This article introduces a series of reviews covering Autoimmunity appearing in Volume 269 of Immunological Reviews. The immune system is often described as a finely tuned balance between host defense and self-reactivity. However, that is a considerable oversimplification as multiple cell types, cell processes, and cellular receptors are repeatedly exposed to microbial challenges and other environmental hazards, as well as self-antigens associated with the routine clearance of cell debris. In fact, immune homeostasis is more accurately described as a disk precariously positioned on a pointed fulcrum that maintains its balance despite repeated adjustments to pressure points around the circumference. Occasionally, the plate tips precariously in one direction or another, leading to either serious infection or preclinical autoimmunity, and additional regulatory mechanisms are called into play, that either succeed, or not, in restoring equilibrium (Fig. 1). The challenge is to identify therapeutic interventions, in many cases tailored to the unique needs of each individual, which can facilitate the requisite readjustment. This requires a clear understanding of the role played by the most relevant cell types and the conditions and pathways most likely to contribute to a specific disease phenotype. Over the past decade, we have come to appreciate the critical role of innate immune system receptors in the identification of both pathogen-associated molecular patterns (PAMPS) and danger-associated molecular patterns (DAMPs). Although a somewhat heretical concept a decade ago, it turns out that many of these innate receptors detect both microbial and endogenous ligands 1, 2. In fact, numerous autoimmune risk alleles result from aberrant activation of innate immune pathways. Thus the major focus of the current issue is how specific conditions, forms of cell debris, modifications of self-components, and imbalance of regulatory pathways can provoke the innate immune system to the point of overt autoimmune disease. As an entry to this topic, Dr. John Harris, a dermatologist with a particular interest in vitiligo, addresses the question of why family members of vitiligo patients have such an increased risk of developing additional tissue-specific autoimmune diseases such as type 1 diabetes, Hashimoto's thyroiditis, multiple sclerosis, pernicious anemia, and Addison's disease 3. Drawing from numerous examples of patient data and animal models, he proposes that each of these conditions is initially triggered by instances of tissue-specific cell stress resulting in an unfolded protein response, inflammasome activation, and/or the release of heat shock proteins and immunogenic antigen-associated exosomes. He suggests that this combination of events, in the context of more general autoimmune-associated risk alleles, leads to innate inflammatory responses that in turn promote the activation of cytotoxic T cells and the eventual destruction of melanocytes. The endocrine nature of the other related autoimmune targets implies potential stress responses in these tissues and a similar sequence of events. Another trigger of autoimmunity is the failure to appropriately clear cell debris, as indicated by numerous systemic lupus erythematosus (SLE)-prone mouse lines with genetic mutations or gene-targeted deletions of relevant scavenger receptors, complement components, or other eat me signals 4, 5. McGaha and Karlsson 6 review the various phases of the clearance process, including the initial markers of apoptosis, signals that then recruit phagocytes to the site of injury, and counterbalancing ‘eat me’/‘don't eat me’ signals. Their article further summarizes the unique role of marginal zone macrophages and B cells in apoptotic cell removal and tolerance induction, and the role of cytosolic DNA sensors and their convergence on STING in DNA-driven regulatory responses. One of the best studied markers of apoptotic cells is phosphatodylserine (PdtSer), and Ravichandran and Penberthy 7 provide an in-depth description of several of the key PdtSer receptors, their downstream pathways, and ways in which these signals can be modified by an inflammatory environment. Failure to appropriately clear cell debris can also result in the activation of the endosomal nucleic acid sensors and promote the expansion and differentiation of plasmacytoid dendritic cells (DCs), autoreactive B cells, and other types of antigen-presenting cells. Under normal conditions, access of endogenous nucleic acids to the compartments containing nucleic acid-sensing receptors is limited. However, Toll-like receptor (TLR)7 and TLR9 deficiency appear to have opposing outcomes in murine models of SLE. Although much remains to be learned, the past few years have led to a much better understanding of the cell biology of these receptors. Major insights regarding the unique features of the individual endosomal TLR trafficking patterns, molecular processing events, interactions with the adapter protein Unc93B1, and nucleic acid detection are now reviewed by Pelka et al. 8. She further discusses the role of nucleic acid-binding proteins and various types of DNase molecules that contribute to the availability and accessibility of endogenous ligands. While we still know remarkably little about the actual role of the individual TLRs in human disease, Clancy et al. 9 summarize data connecting RNA-sensing TLRs to the development of congenital heart block in children of mothers with high anti-Ro60 titers. Cytosolic nucleic