Stanford Microbiology and Immunology 104 204 Innate Immunology Lecture 1 Introduction and genetic manipulation of innate immunity Introduction Day 1 First half Day 1 Second half Introduction of topics Mutations leading to immunity Immunologists define two arms of the immune system Innate that with which you are born Typically covered in half of first lecture of basic immunology course Look at an immunology text 116 1600 pages 7 25 There is more to innate immunity than Toll and macrophages You would be dead without it why is it not studied Adaptive specific B and T cells that raise a response to precise antigens Dependent upon somatic recombination of genes to produce molecules with high binding specificity Better name would be somatic immune system or RAG dependent immunity The names are propaganda Like Healthy skies initiative Compassionate conservative The names are not the opposite of each other but that seems implied The opposite of innate should be not innate or perhaps learned The opposite of adaptive might be non adaptive or stagnant A problem with these names is they do not exclude each other Adaptive We will spend at least one lecture looking at adaptive responses in the innate immune system Specific Innate immune receptors are just as specific as those in the adaptive system and they are looking for the same things nonself altered self and missing self Only jawed fish descendents have RAG system The implication of this is the majority of multicellular organisms survive without an adaptive immune system Summary of the adaptive immune system Stanford Microbiology and Immunology 104 204 Innate Immunology Lecture 1 Introduction and genetic manipulation of innate immunity Dendritic cells talk to T cells which talk to B cells That s about it as far as this course is concerned Much of the recent excitement about innate immunity lies in the role it plays in activating the adaptive immune response A body determines whether a pathogenic event is occurring before raising an immune response Ideally we would teach innate and adaptive immunity together in an integrated manner along with pathogenesis In this course this is the end of our discussion of the Rag dependent immune system Innate immune system In this class I will take a broad approach looking at plants nematodes flies mice and humans There are several reasons for doing this a People and mice are not the only important creatures on the planet Crops protect themselves only with innate immune responses Insects pass on diseases eat and pollinate our food b In a system with no RAG dependent immunity immune responses must be innate Studying these systems simplifies experiments c Immune responses are highly conserved it should cease surprising us that the mechanisms used by other organisms are also used by humans Will always try to teach course with an infection in mind The reductionist approach to science has us discussing immunology in such a way that we seldom mention an infection You begin to think the adaptive immune system evolved to reject transplants and cause autoimmune disease Here we will always try to start with an infection progress to the host s response and then show how microbes can overcome the host A bug s eye view A useful way to organize the innate immune system is to imagine yourself as a microbe trying to enter a body When looking for a host you quickly realize that not all hosts are created equal Infection puts a selective pressure on a population that can lead tot the accumulation of mutations that allow survival to childbearing age Sickle cell anemia is good example of this Heterozygotes for the trait are less likely to die when infected by malaria Stanford Microbiology and Immunology 104 204 Innate Immunology Lecture 1 Introduction and genetic manipulation of innate immunity Where do you enter the body Skin is a formidable immune organ Wounds incite inflammation and summon immune cells Wet surfaces contain antimicrobial compounds antimicrobial compounds like antimicrobial peptides and lysozyme Fluid flow clears out microbes rapidly constant peristalsis and beating cilia induced vomit diarrhea snot Bodies are already inhabited by microbes that are unlikely to give up their niches easily Passing through cells Manipulation of a host cell produces a strong immune response HR response in plants Once inside the body Toll activation recognition of foreign Complement opsonization and killing Phagocytes uptake and killing mechanisms Physiological responses Inflammation Shock Cachexia Neural contributions Neuroendocrine effects glucocorticoids Direct neural signaling Psychological contributions Feeling sick The yuck response of disgust Learned disgust responses Social innate immunity Infected social insects inform their sisters Infected plants inform the field of imminent infection Stanford Microbiology and Immunology 104 204 Innate Immunology Lecture 1 Introduction and genetic manipulation of innate immunity Adaptive innate immunity Immune memory and innate immune responses Loss of function mutations leading to disease resistance Infections can be species specific like smallpox which only infects humans Microbes can also be subspecific like Plasmodium vivax which can only infect people expressing the Duffy antigen on their red blood cells This lecture concentrates on mutations arising in a community that alter resistance to infectious diseases Because of your genetic background you might respond better or worse to an infection Is this innate immunity If we define innate immunity as an inborn method of combating disease then mutations affecting disease progression fit This is not a mechanism that is active at a personal scale like most of the mechanisms we study These mechanisms are active at the population level Lessons learned from these mutations may lead to new treatments Mutations implicated in altered immunity to infection Disease Gene Mechanism Malaria G6PDH Heterozygote survival advantage Sickle cell anemia Heterozygote survival advantage TNF promoter polymorphism Severe malaria Thalassemia Hemoglobin A CFTR cystic fibrosis Receptor for Salmonella typhi CFTR cystic fibrosis Limits diarrhea CCR5 Enhanced NK activity Loss of HIV receptor Typhoid fever Cholera AIDS Stanford Microbiology and Immunology 104 204 Innate Immunology Lecture 1 Introduction and genetic manipulation of innate immunity Leprosy TLR2 Polymorphism leads to shifts tuberculoid to lepromatous TLF Presence of human lytic factor prevents