IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition characterised by elevated serum IgG4 and an abundance of IgG4 plasma cells in involved organs. The natural history of disease and pathogenic mechanisms are poorly understood, and are explored in this thesis. The diagnosis of IgG4-RD is a challenge. Evidence to support a serum IgG4 level of 2.8g/l in differentiating IgG4-RD from non-IgG4-RD conditions, a serum IgG1:IgG4 ratio of 0.24 in differentiating IgG4-sclerosing cholangitis from primary sclerosing cholangitis with elevated serum IgG4, and the role of serum IgE in those with a history of allergy and atopy is provided. Furthermore, observational data highlighting new environmental risk factors and disease associations are revealed. Despite being considered a benign corticosteroid-responsive condition, evidence for disease relapse, organ dysfunction and failure, malignancy and mortality in a prospective cohort is shown. Patterns of disease presentation and levels of serum IgG4 and IgE at diagnosis are used to identify those who relapse and develop multi-organ disease. A single antigen initiating disease has yet to be found. Polyclonal IgG4 responses to multiple environmental antigens in IgG4-RD are reported, and evidence against Helicobacter pylori plasminogen binding peptide as a microbial antigen is shown. Novel HLA class II associations, linked to disease susceptibility in a UK cohort provide support for immune-mediated pathogenesis. Gene expression analysis implicates cytokines in driving IgG4 switch and proliferation, chemokines in trafficking and homing of lymphocytes to end organs, complement proteins in the classical and lectin pathways, and members of the TGF-beta pathway as putative immune drivers of disease. Differences in the phenotype of IgG1 and IgG4 B cells in health and IgG4-RD are reported, including responses to complement activation and immune complexes. Finally, elevated IgE levels, the presence of IgE-positive mast cells in involved tissues, and up-regulation of the Fc-Epsilon receptor on the surface of IgG4 cells, support the role of an IgE-mediated response.

© 2017, © 2017 American Federation for Medical Research. A middle-aged man presents with acute pancreatitis of unknown etiology and is found to have a presentation consistent with the diagnosis of type 2 autoimmune pancreatitis (AIP). AIP is a group of rare heterogeneous diseases that are challenging to diagnose. There are 2 types of AIP. Type 1 disease is the more common worldwide than type 2 AIP. While type 1 AIP is associated with IgG4-positive antibodies, type 2 AIP is IgG4 antibody negative. Both types of AIP are responsive to corticosteroid treatment. Although type 1 AIP has more extrapancreatic manifestations and more commonly relapses, this is a case of a patient with type 2 AIP with inflammatory bowel disease and relapsing course.