MCQ 40 set 1

Lecture 01: Module introduction

• The body has three lines of defense: physical and chemical barriers, innate immunity, and acquired immunity.
• Physical and chemical barriers are continuous and prevent pathogen entry.
• Skin blocks pathogens, while mucous membranes protect nose, throat, and intestines.
• Innate immunity is rapid and nonspecific, involving macrophages, NK cells, and dendritic cells.
• Acquired immunity is slow, long-lasting, and highly specific, involving lymphocytes (B cells and T cells).

First Line of Defense - Physical

• Skin acts as a physical barrier but pathogens can bypass through mucous membranes.
• The epidermis consists of tightly packed epithelial cells with an outer layer of dead keratinocytes.
• The dermis contains densely packed immune cells.
• Skin's pH is slightly acidic & has a high concentration of NaCl which makes it unsuitable for microbial growth.
• Skin provides defense through dryness, AMPs, varied temperature, constant shedding, thick layers of dead cells, and immune cells.
• Epithelial lining functions as a barrier and signals the presence of pathogens.
• Mucus and cilia trap bacteria in the respiratory tract.
• Normal microflora competes with pathogens.
• Expulsive reflexes include coughing, sneezing, and vomiting.

First Line of Defense - Chemical

• Chemical barriers include high pH in the stomach and high salt and pH on the skin.
• Saliva contains lysozymes, an enzyme that targets and cleaves peptidoglycan in bacterial cell walls, weakening them.
• Antimicrobial peptides (AMPs) are cationic and hydrophobic, targeting bacteria, viruses, and fungi.
• AMPs target negatively charged bacterial membranes/cell walls, while eukaryotic cells with lower charge are unaffected.
• Psoriasin, produced by keratinocytes, disrupts bacterial membranes and sequesters zinc, inhibiting bacterial growth, and targets Gram-negative bacteria.
• Defensins are positively charged peptides (30-45 amino acids) found, kills bacteria/viruses, and makes pores in membranes.
• Lactoferricin, found in saliva and breast milk, chelates iron and functions as an antimicrobial.
• Lactoferricin is cleaved by enzymes like pepsin/trypsin into the AMP lactoferricin.

Lecture 02: The Innate Immune System

• Phagocytosis is carried out by macrophages (resident in tissues) and neutrophils (recruited from the blood).
• Steps in phagocytosis include chemotaxis, attachment via receptor binding, ingestion and phagosome formation, lysosome fusion, microbial killing and digestion, and waste release.
• Microorganisms are recognized by PAMPS, which are detected by PRRs on macrophages.
• Toll-like receptors (TLRs) are a type of PRR that detect fungi/bacteria.
• TLRs recognize different PAMs: TLR2 (peptidoglycan), TLR4 (LPS), TLR5 (flagellin), TLR7 (ssRNA), TLR9 (dsDNA), and TLR10 (pili).
• Pathogen Associated Molecular Patterns (PAMPS) are molecules associated with pathogens that are not easily mutated.
• PAMPs include nucleic acids (ddRNA and ssRNA in viruses), proteins (flagellin, pilin), lipids (LPS, lipotechoic acid), and carbohydrates (mannan, glucans, peptidoglycan).
• Opsonization enhances phagocytosis by coating pathogens with opsonins like antibodies or complement proteins.
• Opsonization involves tagging pathogens with antibodies, recognition by macrophage Fc receptors, engulfment, and killing.
• Phagocytosis and cell killing involve recognition of PAMPs by PRRs, ingestion and phagosome formation, and phagosome maturation.
• Phagosome maturation involves fusion with early endosomes, acidification via proton pumps, and fusion with lysosomes containing hydrolytic enzymes and ROS.
• Microbial killing and digestion occur within the phagolysosome, followed by debris clearance.
• Macrophages kill bacteria through acidification, ROS species, AMPs, enzymes, nutrient removal, and cell signaling.
• Upon binding, TLRs combine, and the TIR domain signals the cell to express immune genes, ending on NF-kB.
• NF-kB promotes AMP production, enhances phagocyte capacity, induces cytokine production, controlling mediators to amplify inflammatory response.

