Conversely, when vital organs are involved or patients become symptomatic, aggressive treatment is needed because IgG4-RD can lead to serious organ dysfunction and failure. role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed. Keywords:IgG4, IgG4-related disease, immunology, pathogenesis, review == Introduction == IgG4-related disease (IgG4-RD) is a relapsingremitting fibroinflammatory condition characterized clinically by tumefactive lesions, serum IgG4 elevation in most, but not all cases, and a prompt response to glucocorticoids (GCs). IgG4-RD was described originally in the pancreas in 2001 as sclerosing pancreatitis, now referred to as type I IgG4-related Hyperoside autoimmune pancreatitis (AIP)1. Shortly thereafter, however, the identification of a variety of extra-pancreatic organ involvement linked by unique histopathological features led to the recognition that AIP was part of a systemic condition24. Awareness of this new fibroinflammatory condition has expanded substantially since the first characterization of pancreatic involvement in Hyperoside 2001, but IgG4-RD still represents an underdiagnosed entity. Understanding of the global epidemiology of IgG4-RD remains largely incomplete1,2. A Japanese survey calculated Hyperoside that IgG4-related AIP affects 22 cases per 100 000 individuals and has a predilection for middle-aged to elderly men. However, the multi-organ nature of the disease, the fact that AIP represents only a minority of cases and the likelihood that even many diagnoses of AIP are missed, this figure is almost certainly an under-estimate of the true prevalence of IgG4-RD5. Similarly, few immunological studies have been reported to date, and the pathogenesis of IgG4-RD remains unknown. In general theory, an antigen-driven immune response is supposed to drive both B cell commitment to IgG4 production and secretion of profibrotic cytokines Rabbit Polyclonal to LSHR by activated T lymphocytes. Indeed, rituximab (RTX), an anti-CD20 monoclonal antibody, has been proved to induce rapid clinical responses in patients with IgG4-RD, further suggesting an important pathogenic contribution of the B cell compartment68. Here, we aim to review the clinical and pathophysiological features of IgG4-RD, focusing on Hyperoside the most recent immunological acquisitions in the field. == Overview of clinical manifestations == IgG4-RD typically affects middle-aged to elderly men, with sporadic reports of paediatric cases9. The clinical presentation is usually indolent, with signs and symptoms becoming evident over months or even years. High, spiking fevers and other manifestations of systemic inflammation that mimic infections are classically absent, but weight loss can occur during the subclinical period. A longstanding history of allergies is present in 3040% of patients at diagnosis, but symptoms that overlap with allergic conditions are also reported in some IgG4-RD patients without histories of atopy. These include bronchial asthma, chronic rhinitis and eczema10. IgG4-RD is characterized by pseudotumour-like lesions involving single or multiple organs. Different organs might be affected at the same time or one after the other. Clinical manifestations are largely non-specific and vary Hyperoside according to the spectrum of organs involved. Indeed, IgG4-RD might be asymptomatic or present with signs and symptoms related to the mechanical compression exerted by the fibrotic masses on local structures. IgG4-RD has been described in virtually every anatomical region (Table1)1119, but the most common manifestations include type I AIP, chronic periaortitis, retroperitoneal fibrosis (Ormonds disease) and salivary or lacrymal gland swelling (Mikuliczs disease),.