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Chapter 4. Innate Immunity. Innate immunity is the initial response to microbes that prevents, controls, or eliminates infection of the host
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Chapter 4 Innate Immunity
Innate immunity is the initial response to microbes that prevents, controls, or eliminates infection of the host • Inhibiting or eliminating of innate immunity markedly increases susceptibility to infections, even when the adaptive immune system is intact and functional • Innate immunity to microbes stimulates adaptive immune responses and can influence the nature of the adaptive responses to make them optimally effective against different types of microbes • Innate immunity not only serves defensive functions early after infection but also provides the "warning" that an infection is present
Innate Immune Recognition • Components of innate immunity recognize structures that are characteristic of microbial pathogens and are not present on mammalian cells: • Pathogen-associated molecular patterns (PAMPs) include LPS, N-formyl met., CpG • The innate immune system also recognizes endogenous molecules that are produced by or released from damaged and dying cells. These substances are called damage associated molecular patterns (DAMPs) • Pattern recognition receptors (PRR) • Innate immune system recognizes microbial products that are often essential for survival of the microbes such as ds-viral RNA, LPS, CpG-DNA, N-formylmethionine • Pattern recognition molecules of the innate immune system include cell-associated pattern recognition receptors expressed on the surface of or inside various cell types, and soluble proteins in the blood and extracellular fluids
Because of this specificity for microbial structures, innate immune system is able to distinguish self from nonself, but it does so very differently from the adaptive immune system • PRR of innate immune system are encoded in germline DNA with low diversity 103molecular patterns capable of 107in adaptive immune system
The Inflammasome • Cryopyrin Associated Periodic Syndromes (CAPS) • Autoinflammatory syndromes
Epithelial Barriers • Intact epithelial surfaces form physical barriers between microbes in the external environment and host tissue • Three main interfaces between the environment and the host are the skin and the mucosal surfaces of the gastrointestinal (GI) and respiratory tracts • Peptides that have antimicrobial properties (Defensins and Cathelicidins)
Defensins (secretory): • Paneth cell defensins (major source) are sometimes called crypticidins, in small bowel • protective actions include: direct toxicity to microbes, and the activation of cells involved in the inflammatory response to microbes • Cathelicidins (membranous): • expressed by neutrophils and various barrier epithelia • proteolytically cleaved into two peptides • direct toxicity to a broad range of microorganisms, and the activation of various responses in leukocytes
Epithelial Barriers • Barrier epithelia and serosal cavities contain certain types of lymphocytes, including intraepithelial T lymphocytes and B-1 subset of B cells, respectively, which recognize and respond to commonly encountered microbes • Very little diversity • Recognize structures commonly expressed by many different or commonly encountered microbial species (PAMPs) • Perform similar effector functions as do other lymphocytes and with antigen receptors like other T or B cells • More to effector cells of innate immunity than adaptive immunity
Epithelial Barriers • Intraepithelial lymphocytes: • are distinguished mainly by the type of T cell antigen receptors (conventional αβ, γδ TCRs) • TCRs recognize peptide and non peptide antigens • function in host defense by secreting cytokines, activating phagocytes, and killing infected cells • function in host defense by secreting cytokines, activating phagocytes, and killing infected cells • B-1 cells: • produce IgM specific for polysaccharide and lipid antigens • natural antibodies are produce largely by them • A third population of cellsmast cells: • respond directly to microbial products by secreting cytokines and lipid mediators that promote inflammation
Phagocytes and Inflammatory Responses • Phagocytes, including neutrophils and macrophages, are cells whose primary function is to identify, ingest, and destroy microbes • Neutrophils • polymorphonuclear leukocytes (PMN), nucleus with three to five connected lobules • most abundant population of circulating WBC • 12 to 15µm • The cytoplasm contains granules of two types, specific granules (enzyme such as lysozyme, collagenase, and elastase) that do not stain strongly with either basic or acidic dyes and azurophilic granules (lysosomes containing enzymes and other microbicidal substances, including defensins and cathelicidins) • Production of neutrophils is stimulated by granulocyte colony-stimulating factor (G-CSF) • An adult human produces more than 1 x 1011 neutrophils per day • function for a few hours (6h) and then die