Lecture 03: The Inflammatory Response

• The inflammatory response is a cascade at the site of infection, characterized by redness/edema, swelling, pain, and heat.
• The acute inflammatory response is short-term, while the chronic response is long-term and related to cell damage.
• Key cells involved include neutrophils, macrophages, dendritic cells, and mast cells.
• Neutrophils are the most abundant and circulate in the blood.
• Macrophages are resident cells that encounter microbes first and are found in external barriers.
• Dendritic cells reside in tissues, sense danger, and release cytokines.
• Mast cells reside in skin and mucosal tissues and release histamine and cytokines, linked to allergic reactions.
• Inflammatory response steps include localized tissue damage/bacterial entry, activation of immune cells via PRR/PAMPS, and cytokine release (TNF, IL-8, IL-1).

Inflammatory Response - Capillary Alteration and Extravasation

• Mast cells release histamine, leading to vasodilation (increased capillary and venule diameters) and increased capillary permeability.
• Vasoactive mediators lead to increased blood volume, slowed blood flow, and inflammatory mediators escaping into blood.
• Fluid and plasma proteins enter tissue, resulting in swelling/edema.
• Extravasation involves the attraction of neutrophils, then monocytes, through several steps.
• Rolling: Endothelial cells are activated to express cell adhesion molecules (selectin), causing leukocytes to weakly attach and roll.
• Activation: Cytokines cause endothelial cells to express ICAMs, and chemokines cause leukocytes to express high-affinity integrin.
• Arrest: Leukocytes stop and strongly adhere to endothelial cells.
• Diapedesis: Leukocytes cross into tissues at junctions of endothelial cells, guided by chemoattractants (chemokines).
• Neutrophils arrive first, followed by monocytes that differentiate into macrophages to provide protection.
• DC/macrophages travel to lymph nodes to present antigens, and clotting occurs.

Inflammatory Mediators: Cytokines

• Leukocytes use cytokines to communicate via cytokine receptors.
• Cytokines change cell adhesiveness, affect enzyme activity, determine cell survival, and alter gene expression.
• Cytokine communication steps: inducing stimulus, cytokine gene activation, cytokine secretion, receptor binding, and biological effect.
• Key cytokine families include IL-1, IL-8, TNF, and Interferons.
• IL-1 is released by macrophages and epithelial cells, binding to IL-1 receptors and is proinflammatory.
• TNF is released by macrophages and neutrophils, binds to TNF receptors and is proinflammatory.
• IL-8 (CXCL8) recruits and activates neutrophils.
• Chemokines are chemoattractants that affect cell mobilization, named by conserved cysteine residues and create concentration gradients attracting cells.
• CC chemokines attract monocytes and macrophages, while CXC chemokines attract neutrophils.

Lecture 04: The Complement System

• The complement system is part of the innate system, found in blood plasma, and produced in the liver.
• The three main roles of complement are killing foreign cells (lysis), tagging foreign material (opsonizing), and proinflammatory signaling/chemoattraction.
• The complement system has three pathways: classical, lectin, and alternative; all pathways converge to form C3 convertase and the MAC.

Complement Pathways

• The classical pathway starts with an antibody.
• During the classical pathway, the C1 complex (C1q, C1r, C1s) activates when C1q binds to the Fc region of antibodies, leading to C1r cleavage of C1s.
• C1s cleaves C4 into C4a and C4b, with C4b attaching to bacteria and binding to C2.
• C1s cleaves C2 into C2a and C2b, and C4b and C2a form the active protease C4bC2A (classical C3 convertase).
• The lectin pathway starts with a lectin, such as mannose-binding lectin (MBL) produced by the liver, which binds to repeating mannose on bacteria and yeast.
• MBL-associated serine proteases (MASP) cleave C2 and C4.
• C4b attaches to the surface and combines with C2a, forming C4bC2a (C3 convertase).
• The alternative pathway does not need an antibody/microbe to start.
• C3 in the blood is hydrolyzed to C3(H2O), which binds to Factor B.
• C3(H2O) bound to Factor B is cleaved by Factor D into Bb and Ba, forming C3(H2O)Bb (initial C3 convertase).
• Factor B binds with C3b, and Factor D cleaves Factor B in the C3bB complex into C3bBb, the C3 convertase which amplifies it

