Introduction to the Immune System BIO381 PDF

Chapter 1: Introduction to the Immune System 1 I. The big picture -- why the immune system is important A. Historically, most people have died of infectious disease (or traumatic injury) 1. Death rates for the English colonies of New Engl...

Chapter 1: Introduction to the Immune System 1 I. The big picture -- why the immune system is important A. Historically, most people have died of infectious disease (or traumatic injury) 1. Death rates for the English colonies of New England during the late 1600s: a. 18-20% of children died in the first year of life (0.56% in 2022) b. 35-40% of children failed to reach adulthood c. 2.4-5.0% of adults died annually (0.75% in 2023) d. 1.5-2.0% chance of death during any one pregnancy, or soon after (0.03% in 2021) e. 20% of deaths were caused by tuberculosis f. Other epidemic diseases: smallpox, diphtheria, pneumonia, measles, scarlet fever (death rate varied annually) 2. Read the excerpt from People of the Deer 2 B. Risk of death from some infectious diseases 1. Diptheria: 5-10% in adults; higher in children 2. Measles: 1-2 per 1000 (~0.15%) 3. Pertussis: About 0.66% worldwide 4. Polio: 5-15% with acute infection due to paralysis 3 C. Some recurrent diseases and pandemics 1. Smallpox (Variola virus): death rate as high as 30% in adults, higher in babies -- survivors disfigured, and some blinded -- estimated to have killed 300 million in the 20th century alone, but finally eradicated in 1980 by vaccination 2. Black Death (Ursinia pestis) 1331-1353: Worldwide deaths are estimated at 75-200 million -- in 1348-1349, plague killed 60% of London population -- brought to the Americas by explorers, and still present today -- preventable through public health measures and treatable with antibiotics 3. The flu: (Influenza virus): annual epidemics typically cause ~500,000 deaths worldwide (5,000-52,000 in the U.S.) -- the pandemic of 1918 killed over 40 million people worldwide (~2% of total population) -- vaccination only partially effective 4 D. Death in modern times (2016 in the U.S.) 5 E. Why has death rate from infectious disease declined? 1. Biggest reason: public health efforts such as clean water, clean food, sanitary sewers, garbage collection, pest control 6 2. Secondary reasons: antibiotics/antivirals and vaccination a. Antibiotics: cure rate 69%; success rate (improvement) 92% b. Vaccination also overwhelmingly effective, saving six million lives yearly, worldwide 7 F. General adverse health risks of antibiotics and vaccines in U.S. 1. Antibiotics a. Adverse health events occur at a rate of 2.4%: diarrhea, nausea, vomiting, rash, yeast infections, allergic reactions, dizziness, photosensitivity, rarely life-threatening C. difficile infection b. Anaphylaxis risk is variable -- up to 0.04% for penicillin with 10% mortality 2. Vaccines a. Adverse effects are routine and include: pain, redness, or swelling at the injection site, fever, muscle aches, headache, fatigue, nausea, and temporary localized allergic reactions b. Anaphylaxis -- ~1 per million vaccinations, 5 deaths in 10 years after many hundreds of millions of vaccinations given c. Vasovagal syncope -- associated with needle stick -- one reported death due to head trauma after fall 8 G. Death by infection is caused by pathogenic microbes 1. Most microbes are harmless for reasons such as... a. They lack the physiology to survive in your environment b. They are rapidly recognized and killed by your immune system c. They cause no damage to you 2. Pathogenic microbes have special properties, some or all of which are not shared with other microbes, such as... a. Some capacity to evade our immune defenses -- otherwise they wouldn't survive long enough to cause disease b. The ability to exploit us as a host (as food) -- otherwise they wouldn't survive long enough to cause disease c. The capacity to damage our cells -- otherwise we might both live happily ever after with no disease 9 H. The good of your immune system 1. It provides some resistance to infectious disease a. Defense against infectious or predatory organisms i. Microorganisms: viruses, bacteria, fungi, protozoans ii. Macroorganisms: worms, larvae, other parasites 2. It provides some resistance to noninfectious disease a. Defense against neoplastic disease -- cancers/tumors 3. Support of healing after tissue trauma (wound repair) 10 I. The bad of your immune system (immunopathology) 1. It can attack you directly (autoimmune diseases) 2. It can attack things that mean you no harm (allergies) 3. When over zealous it can be destructive to normal