The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease

Abstract

IgG4-related disease (IgG4-RD) is a spectrum of complex fibroinflammatory disorder with protean manifestations mimicking malignant neoplasms, infectious or non-infectious inflammatory process. The histopathologic features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis together with increased in situ infiltration of IgG4 bearing-plasma cells which account for more than 40% of all IgG-producing B cells. IgG4-RD can also be diagnosed based on an elevated serum IgG4 level of more than 110 mg/dL (normal < 86.5 mg/mL in adult) in conjunction with protean clinical manifestations in various organs such as pancreato–hepatobiliary inflammation with/without salivary/lacrimal gland enlargement. In the present review, we briefly discuss the role of genetic predisposition, environmental factors and candidate autoantibodies in the pathogenesis of IgG4-RD. Then, we discuss in detail the immunological paradox of IgG4 antibody, the mechanism of modified Th2 response for IgG4 rather than IgE antibody production and the controversial issues in the allergic reactions of IgG4-RD. Finally, we extensively review the implications of different immune-related cells, cytokines/chemokines/growth factors and Toll-like as well as NOD-like receptors in the pathogenesis of tissue fibro-inflammatory reactions. Our proposals for the future investigations and prospective therapeutic strategies for IgG4-RD are shown in the last part.

Fevers, Sweats, Weight Loss, Oh My! When IgG4 Related Disease Comes Knocking. . .

“… 3 , 4 The criteria is scored as definite if all 3 are present, probable with only clinical and histopathological and possible with only clinical and hematological. 3 , 4 …”

The Post-hunter-gatherer Era Microbes Hypothesis for Chronic Inflammatory Diseases

“…The traditional view is that IgG4 is anti-inflammatory and not able to activate complement. However, recent research indicates that IgG4 can be proinflammatory and even bind complement under certain circumstances [268,269]. It may be generally relatively anti-inflammatory when compared to IgE, IgG1 or IgG3; however, in certain situations, IgG4 could still cause inflammation.…”

“…In IgG4-related disease, a recently recognized group of CIDs, the role of IgG4 is not yet clear [268]. A polyclonal IgG4 response to multiple environmental antigens, including food antigens, has been found [271].…”

“…Whether or not IgG4 elevation leads to symptoms in the short-term, they potentially could lead to long-term negative consequences due to immune suppression [263] in some cases, or inflammation [268] in others. The PHM hypothesis suggests that the long-term outcome would depend on the pathogenicity of the PHMs that the IgG4 are produced in response to, combined with host factors.…”

Allergic Aspects of IgG4-Related Disease: Implications for Pathogenesis and Therapy

“…I g G 4 -R D a n d a l l e r g i c d i s o r d e r s s h a r e c e r t a i n immunopathologic features, such as activation of Th2-like pathways, elevated IgE and IgG4 production, peripheral blood eosinophilia, and tissue mast cell infiltration (5,16,17). Importantly, clinical and epidemiologic evidence suggests that IgG4-RD and allergic entities are not manifestations of a single disease but rather distinct disease processes that both involve type 2 immune activation (18)(19)(20), overproduction of pro-Th2 cytokines, and the development of IgE-and IgG4-secreting B cells (21,22). The pathogenesis of IgG4-RD remains unknown, and effective medical therapies are limited.…”