Terminal Complement pathway

• Formation of C5 Convertase
• Derived from the Alternative Pathway:
• C'3 convertase combines additional C'3b molecules to form the C5 convertase [C3bBbC3b]
• From the Lectin Pathway :
• C'3 convertase binds to C3b to form C5 convertase [C4b2aC3b]
• Cleavage of C5 C5 convertase cleaves C5 into C5a and C5b
• C5a: A powerful anaphylatoxin that recruits and activates immune cells.
• C5b: The starting point for MAC assembly.
• C6,7 and 8 recruited to the membrane after C5b assembles. C8 inserts and C9 forming cylindrical pore
• Bacterial death [results of a hole something under pressure] : Forming bores in outer membrane - antimicrobial enzymes enter

cytosol leakage, bacterial lysis and cell wall instability

• Completment - function Tag microbe (opsination) Opsonins - tag for immune system. Both C4b and C3b covalently attached to bacteria to act as ligandfor Complement Receptor . Cleaved A products alert immune system (inflammatory responseLyse invader

Complement System Regulation

• The complement system does not kill our own cells due to receptors that inhibit the complement cascade, like CD59 on mammalian cells.
• CD59 inhibits the C5b-C8 complex and prevents recruitment of C9.
• Patients with terminal complement deficiency suffer from recurrent pathogen infections.

Lecture 05: Antibodies and Adaptive Immunity

• All antibodies are produced in B cells, which originate in the bone marrow.
• Each B-cell clone produces a different antibody, with the IgD class serving as B-cell receptors.
• The variable (V) region differs among antibodies, while the constant region remains constant.

Creating Antibodies

• In differentiation, each B cell makes a different antibody by creating its antibody gene.
• The antibody gene is assembled from segments V+J+D [heavy] and V=J [light] on the chromosomes.
• Heavy chains have variable, joining, and diversity gene segments, creating combinatorial diversity through genetic recombination
• The variable region also has Junctional diversity through random mutations at junctions of the segments, and Somatic hypermutations (continues mutation on an antibody).
• In the lymph nodes, when a B cell's Mass proliferation of B-cell clone binds to an antigen, secreted adaptive immunity antibodies increase antibody affinity.

The Adaptive Immune Response

• Vaccine works due to B cells and T -cell [lymphocytes] controlled memory system.
• The adaptive immune response includes the humoral response (antibodies) and the cell-mediated response.
• Dendritic cells in epithelial tissues are antigen-presenting cells (APCs), with long cytoplasmic projections (dendrites).
• When exposed to microbes and cytokines, DCs activate and migrate to lymph nodes to present antigens.
• The lymphatic system and lymph nodes facilitate antigen presentation to B-cells and T cells, where DCs and macrophages present antigens.
• Pathway:

1. External facing barriers breaches
2. Microbes enters
3. DC engulfs and displays the antigens
4. Antigens presented in lymph nodes [ soluble antigens in the blood stream will go to the spleen]
5. Naive B cells bind to antigen and become activated
6. Native T cells bind to antigen and become activated

• The lymphocytes: B cells (humoral immunity) mature in the bone marrow & T cells (cell mediates immunity) mature in the thymus, both originate from stem cells in bone marrow
• The lymphocytes both have receptros that define each B-cell and T-cell - B-cell receptor: A-B heavy chains & chains are connected through disulide bridge with Antigen binding site are at the variable region & recognize carbs, lipids, DNA and proteins - T-cell receptor: It has only 1 receptor site that recognizes peiptede antigen. & Made from L shaped Alpha chain and beta chain joined tgt by used disulfide bridge

B-cell Activation, selection and secretion

• Steps once antigens are in the lymph:

1. Antigens recognised by naive b via BCR
2. B-cells activate & repicate quicky forming clones
3. Clones differential to plasma or memory cells generating range of antobody classes

• plasma cells in the 5-6 days after infections prod many antibodies with plasma celss remaining in bone marrow producing low level antibodies
• memory b cells produces same membrane bound antibody as activated b providing lifelong immunity & quick second response Vaccine work