tissues (damage during inflammation) 4. It attacks transplanted tissues and reduces their life expectancy 11 II. Examples of pathogens A. The different kinds of pathogens 1. Viruses -- intracellular 2. Prokaryotes (bacteria) -- some intracellular, some extracellular, some both 3. Small eukaryotes (fungi, protozoas) -- some intracellular, some extracellular, some both 4. Helminths (worms) -- extracellular 5. Larvae -- extracellular 6. Ectoparasites (e.g., ticks, mosquitoes, flies) -- extracellular, and vectors for other pathogens 12 B. Intracellular vs. extracellular locations for pathogens 1. Typically refers to the location where the pathogen can survive and/or function normally 2. Extracellular pathogen a. Meaning it remains outside of a host cell for all or part of life cycle b. Some of these can be taken up by phagocytosis 3. Intracellular pathogen a. Means it can survive somewhere in a cell (e.g., cytosol or inside a vesicle) for all or part of its life cycle b. These usually originate outside of cells, and somehow manage to enter cells (e.g., fusion, pinocytosis, phagocytosis) c. Some can move between cellular compartments 13 C. Viruses are among the most serious pathogens 1. Smaller than cells and not capable of independent life 2. They need your cells to propagate (produce more virus) 3. They are obligatory intracellular pathogens 14 4. Viruses hijack host cell machinery and disrupt normal function a. Often infecting preferred types of cells (tropism) b. Infected host cells are used to produce more virus particles c. Infection can alter normal cell function to varying degrees that may cause disease: i. Little or no disease -- latency or low pathogenicity ii. Cellular malfunction or altered function sufficient to cause disease if enough cells are infected iii. Cell death (loss of all function) leading to disease 5. Viruses can look different from your cells because of their unique molecular patterns a. Viral proteins and nucleic acids can be very different from ours, some are highly conserved, but other change rapidly over time b. Because viruses damage cells, injury can be an indicator of their presence 15 6. Example of blister caused by herpes virus infection 16 7. Some viruses, disease categories, and diseases a. Many different cells can be infected, including respiratory, digestive, CNS, white blood cells b. Disease presents in many different ways including skin eruptions, hemoragic fevers, warty growths, and many others 17 D. Prokaryotes are among the most serious pathogens 1. Smaller than your cells (0.2 - 2 µm average), but fully alive -- allows them to survive inside or outside your cells, depending 2. They often have rapid rates of cell division, much faster than your own cells -- an advantage that makes them hard to control 3. Infection disrupts or destroys normal host cell function a. Some produce toxins with specific molecular targets b. Some produce enzymes that digest host cell components 18 4. Bacterial toxins: 1) required for survival (endotoxins), or 2) produced as virulence factors (exotoxins) but not required 19 5. Bacterial cells can look different from your cells because of their molecular patterns a. Bacterial proteins, nucleic acids, lipids, and carbohydrates can be very different from ours i. Some bacterial molecular patterns are highly conserved over time ii. Some bacterial molecular patterns change rapidly over time b. Molecular patterns that don't change over time are ideal identifiers of bacteria -- particularly if they are pathogenic bacteria c. Because the molecular patterns of bacteria are usually different from those of viruses, it is possible to differentiate the type of pathogen -- important for knowing how to defend properly d. Because bacteria can damage your cells, cell injury can be an indicator of their presence 20 6. Example of bacterial infection that causes pus formation a. Draining an abscess caused by purulent (pus forming) bacteria 21 7. Some bacteria and the diseases they cause 22 E. Small non-prokaryotic pathogens 1. They are about the same size or even larger than your own cells (10-100 µm average size) 2. Fungi -- can be extracellular and/or intracellular pathogens of two types: a. molds (single-cell or filamentous) b. yeast (single-cell only) 23 3. Protists (endoparasites) -- extracellular and/or intracellular pathogens a. Single-celled organisms only -- the biggest killers include Leishmania and Plasmodium b. At the molecular level, will these organisms look different from viruses and bacteria? 