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Activation-induced cytidine deaminase (AID) is required for the immunoglobulin diversification processes of somatic hypermutation, gene conversion and class-switch recombination. The targeting of AID's deamination activity is thought to be a combination of cis- and trans-acting elements, but has not been fully elucidated. Deletion analysis of putative proximal cis-regulatory motifs, while helpful, fails to identify additive versus cumulative effects, redundancy, and may create new motifs where none previously existed. In contrast, gain-of-function analysis can be more insightful with fewer of the same drawbacks and the output is a positive result. Here, we show five defined DNA regions of the avian Ig locus that are sufficient to confer events of hypermutation to a target gene. In our analysis, the essential cis-targeting elements fully reconstituted diversification of a transgene under heterologous promotion in the avian B-cell line DT40. Furthermore, to the best of our knowledge two of the five regions we report on here have not previously been described as individually having an influence on somatic hypermutation.

Systemic lupus erythematosus (SLE) is a complex prototypic autoimmune disease that is based on genetic factors (complement deficiencies) and is influenced by gender (female), environment (infections and UV irradiation), as well as random events (somatic mutations). The course of the disease is influenced by genes (e.g. FcgammaRIIA) and behaviour (sun-exposure). Inefficient clearance of dying cells and subsequent accumulation of apoptotic cell remnants is an intrinsic defect causing the permanent presence of cellular debris responsible for the initiation of autoimmunity. We favour the hypothesis that post-apoptotic debris accumulates in germinal centres, activates complement, and serves as a survival signal for B-cells that had stochastically become autoreactive in the process of somatic hypermutation (etiology). In the presence of autoantibodies against apoptotic cells or adaptor molecules the accumulation of post-apoptotic remnants (SNEC) causes immune complex formation and their pathological elimination, maintaining auto-inflammation. The SLE-type autoimmunity addresses nucleic acid-containing complex antigens (viromimetica). Autoantibody-protein-nucleic-acid complexes are likely to be mistaken for opsonised viruses. As a consequence, the immune system responds with the production of type-I interferons, a hallmark of SLE (pathogenesis). We conclude that the pathogenicity of autoantibodies is strongly increased if autoantigens are accessible and immune complexes are formed, which may be considered a binary pyrogen formed from less pro-inflammatory components. The accessibility of cognate autoantigens is likely to be related to impaired or delayed clearance of apoptotic cells.