Lecture 5- Immune System

Components of Innate Immunity

1. Barrier defenses (mucus)- we have lysizine in secretion which hydrolyzes the glycochains in the peptidoglycan 2. Chemical defenses (antimicrobial peptides) 3. Cellular defenses (phagocytosis)- phagocyte- provides connection with other type of response where components of the cells that were phagocyted are exposed at surface of phagocytic cell to trigger the adaptive response. These molecules that are displayed-- this is when specific interaction occurs.

Macrophage

A large phagocytic cell** found in stationary form in the tissues or as a mobile white blood cell, especially at sites of infection.

Pathogen

Agents that cause disease (usually microbes or toxins)

Adaptive (Acquired) Immunity

(longer, more specific)- species specific; more complicated process. Once the recognition has been made, the ability to recognize is kept for a very long time and will be much faster during a re-encounter. Develops after exposure to microbes or toxins. Has a large repertoire of receptors. Rather than recognizing LPS or peptidoglycan, the cells recognize antigens Characteristics: 1. Diversity of lymphocytes and receptors 2. Self-tolerance (lack of reactivity against own molecules) 3. B and T cells proliferate after activation 4. Immunological Memory

Activation of Complement

Y-shaped molecules recruit complement proteins that then there will be series of proteolytic reactions in which these complement proteins make smaller fragments that have different roles. One is a pore which leads to lysis of cell that exposes antigen

Proliferation of B or T Cells

binding to an antigen initiates activation of the lymphocyte. once activated, a b or t cell undergoes multiple cell divisions, proliferation is called clonal selection. Two types of B clones are produced 1. Effector cells- (plasma cells) act immediately (short-lived) act on current infection and then just disappear 2. Memory cells- for later encounters with the same antigen (long-lived) circulate in body so they can be efficiently and rapidly activated whenever the same antigen reoccurs in the body

Inflammatory Response

cytokines are both in innate immunity and adaptive immunity. In the innate immunity, they're the principle signal molecules of the inflammatory response- response that started when there's recognition of infection

Antigen

foreign molecules- much more diverse group than in innate immunity. Recognized by antigen receptors found on lymphocytes. Antigen receptors recognize epitope

Self-Tolerance

maturation process= test for self-reactivity in bone marrow or thymus Lymphocytes that react against host molecules are destroyed by programmed cell death (apoptosis) or rendered nonfunctional

Pyrogens

molecules released by macrophages causing elevation in body temperature

Allergies

one symptoms is increase release of hystomine ex. hayfever- take medication that is anti-histamic because they prevent release of histamin

B and T Cell Diversity

rearrangement of DNA--> increases diversity of receptor specificity to large extent

Epitope

small part of an antigen that binds to receptor

Complement System

some are signaling molecules. Attract even more cells or molecules involved in the immune response to site of infection. Others are required for pure formation.

Deficiencies of Immune System

1. Allergies- exaggerated/ hypersensitive responses to antigens 2. Autoimmune diseases- self-directed; distinction between self and non-self doesn't work well ex. MS 3. Immunodeficiency diseases- diminished immune response ex. AIDS targets helper T-Cells

Two Branches of Adaptive Immunity

1. Humoral- antibodies 2. Cell-mediated- cytotoxic T cells Both responses are orchestrated by the helper T-cells which makes cytokines that are recognized by B cells in humoral immunity and T-cells in cell-mediated

Bacterial Strategies Against Complement

1. Use of capsules. Capsule protects against innate immunity because it hides LPS or peptidoglycan. capsule is very slimy- not easily phagocyted. 2. Production of surface components inhibiting formation of MACs. Prevents the binding of antigen receptor or immunoglobulin to the surface because the capsules are very simple in composition and don't offer a lot of antigens to be recognized.

TLRs Signaling Cascade

Activation of TLRs triggers a signaling cascade Signaling cascade leads to activation of specific transcription factors. These factors move to nucleus and turn on the genes involved in the secretions of cytokine and interferons. Interferons are important with dealing with viruses.

