Modeling the immune system

Transkript

1 Master Modeling the immune system nnate mmunity Innate immunity or natural immunity refers to body's defense mechanisms that: are available instantaneously and for the first few day after microbial infection. do not improve by repeated encounters with the same pathogen. Innate defense mechanisms can be classified into two main groups Pre-existing innate immune mechanisms Inducible innate immune mechanisms

2 Innate immune recognition Cells of the innate immune system use germline-encoded receptors to recognize signature molecules of microorganisms Microbial non-self Missing self Altered self The recognition of microbial non-self is based on the detection of molecular structures that are unique to microorganisms. The recognition of "missing self" is based on the detection of molecular structures that are normally expressed by healthy cells but are lost when cells undergo infection and/or transformation. Such recognition is coupled with various inhibitory pathways that block initiation of immune responses against self. Recognition of "altered self" is based on the detection of stress-induced cell surface molecules (MICA & MICB; glycoproteins, altered phospholipid (phosphotidylserine on apoptotic cells) cytoplasmic peptides. The markers tag for assisted apoptosis by NK cells Stress reactions result from infection or cellular transformation.

3 Detection of microbial non-self Bacterial PAMPs Gram-positive bacteria (Staphylococcus aureus Streptococcus penumonia) Lipoprotein (TLR2 ligand) Gram-negative bacteria (Salmonella typhimurium) Teichoic acid Bacterial DNA unmethylated CpG (TLR9 ligand) Lipopolysaccharide (TLR4 ligand) Lipoteichoic acid (TLR2 ligand) Peptidoglycan (TLR2 ligand) Flagellin (TLR5 ligand) Viral PAMPs Single stranded RNA Hepatitis E HIV, influenza, measles, mumps Doubled stranded RNA Rotavirus

4 Microbial non self: pattern recognition receptors ignaling RRs Soluble PRRs Signaling PRRs acts as early warning system. couple PAMP recognition to induction of microbicidal host responses. expresses by innate and epithelial cells at the cell surface or intracellularly. Soluble PRRs bind and mark microbial pathogens for uptake by phagocytes (opsonisation) for activation of the complement system. (acute phase proteins produced by the liver.) Phagocytic PRRs Phagocytic PRRs bind microbial pathogens and mediate their internalization. (expressed by neutrophils, macrophages, dendritic cells and epithelial cells).

5 Microbial non self: pattern recognition receptors ignaling RRs The major signaling PRRs are the Toll-like receptors (TLRs) the nucleotide-binding oligomerization domain (NOD) molecules TLRs a large extracellular domain containing tandem copies of the leucine-rich repeat (LRR) motif followed by one or two cysteine-rich regions. a single transmembrane domain. a cytoplasmic tail that contains a characteristic globular Toll/IL-1 receptor (TIR) domain which is similar to the cytoplasmic domain of IL-1 receptor family members.

6 Microbial non self: pattern recognition receptors ignaling RRs The major signaling PRRs are the Toll-like receptors (TLRs) the nucleotide-binding oligomerization domain (NOD) molecules

7 Microbial non self: pattern recognition receptors ignaling RRs The major signaling PRRs are the Toll-like receptors (TLRs) the nucleotide-binding oligomerization domain (NOD) molecules ell surface LRs ndosomal LRS Because U-rich motif is likely present in viral as well as self ssrnas, it is the abnormal localization of viral ssrna in endosomes that marks them as danger signal.

8 ignaling RRs Microbial non self: pattern recognition receptors

9 Microbial non self: pattern recognition receptors ignaling RRs FκB pathway

10 Microbial non self: pattern recognition receptors ignaling RRs FκB pathway

11 Microbial non self: pattern recognition receptors ignaling RRs FκB pathway

12 NOD and other cytosolic recognition systems OD olecules OAS molecules PKR molecules NOD-family members are characterized by three distinct functional domains: a carboxy-terminal leucin-rich repeat (LRR) region a centrally located NOD domain an amino-terminal effector-binding domain (EBD). NOD-1 & NOD-2 NOD1 and NOD2 recognize bacterial peptidoglycan NOD1 and NOD2 through the RIP2-kinase, which activates NFκB and MAP-kinase signaling pathways. Oligoadenylate synthase (OAS) family of interferon-inducible enzymes synthesize a 2 5 oligoadenylate polymer upon activation by viral dsrna. 2 5 oligoadenylate then induces dimerization & activation of RNaseL (endonuclease that degrades viral and cellular RNA, which blocks mrna translation and leads to apoptosis by binding antiapoptotic proteins (Bcl2 and BclXL). Protein kinase R (PKR) a serine/threonine protein kinase that contains three double-stranded RNA binding domains and a C-terminal kinase domain. PKR is activated by viral but not host dsrna