24 F. Worms (helminths) -- large multicellular pathogens 1. Roundworms (nematodes) -- see below (Loa Loa leading to River Blindness) 2. Tapeworms (cestodes) 3. Flukes (trematodes) 25 4. Example of infection with Ascaris lumbricoides (nematode) causing fever, malnutrition, gastrointestinal disease, hepatitis, pulmonary inflammation, pancreatitis, etc. a. At the molecular level, will these organisms look different? 26 5. Example of elephantiasis caused by filarial nematodes blocking lymphatic ducts 27 III. Recognizing a threat by its molecular pattern A. Receptors are used to distinguish different molecular patterns 1. Life is made up of proteins, carbohydrates, lipids, nucleic acids 2. Your immune system has receptors to recognize all these types of molecules 3. At the molecular level there are lots of similarities, but lots of differences too 4. Proteins are recognized most often B. How to recognize pathogens 1. Many of your macromolecules share similar molecular patterns to those from other life forms -- especially those most related 2. The key to recognizing a pathogen is to recognize the molecular patterns that don't look anything like yours a. Some molecules are totally unique to a pathogen and essential for its survival -- conserved over evolutionary time -- these are good targets for immune receptors b. Some pathogen molecules are similar to yours in structure and function, but they can have unique subparts -- these are good targets for immune receptors c. Some pathogen molecules are similar to or the same as yours in structure and function -- these are bad targets for immune receptors C. Molecular pattern categories recognized by your immune system 1. Pathogen-associated molecular patterns (PAMPs) a. A limited set of molecular patterns that are mostly unique to pathogens b. Good targets, and indicators of the presence of "danger" 2. Damage-associated molecular patterns (DAMPs) a. A limited set of molecular patterns associated with damaged self b. Not targets, but indicators of the presence of "danger" 3. Antigens (Ag) a. An extremely large set of molecular patterns (>1011) that can be found on pathogens, non-pathogens, self, all living things b. Good targets if the pathogen-specific antigens can be distinguished from self antigens c. Inappropriate recognition can occur (e.g., autoimmunity, allergy) D. The universe of molecular patterns includes antigens, PAMPs and DAMPs E. The main soluble and cellular receptors of the immune system 1. Pattern recognition receptors (PRRs) a. Found both on cells and soluble in fluids (humoral factors) b. Able to recognize about 1000 distinct molecular patterns in two categories: i. Pathogen-associated molecular patterns (PAMPs) ii. Damage-associated molecular patterns (DAMPs) c. The genes for PRRs have been passed down from ancestors over many millions of years -- all of your cells have these genes d. The molecular patterns recognized by PRRs are typically highly conserved over time -- probably essential for function 2. Antigen receptors (AgRs) a. Found on cells: T cell receptors (TCR) and B cell receptors (BCR) b. Found soluble in fluids: antibodies (Ab, the secreted form of BCR) c. Antigens are defined as molecules containing molecular patterns that can be bound by an antigen receptor d. Genes for antigen receptors are not inherited -- only the pieces i. Each B and T cell has to create its own antigen receptor gene from the pieces -- a different receptor specificity for each cell ii. Because of this, B and T cell can recognize molecular patterns that are not conserved over time -- in case microbes change F. The concept of "danger" as an essential trigger for a response 1. Proposed by Matzinger, 1994 (pretty recent): An immune response is only initiated in the presence of "danger" 2. The immune system distinguishes safe from dangerous when danger signals are present: a. DAMPs: Every cell in the body can release danger signals if it becomes distressed because of injury or infection (e.g., DNA, RNA, histones, ATP, mitochondrial molecules) b. PAMPs: Molecular patterns that are specific to pathogens (i.e. dangerous foreign, or dangerous strangers) are recognized as danger signals -- evolutionarily conserved molecular patterns associated with danger 3. Generating an immune response only when there is danger allows you to be "tolerant" of yourself and most other things, usually (but not always) 4. Strangers and dangers stimulate an immune response a. In the absence of danger, there is tolerance G. Where to find receptors for PAMPs and DAMPs 1. PRRs are on all immune cells 2. PRRs are soluble (humoral) too IV. A historical perspective on immunity and immunology A. People who recovered from