Immunology Test 1

Two types of T-Cell Co-Receptors:

CD4 t cells = cd4 receptors (MHC 2) CD8= CD8 receptors (MHC 1)

CXCL8 is a ______, which is a cytokine that is used to attract neutrophils to the site of infection, allowing them to leave blood vessels and enter tissue spaces.

Chemokine Stimulate recruitment of immune cells Cytokines that act as chemical attractants. For example, CXCL8 (also called IL-8 or neutrophil chemotactic factor) is a chemokine produced by innate immune cells, such as macrophages, in response to TLR stimulation. Phagocytic neutrophils in circulation will respond to CXCL8 when the chemokine binds to its receptor (CXCL8R). The response stimulates increased adherence of neutrophils to endothelial cells, migration out of the blood vessel and movement towards the source of the chemokine. This form of chemotaxis is integral to the recruitment of immune cells to the site of infection.

Notes

Coevolution: Balanced relationship Seasonal flu: Spreads easily but has a low mortality rate, population develops adaptive immunity to a strain, virus mutation creates new strain, population may have partial protection Pandemic flu (pan means world): Influenza virus jumps species (bird or swine flu), no pre-existing immunity, death BEFORE adaptive response (high mortality rate) Jump in species = something totally new = more deadly Microbes evolve faster than humans Waves that help move mucus: cilia RNA Genome: Instructions for how to make more virus VIRUSES DON'T HAVE FLAGELLA Cellulose cell wall: microalgae, plants Spore coat: Bacteria and fungi have one

As he developed his hypothesis for a 'vaccine' against smallpox, all the following observation were made by Edward Jenner except: A dairy maids previously infected with cowpox did not get infected with smallpox B cows that were not infected with cowpox were susceptible to infection by smallpox C children previously infected with variola major did not get infected with smallpox as adults D individuals previously inoculated with variola minor did not get infected with smallpox

Cows that were not infected with cowpox were susceptible to infection by smallpox

When a PAMP binds to its PRR, it generates an intracellular signal that activates gene expression by that immune cell. The most common gene expressed is for a chemical signal called a(n) <CHOOSE ANSWER>, which is used for communication and coordination of immune responses.

Cytokine Immune cells also express receptors for communication signals, called cytokines, which are used to recruit and coordinate immune cell activity against foreign invaders. Inflammatory Cytokines: Second line of defense, general response = increased blood flow/swelling (more immune molecules to site of infection)

During viral infection, ____________ antigens of the virus (e.g. viral capsid protein) can be processed and presented with MHC I to activate a cytotoxic T cell response against the virus.

Endogenous MHC I is used to present endogenous antigens, or antigens that have been synthesized within the pAPC (e.g. a viral capsid protein during infection).

When a virus invades a host cell, viral PAMPs (e.g. viral double-stranded RNA) will bind to and activate <CHOOSE ANSWER> Toll-like receptors (e.g. TLR3), which will generate the type-I interferon antiviral response.

Endosomal

Progress of an Infection

Enter the host (Get past 1st line of defense) Colonize (Microbe trying to establish self, attachment factors, what is it attaching to?) -Mucus is defense against colonization Invade Multiply Evade host defenses (avoid phagocytes) (2nd and 3rd lines of defense) Exit the host

Thucydides observed of a plague during the Peloponnesian Wars that those who previously contracted the disease and recovered could care for the sick because they would not contract the disease again. In this respect, the term 'immunity' is derived from the Latin 'immunis,' which means:

Exempt Immunity: the defense system that protects us against infection and disease

Which microbe has lipopolysaccharide (LPS), an important PAMP for stimulating innate immunity?

Gram-negative bacteria

TCR (T-Cell Receptors)

Have a series of proteins in membrane called CD3 complex, those help with signal transduction/affect gene expression - helps activate t cell, cytokine signals also help activate t cell (second intracellular signal) - T cells made up of two chains ( alpha and beta) They only recognize antigens if antigens are being presented with MHC Each T cell has a single antigen-binding specificity, i.e. its TCRs recognize one antigen only. The TCR has domains for both MHC binding and antigen binding. Therefore, T cells are only activated by antigens that have been processed (e.g. a viral capsid protein broken down into a peptide) and presented by an APC with use of MHC. T cells also express one of two co-receptors - CD4 to bind MHC II and CD8 to bind MHC I.

High vaccination rates in children makes sure that new members of a population become immune, which reduces transmission of disease to non-immune adults and to children who cannot be vaccinated. This phenomenon of protecting non-immune individuals by surrounding them immune individuals is called ____ immunity.

Herd

The observation that those who had recovered from a disease could safely care for those with the same disease was the foundation for understanding immunity. It was still important in the proceeding centuries to gather experimental evidence that supported this practice. An explanation for this phenomenon, or <CHOOSE ANSWER>, must be proposed and then tested experimentally to determine whether the explanation was supported.

