Human Body's Defenses

1st Line of Defense

• Physical barriers limit microbe attachment or replication in tissues
• Skin, mucus membranes, and fluids are physical barriers
• Chemical barriers destroy microbes
• Sebum, earwax, gastric juice, and urine are chemical barriers

Physical Barriers

• Skin is the first line of defense
• The epidermis has many layers of tightly packed dead cells that contain keratin
• Shedding the top layer removes microbes
• The skin is dry, salty, and acidic for competative exclusion
• Mucous membranes secrete mucus, a thick glycoprotein, for protection
• Bodily fluids such as earwax and urine, along with vomiting, defecation, and diarrhea, protect the body

Chemical Barriers

• Sebum inhibits bacteria, viruses, and fungi on the skin via antimicrobial peptides
• The skin surface has a pH of 3-5
• Perspiration cools the skin and contains lysozyme
• Lysozyme is an enzyme that breaks down peptidoglycan and is also found in tears
• Earwax is a physical barrier and lowers the pH of the ear canal
• Saliva starts breaking down starches with amylase
• Saliva also has lysozyme, uric acid, and IgA, giving it a slightly acidic pH
• Gastric juice has a pH range of 1-3
• Vaginal secretions contains mucus to inhibit microbial attachment
• L. acidophilus in vaginal secretions creates an acidic pH range that inhibits growth
• Urine contains lysozyme and is acidic, with a pH of 6

Cells of the Immune System

• Leukocytes, or white blood cells, are produced with diversity and fight infection
• Innate white blood cells are for inflammation and killing parasites
• Basophils, mast cells, and eosinophils are part of the innate immune system
• Neutrophils, monocytes/macrophages, dendritic cells, and NK cells are part of the innate/both immune system
• Lymphocytes (T and B cells) are adaptive

White Blood Cells and Hematopoiesis

• During infection, blood cells and platelets are produced through Hematopoiesis
• Production of more immune cells is stimulated by hematopoietic cytokines
• All cells are produced in the bone marrow from pluripotent stem cells
• Platelets, RBC, and innate immune cells stem from myeloid
• T cells, B cells, and NK cells stem from lymphoid

Basophils and Mast Cells

• Basophils patrol for foreign bodies
• When a microbe is recognized, histamine is secreted to recruit more immune cells
• Histamine causes inflammation to allow immune cells to reach the infection site
• Mast cells are in tissues looking for foreign bodies
• Very similar to basophils, but they stay in tissues instead of patrolling
• Located under the skin and in the mucous membrane, histamine and other chemicals are released to induce inflammation

Eosinophils, Neutrophils, and Monocytes

• Eosinophils target parasitic infections and play a role in allergic reactions
• Peroxide ions are discharged and attached to parasites to destroy them
• Increased in number due to allergies
• Neutrophils are the most numerous
• They are the first to be recruited to the infection site
• Bacteria and foreign bodies can be destroyed through phagocytosis
• Use lysosomes, bacterial toxins are destroyed in body fluids
• Neutrophils only live a few days
• Monocytes/macrophages are in tissues
• Internalize and kill microbes, old ells, and foreign bodies through phagocytosis
• Known as macrophages in tissues
• Kill variety of pathogens with better enzymes
• Present pieces of dead microbes on their surface for antigen presentation
• Fixed macrophages reside in tissues and organs
• Free macrophages roam tissues to gather at infection sites

Dendritic Cells and Natural Killers

• Dendritic cells phagocytize microbes
• Surface presentation of pieces of dead microbes activates the adaptive immune system
• Natural killer (NK) cells primarily kill virally infected and cancerous cells/bacteria
• NK cells recognize cells that do not display major histocompatibility complex I (MHC1) proteins
• If cells lack MHC 1 and display a stress protein, NK cells activate to destroy target cancerous or infected cell
• Granzyme is an enzyme that induces programmed cell death (apoptosis)
• Perforin creates holes in (perforates) the target membrane
• T cells will kill the infected cell if it displays MHC 1

Infection Stimulation

• A patient is exposed, through the skin, mucous membrane, and parenteral route, to a pathogen
• Mast cells and fixed macrophages are the first to respond, then basophils and eosinophils
• Cytokines are released to recruit the rest of the immune system through inflammation and fever
• Fixed macrophages respond first to phagocytosis, then neutrophils (major phagocytic cells), free macrophages, and dendritic cells
• Complement is induced; a cell-free system to kill and target microbes
• Interferon and dendritic cells are also used, type of cytokine, to combat viruses

