Immunoglobulin G4
There are four subclasses of immunoglobulin G, IgG1, IgG2, IgG3 and IgG4. These subclasses have Fc regions that are almost identical, but small differences in their primary structure give the subclasses different functions. IgG1 is the dominant subclass in serum, while IgG4 only constitutes about 5 % of the total IgG concentration in healthy individuals (7). Elevated serum IgG4 levels are seen in about 60 % of patients with IgG4-related disease. This is a non-specific finding, as elevated serum IgG4 is also found with other conditions (7, 8).
IgG1 is a proinflammatory immunoglobulin that induces potent activation of macrophages and complement. This is also true, to varying degrees, of IgG2 and IgG3. IgG4 does not have the same property of activating effector systems, and therefore has a limited proinflammatory effect. IgG4 can also bind to, and neutralise, the Fc region of other IgG subclasses (7). IgG4 therefore has a net anti-inflammatory effect, which may seem paradoxical given that IgG-related disease is characterised by inflammation. This has challenged the theory of the role of IgG4 in the pathogenesis of the disease.
One theory is that the high levels of IgG4-positive plasma cells are a consequence, and not a cause, of the inflammation associated with IgG4-related disease (1). According to this theory, the tissue destruction is due to persistent activation of CD4-positive T-lymphocytes, which in turn activate fibroblasts and macrophages, resulting in fibrosis formation. It is further postulated that release of cytokines by activated T-lymphocytes stimulates local plasma cells to undergo a change of class to IgG4. According to this hypothesis, the IgG4 predominance is therefore secondary to the underlying pathological process. IgG4-related disease is a hyperinflammatory condition, and it seems plausible that IgG4 is not directly causative in view of the protein's lack of proinflammatory properties. This theory is challenged by the fact that the monoclonal anti-CD20 antibody rituximab appears to be an effective treatment for IgG4-related disease. Rituximab acts through antibody-, cell- and complement-dependent mechanisms to cause selective depletion of B-lymphocytes, as these are the only cells that express the CD20 protein in the cell membrane. This results in reduced plasma cell levels and hence reduced production of immunoglobulins, mainly IgG and IgM. Why, then, does B-lymphocyte depletion have a therapeutic effect, if the disease is mediated by T-lymphocytes, and B-lymphocytes and IgG4 are not involved in the pathogenesis? One possible explanation is that it is antigen-presenting B-lymphocytes that mediate the persistent activation of the T-lymphocytes, and that depletion of these B-lymphocytes brings the pathological T-lymphocyte response to a halt (9). This is consistent with the theory that the immunoglobulins are only passive participants in the pathogenesis of the IgG4-related disease.
Other theories concerning the pathogenesis of IgG4-related disease indicate mast cells, basophils, eosinophils and plasmablasts as influential participants. Activation of macrophages and complement has also been postulated as a central mechanism (8). As with other chronic inflammatory conditions, it is plausible that an environmental factor such as infection in genetically predisposed individuals results in loss of immunological tolerance, with a consequent persistent immune response (1).
Genetic factors have only been partially mapped, but candidate genes have been identified that may be associated with the development of IgG4-related disease with pancreatic involvement, including the HLA alleles DRB1*0405 and DRB1*0401, and polymorphisms in the genes FCRL3 and CTLA4, which are involved in regulating B- and T- lymphocytes, respectively (7, 10).
The pathogenesis of IgG4-related disease is probably multifactorial and complex, and has only been partly determined.