13 Cellular effectors of innate Immunity hagocytic ells Neutrophils Mononuclear phagocytes Innate host defense is provided by the coordinate action of several effector cell types. Phagocytic cells Natural killer cells (NK cells) Eosinophils Mast cells Mucosal epithelial cells Neutrophils and mononuclear phagocytes Neutrophils (or polymorphonuclears or PMN) are instrumental inbacterial destruction. They contain two kinds of granules: Primary granules contain cationic proteins, defensins,proteases (elastase, cathepsin G), lysozyme and myeloperoxidase. Secondary granules contain lysozyme and NADPH oxidase cofactors, lactoferrin and B-12 binding protein. Mononuclear phagocytes Circulating monocytes Tissue histiocytes, brain microglial cells, liver Kupfer cells Macrophages in serous cavities & lymphoid organs Dendritic cells in epithelial tissues and in lymphoid organs

14 Cellular effectors of innate Immunity Mast cells Mast cells Mature mast cells reside in mucosal and connective tissues where they take up invading microbes and produce pro-inflammatory cytokines mediating leukocyte recruitment and a vaste array of cytokines, including the "type II cytokines" IL-4 recruitment of neutrophils to the site of infection. Mast cells also produce lipid mediators of inflammation and a vast array of cytokines. NK cells Natural killer cells NK cells are important in defense against viral infections and malignancies. They are large and granular lymphocytes. Their granules contain cytolytic proteins ( perforin and granzymes. NK cells recognize the difference between normal and malignant or virus-infected cells in a nonspecific manner via sugar-lectin interaction.

15 Detection of missing self ack of MHC lass I olecules Missing self recognition is based on the detection of markers of self that are constantly expressed by healthy host cells down-regulated or absent in infected, transformed or damaged host cells. These markers normally engage inhibitory receptors on the cell surface of natural killer cells and block the effector function of these cells

16 Detection of missing self he NK eceptors -type lectine receptors NK receptors are divided into two functional groups with opposing signaling effects, the inhibitory and activating receptors. These receptors belong to two main structural superfamilies: C-type lectin-like receptors The CD94/NKG2 receptor is a disulfide-linked heterodimer composed of two lectins: the invariant "common" CD94 chain and a member of NKG2 family, KIR2DL g-like eceptors Immunoglobulin-like receptors KIR family members consist of type I glycoproteins containing tandem Ig-like extracellular domains. KIR that have a long cytoplasmic tail (L) deliver an inhibitory signal, KIR with a short cytoplasmic tail (S) deliver an activating signal. ITIM SHP-1 SHP-2

17 Molecular effectors of innate Immunity The innate immune system possesses a wide variety of molecular effector systems that fight disease-causing microorganisms and influence surrounding cells. nti-microbial olecules Anti-microbial molecules produced by innate leukocytes, mucosal and skin epithelia. Lysozyme, chitinases and phospholipase A2 that hydrolyze components of microbial cell walls. BPI, defensins, cathelicidins,complement components and eosinophil cationic protein that disrupt the integrity of microbial cell walls. Microbicidal serine proteases (serprocidins). Bacteriostatic proteins such as lactoferrin, NRAMP and calprotectin that sequester iron and zinc and thereby prevent the growth of bacteria. Enzymes such as NADPH-oxidase, nitric oxide synthase and myeloperoxidase that generate oxygen and nitrogen derivatives that are toxic to microorganisms. cute phase roteins omplement acute phase proteins produced by the liver. the complement system whose most molecular components are produced by the liver.

18 Molecular effectors of innate Immunity cute phase roteins plasma proteins whose concentration increases or decreases by at least 25% during acute & chronic infection. Acute phase protein synthesized primarily by the liver and secreted into the circulation. Modulation of acute phase protein production occurs when hepatocytes are exposed to inflammatory cytokines omplement The complement protects against extracellular pathogens. It consists of a set of about 30 proteins that are normally present in serum and tissue fluids or on cell membranes in inactive form. These proteins can be activated at a specific signal (mostly on pathogen recognition) through a cascade of proteolytic steps involving the cleavage and resulting activation of the various components.

19 Master Modelling the immune system Describe two types of systems that integrate microbial signals earning bjectives Explain the difference between PAMPs and antigens. Describe which molecular and cellular components mediate innate immuni State which innate immune cells instruct the adaptive immune system Describe how NK cells become activated and how they kill target cells

20 Home work ase-base earning Study the complement system through 2 exercices Two groups: Group 1: exercise 1 on NK cells. Group 2: exercise 2 on complement Address the questions and prepare a Powerpoint presentation for the return session Return session. Powerpoint presentation by members of each group: 20 min + 5 min discussion Webpage