Pathogens and Microbial Invasion

• Pathogen-associated molecular patterns (PAMP)
• Pathogens have structures and molecules not found in or on host cells
• Pattern recognition receptors
• Leukocytes have membrane bound or soluble proteins that recognize PAMPs
• TLRs and PAMPs/ligand are examples
• PAMPs/Ligands recognize specific microbes instead of human cells
• Microbial invasion is when pathogens enter cells/tissues, and spread, and cause multiply and cause disease
• Tissue damage causes cytokine release and triggers recruitment of phagocytes

Cytokine Release and Inflammation

• Tissue damage and cytokine release
• Resident leukocytes and damaged cells release cytokines for communication
• Cytokines draw macrophages and neutrophils as they leave circulation (extravasation/diapedesis)
• Inflammation is the nonspecific reaction to noxious stimuli
• Redness, swelling, pain, and heat are localized
• Proteins draw white blood cells to inflammation site, dilating blood vessels and slowing the speed
• Diapedesis moves white blood cells across the blood vessel
• Effective inflammatory response isolates and limits tissue damage, destroys cells and pathogens

Fever

• Cytokines cause the host's body temperature to rise
• Fever-causing cytokines are pyrogens generated by heat
• A fever helps increase circulation rate and causes leukocytes to get to the infection site
• Pathogens cannot tolerate the increasing temperature
• Transferrin is increased to sequester iron and limit pathogen growth
• Bacteria produce siderophores to combat this system

The Process of Phagocytosis

• Microorganisms are attracted by Chemotaxis, using chemical signals (cytokines)
• Phagocyte attaches to microorganism during Adherence
• Microorganism is internalized through Ingestion
• Phagosome creation occurs as pH drops
• Phagolysosome is created
• Digestion occurs
• Residual body of indigestible material forms
• Waste material is discharged

Microbes that Inhibit Phagocytosis

• Pathogens can survive the pagolysosome
• Mycobacteria tuberculosis is able to live and divide within
• Bacteria produces leukocidins, which kill white blood cells such as Streptococcus pyogenes
• The phagocyte has difficulty engulfing some pathogens due to their capsule

Opsonization and Induce Complement

• During Opsonization, an antibody attaches to the bacteria when the phagocyte is grabbed
• Promotes bacteria phagocytosis
• the complement system is a set of circulating, sequentially activated proteins that respond to pathogens

Activated Complement System

• The complement system is activated by:
• Classical pathway: antibody-dependent
• Lectin pathway: antibody-independent
• Alternative pathway: antibody-independent

Classical and Lectin Pathways

• C1 binds to antibodies on the microbe and cleaves C4 and C2 in the Classical Pathway
• Lectins recognize carbohydrates on pathogen surface, paired with proteases to cleave C4/C2 (MASP1/MASP2) in the Lectin Pathway
• C4 and C2 cleave to form convertase to creates C3 in C3a and C3b
• Needed to activate the complement system

Alternative Pathway

• Factors B, D, and P recognize and bind to the microbe surface
• Factor D cleaves Factor B to allow C3b binding, producing C3bBb
• C3bBb is anchored with the help of Factor P
• It converst C3 as well as C5 downstream, cleaving additional C3 in the complement system
• The complement system is activated once C3 is cleaved

Cytolysis and Opsonization

• C3b cleaves C5, resulting in C’activation (C6, C7, C8, C9) and Membrane Attack Complex pore in membrane
• Opsonization cleaves C3b for phagocytosis efficiency during alternative pathway activation
• Complement Receptor 1 recognizes C3b and phagocytoses the pathogen on all phagocyte membranes

Inflammation and Viral Combat

• C3b cleaves C5 and the cleaved C3a/ C5a bind mast cells/basophils via receptors
• The cells release additional histamine to act as an inflammatory mediator
• C3a and C5a help with chemotaxis
• Viral Combating occurs with interferons stress response to NK/T cells when the virus hides in a normal cell
• Interferons are small cytokine proteins produced by virally infected cells

Interferons, Stress, and Immunity

• Stress works with the interferon response and inhibits translation within cell
• Cells suppress MHC I, and are subsequently killed by NK cells
• T cells kill cells that expresses MHC I with a viral antigen

Interferons, Stress Response, and Adaptive Immunity

• Interferons are released, upon recognizing a viral infection, to warn other cells
• Cells also release interferon-stimulated genes (ISGs)
• ISGs are used to combat viral infections
• In the stress response, eIF2α is phosphorylated
• Necessary during translation to scan for the AUG codon
• Some viruses use eIF2α-independant modes to bypass

