INNATE IMMUNITY Taufik Hilmansyah

Introduction Innate immunity also called natural immunity or native immunity Innate immunity is the critical first step in host defense against infections. It blocks microbial invasion through epithelial barriers Destroys many microbes that do enter the body Capable of controlling and even eradicating infections. The innate immune response is able to combat microbes immediately upon infections. In contrast, the adaptive immune response needs to be induced by antigen and therefore is delayed.

GENERAL FEATURES AND SPECIFICITY OF INNATE IMMUNE RESPONSES The two principal types of reactions of the innate immune system are inflammation and antiviral defense. Inflamation consists of the accumulation and activation of leukocyte and plasma proteins at site of infection or tissue injury. These cells and protein act together to kill mainly extracellular microbes and to eliminate damage tissue. Innate immune defense agants intracellular viruses is mediated by Natural killer (NK) cells, which kill virus-infected cells, and by cytokines called type I interferons, which block viral replication within host cells. The innate immune system does not remember prior encounters with microbes and resets to baseline after each such encounter, whereas memory is a cardinal feature of the adaptive immune response.

CELLULAR RECEPTORS FOR MICROBES AND DAMAGED CELLS Toll-Like Receptors TLRs specific for microbial proteins, lipids, and polysaccharides Different TLRs are specific for different components of microbes TLR-2 recognizes several bacterial and parasitic glycolipids and peptidoglycans; TLR-3, -7, and -8 are specific for viral singlestranded and double-stranded RNAs; TLR-4 is specific for bacterial LPS (endotoxin); TLR-5 is specific for a bacterial flagellar protein called flagellin; TLR-9 recognizes unmethylated CpG DNA, which is more abundant in microbial genomes than in mammalian DNA.

NOD-Like Receptors and the Inflammasome The NOD-like receptors (NLRs) are a large family of cytosolic receptors that sense DAMPs and PAMPs in the cytoplasm. Three important NLRs are NOD-1, NOD-2, and NLRP-3. NOD-1 and NOD-2 are cytosolic proteins containing N-terminal CARD (caspase related) domains. They are specific for bacterial peptidoglycans, which are common components of bacterial cell walls. NLRP-3 (NOD-like receptor family, pyrin domain containing 3) is a cytosolic NLR that responds to many unrelated microbial structures or pathologic changes in the cytosol and reacts by enhancing production mainly of the inflammatory cytokine IL-1β.

Other Cellular Receptors of Innate Immunity The RIG-like receptor (RLR) family recognizes RNA produced by viruses in the cytosol and activates signaling pathways that lead to the production of type I interferon (IFN). Cytosolic DNA sensors (CDSs) include several structurally related proteins that recognize cytosolic viral DNA and also induce type I IFN production. Lectin (carbohydrate-recognizing) receptors in the plasma membrane are specific for fungal glycans (these receptors are called dectins) and for terminal mannose residues (called mannose receptors); A cell surface receptor expressed mainly on phagocytes recognizes peptides that begin with N-formylmethionine, which is specific to bacterial proteins, and promotes the migration as well as the antimicrobial activities of the phagocytes.

COMPONENTS OF INNATE IMMUNITY The components of the innate immune system include : Epithelial cells Sentinel cells in tissues (macrophages, dendritic cells, mast cells, and others) Innate lymphoid cells, including NK cells; and a number of plasma proteins.

Epithelial Barriers The major interfaces between the body and the external environment : the skin, gastrointestinal tract, respiratory tract, and genitourinary tract are protected by continuous epithelia that provide physical and chemical barriers against infection. Microbes may enter hosts through these interfaces by physical contact, ingestion, and inhalation. All these portals of entry are lined by continuous epithelia consisting of tightly adherent cells that form a mechanical barrier against microbes. Keratin on the surface of the skin and mucus secreted by mucosal epithelial cells prevent microbes from coming in contact with and infecting the epithelia. Epithelial cells also produce peptide antibiotics, called defensins and cathelicidins, which kill bacteria and thus provide a chemical barrier against infection.

Epithelia contain lymphocytes called intraepithelial T Some of these T cells express receptors composed of two chains, γ and δ Intraepithelial lymphocytes often recognize microbial lipids and other structures that are shared by microbes of the same type. React against infectious agents that attempt to breach the epithelia, but the specificity and functions of these cells are poorly understood.

Phagocytes : Neutrophils and Monocytes/ Macrophages Neutrophils Also called polymorphonuclear leukocytes (PMNs), numbering 4000 to 10,000 per µL. The production of neutrophils is stimulated by cytokines, known as colony-stimulating factors (CSFs), which are secreted by many cell types in response to infections and act on hematopoietic stem cells to stimulate proliferation and maturation of neutrophil precursors. Neutrophils are the first cell type to respond to most infections, particularly bacterial and fungal infections. The dominant cells of acute inflammation Neutrophils ingest microbes in the circulation, and they rapidly enter extravascular tissues at sites of infection, where they also phagocytose (ingest) and destroy microbes. Monocytes/ Macrophages