Lecture 06: T-cells and B-cell Activation

• T cells mature in the thymus and have a T-cell receptor (TCR) on its surface
• T-cells recognises antigens presented on the surface of infected cells
• Effective against viruses and intracellular pathogens
• Cytotoxic T cells (CD8 / Tc cells) kill cancerous/infected cells.
• Helper T cells (CD4 / Th cells) activate the immune system with cytokines.
• T cells recognize infected cells through antigens presented on MHC molecules
• The body cells presents antigens.
  • MHC1 molecules: are in all neucleated cells, Foreign proteins digested by proteasome are delivered to MHCI
  • MHCII molecules: are in deneritic cells and macroophages, where microbes digested in phagosome are loaded onto MHC II
• MHC1 is recoginsed by T-cells in the infected tissue, where they kill it [granenzyke and perforin]
• MHC1 is presentated, where large amounts of cyotkines are realeased.

Types of T-Cells & Antigen Presentation

• Cytotoxic T cells (CD8 / Tc cells) kill cancerous/infected cells.
• Helper T cells (CD4 / Th cells) activate the immune system with cytokines.
• TCR recognised antigens and presents it in MHC
• Antergen Presentation Summary Overview:
  1. Infection occurs
  2. DC present antigens to T cells in lymph nodes
  3. T cells are then activates & released
  4. Tc cells kill any infected cell
  5. Th cell activates DC/macrophages presenting the antigen
  6. Memory t cells produced Clonal expansion T cells Activated by DC proliferation 1-2 days Effector cells [Th CD4 / Tc CD8] are activate leave lymphoid tissue

T-cell Activation, HIV

• Th cells: Activate B-cells & stimulate & Kill
• If HIV targets CD4 cells there becomes no effective immune sytem
• B-cells and t cells start process after naive start
• the antigen gets sorted based on molecular size - T Cell activate if soluable antigen are detected and B cells will wait to be activated by

Summary

• T cells are important to ensure immune functions
• T cells are involved in the activatoin of B cell
• Lack to memory cells could lead to chronic problems

Lecture 07: The Mucosal Immune Response

• The mucosal immune system (MIS) protects toxic elements that enter via mucous membranes, and is the largest immune organ.
• The MIS consists of a single layer epithelium, is covered by mucous and anti-microbial proteins, and is reinforced by innate and adaptive immunity.
• Microbiota found in the gut, skin, nasal, and oral cavities can be commensal, symbiotic, or pathogenic
• MALT: mucosa-associated lymphoid tissues and GALT: gut-associated lymhoid tissue & NALT: nasopharyngeal-associated lymphoid tissue is cont supply activated memory B and T cells moving to effector sites
• Antigen-specific cells of the G.I tract are incluive of: antibody-producing cells, naive memory B and T cells

MIS Organization and Function

• Homeostasis protection against pathogenic bacteria in the gut, immune cells, nutritional role. Microbes can be detrimental + mechanism evolves.
• Regulation of gut immune homeostasis critical for DC
• DC - sampling antigen, process and present to T cells. DC travels to peyes patches to present T cells and stimulate their differentiation to Tregs

Antigen Presentation Regulation

• Tolerance via is via deletion of auto reactive T cells, Immune- regulators, microbai sensing, speficifc adaptive response, linking
• Treg WBC controle - system immune excess attacks by stopping other T cells Early stages of IBD immune reposne/ gut inflammation can lead to broken barriers and resident immune cells

Gut organization

• Villi helps nutrient by creating pop of immune cells, removal of pathogen/ tolerance, network of blood and lamina
• dysgregation breakdowns lead to inflammation. Mechanical, chemical and pathogen
• Innates are essentionl fo rimmeues

ILC pathways & Infection

• The dysregulation / breakdown of homeostasis in the gut can lead to inflammation, such as mechanical, chemical and pathogen factors
• Bacteria can activate epithelium releasing IL-25
• The pathways causes for: Inflammation, activated DCs, key inflammatory cytokines
• There is NETs causing dame and restoriation through epitheilial cells.

Therapeutical application

• MIS target used effectively for therapy via Dysregulation =
• vaccination, pathogen treatments + treating imuune cells (gut cells regulated by other aspects)

IBD signals

• