The Critical Role of Toll-Like Receptor Signaling Pathways in the Induction and Progression of Autoimmune Diseases

Abstract

Toll-like receptors (TLRs) form a large family of pattern recognition receptors with at least 11 members in human and 13 in mouse. TLRs recognize a wide variety of microbial components and potential host-derived agonists that have emerged as key mediators of innate immunity. TLR signaling also plays an important role in the activation of the adaptive immune system by inducing proinflammatory cytokines and upregulating costimulatory molecules of antigen presenting cells. The dysregulation of TLR signaling may cause autoimmunity. This review discusses the contribution of TLR signaling to the initiation and progression of autoimmune diseases, such as rheumatoid arthritis, experimental autoimmune encephalitis, myocarditis, hepatitis, kidney disease, systemic lupus erythematosus, diabetes, obesity, and experimental autoimmune uveitis as well as aging. The involvement of TLR signaling in the pathogenesis of autoimmune diseases may provide novel targets for the development of therapeutics.

The Lifelong Effects of Early Childhood Adversity and Toxic Stress

“…[61][62][63][64][65][66][67] Beyond its strong association with later risk-taking and generally unhealthy lifestyles, it is critically important to underscore the extent to which toxic stress in early childhood has also been shown to cause physiologic disruptions that persist into adulthood and lead to frank disease, even in the absence of later healththreatening behaviors. For example, the biological manifestations of toxic stress can include alterations in immune function 68 and measurable increases in inflammatory markers, [69][70][71][72] which are known to be associated with poor health outcomes as diverse as cardiovascular disease, 69,70,73 viral hepatitis, 74 liver cancer, 75 asthma, 76 chronic obstructive pulmonary disease, 77 autoimmune diseases, 78 poor dental health, 72 and depression. [79][80][81] Thus, toxic stress in early childhood not only is a risk factor for later risky behavior but also can be a direct source of biological injury or disruption that may have lifelong consequences independent of whatever circumstances might follow later in life.…”

Toll-Like Receptors and Danger Signaling in Kidney Injury

“…[1][2][3][4][5][6] Infectious, toxic, metabolic, ischemic, traumatic, and genetic causes of kidney injury all share an unexpected component of tissue inflammation. How does this happen?…”

“…11 In addition, kidneys engage extrinsic help for controlling danger by sending dendritic cells to regional lymph nodes 12 or releasing cytokines and chemokines that alert and recruit the professional danger controllers of the immune system. 4,13,14 The early sequential influx of neutrophils, macrophages, and T cells to the site of danger amplifies the risk for nonspecific inflammation, which is sometimes followed later by antigen-specific injury. 11,15 This conventional model of immune activation may apply to acute infections in the kidney, but is it helpful in understanding inflammation in more common, nonpathogen types of acute and chronic kidney disease?…”

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

“…Toll-like receptors (TLRs), which are expressed on leukocytes, play a central role in the detection of bacterial and viral pattern recognition, which facilitates enhanced cell-mediated inflammation (16). TLR activation can exacerbate autoimmunity in clinical and experimental settings (17), including vasculitis and renal diseases (18). TLRs provide a link between infection and disease initiation and relapse in AAV, potentially as a consequence of enhanced adaptive autoimmunity.…”