Adaptive Immune Response and Humoral Immunity

• Adaptive Immune response occurs after the innate immune response
• Has two-tiered response of humoral versus cellular
• Humoral immunity via B cells recognize antigens of nonself cells and destroys invaders outside of the cell
• Cellular immunity T cells target antigens, and produce cytokines to attack through infection and memory cells

B Cells

• B cells originate and mature in bone marrow
• and mature into plasma or memory cells
• Plasma cells fight infection by producing antibodies attatching to bacteria or viruses
• Antibodies produce Agllutination, enhances Phagocytosis, activates the complement system, and/or Neturalization
• Antibodies can be Ab dependent cell-mediated cytotoxic
• Memory cells differentiate into many plasma cells during subsequent infections

Cellular Immunity

• Cellular immunity is carried out by T cells
• Originate in bone marrow but mature in the thymus
• 98% of these cells are killed in the thymus
• Attack foreign and infected cells directly, including organ transplants

T Cell Types

• Foreign cells are destroyed via membrane popping
• The process of attack include cells that have become infected with a virus
• The main types of T calls are Helpter T cells (CD4+) in which the
• Release cytokines to call on reinforcements
• Memory T cells, Helper T cells, Cytotoxic T cells, and Regulatory T cells are produced when activated
• Cytotoxic (Killer) T cells (CD8+) kill infected host cells and bacteria cells
  • Using granzymes and pore forming perforin
  • Look for antigens presented on MHC 1 infected host cell
• Regulatory/Suppressor T cells (CD4+) stop immune responses and inhibit food allergies
• Memory T cells (CD4+ or CD8+) are long lived and help speed up later infection processes

Lymphocytes

• Leukocytes are all white blood cells
• Lymphocytes are all immune cells in the lymph nodes
• The primary type is T cells and B cells

Proteins, Antigens, and Immunity

• Each T and B cell has a unique receptor to recognize an antigen- usually a foreign protein or microbe
  • T cell receptors are TCRs (T cell receptor)
  • B cell receptors are BCRs (B cell receptor)
• Antigens are proteins or polysaccharides that stimulate immune systems
• Antigens also react with antibody molecules.
• Epitopes or antigentic determinants are the fragments of an antigens.
  • 5-15 residues or 3-4 sugar residues

Infectious and Noninfectious Materials as Antigens

• The types of infectious disease can act as antigens include microbial toxins
• Noninfectious materials are recognized as non-self by the body and act as antigens:
  • allergens: dander, pollen, dust, hair, bee venom, foods, drugs, etc.
  • foreign tissues/cells from transplants/transfusions
  • cells the body fails to recognize as "normal self"

Antigen-Presenting Cells

• Antigen-Presenting cells (APCs) engulf, process and present antigens
• Use both MHC 1 and MHC 2 receptors to communicate
• Key APCs: macrophages, dendritic, and B cells
• Dendritic cells are the biggest players and main focus
• Normal cells:
  • Use MHC 1 to express antigens found inside its cytoplasm.
  • Load fragments onto MHC 1 via proteasomes and complexes

MHC Types and functions

• MHC 1 -Found on all nucleated cells - Are in vesicle and in the ER - Signal that the cell is Infected - CD8+ cytotoxic or killer T cell types.
• MHC 2
  • Only on some immune cells
  • Are in vesicle
  • Signal that the cell needs Help
  • The T cell call is: Cd4+ (Helper) T cells -T helper cells activate B and other T Cells that need help.
• Helpful math tip* Both responses always multiply to equal 8!! - CD4+ x MCH 2 = 8
• This means: if it CD8+ then its connected to MCH 1. CD8+ c MCH 1 = 8

Priming Antigen recognition

• In how T + cells learn antigen - the APC phagocytizes.
  • The microbe's proteins are chopped up into fragments
  • The chopped up antigens are then are expressed on MHC 1 + 2 proteins.
• The DC migrates allow presentation to T cells inside lymph nodes to make the connection
• Typically a connection to naive CD4+ T cells - Th1- induces cell-mediated immunity, -Th2 - induce humoral immunity Th17– induce inflammatory responses, -Treg- induce tolerance.
  • Then the Activated CD4+ Then activates CD8+ cytotoxic killer or B cells,

Immune System and Antigenic Activation

• CD8+ CTLs require communication with APC - while on the other hand B can preform phagocytosis
• Only when they Antigenic Activation from MCH can slow Infection!

Clonal Selection and Expansion

• In order to be activated by Ag, T and B cells need a receptor that recognizes it
• Once the T or B cell recognzes Ag it can become clonally exapaned

Immune Cells

• There are three ways generate limitless # of the immune cells
• somatic Recombination
• Coding for Joint diversity
• Random change reassortment

Somatic Recombination

• Key concept:: Somatic recombination is how the a limited # of genes do so much
• B cell receptors (BCR) with Heavy and light chains and (TCR)T cell receptors with alpha/beta chain
• BOth have variable variable and constant region that is
• Variable region is made from: V(D)J Recombination

Recombination

• RAG1/2 enzyme cleaves so only one variable (V), Diversity (D) and Joining (J)region remains.
• The Diversity region only present in alpha chains !!
• V(D)J also allow to create diversity in general!!

Last key points Receptor creation

• During V(D)J terminal deoxynucleotidyl transferase (TdT) protein adds nucleotides at fragements Last way for receptors to be varied is how they differ chain combos
• Alpha and beta (heavy with light chain) create a variance from there alone
• B cells can in theory combine to create more diversity!
• In thero B cell receptor ability comes at around 2-3 million!

Somatic Mutation

There are 4 ways to create somatic mutation

• Just accounting and random chains, may increase total variance to the to equal 10^16!!
• This means we are able recognize more antigens in immune response!

Cytokines and more adaptive responses

• Release of cytokines are signal help signal and recruit others Here the breakdown! - Interleukins for communication amongst Leukocytes

      -Chemokines that assist the migration of others 
  

  -TNF - Tumor Necrosis Factor Cytokines involved In tumors and inflammation that come for them

• hematopoietic Cytokines that regulate WBC recruitment and maturation -Cytokine storms: when feedback loops get supercharged, resulting in cytokine overproduction!! . - Examples is what happens in COVID-19 patients

Viral defense and Antibodies

• DC expresses via MCH II and helps aid activation of of T killer cells (via MHC I) - T killer cells than mobilizer and attack In the infected
• Cells degrade intracellular proteins into small pieces that display on MCH
  • these fragments are typically self cells- T killer cells won't recognize and react to them because there there already!
    • When a viruses are present the killer cells will react to the viruses,
  • Killing is carried out with perforins that Poke and Granzymes that lead to cell breakdown!
  • The macrophage comes in to fix the place once done! - Viral protections also start once done! Antibody release is when the B cells are clonally selected- helping is expansion

Antibodies and their Functions

• When the cloned cells differentiate into plasma they create antibodies + memory clones) - Immunoglobulins
• Antibodies are created by immune system in response to infection
• Are proteins that come in as _ Y shape types!
• types! -
• There able to bind and neutralizing to toxins with viruses.
• Make foreign cells easier to engulfed via phagocytosis (opsonization) - are found in the blood, milk, secretions. -All share structural traits + function!

The 5 Antibody Classes (IgG, etc)

• The 5 Major Antibody Classes IgG,IgA,IgM,IgE,IgD. are all based on amino acids Heavy chain sequences:
• IgG is the most abundant that is typically circulating.
  • Is made of two polypeptide chains
  • Are able to produce Billions of different Antigen targeting regions

Memory and Time

Memory cell creation timeline!

• Early Exposures: Will have the fastest responses
  • Initial is a Short run, week long response
    • Produces mostly IgM
• Later/Re-exposures: Are quicker
  • Does not always need T cell help
• Antibodies can produced 10 100 more times!

Antibodies Switching

• Switches the constants type to the antibody!
• Dependent on what The cytokine present will splice other constant regions

Maturation

• The switch occur downstream and can affect future responses. This is all down to isotype switches help for B Cell The chain can only be is IgG/IgAn

• There better as somatic hypermutation

Breakdown of Immune System Failure!

• When does does the immune system fail
• Hypersensitivity -This is a Inappropriate immune response = damage for host -Includes autoimmunity and alergies. 4 -There also breakdown of what happens when Hypersensitivity occurs.
• breakdown is based off what antigens and effector mechanisms lead to what is happening.

Hypersensitivity Type Chart

• Type 1 Response: This process is down to release of products from MAST cells

  • Reactions occur when exposures
  • Can be life threaten / mild
  • 20 % pop allergen exposure.

• Type 2 + 3 Response: is for IgG and result in damage to hosts within day-28

• -Type II is when is when IgG antigens mind to an antigen to one's cell

• Type |||: bind to more soluble antigen

• Rheumatoid arthritis is what occurs!

• type 4:T killer comes and begins the cell attack on host by inflammation. immune systems mistakes protein and destroys!

• Results in microbial diseases

• Microbes often attach! Poison ivy also simulates inflammation with hypersensitivity

Immunodeficiencies: Adaptive, Genetic, and Aquired

• Immune system failure starts down to Active adaptive immunity Animals -human - that are deficient cells result in infections Serious combined SCID which congenital deficiency
• AIDs causes is due to CD4 attacks

Vaccinology and Vaccines

Activation and Immune System

Is based on how

• it Activates that leads to immune system
• Vaccines are Important- eradicated and reduce infection
• All products run through rigorous research
• Vaccines - require boosters

There 2 types

Immunity Types

• Natural no intervention needed. - Active: is via exposure+ passive is transfer from parents !
  • IgG pass thru to infant

Artificial :

• Actie is via vaccination- help with a response
• Passive- is antibodies
• *This leads to Passive response ** NO MEMORY

Variolations

• Start via lesson
• Old practice in late. Asia! First recorded
  • variolation to help reduce cases
• the broken virus leads to death

Vaccinations

Vario major: 30% Varilo minor leads

• Vaccinations- does not resolve the death cases but does not give the virus that the body is being immune too! _This come downs with Jenner

Jenner

• Knew that Milk maid did not get smallpox so it was recorded

• Vaccino can neutralize infection! -The envelop is 64 % same

Vaccine type- whoel are antigen -

• attenuation* 3rd response - attenuated small issues in patient

More complex types of vaccines

• live Attenuate - is to create low virus infection!

Viruses

• Are also low viral generation via passging

  • All also need mutations There are

• Advantages

• Produce a robust responses

• Immune systems work Disadvantages

  • Has a virus reversion
    • Inactivated- Non-infection microbe virus that killed
  • -Exa polio rabies

Vaccine Inactivation

Involves

• Chemicals
• Or heat
  • Lease infect but not to much

The U.S vaccine had little paralysis

• Also, boost
• Disadvantages due the amount with need them -All must be completely inactive and The lab code: The cutters lab code is high

Further Vaccine Subunits

• There is * non and recombinant microbes*
• Microbes proteins will be extracted!

recombinations

Partial genome expression for bacteria protein - -Flu blok is a example

New scarecrows viruses

• Are like * Gardasil* for HPV virus!
• Creates high response via Toxiod

Conjugated: * This what is use when the cell is the sugar +

• The sugar- will cause infection, but the protein antigen helps!

The antigen types are Safe + helps us

• Target more responses

nucleic

There some + vaccine

• Modern is new

The goal is get to the nuke!

Advantage!

• Safety!
• And higher responses

Disadvantage due to the need of protein

Vaccine Enhancement Contradictions

• Some don't know
• Dengue* with will affect

There four

• Herd *Immunity
• 80 % for effects
• Limits fungi with what can be do

antimicrobial

That is the only way kill virus - Umbrella All 3 work in different directions

1: kill the microbes 2: create protection 3: be selective

Properties Antimicrobial

The ability- be reliable The safety- create less harm Easy - administer

• Mechanism of Antibiotics : Three Classes (Cell wall, Nucleic acid protein) -Cell Wall: is a drug, is an allergy
  • Beta Lactam: is ring for protein -Protein target synthesis : ribosome in bacteria

Bacteria and antiviral

• Bacteria is slight differ Sulfa : inhib the production

antivirals

60% virus -limited. Virus : mutate quicker and cause problem

The major are enter

• AZT : Helps the DNA sequence but will create in the host:

the last

N/A - The flu treatment

• The end result is help, that small protein has ability and can target a good type!

Eukaryotic

• The goal is to inhibit synthesis Has antifungus + It kills them
• Antimicrobial*

-Can to be come a superbugs The ability to overcome the drug! -The cell is target has ability to the to pump out

Persist and Short Term Antibiotics

Persist- is that it cant reproduce and has littler effects on cell! Penicillin- discovery year of antibiotics! the Gold age discovery is when there were struggle to work The new is when to work against it.

History

Overuse + misuse help!

• 50 % of prescribe- is misuse with will help the cause =
• The Fda- beginning the testings!

Real test

All can tested for

• The UTI Can to see bacteria

• That need Antibiotics*

• The microbes has resistance- it use often! But, the

• The long term = The antimicrobial is developed- for high the response - Automatic