Pathogens/ microbesCells of the immune systemHumoral and extracellular mechanisms involved in Innate ImmunityThe Interplay between Innate and Adaptive Immunity- the action begins in secondary lymphoid organsToll Like Receptors (TLRs) activate phagocytes and DCsGETTING YOUR BEARINGSBASIC “CONCEPTS” IN ADAPTIVE/SPECIFIC IMMUNITYCells of the Immune System and Innate Immunity Recommended reading: Abbas et al., 4th edition, Chapters 2 and 12 Janeway and Travers, 5th edition, Chapters 1 and 10 The innate immune system is made up of molecules and cellular processes that defend the host within minutes and hours after exposure to a noxious stimulus. It is the only immune system in plants and invertebrates. Innate immune responses may initiate acute inflammation, which basically involves the accumulation and activation of phagocytes (mainly polymorphonuclear cells in man) and of vascular endothelium at sites of injury. In vertebrates, the innate and adaptive immune systems talk to each other and there is an important reciprocal interplay that operates between these systems. In these animals the cells and molecules of the innate immune system provide immediate protection and then set in motion the activation of the adaptive immune response. The adaptive immune response in turn “revs” up innate immune mechanisms of host defense. The innate immune system uses non-clonal “pattern recognition” receptors (PRRs) which cannot recognize host structures but which do recognize patterns found on microbes.These are sometimes called PAMPs for Pathogen Associated Molecular Patterns. Pathogens/ microbes The most common organisms that cause disease are viruses, bacteria, fungi, protozoa, and worms. A microbe (a small invader) or a worm that does not cause disease in most people may generally be classified as non-pathogenic. Such an organism will provoke an immune response in a normal immunocompetent host. In an immunocompromised person this very same organism may be invasive and cause disease. The term “pathogen” is therefore sometimes a relative one. Pathogens will be considered in detail in Microbiology at a later date. At this point a few of their features will be considered in order to better understand various aspects of innate and specific immunity. All viruses, some bacteria (e.g. Mycoplasma, Chlamydia, Listeria, Mycobacteria, Salmonella), some fungi (e.g. Histoplasma, Cryptococcus, Coccidoides, Pneumocystis), and some protozoa (e.g. Trypanosomes, Toxoplasma, Leishmania, Plasmodium) grow within cells and are referred to as intracellular pathogens. Antibodies and agglutinins are unlikely to be very useful against such pathogens once they are established in the host. Cell mediated immunity is required to deal with these invaders. Many common bacterial pathogens multiply extracellularly and are cleared by antibodies and complement. Pathogens have evolved numerous strategies to evade host defense. We will discuss some of these strategies as the course progresses. Unique structural features of certain microbes serve as patterns for recognition by the innate immune system • Bacteria, have cell walls, which are made up of peptidoglycans which are never found in vertebrates. • Many bacterial cell surface polysaccharides, such as mannans, are not found on the surfaces of host cells. • Gram negative bacteria (such as E.coli, Pseudomonas, Salmonella etc) all make Lipopolysaccharide (LPS/endotoxin), which is made up Lipid A and carbohydrates. Harvard-MIT Division of Health Sciences and TechnologyHST.176: Cellular and Molecular ImmunologyCourse Director: Dr. Shiv Pillai• Some bacteria contain distinct structures known as teichoic acids and lipoteichoic acids, not found in vertebrate cells. Teichoic acis are phosphate linked polymers of ribitol or glycerol • The N-terminal amino acid of most bacterial proteins is formyl-methionine. This is not found in vertebrates except in mitochondria • Bacterial lipoproteins (BLPs) contain a unique N-terminal lipo-amino acid, N-acyl S-diacylglyceryl cysteine. • Bacterial DNA contains specific unmethylated CpG repeats that are not found in vertebrate DNA • Double stranded RNA produced during viral infections may induce the secretion of Type I inteferons which have anti-viral properties. Cells of the immune system The major phagocytic cells in man are known as macrophages and granulocytes. Macrophages of different sorts exist in tissues and they are derived by the differentiation in tissues of circulating monocytes. Blood cells include erthrocytes (RBCs or red blood cells), leukocytes (WBCs or white blood cells), and thrombocytes (platelets). These cells will be discussed in more detail in Pathology, but are being covered here for completeness. White cells involved in innate immune responses include granulocytes, monocytes/macrophages, and Natural Killer or NK cells (which should be considered a lymphocyte like cell that participates in innate immune responses). On morphological criteria in stained blood films, leukocytes are divided into cells which contain obvious cytoplasmic granules (granulocytes) and those that do not. The latter include lymphocytes and monocytes, and are sometimes collectively called agranulocytes or mononuclear cells. It should be kept in mind that although monocytes and lymphocytes look very much alike in blood smears, monocytes are of myeloid origin. Granulocytes and macrophages are involved in inflammatory responses, and acute inflammation is initiated by these phagocytic cells of the innate immune system. There are three types of granulocytes: neutrophils, basophils, and eosinophils. All these cell types contain distinct cytoplasmic granules, hence their name. Neutrophils or polymorphonuclear leukocytes have multi-lobed nuclei, and two types of cytoplasmic granules. Specific granules are small and numerous, while azurophilic (they stain blue) granules are modified lysosomes. Neutrophils are shortlived cells with a lifespan of 6-7 hours in blood and 1-4 days in tissue sites. They are particularly effective in phagocytosing small particles such as bacteria. Uncoated or opsonized bacteria may be phagocytosed into a vacuole, known as a phagosome. Specific granules fuse with the phagosome. Proton pumps lower the pH and azurophilic granules discharge their contents into the phagosome resulting in the destruction and digestion of microbes. The contents of granules include proteases such