Hypothesis

The ability of the immune system to not attack self antigens and nonharmful environmental antigens is called:

Immune Tolerance Food antigens, because they lack PAMPs (not carrying the ball) will not stimulate immune responses.

Cytokines

Immune cells also express receptors for communication signals, called cytokines, which are used to recruit and coordinate immune cell activity against foreign invaders. Chemical signals used to communicate/ Intercellular communication For example, when a PAMP binds to its PRR, the immune cell will be stimulated, and it will begin to secrete chemical signals called cytokines. These signals can stimulate nonspecific innate responses, such as inflammation, by binding to cytokine receptors on other cells. Cytokines also help influence specific adaptive responses, such as T lymphocyte activation.

Background to Immunology

Immune cells attacking self: dead cells (apoptosis), dying cells, cancer cells Plague: 430 BC : Peloponnesian War and Thucydides Immunis = exempt (Only those that recovered from disease could safely nurse the sick/not get sick The observation that those who had recovered from a disease could safely care for those with the same disease was the foundation for understanding immunity. It was still important in the proceeding centuries to gather experimental evidence that supported this practice. An explanation for this phenomenon, or HYPOTHESIS, must be proposed and then tested experimentally to determine whether the explanation was supported. Smallpox (variola) High mortality rate (30% die), complications in survivors: Scarring, internal organ damage 16th century china Variola minor exposure protects you from variola major VARIOLATION: If you get one variation, you are safe from all variation First example of us intentionally harnessing immune system Still a chance of death: Unfortunately, variolation was by nature a dangerous, and sometimes unpredictable, practice. Despite the reduced complications in comparison to variola major exposure and the benefit of subsequent immunity, the risk of severe complications and death still made it problematic. 1790's England: Dr. Edward Jenner observed the beauty of milkmaids (no smallpox scars): Cowpox: Similar to smallpox but not lethal NAIVE: Never previously exposed If a naive individual is given non harmful cowpox and recovers, then they should be immune to smallpox 1798 England: Jenner took pus from cowpox lesions (milkmaid Sarah Nelms) into 8 year old James Phipps.... Then exposed boy to smallpox Why did Jenner test it on young child? Jenner had been variolated as a child but James Phipps had not been exposed - he needed naive individual Conclusion: Jenner's cowpox (vaccinia) inoculation proved to be a much safer and effective means for small pox prevention - develops word "vaccine"

Second Line of Defense

Innate cellular Systemic Non-specific recognition and elimination (responses are general, they aren't distinguishing between types of bacteria) Leukocytes (white blood cells) Contained within circulation/travel throughout body Phagocyte: LOVES TO EAT - Embedded in tissue spaces and circulating in fluids throughout the body. These cells express receptors that are activated by PAMPs. Phagocytes will non- specifically recognize, ingest and destroy invading bacteria, fungi or viruses. This response is intrinsic to the host and acts within seconds-to-minutes following microbial exposure. Non-specific: They'll eat pretty much anything The defensive players are leukocytes, or white blood cells (except for lymphocytes, which are part of adaptive immunity). Innate immune cells utilize circulatory systems (cardiovascular and lymphatic) of the host to surveil the body and eliminate threats. For example, phagocytosis is an innate cellular response.

Innate Barriers

Innate=born with it Meant to keep microbes out of body Skin (epidermis): First line of defense Non-specific (works the same for virus,bacteria, chemicals, etc. Epithelial tissues (epidermis and mucosa) with their associated secretions and microbial flora constitute this first line of defense, or natural barriers. Immediately upon exposure, this surface barrier non- specifically blocks the invasion of a wide variety of threats, including microbes. Epidermis prevents microbes from accessing host resources. The function of skin remains constant from birth to death.

For variolation, the process of introducing a microbe or its antigens into a patient is called:

Inoculation The most common method was to use a needle to retrieve material from pustules from a patient with variola minor and then stick the recipient in the arm with that needle. This was known as inoculation

Types of microbial pathogens: Intracellular

Invade host cells/ microbes must enter host cell Replicate within host cells Phagocytes can't get to them, so we use NK (natural killer cells= second line of defense)- recognize any cell of the body that is unnatural (they can kill your own cells) TB, Chlamydia

When a ligand binds its receptor, an intracellular signal is generated via phosphate groups being transferred from adapter molecules to transcription factors. The intracellular enzymes that typically mediate this type of signalling are called:

Kinases Many types of signal transducers are kinases, or phosphorylating enzymes, that transfer phosphate groups to activate key intracellular signaling molecules. Eventually, the signal activates transcription factors (e.g. NF- κB) in the nucleus, which in turn, activate expression of certain genes

Intracellular signaling

Ligand binding to receptor, signal transducers (Larger intracellular domain, goes from membrane into cell), intracellular adapters/ adapter molecules (Send signal using phosphate groups (Kinase used to transfer phosphate groups)), transcription factors (Molecules that will enter the nucleus and becoming activated, usually through phosphorylation- Transcription = copying DNA into mRNA- Transcription factors turn genes on, resulting in gene expression of proteins), gene expression