an illness were often resistant to getting sick again, and they could then aid the sick 1. Some survivors of 1918 influenza were still making neutralizing antibodies 90 years later 2. This resistance to reinfection is due to immune memory 38 B. Inoculation -- the first attempt at generating immune memory 1. The practice of infecting a person with a small dose of a disease causing agent 2. Used to combat smallpox (Variola virus) as early as the tenth century in China, and by the early 1700s in parts of Africa, India, and the Ottoman Empire 39 C. Inoculation in the west by the process of variolation -- the role of Lady Mary Wortley Montague 1. Natural infection with the Variola virus had a 20-30% death rate, and survivors were often disfigured and/or blind 2. In 1718, while in Turkey, Mary observed the positive effects of variolation (innoculation) with smallpox exudate in children which commonly led to resistance 3. She performed the technique on her own children and then convinced the British royal family to perform it on their children 4. Variolation suffered from a 1-2% death rate, but resulted in resistance to subsequent reinfection with 97-99% survival 40 D. Vaccination -- a safer process using a less virulent pathogen or parts of a pathogen -- first reported by Edward Jenner 1. Milkmaids were renowned for having clear skin -- absence of smallpox disease or milder form of smallpox 2. Edward learned from a farmer, Benjamin Jesty, how to inoculate against small pox using cow pox pus 41 E. Cowpox infection generates cross-protective memory 1. Cowpox is caused by the Vaccinia virus, a relative of Variola 2. Cowpox is less severe than smallpox in humans 3. Edward took cowpox exudate from a milkmaid's hand and introduced it into the skin of James Phipps, a small boy 4. Edward later infected James with smallpox exudate more than 20 times to no significant detriment 5. Edward published in 1798 and later gave James a cottage 6. Louis Pasteur called the procedure "vaccination" 42 F. The important sequence of events that demonstrated vaccination as a viable strategy to stimulate immune memory 43 G. A trip to the place where vaccination got its start 1. The Edward Jenner home in Glaucestershire, England 44 2. Blossom, the cow -- she "donated" the vaccinia virus 45 H. The anti-vaccination movement got started early in the 1800s 46 I. Cell-mediated immunity 1. 1882 - Elie Metchnikoff discovered phagocytes (macrophages) by inserting thorns into starfish larvae -- cells surrounded the thorns to engulf bacteria – phagocytosis 2. He said: "Phagocytosis must be the prime source of immunity, therefore cells are the key contributors to immunity" -- but it was not that simple 3. Cell-mediated immunity is now recognized as the activity of phagocytes and T cells 47 J. Humoral immunity -- demonstrated in the 1890s 1. Defensive macromolecules in extracellular fluids can neutralize toxins, precipitate toxins, and agglutinate pathogens 48 2. Evidence for humoral memory was also reported a. Serum from animals previously immunized with diphtheria could transfer immunity to unimmunized animals b. This is now called passive immunization 3. What are the humoral factors? a. Antibodies were first described in the 1930s as the components in serum responsible for humoral immunity (immunoglobulins) b. Complement proteins, lectins, and other proteins are now also recognized as important humoral factors 4. But humoral factors contribute to cell-mediated immunity too, so both arms are essential for normal defense 49 K. Using antibodies to monitor immune responses in modern times 1. Production of pathogen-specific antibodies is common after infection or immunization 2. Structure of a generic antibody (a soluble defensive protein) 50 L. Antigen-specific antibodies can be detected using assays like an Enzyme-Linked Immunosorbence Assay 1. See explanation of ELISAs on Canvas 2. This type of test can be used to measure an antibody titer (the amount of antibody) 51 M. The type of antigen-specific antibody that you produce can tell you something about when an infection took place 1. IgM first, then others like IgG -- measured in blood 52 V. Conceptual organization of the immune system A. Traditional view: a set of cells and soluble factors in two fundamental categories: 1. Innate (natural) -- defenses that are rapid in response but limited in their ability to recognize molecular patterns that are threats 2. Adaptive (acquired) -- defenses that are slow in response but are capable of recognizing almost any molecular pattern a. The capacity for memory is restricted to the adaptive arm B. Non-traditional view: the entire body is involved (holistic) 1. Behaviors, fundamental structures, physiological adaptations, cells and soluble factors all cooperate to maintain homeostasis, facilitate the thriving of our old friends (commensal microbes), and resist the survival of detrimental bad actors (pathogens) 53 C. The functional parts of the immune system 1. Soluble (humoral) factors (mostly proteins, but not all) that... a. are defensive -- they neutralize, inhibit, or injure disease agents (pathogens) b. communicate information and coordinate the functions of the various immune system components c. are both defensive and communicative -- e.g., antibodies can bind to pathogens and label them for destruction 2. Cells and tissues that... a. act as barriers to prevent entry of pathogens into the body b. produce soluble defensive and communication factors c. destroy pathogens directly, or even kill self cells as a defensive strategy 54 D. Communication molecules 1. Subtle communication is essential because cells need to function in a coordinated manner a. Regulation of inflammation and healing b. Control of activation and differentiation c. Stimulation of migration and killing d. Suppression of activation and response 2. Multiple different categories of communication molecules: a. Cytokines and chemokines (proteins) -- hundreds known b. Lipid mediators (e.g., prostaglandins, leukotrienes, etc.) c. Amines, neurotransmitters, and various other small molecules 55 E. Immune defenses are organized into layers (stages) 1. The innate defensive layers (stages) a. Layer 1: barriers between you and the outer world (eg. skin, mucosa) -- pathogens must cross to cause infection b. Layer 2: the front line of defense just under the barriers -- these include sentinel cells and sentinel soluble defensive factors that are present all the time and can detect PAMPs/DAMPs c. Layer 3: the defenses that are recruited once an infection is detected (evident by inflammation) -- cells and soluble factors that can recognize PAMPs/DAMPs 2. The adaptive defensive layer (stage) a. Layer 4: the defenses that can recognize and kill almost any microbe (and you too if it gets confused) because of antigen receptors -- an ability to recognize molecular patterns that are not highly conserved over time 56 F. The functional logic of the defensive levels (stages) 57 G. Different pathogens require different defense strategies 1. Innate responses recognize and target conserved differences 2. Adaptive responses add to and enhance innate responses 3. Anti-pathogen responses fit into three categories (types) a. Type 1: Intracellular -- defense mechanisms include binding proteins, killer cells to target infected self, phagocytic cells, pore forming proteins, and anti-viral capabilities of every cell b. Type 2: Large extracellular (worms) -- defense mechanisms include binding proteins, cells that secrete toxins, and various barrier tissue responses and enhancements c. Type 3: Small extracellular (bacteria, fungi) -- defense mechanisms include binding proteins, phagocytic cells, pore forming proteins, and various barrier enhancements 58 H. Fundamental features of innate immunity 1. Response time: Rapid -- seconds-minutes a. Inflammation -- the most common visual evidence of this response b. Anti-viral posture -- most cells can change their physiology to resist viral infection if they know one is present 2. Danger recognition: PRRs bind PAMPs and DAMPs -- triggers defensive responses 3. Communication: Release of alarm signals to the rest of the body after recognition of danger a. Coordinates the response, recruits blood humors and cells b. Stimulates production of more cells by the bone marrow and production of more soluble defensive factors 4. The response is mediated by soluble anti-pathogen effector factors and activated effector cells (e.g., phagocytes) 59 I. The fundamental features of adaptive immunity 1. An ability to recognize almost any molecular pattern, even those that are not highly conserved over time -- needed because... a. Some pathogens are extracellular, but they resist innate defenses, are hard to kill, and/or they produce toxins b. Some pathogens are intracellular so innate defenses can't see them, or they inhibit the anti-viral posture of cells c. Pathogens evolve, and some of their molecular patterns change over time 2. Effector responses are both humoral (highly specific antibodies) and cellular (highly specific killer cells and helper cells) 3. Responses are slow to develop, but thereafter is memory! 