Loss of immunological tolerance results in autoimmunity and may finally end in autoimmune disorders. For an autoimmune response against chromatin, autologous chromatin (nucleosomes) is assumed to activate both chromatin-specific B and T cells with a resulting anti-chromatin antibody response. As only fragmental elements of this process have been described, we do not have the full insight to justify this model in vivo. Early experimental immunization with methylated bovine serum albumin-DNA complexes elicited antibodies to various forms of synthetic ssDNA/dsDNA, but notably not to mammalian dsDNA. Thus, for a long time with intense research, the general result was that all forms of ssDNA and dsDNA, but mammalian B helical DNA, had an immunogenic potential. Summarizing these results, a preliminary conclusion was settled, saying that mammalian dsDNA was not immunogenic while other forms of DNA were really immunogenic in the situation where they were in complex with proteins. Recent studies have focused on nuclease deficiencies as a condition where chromatin may be presented to the immune system in an immunogenic form. However, although such deficiencies may provide information as to how chromatin may be exposed and targeted by relevant antibodies, data demonstrate that nuclease deficiencies is not in general correlated with autoimmunity to components of chromatin. This review discusses these topics, and provides information that may explain processes that account for anti-dsDNA antibody responses in vivo.