Lymphocytes

Lymphocytes are adaptive immune cells that have receptors to recognize microbial antigens Lymphocytes (B and T cells) have antigen receptors on their surfaces to recognize and bind to unique, nonself antigens Lymphocytes express antigen receptors

Match the immune receptor with its description. MHC 1 MHC 11 BCR TCR

MHC 1: Presents peptide antigens, recognized by CD8 Co-receptor MHC 11: Presents peptide antigens, recognized by CD4 co-receptor BCR: Recognizes epitope of native antigen (viral spike protein or bacterial toxin), associated with Ig alpha and Ig-beta comprised of four polypeptide chains of two different types - heavy chain and light chain. Each B cell has a single antigen-binding specificity, i.e. its BCRs recognize one antigen only. BCR has two antigen-binding sites, each comprised of a heavy chain and a light chain TCR: Recognize peptide antigen presented with MHC, associated with CD3 complex. Receives antigen presentation: T cell (recognizes antigens MHC combination) T-cell = adaptive immune cell: recognizes one antigen and one antigen only Antigen receptor found on t cells= t cell receptor (TCR)

Types of microbial pathogens: Extracellular

MRSA, Group A strep Colonize surfaces Circulating fluids Replicate outside of host *Binary fission= bacteria Easiest way to get rid of it = immune cells (phagocyte= non-specific, they just eat everything, part of the second line of defense) Most pathogens are extracellular, where their reproduction occurs on host surfaces, in tissue spaces or in circulation. Phagocytes are the main response to extracellular threats, which include most bacteria and fungi. On the other hand, some pathogens, and viruses in particular, are intracellular. They reproduce inside host cells. Phagocytes are not effective against intracellular pathogens in hiding, so cytotoxic T cells are used to target infected host cells for destruction

Other type of active immune cell: B cell

Made up of two different chains (like t cell), but its made up of two PAIRS Leads to production of antibodies Does not require MHC presentation Can recognize native antigens Recognizes antigen through single epitope

Eukaryotic Parasites

Most are extracellular pathogens with complex life cycles (Can be both intracellular and extracellular) Much more complex than fungi More difficult for the body to combat Unicellular eukaryotic microbes (Protozoa, Plasmodium falciparum (malaria)) Multicellular eukaryotic animals Helminths (parasitic worm) Taenia solium (tapeworm) Not micro, physically an animal, but considered in microbiology because it's transmitted when it's much smaller (egg), so some of your defenses will be tailored against small animal.... Once it grows, the defenses are no longer useful Eosinophil: Anti-parasite immune cell- recognizes larger things and attaches and releases digestive enzymes and things to break parasite down enough for phagocytes to eat. Larger in size, immune mechanisms such as phagocytosis will be of little use. Infections are recognized as parasitic due to PAMPs (e.g. nucleic acids and glycosylphosphatidylinositol of Plasmodium), and specific targeting of each parasite species is mediated by antigen recognition. A typical parasite response is the recruitment of innate cytotoxic cells that produce destructive enzymes and chemicals. These immune cells can be assisted by 'tagging' antibodies.

Binding of ligand to receptor results in the generation of an intracellular signal. To activate gene expression, where does this signal get directed?

Nucleus

Scientific Method

Observation Question Hypothesis Experimentation Conclusion (Then goes back to observation)

Interleukins (IL)

One group of cytokines, called interleukins (IL), are used by leukocytes to communicate with one another. For example, when a dendritic cell presents an antigen to a CD4 T cell, it will secrete interleukin-12 (IL-12).

Immune cells contain receptors that recognize two groups of microbial molecules:

PAMPs and antigens

How are PAMPs and antigens similar? How are they different?

PAMPs and antigens are similar because both alert the immune system to the presence of a virus or microbial threat and allows it to determine what needs to be attacked. Pathogen-Associated molecular patterns (PAMPs); Conserved microbial molecules of related microbes that are recognized by innate immune cells Conserved across evolution Not super specific/ more general/ broad classifications Tells us "Is that harmful" (Lipopolysaccharides/LPS of gram-negative bacteria, double stranded RNA of viruses) -Flagellin Antigens: Specific molecules that differentiate microbes and are recognized by adaptive immune cells Diverse molecules that are unique to individual microbial species (specific) Useful in determination of Non-self H-Spike on flu is an antigen Mutations to H spike H1N1 -Exotoxin Antigens are unique molecular identifiers of viruses. -Capsid and envelope spike proteins. Antigens differ from PAMPs because they are less conserved and they also vary significantly across species within the same general classification. PAMPs display minimal variation within a broader classification of microbes. Key (ligand) = microbe, lock = receptor on cell Ligans bind to receptors

Helper T cells secrete cytokines to activate nearby immune cells (e.g. B cells, Tc cells, macrophages). This type of signaling is characterized as:

Paracrine This co-stimulatory signal will help activate the T cell. Close- proximity signaling to a nearby cell is called paracrine signaling (this contrasts with endocrine signaling, where a chemical signal, e.g. hormone, travels a longer distance to its target). Most reactions that we talk about are paracrine (nearby response) They don't have to be bound, but do have to be close Hormones are different, they communicate at distance sights/areas (endocrine)

What are PAMPs and what is their role in host immune responses? Include a specific example in your response.

Pathogen (some sore of microbe) Associated Molecular Pattern They bind to receptors called PRRs they stimulate the second line of defense (innate cellular immunity) For instance, Lipopolysaccharide (LPS) is a PAMP that binds to.........

PRRs

Pattern recognition receptors Receptors on immune cells bind to ligands (PAMPs) and become stimulated Type of PRR: Toll-like receptors (TLRs) bind different classes of PAMPs LRR domian (ligand binding): Extracellular Transmembrane TIR domain (signaling): Intracellular TLR 4 binds to Bacteria LPS TLR 3/3: Endosomal TLR for viruses- Activates a different transcription factor through phosphorylation (Interferon pathway, instead of. inflammatory cytokines) Additional PRRs include the NOD-like receptors (NLRs), which are cytosolic receptors that recognize ligands from microbes (e.g. bacterial peptidoglycan), host (e.g. ATP) and environment (e.g. alum). NLRs are involved in signal transduction (like TLRs) but also play a role in inflammasome formation. When activated, the inflammasome induces the formation of IL-1 and IL-18, two inflammatory cytokines.

Match the immune disease/disorder with its category DiGeorge syndrome is caused by an inborn genetic defect in thymus development Multiple sclerosis is caused by an immune response against host neurons Pollen allergies are caused when the immune response mistakenly attacks nonharmful antigens AIDS is caused when a virus attacks and depletes immune cells in a previously healthy individual

Primary Immunodeficiency: Individuals born with certain genetic disorders (e.g. DiGeorge syndrome, hyper-IgM syndrome) have primary immunodeficiencies, or immune hyposensitivity, where the immune system lacks the ability to fight infection normally and leaves the individual highly susceptible to infection. Autoimmunity: Multiple sclerosis is caused by an immune response against host neurons Hypersensitivity: Allergies/anaphylaxis reactions Individuals with hypersensitivities suffer from immune responses against nonharmful substances. Unnecessary/Overactive. -Some hypersensitivities cause chronic debilitation, as in autoimmune diseases (e.g. type I diabetes or multiple sclerosis), where the immune system mistakenly targets and attacks self antigens (e.g. insulin-producing beta islet cells of the pancreas or myelin sheath of motor neurons, respectively). To counteract some autoimmune hypersensitivities, therapy consists of an immunosuppressive drug, which helps to calm the overactive response, but again renders the patient vulnerable to infection. Secondary Immunodeficiency: Likewise, individuals with underlying disease (e.g. AIDS) or undergoing medical interventions (e.g. cancer chemotherapy) acquire immunodeficiencies during their lifetimes. This population afflicted with secondary immunodeficiencies is growing steadily

Peptide

Short chains of amino acids

Intracellular Signaling

Signal transducers (Larger intracellular domain, goes from membrane into cell) Intracellular adapters/ adapter molecules (Send signal using phosphate groups (Kinase used to transfer phosphate groups)) Transcription factors (Molecules that will enter the nucleus and becoming activated, usually through phosphorylation- Transcription = copying DNA into mRNA- Transcription factors turn genes on, resulting in gene expression of proteins) Gene expression *Specific shut down of immune cell = receptor (Then everything downstream gets turned off)

MHC and antigen presentation

Specialized immune cells, known as professional antigen-presenting cells (pAPCs), bridge innate and adaptive immune responses. Dendritic cells and macrophages are innate immune cells that phagocytose and process microbial antigens (typically, proteins are digested into peptides). They present these antigen fragments to T lymphocytes, which are adaptive immune cells. A T lymphocyte uses an antigen receptor (T-cell receptor) to recognize the presented antigen. Upon binding of the antigen, a signal transduction cascade stimulates T lymphocyte activation and subsequent adaptive immune responses. pAPCs use membrane proteins called major histocompatibility complex (MHC) proteins to display the processed antigen on the cell surface, so that the antigen-MHC complex is recognized by the T-cell receptor (TCR). Two types of MHC are expressed -MHC I is comprised of two polypeptide chains - α chain and β2-microglobulin. MHC II is comprised of two polypeptide chains - α chain and β chain (try not to confuse these chains with those of TCR, described later). Each MHC molecule has a general peptide-loading domain. Peptide binding to MHC does not have the specificity of antigen receptors. The APC uses MHC to present a peptide antigen to T cell by interacting with the T-cell receptor and a co-receptor MHC I also has a recognition domain for the CD8 co- receptor on T cells. So, if a pAPC is infected with a virus, it will present these antigens with MHC I to a CD8 T cell. This activates cytotoxic T cells that target virus-infected host cells. MHC II also is recognized by the CD4 co-receptor on T cells. So, if a pAPC phagocytoses a bacterial cell, it will present these antigens with MHC II to a CD4 T cell. This activates helper T cells that coordinate the activities of macrophages to phagocytose bacteria. In this fashion, the pAPC helps activate the correct T cell response against either intracellular (e.g. viruses) or extracellular (e.g. bacteria) pathogens.

Interferons

Stimulate antiviral responses

Proinflammatory Cytokines

Stimulate inflammation and fever response

To activate an adaptive response, professional antigen-presenting cells (pAPCs) use MHC molecules to present nonself antigens to:

T-Lymphocytes Specialized immune cells, known as professional antigen-presenting cells (pAPCs), bridge innate and adaptive immune responses. Dendritic cells and macrophages are innate immune cells that phagocytose and process microbial antigens (typically, proteins are digested into peptides). They present these antigen fragments to T lymphocytes, which are adaptive immune cells. A T lymphocyte uses an antigen receptor (T-cell receptor) to recognize the presented antigen. Upon binding of the antigen, a signal transduction cascade stimulates T lymphocyte activation and subsequent adaptive immune responses. pAPC helps activate the correct T cell response against either intracellular (e.g. viruses) or extracellular (e.g. bacteria) pathogens.

Gram positive vs gram negative bacteria

Take cell envelope (coating) and do cross section: Both have cell wall and at least one membrane Gram positive: Thicker cell wall (Teichoic acid/lipoteichoic acid (TA or LTA)-Carbohydrate) Gram negatives have inner membrane, cell wall, outer membrane Lipopolysaccharides-carbohydrate Gram Negative: have a thin cell wall enclosed between two membranes with lipopolysaccharide (LPS) embedded in the outer membrane. LPS, also known as endotoxin when it is released by dead Gram-negative bacteria, can cause detrimental effects to the host during infection. Endotoxin is a potent stimulator of inflammation and fever response. Systemic release of endotoxin causes a drop in blood pressure that can cause the host to go into shock.

The immune system is programmed to recognize, attack and eliminate nonself enitites, such as microbes. Why does the immune system not attack other nonself entities, such as food?

The immune system is programmed to recognize, attack and eliminate nonself enitites, such as microbes. Why does the immune system not attack other nonself entities, such as food?

How are PRRs and antigen receptors similar? How are they different?

The structures that allow phagocytic cells to detect PAMPs are called pattern recognition receptors (PRRs). Immune cells, as well as some other host cells, recognize and respond to PAMPs with use of receptors called pattern-recognition receptors (PRRs), which are connected to signal transduction systems. PAMPs represent warning signals to the immune system that something potentially harmful, i.e. an infectious agent, has entered the body. PRRs (Pattern recognition receptors) and antigens are similar because both are in response to ligand-receptor interactions, but antigens bind to antigen receptors, and PRRs are receptors that bind to PAMPs. Pathogen-Associated molecular patterns (PAMPs), are conserved molecules of related microbes that are recognized by innate immune cells. They are not super specific, but can determine if something is a virus, bacteria, etc. Antigens are more specific and can differentiate specific microbes. They are recognized by the adaptive immune cells. Receptors on immune cells: PRRs and antigen receptors: Bind to tagged microbes because they are tagged by PAMPs or antigens Antigens are only one lock, one key

Why might the use of oncolytic viruses or CAR T-cell therapy be better for the treatment of cancers than current chemotherapies?

The use of oncolytic viruses or CAR T-cell therapy might be better for the treatment of cancers than current chemotherapies because although chemotherapy is successful in targeting rapidly dividing cancer cells, it also targets immune cells. This means that the already weakened host will be even more susceptible to infections. On the other hand, oncolytic viruses, which are viruses that are genetically- modified to target and kill cancer cells, are useful because they do not weaken the patient in order to destroy the cancer. CAR T-cell therapy has also shown to be useful for combatting cancer. T-cells patrol looking for disease, but sometimes cancer cells disguise themselves or sprout so many antigens that T cells are not able to attack. With CAR T-cel therapy, thousands of patients T-cells are collected and injected with a modified and inactive virus that introduces genetic information into cell and programs it so that T-cell now produces chimeric antigen receptors (CAR). When the CAR -T cells are infused back into patient, the new receptors enable T-cells to identify and latch onto specific antigens in the patient's tumor cells and destroy them without harming the immune cells. Overall, because both oncolytic viruses and CAR T-cell therapy specifically target cancer cells, the potential side effects should be minimized. There have also been early successes with use of CAR T-cell therapy, where the patient's own T cells are harvested, genetically programmed to recognize a cancer cell (chimeric antigen receptor, or CAR), and then transferred back into the patient. Since these targeted therapies are specific for cancer cells, the potential side effects in the patient should be minimized.

Metastasize

To spread

Exogenous VS Endogenous

Two different types of MHC: MHC 2 does Exogenous (usually bacteria) and MHC 1 does endogenous (usually viruses) MHC II is used to present exogenous antigens, or antigens that originate outside the pAPC and are phagocytosed for processing (e.g. an adhesin protein on the surface of a bacterial cell). MHC 1 used to present endogenous (intracellular pathogens) antigens (antigen presenting cell becomes infected with virus, cell begins producing pieces of virus, antigen presenting cell steals viral proteins, chews them up, combines them with MHC 1, displays them on surface of cell)

Bacteria

Unicellular prokaryotic pathogens have a peptidoglycan cell wall Extracellular and intracellular Not all bacteria cause infection Simple, unicellular, prokaryotic microbes (before nucleus/no nucleus) Ribosomes, pili, plasma membrane, plasmid (DNA), cytosol, flagellum, capsule or slime layer, nucleoid region Binary fission Divided into gram-positive or gram-negative -PAMPs target: Most bacteria has these (Not found in fungi or viruses) PAMPs can be broad classification, but there are some specific components that can be unique Some PAMPs can also serve as antigens, but not all antigens are PAMPs Help trigger second line of defense: Innate cellular Peptidoglycan Teichoic acids LPS (Gram negative bacteria) Flagellin- makes up flagella (tail) Capsule -Antigens target (found in all microbes): Epitope: what we actually recognize as unique (Both b and T cells recognize specific epitopes - gives you different responses) Stimulate third line of defense Specific Can tell one strain of bacteria from another Surface proteins: Proteins are ideal because of their diversity (Made up of combo of 20 different amino acids) Exotoxins Capsule

Host Pathogen relationship: The goal of a pathogen is to:

Use host resources for reproduction Too successful= no more host = no more pathogen Not successful= no more pathogen

Dates

Vaccine used in Western Europe and then the US in the 1800s By 1950's smallpox was eliminated in US and vaccines were discontinued WHO distributed vaccine to developing countries with smallpox epidemic Ring vaccination: area where the disease is prevalent, vaccinate those in contact with infected - surround disease so that it can't escape Herd immunity: Last natural case of smallpox in Somalia in 1977 ; Smallpox declared eradicated in 1980: If you have enough immune people in population , disease cant be transmitted - Even if you aren't immune, you are still protected Vaccines aren't always 100% effective (More like 75%) Re-Vaccination may b needed- effects not as long lived as getting disease 1963 Enders and Katz' measles vaccine is licensed - Intinuated vaccine? Grown in chicken embryo - wouldnt cause measles, but immune system developed response against real thing Measles: Lower mortality rate, but very contagious and could have lasting damage 1970s MMR vaccine put into use in US: COmbo vaccines )Measles, mumps, rubella) 2000 measles virtually eliminated from US 1980's MMR Vaccine becomes more common in UK 1998 Andrew Wakefield (UK) suggests MMR vaccine linked to autism in children 2000s UK measles vaccination rates decline as lawsuits increase, and measles outbreaks pop up 2007 Jenny McCarthy (US) on Oprah declared son's autism caused by MMR vaccine 2008 measles outbreaks emerge in US 2010 Wakefield publications retracted and declared a fraud by the Lancet 2014 outbreak in unvaccinated amish community in Ohio 2015 origin of recent measles outbreak traced to Disneyland 2017 outbreak in Minnesota Somali-American community with poor vaccination coverage 2018-2019 multi state measles outbreak in US is highest in 25 years - NYC Forced vaccinations? Most refuse due to religious/philosophical reasons Also a large portion of the population that are ineligible for vaccines: 2 young, suppressed immune systems, they rely on herd immunity

Which group of microbes are obligate intracellular parasites, i.e. all members of this group must invade a living host cell to reproduce?

Viruses Obligate: Has to happen, no other option Means the only way viruses can reproduce is intracellularly All viruses must invade host cell to repodruce Viruses are acellular: They are not made up of cells (thus they are not considered living), so they can't reproduce on their own

Autocrine:

When a cell produces cytokine, but cytokine binds to its same receptor (self-stimulation) It starts producing more of that cytokine, and more, and more, it's a cycle (Positive feedback loop) Autocrine signaling creates a positive-feedback loop that induces rapid cell proliferation to increase the number of antigen-specific, activated T cells in response to infection. T cell activation also involves autocrine signaling, where the cell secretes IL-2, which binds to the IL-2 receptor (IL-2R) on the same cell. This stimulates more IL-2 production by the cell, and in turn, more IL-2R binding.

Because of difficulties finding tissue matches for transplants, scientists are exploring other options including bioengineered tissues made from the patient's own cells or the transplantation of animal tissue called a:

Xenograft

Fungi

Yeasts infections are caused by unicellular eukaryotic pathogens that have a chitin cell wall Complex, unicellular, eukaryotic (cellular ) microbes ("true nucleus") More complex than bacteria, but similar defenses (bacteria and fungi are most similar) Most are extracellular pathogens (use phagocytes) Yeasts and molds Candida albicans: yeast infections PAMPs: Such as the complex carbohydrates of the cell wall (e.g. chitin, mannans and glucans) Antigens: Surface proteins Antifungal immune responses, like phagocytosis, will be similar to those used to eliminate bacteria

Mucus is a secretion that can protect your respiratory tract from infection by preventing adherence of flu virus to respiratory epithelial cells. This 1st line of defense can be helped by the production of antibodies that bind to the virus and block adhesion. Against which flu virus molecule would be the most useful antibody response in the respiratory tract?

hemagglutinin spike protein Surface protein often used to attach Surface adherent of virus Allows it to attach to host cell, signals invasion/penetration When you hear spike, think virus

Host phagocytes are useful against all the following forms of a microbial pathogen except: influenza viruses multiplying within the cytosol of a respiratory epithelial cell B Staphylococcus bacteria multiplying in tissue spaces within an infected skin wound C yeast cells multiplying on the mucosal surface of the vaginal tract D measles viruses circulating in blood and searching for new host cells to infect E Salmonella bacteria spreading from the digestive tract into lymphatic circulation

influenza viruses multiplying within the cytosol of a respiratory epithelial cell

Four types of receptor-ligand interactions are important for immune system function:

• PAMPs and PRRs • MHC and antigen presentation • Antigen receptors • Cytokine receptors

If both produce similar immunity, why is vaccination for protection against smallpox preferred over variolation?

-Variolation is more dangerous and unpredictable. Variolation was the first method used to immunize people, using variola minor instead of variola major, and it is dependent on infected hosts as a source and it uses a live strain of the smallpox virus. It worked by taking fluid from pustules and inserting it into the skin of a healthy individual in the hopes that a more mild reaction would take place. The patient would still develop pustules and symptoms of small pox, but when (or if) the symptoms would subside, the patient had immunity. This can lead to moral conflicts, as demonstrated by the disturbing trend of exploited orphans being used as carriers of smallpox for its propagation and transport. Vaccination, on the other hand, is inoculation against smallpox using the related, but less dangerous, cowpox virus. No live smallpox strains are used, but the patient still gains immunity. Vaccines are also preferred over variolation because vaccines do not need to be administered to every person. For example, once enough people were made immune to smallpox, it created herd immunity.

Three lines of defense

1st LINE Innate Barrier Immunity 2nd line Innate Cellular Immunity 3rd line Adaptive Immunity The three lines of host defense occupy two branches of the immune system - innate immunity and adaptive immunity. Innate immunity (first and second lines of defense) -host is born with these defenses in place and they remain ever present (the term innate is defined as inborn, intrinsic, or inherent). Response time against threats is rapid, but the mechanisms of innate immunity are non-specific, and generally, do not change over time. Innate immunity can be further divided into surface defenses (first line) and systemic defenses (second line).

Match the host component to its line of defense: Lymphocytes Phagocytes Antibodies Epidermis

3rd line 2nd line 3rd line 1st line

Mutation of a surface antigen of a microbe is most likely to interfere with which aspect of host defense?

3rd line: Adaptive immunity

Which line of defense is stimulated by vaccination to create immunologic memory, which provides long-term active immunity against infection?

3rd line: adaptive immunity

Which statement about bacterial lipopolysaccharide (LPS) is true? (choose all correct answers) LPS is an antigen B LPS is a PRR C LPS is a PAMP D LPS is a TLR E LPS is a cytokine

A and C LPS is an antigen and PAMPs LPS is molecule found in all gram negative bacteria There can be different forms of LPS PAMPs can also be antigens TLRs are receptors

Helminths

multicellular eukaryotic pathogens that cause malaria have a complex life cycle

Viruses

Acellular infectious particles use spike proteins to attach to and infect host cells Most unique, only one to not be cellular Has to be intracellular - Obligate intracellular pathogens (host required for reproduction) Extracellular defenses can still be used, because before it attaches to the cell, it is extracellular (also when it exits cell) HIV to AIDS, VZV to chicken pox to shingles Lipid envelope with glycoprotein spikes budding from host cell membrane -PAMPs: DNA, RNA, Glycoproteins -Antigens: Capsid (protective protein coating), Spike proteins -Nucleic acid genome: Composed of nucleic acids (DNA or RNA) (high mutation rate) Completely dependent upon invasion of a living host cell for their reproduction When viruses enter the body or are in the process of spreading from cell to cell, they are vulnerable to responses (e.g. phagocytosis) that target extracellular pathogens. But when a virus invades a host cell, these immune responses can no longer reach the hiding virus. Similar to the response against parasites, cytotoxic cells are recruited, not to attack the virus directly, but rather to target the infected host cell. The host cell is sacrificed so that the virus cannot multiply and spread to other cells. The immune system is informed of the presence of viruses by their PAMPs (e.g. viral DNA, ssRNA, dsRNA or glycoproteins). This, in turn, directs intracellular responses to target the viral antigens (e.g. capsid and spike proteins), so that cytotoxic cells can recognize which host cells are infected and target them for destruction.