Helper T Cells

Antigen receptors bind to the class II MHC molecules that are found mostly on phgagocytic cells like macrophages, dendritic cells, and some B cells. They also lead to cytokine production 1. Activation of B Cells 2. They lead to higher production of antibodies in cell mediated response which leads to activation of cytotoxic T cells

Natural Killer Cell

B and T lymphocites do the recognizing but the killer cells can't recogtnize. They are important in inhibiting spread * of cancer cells, virally infected cells, etc. Recognize them in slightly different way. More typical of innate immunity but play roles in both Kill cells by releasing chemicals that will trigger the death of the cells that recieve those compounds by apoptosis

Neutralization

Binds to toxins to prevent entry into host cells Binds to viral surface proteins to prevent interaction with recpetors

Blood/ Tissue Rejection

Blood: red blood cells have carbs on their surface that are specified by different types of genes- O has neither antigen- universal donor. AB- universal recipient Tissue and Organ: Differences in MHC molecules stimulate rejection Chances of successful transplantation increase if donor and recipient MHC tissue types are well matched Immunosuppressive drugs facilitate transplantation

Barrier Defenses

Body fluids- saliva, tears, mucus, sweat Skin- cutaneous barrier Mucous membranes of respiratory, urinary, and reproductive tracts pH of skin and digestive tracts- pH is also a type of defense. In our stomach we have a very low acidic pH and this is a barrier for a lot of organisms. very few bacteria can grow in acidic pH

Opsonin

C3b- derived from complement proteins by proteolysis of C3 and coat the surface of microbes

Antibody Function

Do NOT kill pathogens; they mark them for destruction 1. Neutralization of toxins and viruses 2. Activation of complement system- system complementing the adaptive immunity but also involved in innate immunity 3. Favoring opsonization of microbial cells- more efficient type of phagocytosis If the pathogen is small enough, it might be enough to completely surround it with antibodies and prevent the virus from being able to bind to the receptor of the cell it's using to invade or for toxin to prevent it from being able to reach its destination.

Antigen Receptor

Each individual lymphocyte is specialized to specifically recognize one epitope. Each branch of the Y can recognize the antigen and other branch will recognize the same. Each cell recognizes a different epitope and only able to recognize one epitope. One antigen can have several epitopes that can be recognized by several cells.

Opsonization

Efficient phagocytosis Phagocytosis is slow and inefficient unless phagocytes are triggered by opsonins Phagocytes have receptors for opsonins and IgG Zipper-like interaction favors engulfment Have antibodies that are recognized by receptors to IGG immunoglobulin on surface of phagocytes and receptors for molecule of complement- C3b which is sometimes directly bound to atibody and sometimes directly to the surface. Promote zipper like interaction which favors phagocytosis. So, you have macrophage or neutraphyl that has the receptors for the invariable part of the immunoglobilin, not the one bound to the antigen but the other side of the C3b. Both internalize the pathogen and then the pathogen can be destroyed inside the phagosome

Phagocytosis

Find the bacterium inside a structure that resembles a vesicle and vesicle is called a phagosome because it comes out of the phagocytosis process. Once the phagosome is inside the cell, it will fuse with another vesicle, the lysosome, and the lysososme contains a series of enzymes including lysisime but also protease, etc. anything that can destroy part of the bacterial cell. All the enzymes contribute to the destruction of the pathogen inside the vesicle called the phagolysosomel vesicle because it's a combination of phagosome and lysosome. So, now you have fragment of this pathogen that can be used to be exposed at the surface of the macrophage to trigger the adaptive response. Most of the debris will be excreted and the infection prevented.

Innate Immunity

Immediate, less specific Present before any exposure to pathogens Recognizes some molecules that large classes of pathogens have- surface molecules in bacteria or genomic content of virus that's distinct from DNA of human cells. No memory

Evasion from Innate Immunity

Immune system co-evolves with the pathogen so some pathogens have found ways to exploit the host response to gain access to certain cells/ tissues examples of persistence after phagocytosis 1. listeria monocytogenes- gram pos- can be present on food like cheese. causes listeriosis 2. mycobacterium tuberculosis. causes TB

Systematic Inflammatory Response

Infections can be local but they can also progress and become systematic and sometimes the body response can be so strong and overwhelming- septic shock fever is a systemic response- triggered by pyrogens

Moving in Cytoplasm after Evasion

It can move inside the cytoplasm because it will exploit the presence of actin, the host's cytoskeleton, to propel itself first isnide the host's cytoplasm but even to from one cell to a neighboring cell Bacterial protein acts as an anchor for the host's actin ad triggers the polymerization of actin and this happens only at one pole of the cell

Immunological Memory

Long-term protection against diseases Primary immune response- 1st exposure to an antigen Secondary immune response- faster, more efficient Acquired by prior infection or vaccination Vaccines work because of immunological memory. Vaccine stimulates the immune response-- > production of T and B cells. when there's an encounter of a more pathogenic form of these, it can be eliminated because there's memory against it Diagram: 1st encounter with antigen leads to slow building of adaptive response. Need to wait about a week. After 7 days you start production of antibodies and then they go away. Re-expose and response is very rapid and in bigger numbers. If yiou change the exposure and have a different antigen, then you have the same pattern for the beginning. Adaptive response is the slowest response unless it's being re-exposed, then it's very rapid.

Human Lymphatic System

Lymphatic system is similar to blood except it doesn't contain the oxygen carrying cells- the red blood cell. Only has white blood cells. Cells accumulate in lymph nodes and when you see symptoms of swelling, that's response to infection- lymph nodes become larger

Local Response to Infection

Macrophages recognize presence of pathogen because the macrophages have TLR on their surface. Once they're recognized, there will be phagocytosis where they import molecules inside them and destroy them and also send cytokines and by doing that they recruit additional cells to help get rid of bacteria. These 2nd types of cells are called neutrophils- also phagocytic cells.

MHC

Mahor Histocompatability Complex host proteins that display the antigen fragments on the cell surface. T cells can only recognize antigens if they are presented to them by another cell Other cells that present antigen need to be able to present MHC which presents the antigen to the T-cell antigen receptor. Usually it implies that it's a cell that aHs been infected by a virus and then some of the viral particles will be expressed while they're being made by the MHC molecule or the antigen presenting cell is a phagocyte and has been able to phagocyte a pathogenic cell and destroy it into pieces which are then exposed and the T-cell can recognize them. So, the T-cell binds both the antigen fragment and the MHC molecule MHC1- recognized by cytotoxic T cells MHC2- recognized by helper T cells

TLRs Molecular Structure

they're anchored in the membrane. They have an extracellular domain and intracellular domain which propogates the info that the cell has been in contact with pathogen. Extracellular binds to the structure

Cell-Mediated Immune Response

No B Cells. Just Helper T cells (Cytotoxic) which is much more specific than Killer T Cells Cytotoxic T cell produces enzymes and proteins that will destroy the cell that's presenting the antigen. Previous type of response had antigen presentation by specialized cells like macrophages, there it's any type of cell that has been infected that can make the presentation. Most cells can make the class I MHC that's necessary to present the antigen to the cytotoxic T cells. Only specialized cells can make the MHC class 2 to activate the helper T-cells. So imagine the cell is infected y virus. It makes viral particles, some of which are presented by MHC class 1. Cytotoxic T-cells recogtnizes molecules as foreign and makes two types of molecules 1. perphonin 2. pores Leads to lysis of cell and grandzyme enzyme that leads to lysis. So infected cell is killed before virus can spread to other cells. Presence of MHC has consequences for tissue organ transplants. From one person to another, the genes for MHC can vary. If they're not compatible, you can't donate to that person.

TB

Not all carriers will develop the disease because the bacteria reaches a dormant stage inside the body and sometimes never emerges the dormant stage but when there's decrease in immune system efficiency, it does. 2 billion people infected (carriers); 2 million deaths every year. Symptoms: Necrosis of the lungs

Immunoglobulins

Once B cell is activated, you get production of the immunoglobulin in succession Antibodies are immunoglobulins (Ig) 5 classes 1. IgD: Membrane bound (Ag receptor) corresponds to antigen receptor directly on the B cell membrane 2. IgM: Soluble; produced first 3. IgG: Soluble; most abundant; produced second 4 & 5. IgA and IgE: remaining soluble classes All have the same binding specificity

B Cells Antibody Secretion

Once a antigen is recognized as it binds to the receptor, there will be a mechanism to activate the B cell and one goal is to make more B cells and there will also be secretion of more proteins that can bind to antigen. Now these molecules will be soluble. Antibody- still have Y shaped Structure but now travel away from the cell that produced them and bind to surface of the pathogen where they'll be recognized by other molecules including proteins that will favor the process of phagocytosis. So here adaptive and innate system is working together.

Killing of microbes with phagolysosome

Oxidazes are important enzymes for destroying bacteria. They use oxygen to convert it to H2O2 or N2O2 which contribute in destruction of bacteria. So, you can measure the increase in oxygen as a result of phagosytic event- respiratory burst. This can be seen on a macroscopic level because it results in increased blood flow and outpouring of fluids. reddening- erythema- increased blood flow swelling- edema- outpouring of fluids pus- fluid rich in white blood cells (phagocytes are white blood cells), dead pathogens, cell debris heat- fever

Neutrophil

Phagocytic Cell **Found in blood stream. To go from blood stream to infected tissue, they have to move away fro the capillary and what attracts them is the presence of cytokine and they can cross permeability barrier because the mast cell makes histanine which increases the permeability Mast cell--> histamine--> triggers dilatation of blood vessels--> permeability increases--> neutrophil can reach infected tissue.

Immune System Evasion via Lysis of Phagosome

Phagtocytosis of organism works well but once it's in phagosome, before the phagosome fuses with the lysosome, the bacteria expresses a protein called LLO and this induces the formation of holes in the phagosome and the bacteria can escape from the vesicle into the host cytoplasm** and there it will start replicating its DNA.

Innate Immunity Triggers

Recognition of typical microbial signaturs MAMPS= microbe-associated molecular patterns (Peptidoglycan, LPS, flagellin) PAMPS= pathogen-associated molecular patterns Recognized by PRMs (Pattern recognition molecules) aka PRRs (pattern-recognition receptors) Most bacteria have cell wall which can be exposed at surface if gram positive. But if it's gram neg., they have outer membrane and on top of it they have LPS. Both the LPS and peptidoglycan can be recognized as structures that are typical of bacteria and can inform the body that there is a bacteria there. The flagellum (main component- protein flagellin) can also act as a trigger. Cells have receptors that can recognize these types of structures via receptors- TLR (toll-like receptors; usually found on phagocytes; toll is a protein) originally identified in flies in a developmental pathway and then it was realized these cells are also involved in immunity bboth in flies and in mammals. When idenfitied in mammals, they're called toll-like. They recognize peptidoglycan, LPS, and flagellin

Immune System

Role is to recognize and eliminate pathogens Once animals evolved ways to deal with microbes, that caused evolution in the microbes and in some cases to evade the immune response or take advantage of it to infect more efficiently Two types of responses 1. Innate Immunity 2. Adaptive Immunity

Humoral Immune Response

Secretion of antibodies Need to activate the helper T-Cells Need to activate the B cells There's a macrophage that leads to the presentation of the antigen and the activation of the T cell. There it's the B cell that recognizes the antigen that has the MHC class II present one molecule or one antigen from this pathogen to activate the helper T-Cell and production of cytokines. Then, you get the activation of B cells which differentiate into 1. plasma cells - antibody secreting 2. memory B cells

TLRs and PRRs

Some of these receptors recognize molecules that are surface of cells but some of them also recognize internal components of pathogens like DNA/RNA. Difference between human DNA and bacteria DNA is the pattern of methylation. In bacteria, the CG bp are not methylated. Especially if you have double strand RNA genome, this is a structure you can find in only viral genomes, indication it's foreign DNA. so you recognize it and then send signals and molecules that are made in response to binding to TLR and are called cytokines.

2 Stages of TB

Stage 1: Exposure, mild disease host-to-host transmission via respiration and then moves to lungs. Initial infection can be very mild. Sometimes it doesn't go past 1st stage Then, you get immune response. Bacteria is detected by macrophages and phagocyted by macrophages. Other cells are also recruited like neutrophills as well as components of adaptive response so T-cells and B-cells. Form structure referred to as the Granuloma. In 90% of individuals, that's sufficient to contain the disease but the bacteria in the center is still not killed Stage 2: Reactivation, starts proliferation again.

Lymphocytes

T Lymphocytes- mature in the thymus B Lymphocytes- mature in the bone marrow do the recognizing Natural Killer Cell All of these cells originate in the bone marrow but then there's a process where they're selected by processes that are negative and positive selection. One type of selection is to make sure tat these cells are not going to recognize the cells of the host. Need to distinguish between the self and nonself. So, everything recognized as the self will be eliminated and this process occurs in the thymus for T lymphocites. and in bone marrow for B lymphocites

T Cell Antigen Recognition

Their receptors are also made of 2 different chains and coded by different genes. One is the alpha chain and one is the beta chain There's a constant region and a variable region that recognizes antigens.