acid sensors of retroviral transcription products have also been implicated in B-cell activation 10. The article by Yu 11 further explores studies that do or do not support this concept. TLRs and other pattern recognition receptors are abundantly expressed by both DCs and B cells, and as pointed out by Diamond et al. 12, many of the genes associated with SLE risk alleles are expressed by these same cell types. Diamond et al. provide a detailed review of the phenotypic and functional properties of the major DC subsets, and then go on to describe how SLE risk alleles modulate DC function, with a particular focus on BLIMP-1, FcγRs, and C1q. Naradikian et al. 13 describe a newly identified B-cell subset, age-associated B cells (ABCs). Although originally described as a subset predominantly expanded in aged individuals, recent data suggest that this subset is preferentially activated by nucleic acid-associated antigens. Moreover, in an inflammatory melieu, ABCs switch to IgG2a/c, isotypes frequently associated with pathogenic autoantibodies in the context of SLE. B cells can also promote autoimmune diseases by serving as antigen-presenting cells and through the production of proinflammatory cytokines. Fillatreau et al. 14 now summarize our current understanding of B-cell cytokine production in a number of autoimmune conditions that respond to B-cell depletion therapy. The role of well-defined B-cell subsets in the production of protective and pathogenic antibodies, as well as the innate immune pathways in promoting B-cell cytokine production, will be important topics to address in future studies. Many glycan-linked proteins can incorporate terminal sialic acid and these sialic acid-containing ligands can be detected by a class of pattern recognition receptors, commonly referred to as Siglecs. Siglecs are expressed by B cells, DCs, and other hematopoietic lineages. As these sialated glycans commonly transmit a negative regulatory signal, as opposed to the proinflammatory signal of more conventional DAMPs, Mahajan and Pillai 15 have coined the term SAMP (self-associated molecular patterns) to describe their activity. The proportion of terminal sialic acid glycans can be readily controlled by any number of sialic acid-modifying enzymes, as evidenced by the decreased expression of sialic acid-modified IgG in individuals with ongoing inflammation 16, and Siglec–ligand interactions are likely provide a useful therapeutic target in the near future. The Mahajan article provides a very useful and detailed up-to-date review of the structure, ligands, and signaling pathways regulated by these I-type lectins, with a particular focus on CD22 (Siglec-2) and Siglec-G-mediated B-cell regulation, and the potential role of these receptors in the constraint autoimmune disease. Post-translational modifications can also result from environmental exposure to noxious agents. In genetically predisposed individuals, these changes can be detected by innate immune receptors, and chronic stimulation then provokes an inflammatory response that can eventually progress to full-fledged systemic autoimmune diseases. One of the best-described examples of this kind of association is the link between smoking, or other agents that promote lung injury, and rheumatoid arthritis. Catrina et al. 17 summarize the evidence that connects smoking-induced citrullination of self-antigens to the production of anti-citrullinated protein antibodies, a now definitive criteria for rheumatoid arthritis, and eventual chronic joint inflammation. The molecular mechanism they propose for joint pathology begins with innate immune responses in the lung or oral cavity that can then lead to enhanced osteoclast differentiation and the activation of HLA major histocompatibility locus-restricted T cells specific for citrullinated epitopes. This sequence of events provides an important example of how the injury of one tissue can result in the autoimmune attack of another. A number of risk alleles associated with seemingly unrelated autoimmune diseases turn out to regulate innate immune receptor triggered responses. The last set of papers in this issue summarize recent insights pertaining to the mechanistic basis of these regulatory activities. Mayadas and Rosetti 18 elegantly explain how loss of function mutations in Mac-1 (Itgam) result in increased susceptibility to autoimmune diseases, despite Mac-1's established function in leukocyte adhesion. Espele et al. 19 then describe how FcγRIIB, originally characterized for its capacity to limit BCR activation, can also attenuate responses initiated by TLRs or complement receptors and negatively regulate DC migration. Hamerman et al. 20 add to the list of pattern recognition receptors (PRR) -negative regulators with an in-depth discussion of the regulatory activity of A20, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), and B cell adapter for PI3K (BCAP). Finally, Holmdahl et al. 21 expand on the unanticipated role of reactive oxygen species (ROS) in limiting the extent of chronic inflammation in several examples of systemic autoimmunity. Taken together, the reviews in this issue challenge our current perception of innate immune regulation, as the contributors define and explain an ever-increasing number of feed forward and feed back loops that regulate discrete aspects of PRR activity. These conceptual advances provide a framework for more precisely tailored preventative and therapeutic options in the near future. The author has no conflict of interest.