Phagocytes and Inflammatory Responses • Mononuclear Phagocytes (MMN) • play central roles in innate and adaptive immunity • unlike neutrophils, macrophages are not terminally differentiated and can division at an inflammatory site • incompletely differentiated and is called monocyte • some develop abundant cytoplasm and are called epithelioid cells • later stages of the innate immune response, 1 or 2 days after infection • Macrophages in different tissues, microglial cells (CNS), Kupffer cells (liver), alveolar macrophages (pulmoner); osteoclast(bone)
Natural Killer Cells (NKC) • A lineage of cells related to lymphocytes that recognize infected and/or stressed cells and respond by directly killing these cells and by secreting inflmmatory cytokines • 5% to 20% of the mononuclear cells in the blood and spleen • By surface phenotype and lineage, are neither T nor B lymphocytes • A major source of IFN-γwhich activates macrophages to kill ingested microbes
Natural Killer Cells (NKC) • Term natural killer derives from the fact that if these cells are isolated from the blood or spleen, they kill various target cells without a need for additional activation • In contrast, CD8+ T lymphocytes need to be activated before they differentiate into CTLs with the ability to kill targets • Large lymphocytes with numerous cytoplasmic granules, because of which they are sometimes called large granular lymphocytes • NKC activation is regulated by a balance between signals that are generated from activating receptors and inhibitory receptors • Many of these receptors recognize class I MHC molecules • NKC use fundamentally different types of receptors than do T cells to recognize class I or class I-like MHC molecules
NKC and Cytokines • Are a majorsource of IFN-γ, and expansion and activities of NK cells are also stimulated by cytokines, mainly IL-15 and IL-12 • Macrophage-derived cytokine IL-12 is a powerful inducer of NK cell IFN (Interferon) -γ production and cytotoxic activity • Type I IFNs, IFN-α and IFN-β, also activate the cytotoxic potential of NK cells
Inhibitory Receptors of NKC • Inhibitory NKC receptors fall into three main families and all three families is the presence of immunoreceptor tyrosine-based inhibition motifs (lTIMs) in their cytoplasmic tails • First family is named KIR (killer cell Ig-like receptor): • recognize different alleles of HLA-A, -B, and -C molecules • Some members of the KIR family have short cytoplasmic tails without ITIMs, and these function as activating receptors
NKC Activating Receptors • CD16 (FCγRIIIa), one of the first activating receptors identified on NK cells, is a low-affinity IgG Fc receptor and is responsible for NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) • Ligand binding to activating NK cell receptors leads to cytokine production, enhanced migration to sites of infection, and killing activity against the ligand-bearing target cells • Activating receptors associate with subunits that contain immunoreceptor tyrosine-based activation motifs (lTAMs) in their cytoplasmic tails
Circulating Proteins of Innate Immunity • Soluble pattern recognition proteins and associated effector molecules are sometimes called the humoral branch of innate immunity, analogous to the humoral branch of adaptive immunity mediated by antibodies • 1. Complement System:
Circulating Proteins of Innate Immunity • 2. Pentraxins: • Prominent members of this family include the short pentraxins C-reactive protein (CRP) and serum amyloid P (SAP) and the long pentraxin PTX3 • Increase up to 1000-fold during infections • Increased synthesis by the liver induced by the cytokines IL-6 and lL-l • CRP functions as an opsonin by binding Clq • PTX3 is produced by several cell types, including dendritic cells, endothelial cells, and macrophages, in response to TLR ligand and the innate immune system cytokine TNF and against Asp. Fum.
3. Collectins and Ficolins: • Three members of this family include MBL and pulmonary surfactant proteins SP-A and SP-D • MBL binds carbohydrates with terminal mannose and fucose, which are typically found in microbial cell surface glycoproteins and glycolipids and functions as an opsonin • SP-A and SP-D act as opsonins and can directly inhibit bacterial growth • Violins bind several species of bacteria, opsonizing them and activating complement
FEEDBACK MECHANISMS THAT REGULATE INNATE IMMUNITY • The magnitude and duration of innate immune responses are regulated by a variety of feedback inhibition mechanisms that limit potential damage to tissues • IL-10 is a cytokine that is produced by and inhibits activation of macrophages and dendritic cells • Mononuclear phagocytes produce a natural antagonist, IL-1 receptor antagonist (IL- 1RA) • Negative regulatory signaling pathways
