In murine lupus nephritis, anti-DNA antibodies gain their pathogenic potential when chromatin fragments are exposed in glomeruli. Chromatin fragments thus represent the axis in a circulus vitiosus
, where chromatin - the inducer of nephritogenic autoimmunity - is the glomerular target for the autoantibodies, and thereby accounts for the organ disease (discussed in [60
Chromatin fragments exposed in the kidneys may derive from either increased apoptosis or deficient clearance of apoptotic or secondary necrotic material [61
]. How tolerance against chromatin components is terminated is not fully understood. Chromatin undergoes alterations during apoptosis and is normally not exposed for the immune system. In the case of increased apoptosis or deficient clearance, however, these components may be exposed as secondary necrotic chromatin with the potential to induce an antigen-selective immune response [64
]. For example, plasma chromatin found in SLE patients is hypomethylated [66
], and hypomethylated DNA is more immunogenic and can induce maturation of dendritic cells and potentially activate autoimmune T cells and B cells [67
]. Furthermore, sera of SLE patients contain circulating chromatin fragments complexed with the DNA-binding protein HMGB1 [61
]. This protein is a proinflammatory mediator that binds chromatin of apoptotic cells. The HMGB1-nucleosome complexes may activate antigen-presenting cells, which have the potential to promote activation of relevant T-helper cells and then DNA-specific B cells, with production of chromatin-specific autoantibodies as a net result [61
]. Exposed and retained chromatin may therefore promote production of chromatin-specific autoantibodies.
In an infectious context, viruses such as polyomavirus BK may induce cell death as a consequence of virus replication. This process may be relevant to lupus nephritis, since there are several reports that demonstrate productive polyomavirus infection in human SLE (see [35
] and references therein). Productive renal polyoma virus activation may be imposed by treatment of the disease with immunosuppressive drugs, and may not be specifically linked to the lupus pathogenesis [68
]. This expression pattern is similar to what is seen in renal transplants during immunosuppresion [70
Irrespective of the cause for polyomavirus replication, the viral transcription factor large T antigen forms complexes with the host cell chromatin. This complex may affect the immune system in analogy with a hapten-carrier complex, where B cells bind nucleosomal DNA (the hapten) through the DNA-specific antigen receptor and process and present T-antigen-derived peptides (the carrier) to nontolerant T cells (this model is extensively reviewed in [35
]). Chromatin may thus generate autoimmunity by quite different pathways linked to modification of chromatin and various infections [36
We recently performed in vitro
studies demonstrating that nucleosomes and nucleosomes in complex with anti-DNA antibodies have high affinity for glomerular and epidermal basement membrane components such as laminin and collagen [73
]. This affinity may be a major factor that explains why chromatin-containing immune complexes associate with membrane and matrix structures in human nephritis [47
One factor that may contribute to deviation in chromatin composition and size is DNaseI, which is the major nuclease in kidneys [21
] but also in serum, where it may participate in chromatin degradation in context of necrosis [55
]. Several studies have demonstrated reduced levels of serum DNaseI in SLE patients [50
]. This reduction could provisionally explain why the chromatin concentration in circulation of lupus patients with nephritis is reported to be higher than in control individuals [77
]. Another reason for this reduction could be that immune complexes in SLE patients are protected against nuclease attacks by DNA-binding proteins and immunoglobulins, present in sera. A problem that needs to be solved is therefore whether circulating chromatin-containing immune complexes in lupus nephritis patients are less sensitive to DNaseI than chromatin fragments in anti-chromatin antibody-negative healthy donors.
Most of the data on lupus nephritis so far relate to studies of murine models of the disease. In the next section, we will translate available basic data into a detailed evidence-based model for human lupus nephritis. We shall subsequently convert this information into new and rational treatment modalities.