• antigen presentation
• autoimmunity
• B cell
• immunology
• autoimmune disease

Immunoglobulin G4-related disease (IgG4-RD) is the name applied to a corticosteroid and/or B-cell depletion responsive illness, in which patients present with the consequences of usually multiorgan, relapsing and remitting, fibroinflammation.1 The disease is histologically characterised by obliterative phlebitis, storiform fibrosis and a dense lymphoplasmacytic infiltrate.2 IgG4-RD is not a new disease, but is benefiting from the application of new technologies in the pursuit of better biological understanding. The histologic enrichment of IgG4-expressing plasma cells is a diagnostic hallmark of disease that additionally serves as a biological phenomenon driving scientific evaluation.3 Key disease themes have evolved to include a large clonal expansion of activated plasmablasts and CD4+ cytotoxic, inflammatory and profibrotic lymphocytes. Therapeutically, a reduced frequency of CD4+ cytotoxic lymphocytes are seen after B-cell depletion; such therapy may consequently impact on antigen presentation.4–6 To date, the activity of IgG4-RD is not readily tracked by disease biomarkers with even serum IgG4 concentration remaining an imperfect diagnostic and prognostic tool for many patients.7

IgG4 molecules have structural and functional characteristics suggesting anti-inflammatory and tolerance-inducing effects,8 9 and in IgG4-RD a reported oligoclonal reactivity to multiple antigens.4 10 In Gut, Hubers et al describe a body of work that identifies the first IgG4 autoantibody against an antigen which appears to be specific to IgG4-RD (IgG4-associated cholangitis (IAC) and autoimmune pancreatitis (AIP)), at the exclusion of its major differential diagnoses: primary sclerosing cholangitis and cholangiocarcinoma.11 The authors demonstrate that patients with IgG4-RD raise IgG1 and IgG4 in their sera that recognise a 56 kDa cytosolic protein in an immortalised cell line lysate (H69 cholangiocytes) and in human liver lysate. Both IgG1 and IgG4 antibodies recognise the same 56 kDa protein, and subsequent label-free quantitative liquid chromatography-tandem mass spectrometry analysis and immunoprecipitation identifies the cytosolic protein, Annexin A11, as the target. Annexin A11 IgG4 …