Since the discovery of auto-reactive, natural antibodies more than two decades ago, a great deal of effort has been devoted to describing their generation, regulation, and function Much of this effort has focused on natural IgM antibodies. It has been determined that natural IgM antibodies are present in experimental animals completely deprived of potential antigen, and that their reactivity profiles are remarkably conserved between individuals 
. These natural IgMs have also been shown to be universally present in human serum 
. The fact that some of these natural antibodies are auto-reactive has led to suspicions that they might function in maintaining tissue homeostasis 
. Subsequent investigations determined that IgM autoantibodies do indeed bind to common apoptotic neo-antigens, such as phosphatidylserine, cardiolipin, and annexin IV, and that they also recognize markers of cell senescence 
. Given these patterns of reactivity, it is hypothesized that natural IgM antibodies serve as a conserved way to assist in the clean-up of apoptotic cellular debris.
Natural IgM antibodies are produced by the relatively class-restricted B-1 cells, while IgG antibodies are known to be produced via the T cell-dependent interactions of follicular B-2 cells 
. The former are positively selected for when faced with self-antigen, while the latter is thought to be strictly held within the confines of self-tolerance 
. Therefore, any presence of IgG autoantibodies in the blood is usually considered to be the result of a pathological breakdown in self-tolerance. This notion is supported by the fact that many autoimmune diseases, including rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosis, are initiated or exacerbated by IgG autoantibodies to specific cellular and tissue components 
. Thus, it is still generally assumed that all auto-reactive IgG are not purposeful products of the human immune system.
Although IgG autoantibodies in the blood can be a serological hallmark of autoimmune diseases, the low specificity of most of these disease-associations implies the presence of autoantibodies even in healthy individuals. An increasing number of studies have also revealed a link between autoantibodies and many non-autoimmune phenomena, like cancer and neurological disease 
. New serum autoantibodies are continuously being identified in the literature as related to various conditions, but most attempts to connect them more directly to known risk factors, pathogenesis, or prognosis are tenuous. This is often compounded by limited study methodologies and a singular focus on one individual disease process. A systemic investigation into the extent of natural serum IgG autoantibodies may help provide us with a clearer understanding of the role of these autoantibodies and their relationship with disease.
To accomplish this, we probed protein microarrays containing nearly 10,000 human proteins with sera collected from individuals of different ages, genders, and pathological states. All samples contained auto-reactive IgG, and the majority possessed autoantibodies to more than one thousand discrete human protein antigens. The total number detected was significantly influenced by gender, age, and the presence of specific diseases. Furthermore, the unique profile of autoantibodies present in an individual was relatively consistent over time. Rats and swine were also found to possess serum IgG autoantibodies and demonstrated similar stability in individual IgG autoantibody profiles over time. The number, diversity, and apparent conservation of IgG autoantibodies in mammals have led us to suggest that abundant IgG autoantibodies are a normal feature of the blood and, like auto-reactive IgM, they may play an important physiological role such as maintaining tissue homeostasis through adaptive debris-clearance as suggested by Avrameas nearly two decades ago 
. Indirect evidence in support of this concept comes from our recent studies showing that small panels of disease-specific autoantibodies, presumably linked to debris clearance, can be used for the detection and diagnosis of diseases such as Alzheimer’s and Parkinson’s diseases