Toll-like receptors: immunodeficiency and cancer
Division of Allergy and Immunology, Department of Pediatrics, University of South Florida, All Children's Hospital, St. Petersburg, Florida, United States
AIM: The innate immune system preexists in healthy individuals and acts within minutes of infection, forming early barriers to a variety of microbial pathogens. The innate immune defense mechanisms recognize microbes through a set of nonclonal germline-encoded pattern-recognition receptors (PRRs) that detect conserved microbial molecular structures, pathogen-associated molecular patterns (PAMPs). Among the PRRs, Toll-like receptor (TLR) is the most characterized signaling receptor that is expressed in the majority of immune cells including macrophages, dendritic cells, NK cells, T cells and B cells. In response to PAMPs, TLRs generate the Toll/interleukin-1 receptor signaling pathways, leading to the induction of proinflammatory cytokines, chemokines, and anti-microbial peptides as well as up-regulation of cell-surface expression of co-stimulatory molecules on antigen-presenting cells (APCs). These events are crucial for APCs to signal T cells and initiate adaptive immune responses, especially Th1 responses. Herein, we discuss the role of TLR in immunodeficiency and cancer, demonstrating interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency in a child with recurrent infections. METHODS: Analyses performed by previously well defined methods. RESULTS: The first characterization of patients with a defect in the TLR immune system has recently been demonstrated by us and others (Science 299:2076, 2003; J. Exp. Med. 198:521, 2003). In these studies, immunodeficiency patients with a defect in the gene encoding IRAK-4, a central mediator in the TLR signaling pathway, have been identified. These patients have suffered from recurrent pneumonia and frequent infections caused by high-grade pyogenic bacterial pathogens, including Streptococcus pneumoniae or Staphylococcus aureus, and failed to respond to all of TLR agonists tested to produce cytokines in vitro. These findings establish the significance of the TLR innate immune mechanism in the human immunodeficiency disease. In addition to infectious disease, the TLR immune mechanism is implicated in multiple diseases such as cancer, autoimmunity, sepsis, and allergy. Consequently, therapeutic approaches to these pathological conditions using TLR agonists or antagonists have been attempted. Since the TLR immune system is a potent inducer of Th1 responses, recent studies have extended the role of TLRs to powerful adjuvant receptors that augment the activation of tumor antigen-specific T cells. The results are encouraging, showing that the activation of TLRs is useful in preventing or treating tumor development or metastasis. CONCLUSION: Growing evidence indicates that TLRs play a critical role in the immune system and will represent strategic therapeutic targets for multiple diseases including immunodeficiency and cancer. Dedicated to the memory of Robert A. Good. Supported in part by the Eleanor Naylor Dana Charitable Trust and Pediatric Cancer Foundation to the Children’s Hospital.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 903 (Cancer immunity).