Third Line of Defense

Adaptive- not born with it Most effective Specific recognition and elimination Memory response Downside: First time you are exposed, its sssslllllooooowwww Based on lymphocytes: Tailored response to specific microbes Specific response=highly effective, but will not help you against other microbes Immune protein= antibody (Y shaped molecule) - Specifically recognizes and attaches to surface proteins (antigens) on the surface of microorganisms. Antigens= molecules that can be recognized (Tagged by antibodies, that's how phagocytes know what to get rid of) Don't produce this response until you have already been exposed If microbes escape innate cellular responses, then adaptive immunity will be activated. This third line of defense is named because of its ability to change, or adapt, according to each infection it faces. Although the initial response to a new invader is delayed, it compensates with highly specific targeting of each threat. Once introduced to a microbe for the first time, adaptive immunity not only recognizes it, but it also retains memory of the encounter. It uses this information to fight the microbe more efficiently during future encounters. -Can get better with age and exposures. -Can be activated by vaccination to provide immunologic memory and long-term protection against diseases. Adaptive responses are mediated by white blood cells called lymphocytes, which express receptors that specifically recognize antigens of each invading microbe. These cells can distinguish between measles virus and polio virus, and only produce a response to the current threat. Requires assistance from cells and molecules of innate immunity. Once activated, adaptive immune responses enhance the mechanisms of innate immunity. For example, a B lymphocyte is activated by invasion of a virus. It produces antibodies (immune proteins) that specifically attach to viral surface antigens and "tag" the virus. Tagging neutralizes the virus, so it cannot invade host cells and helps phagocytes (innate cells) recognize viruses for elimination. While humans are born with B cells, they do not produce antibodies until they are challenged with foreign agents, like microbes. Once they learn to produce these antibodies, they can do so more easily during subsequent exposures to the same microbe.

Linking innate and adaptive immune responses

Antigen presenting cell (APC) MHC + antigen (Combine piece of microbe/antigen with MHC, then display on surface- way of presenting antigens to adaptive immune cells to get them activated) T Lymphocytes (CD4 or CD8) -T-cell receptor (TCR) -CD3 -T-cells need antigen to be presented to them -Produces chemical signals to further activate B-cell -B-Cell receptor -IG alpha and IG beta -Antigens can just be floating around, doesn't;t need to be presented -Third line of defense -Turns into plasma cell, releases antibodies to tag antigens *Antigen is a ligand

All the following molecules are involved in activation of the helper T cell response by antigen presentation except: A. B cell receptor B. T cell receptor C. MHC II D. CD4 co-receptor E. Exogenous antigen

B cell receptor

B-cell receptor

B cells express B-cell receptors (BCR) that are comprised of four polypeptide chains of two different types - heavy chain and light chain. Each B cell has a single antigen-binding specificity, i.e. its BCRs recognize one antigen only. BCR has two antigen-binding sites, each comprised of a heavy chain and a light chain. The antigen-binding site interacts with an epitope of a native antigen (e.g. viral spike protein or bacterial toxin). The two heavy chains are anchored in the cytoplasmic membrane and stabilized by two proteins, called Igα and Igβ. These two membrane proteins have large cytoplasmic domains with ITAMs involved in intracellular signaling when antigen binds the BCR. B cell- antigen binds to b -cell receptor B cell activation leads to antibody synthesis Eventually we get cell that produces antibodies

Unicellular prokaryotic pathogens have a peptidoglycan cell wall:

Bacteria

Peptidoglycan

Bacteria Stuff the cell wall in bacteria is made of Example of a PAMP Peptidoglycan is uniquely produced by bacteria, serves as a good identifying molecule during infection. Immune cells are programmed to see PAMPs as a threat. Therefore, when peptidoglycan is recognized by immune cells, this information can be used to stimulate the appropriate response against bacterial infection. Bacterial PAMPs, like peptidoglycan, help stimulate inflammation and the recruitment of phagocytes to eat pathogenic bacteria, which is useful against this extracellular pathogen.

Which two types of microbe produce the most similar host immune response?

Bacteria and fungi

Why are the typical defenses against bacteria and fungi not well suited to the elimination of helminths?

Bacteria and fungi are unicellular organisms that defended against using phagocytes. Helminths, also known as parasitic worms, are multicellular animals that are sometimes able to hide and evade host defenses. They are much larger than bacteria and yeasts, so immune mechanisms like phagocytosis are not useful in combatting them. Specialized responses, like the use of PAMPs, have evolved to deal with parasite infections.