MEDICAL PROGRESS INNATE IMMUNITY AND TOLL-LIKE RECEPTORS: CLINICAL IMPLICATIONS OF BASIC SCIENCE RESEARCH MARIA T. ABREU, MD, AND MOSHE ARDITI, MD H umans are constantly exposed to a wide variety of microorganisms that can cause infection. In self-defense, the human host has evolved complex protective mechanisms, and Toll-like receptors (TLRs) have emerged as a central point in defense. These receptors bind molecular structures that are expressed by microbes but are not expressed by the human host, eg, lipopolysaccharides (LPS) or double-stranded RNA (dsRNA). Activation of these receptors initiates an inflammatory cascade that attempts to clear the offending pathogen and set in motion a specific adaptive immune response. Defects in sensing of pathogens may predispose the host to recurrent infections. The relative rarity of these syndromes of defective innate immunity, however, speaks to the redundancy in sensing of pathogens by the innate immune system. More common, polymorphisms in TLR4 are associated with increased predisposition to severe and recurrent infections but protection against atherosclerotic disease due to diminished inflammation. Toll-like receptor signaling may also contribute to the pathophysiology of disease and injure the host by activating a deleterious immune response such as in sepsis or inflammatory bowel disease (IBD). The focus of this article is to describe the role of TLRs in the innate immune response in health and disease. INNATE VERSUS ADAPTIVE IMMUNITY Immunity can be broadly classified as adaptive immunity or innate immunity. Adaptive immunity is mediated by T and B lymphocytes that proliferate clonally in response to a specific pathogen or antigen. The generation of adaptive immune responses (humoral and cellular) requires a number of days but is anamnestic through the generation of memory T and B lymphocytes. By contrast, the goals of the innate immune system are to provide protection in the first minutes to hours after an infectious challenge. Innate immunity was once thought to be a nonspecific response characterized by engulfment and digestion of microorganisms and foreign antigens by macrophages. A sophisticated system of receptors, the TLRs, provide considerable specificity for microbial pathogens and discrimination between pathogens and the host while providing an immediate response system in the setting of danger. 1 The activation of the innate immune response can be a prerequisite for triggering and shaping the adaptive immune response. 2 During the past few decades, most immunologic research has focused on adaptive immune responses. Interest in innate immunity followed the discovery of Toll receptors in the fruit fly, Drosophila, and their counterparts in humans, TLRs. The role of TLRs in the innate immune response has been the subject of intense investigation. Research on TLRs and their role in the innate immune response can be divided into understanding how TLRs recognize pathogens and protect the host, understanding the relationship between the innate immune response and the adaptive immune response, and examining the role of the innate immune response in pathogenesis of disease. See related articles, p 512, p 519, and p 524. From the Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, and Division of Pediatric Infectious Diseases, De- partment of Pediatrics, Steven Spiel- berg Pediatric Research Center, Burns and Allen Research Institute, Cedars- Sinai Medical Center, Los Angeles, LA School of Medicine, Los Angeles, California. Supported by NIH grants HL66436 and AI40275 (to M. A.) and AI52266 to (M. T. A.). Submitted for publication Aug 13, 2003; last revision received Dec 9, 2003; accepted Jan 28, 2004. Reprint requests: Moshe Arditi MD, Department of Pediatrics, Cedars- Sinai Medical Center, 8700 Beverly Blvd, Room 4220, Los Angeles, CA 90048. E-mail: moshe.arditi@cshs.org. J Pediatr 2004;144:421-9. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.01.057 CpG DNA Unmethylated cytosine– guanine-rich DNA dsRNA Double-stranded RNA IBD Inflammatory bowel disease IFN Interferon IL Interleukin IRAKS Interleukin-receptor–associated kinases LAM Lipoarabinomannan LPS Lipopolysaccharides NF-jB Nuclear factor- jB PAMPs Pathogen-associated molecular patterns PKR Double-stranded RNA-dependent protein kinase PRR Pattern recognition receptors RSV Respiratory syncytial virus TIR Toll/IL-1 receptor TLR Toll-like receptor TLR (1,2,3,4,5,6,9) Toll-like receptor 1,2,3,4,5,6,9 TNF Tumor necrosis factor Tregs Regulatory T cells 421