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Mechanisms of Host Defense

Research Summary

Ruslan Medzhitov is interested in the analysis of the immune system, host-pathogen interactions, inflammation, cell signaling, and gene regulation.

The immune systems of humans and other vertebrates have two components: innate and adaptive. The innate immune system is evolutionarily ancient and is found in one form or another in all metazoans. Adaptive immunity is present only in vertebrates. The two systems use fundamentally different strategies to recognize invading pathogens. Innate immune receptors recognize conserved macromolecules of microorganisms that are structurally distinct from host macromolecules. Therefore, innate immune receptors can discriminate between self and nonself and are specifically activated only when a pathogen is present. The receptors of the innate immune system are therefore referred to as pattern-recognition receptors because they recognize conserved pathogen-associated molecular patterns (PAMPs).

Adaptive immune recognition, on the other hand, relies on two types of antigen receptors: T cell receptors (TCRs) on T cells and immunoglobulin (Ig) receptors on B cells. These antigen receptors are generated by random somatic gene rearrangement and are expressed in a clonal fashion on lymphocytes. Because the specificity of these receptors is generated randomly, the receptors of the adaptive immune system cannot determine the origin (self or nonself) of the antigen for which they are specific. Consequently, to become activated and differentiated into an appropriate class of effector cells that provide protection from infection, T and B lymphocytes require instructions from the innate immune system. There are several types of instructive signals, and we are interested in their analysis.

A family of pattern-recognition receptors called Toll-like receptors (TLRs) plays a critical role in innate immune recognition. These receptors recognize PAMPs such as bacterial lipopolysaccharide (LPS), lipoteichoic acids, and viral nucleic acids, and thus function as sensors of microbial infection. Upon recognition of PAMPs, TLRs induce inflammatory responses and a variety of antimicrobial effector responses. In addition, TLRs and other pattern recognition receptors couple detection of infection with the induction of pathogen-specific adaptive immune responses.

Innate Immune Recognition and Control of Adaptive Immunity
Adaptive immune response against infectious agents is generally beneficial for the host. However, the response against self-antigens or innocuous nonself-antigens is detrimental, as it can lead, respectively, to autoimmune diseases and allergy. The immune response against these antigens is normally avoided as a result of several mechanisms of immunological tolerance. Central tolerance is a process that eliminates developing lymphocytes that are specific to certain self-antigens. Peripheral tolerance prevents mature lymphocytes from reacting against self-antigens. At least three mechanisms of peripheral tolerance are known: control of costimulatory signals, tolerogenic dendritic cells, and control by regulatory T cells. We are investigating how these seemingly distinct mechanisms of tolerance are functionally related to each other, and how they are controlled by the innate immune system. This knowledge should help us to understand the common themes and mechanisms of autoimmune diseases.

Cellular and Molecular Mechanisms of Allergen-Induced Immune Responses
One of the biggest puzzles in current immunology is how and why allergens induce immune responses. Allergens are nonmicrobial in origin and generally innocuous environmental agents, and the current theories of immune recognition do not account for their ability to trigger immune responses. Moreover, allergens are highly heterogeneous in nature and include food antigens, pollen, small chemicals such as penicillin, and insect venoms. Although these agents appear to have little in common, they all induce the same type of immune response. Even more puzzling, this same type of immune response (known as Th2 response, i.e., T cell response characterized by production of cytokines interleukin 4 [IL-4], IL-5, and IL-13) is normally triggered upon infections with multicellular parasites. We are investigating the mechanisms responsible for allergen-induced immune responses. Our findings so far indicate that allergen-induced immune responses do not follow the same rules that have been defined for microbial-induced immune responses. We found basophils to play an essential role in allergen-induced immune responses. We are now characterizing the mechanism of basophil function in allergic responses.

Host-Commensal Interactions
Microbial macromolecules recognized by TLRs are common to entire classes of microorganisms, whether they are pathogenic or commensal (e.g., LPS is made by all gram-negative bacteria). This makes it difficult to distinguish between commensal and pathogenic bacteria. Uncontrolled immune response to commensal intestinal microflora can lead to inflammatory bowel disease. We have found, however, that the interaction of commensal bacteria with TLRs plays an essential physiological role in intestinal epithelial homeostasis and protection from epithelial injury. This suggests an evolutionary relationship between immune defense and host-commensal interactions, and reveals a novel aspect of pathophysiology of intestinal inflammatory disorders.

Inflammation and Metabolism
Chronic, low-grade inflammation underlies many pathological conditions, including insulin resistance, obesity, and type 2 diabetes (a cluster of diseases referred to as metabolic syndrome), as well as many other human diseases. In general, the mechanisms responsible for the induction of chronic inflammation under most pathological conditions are unknown. We are investigating physiological functions of inflammation under normal conditions, mechanisms that account for persistence of chronic inflammation, and the effects of chronic inflammation on various (patho)physiological processes, including tumor progression. We are particularly interested in the role of inflammation in switching homeostatic set points and in the role of epigenetic programming in chronic inflammation and in stable alteration of metabolic homeostasis.

Regulation of Inducible Gene Expression
Activation of macrophages by TLR ligands leads to transcriptional induction of hundreds of genes. These genes fall into multiple categories, based on their functions and mechanisms of regulation, and different types of chromatin modifications are induced by TLR signals in a gene-specific manner. We are interested in studying inflammatory gene expression in macrophages as a model system to understand general principles of inducible gene expression.

A grant from the National Institutes of Health provided support for the work on TLR signaling, innate control of adaptive immunity, and host-commensal interactions.

As of April 14, 2009

Scientist Profile

Yale University
Cell Biology, Immunology