found in salivary glands of patients with Sjӧgren syndrome and in patients with IgG4-RD, compared to healthy population. Only in a group of patients with IgG4-RD, overexpression of genes related to cell proliferation, organization of extracellular matrix and tissue fibrosis was confirmed [38]. Also, the relationship was found between AIP and class II antigen of the major histocompatibility complex HLA-DRB1\*0405-DQB1\*0401 and nuclear factor κB gene polymorphism and a molecule for type Fc-3 receptor on B cells [39].