60 VI. Epithelial barriers -- the first layer of defense A. Generally a layer of cells that are tightly bound together -- e.g.: tracheal epithelium 61 B. The external surface of barriers is typically coated with defenses of different kinds (e.g., antimicrobial peptides) 62 C. Barriers are continually being cleaned 1. Sneezing, coughing, cilial movements 2. Urination, defecation, mucus production, etc. 3. Washing with soap and water, licking D. To cross barriers, some pathogens require help 1. Burns, cuts, scrapes, etc. 2. Insect or other animal bites 3. Human behavior (e.g., injection) E. Other pathogens can penetrate barriers on their own 1. Some worms can burrow through skin 2. Some microorganisms infect epithelial cells first, then they may exit to the rest of the body 63 F. Sentinel cells at barriers 1. Some immune cells hang out in barrier tissues where pathogens are likely to be encountered 2. If they encounter pathogen or tissue damage ("danger"), they signal for the start of inflammation a. Mast cells b. Macrophages c. Dendritic cells d. Various innate lymphocytes G. Soluble factors can also act as sentinels at barriers 1. Recognition of danger leads to release of signals to start inflammation a. Complement and clotting factors 64 VII.Immune cells are leukocytes A. Some of the leukocytes that are worth knowing about 1. Mononuclear phagocytes: monocytes, macrophages, and dendritic cells 2. Granulocytic phagocytes: neutrophils, eosinophils, basophils, and mast cells -- these are spotted after staining (granules) 3. Polymorphonuclear cells (PMNs, multilobed nuclei): neutrophils, eosinophils, basophils 4. Lymphocytes: B cells, T cells, and innate lymphoid cells 5. Effector cell: any immune cell that mediates resistance to disease (e.g., killer, helper, phagocytic, etc.) 6. Memory cell: Adaptive cell that reactivates upon antigen exposure to divide and produce both effector and memory cells 65 B. All leukocytes are derived from stem cells in the bone marrow 1. Stem cells regenerate themselves with each division 2. They provide daughter cells that can further differentiate 3. Some daughter cells can become different types of stem cells 4. Some stem cells are called precursor cells 66 C. The bone marrow lineages 67 D. Blood fractions -- some contain leukocytes 1. Whole blood -- unclotted a. Hematocrit is percentage of packed erythrocytes after centrifugation: 40-50% (male), 35-45% (female) b. Plasma is the fluid fraction at the top c. Buffy coat is packed leukocytes with extremely thin layer of platelets above 2. Clotting of blood followed by centrifugation gives: a. Clot at bottom (with cells) b. Serum (fluid) above clot -- depleted of clotting factors (e.g., fibrinogen) 68 E. Characteristics of different blood cells 69 VIII.Some important innate immune cells A. Tissue macrophages 1. A sentinel cell (layer 2) -- highly phagocytic 2. Detection of "danger" triggers antimicrobial activity, signaling for inflammation, and recruitment of other immune cells 70 B. Tissue mast cells 1. A sentinel cell (layer 2) -- rapid stimulator of inflammation and recruitment of other immune cells 2. Detection of "danger" triggers release of vasoactive factors (e.g., histamine) and antimicrobial factors a. A major driver of increased blood flow and vascular permeability b. Notorious for involvement in allergic responses 71 C. Tissue dendritic cells 1. A sentinel cell (layer 2) -- most important professional APC for priming a cellular (T cell) adaptive immune response 2. detection of "danger" triggers release of signals for inflammation and migration to lymph nodes 3. Also referred to as conventional dendritic cells (cDCs) 4. Picture shows the activated form in a lymph node with long processes (dendrites) 72 D. Neutrophils ("microphages") -- in blood until needed elsewhere 1. A PMN in blood (layer 3) -- highly phagocytic 2. 60-70% of WBC -- rapidly recruited into inflamed tissues after acute injury that includes bacteria -- associated with type 3 pathogens 3. Major component of pus 73 E. Monocytes -- in blood until needed elsewhere 1. A mononuclear cell in blood (layer 3) -- ~10% of WBC 2. Recruited to sites of inflammation where they become macrophages 3. As macrophages, they take up extracellular pathogens, clean up debris, and prepare tissues for repair and healing 4. Can be associated with all types of pathogens (1-3) 74 F. Eosinophils -- in blood until needed elsewhere 1. A PMN in blood (layer 3) -- 2.5% of WBC 2. Recruited into inflamed tissues containing worms (pathogen type 2) 3. Releases toxins specifically targeting worms 75 G. Basophils -- in blood until needed elsewhere 1. A PMN in blood (layer 3) --