Monocytes less abundant in the blood than neutrophils, numbering 500 to 1000 per µL They also ingest microbes in the blood and in tissues. During inflammatory reactions, monocytes enter extravascular tissues and differentiate into cells called macrophages, blood monocytes and tissue macrophages are two stages of the same cell lineage, which often is called the mononuclear phagocyte system (This has been called the reticuloendothelial system,

Dendritic cells Respond to microbes by producing numerous cytokines. Serve two main functions : they initiate inflammation and they stimulate adaptive immune responses. Mast Cells that are present in the skin and mucosal epithelium. can be activated by microbial products binding to TLRs, as part of innate immunity, or by a special antibody-dependent mechanism. Mast cell granules contain vasoactive amines such as histamine that cause vasodilation and increased capillary permeability, as well as proteolytic enzymes that can kill bacteria or inactivate microbial toxins. Mast cells also synthesize and secrete lipid mediators (e.g., prostaglandins) and cytokines (e.g., tumor necrosis factor [TNF]), which stimulate inflammation. Mast cell products provide defense against helminths and other pathogens and are responsible for symptoms of allergic diseases

Innate Lymphoid Cells Innate lymphoid cells (ILCs) are lymphocyte-like cells that produce cytokines and perform functions similar to those of T lymphocytes but do not express T cell antigen receptors (TCRs). ILCs provide early defense against infections and also guide the subsequent T cell response. Natural Killer Cells Natural killer (NK) cells recognize infected and stressed cells and respond by killing these cells and by secreting the macrophageactivating cytokine IFN-γ. NK cells function to eliminate cellular reservoirs of infection and eradicate infections by obligate intracellular microbes, such as viruses. Activated NK cells also synthesize and secrete the cytokine interferon-γ IFN-γ activates macrophages to become more effective at killing phagocytosed microbes. Cytokines secreted by macrophages and dendritic cells that have encountered microbes enhance the ability of NK cells to protect against infections. Three of these NK cell–activating cytokines are interleukin-15 (IL-15), type I interferons (type I IFNs), and interleukin-12 (IL-12). IL-15 is important for the development and maturation of NK cells, and type I IFNs and IL- 12 enhance the killing functions of NK cells. Macrophages ingest microbes and produce IL-12, IL-12 activates NK cells to secrete IFN-γ, and IFN-γ in turn activates the macrophages to kill the ingested microbes.

Innate Lymphoid Cells

Lymphocytes with Limited Diversity γδ T cells are present in epithelia. NK-T cells express TCRs with limited diversity and surface molecules typically found on NK cells. They are present in epithelia and lymphoid organs. They recognize microbial lipids bound to a class I MHC–related molecule called CD1. B-1 cells are a population of B lymphocytes that are found mostly in the peritoneal cavity and mucosal tissues, where they produce antibodies in response to microbes and microbial toxins that pass through the walls of the intestine. Another type of B lymphocyte, marginalzone B cells, is present at the edges of lymphoid follicles in the spleen and other organs and also is involved in rapid antibody responses to blood-borne polysaccharide-rich microbes.

Complement System The complement cascade may be activated by any of three pathways The alternative pathway is triggered when some complement proteins are activated on microbial surfaces and cannot be controlled, because complement regulatory proteins are not present on microbes (but are present on host cells). The alternative pathway is a component of innate immunity. The classical pathway is most often triggered by antibodies that bind to microbes or other antigens and is thus a component of the humoral arm of adaptive immunity. The lectin pathway is activated when a carbohydrate-binding plasma protein, mannose-binding lectin (MBL), binds to terminal mannose residues on the surface glycoproteins of microbes.

Other Plasma Proteins of Innate Immunity Several circulating proteins in addition to complement proteins are involved in innate immune defense against infections. Cytokines of Innate Immunity In response to microbes, dendritic cells, macrophages, mast cells, and other cells secrete cytokines that mediate many of the cellular reactions of innate immunity

INNATE IMMUNE REACTIONS The innate immune system eliminates microbes mainly by inducing the acute inflammatory response and by antiviral defense mechanisms. Inflammasion Inflammation is a tissue reaction that delivers mediators of host defense—circulating cells and proteins—to sites of infection and tissue damage

Phagocytosis and Destruction of Microbes Phagocytosis is a process of ingestion of particles larger than 0.5 μm in diameter. It begins with membrane receptors binding to the microbe. The principal phagocytic receptors are some pattern recognition receptors, such as mannose receptors and other lectins, and receptors for antibodies and complement.

Antiviral Defense Defense against viruses is a special type of host response that involves interferons, NK cells, and other mechanisms.

Regulation of Innate Immune Responses Innate immune responses are regulated by a variety of mechanisms that are designed to prevent excessive damage to tissues

Microbial Evasion of Innate Immunity Pathogenic microbes have evolved to resist the mechanisms of innate immunity and are thus able to enter and colonize their hosts

ROLE OF INNATE IMMUNITY IN STIMULATING ADAPTIVE IMMUNE RESPONSES Innate immune responses generate molecules that provide signals, in addition to antigens, that are required to activate naive T and B lymphocytes Different types of microbes induce different innate immune responses, which then stimulate the types of adaptive immunity that are best able to combat different infectious pathogens.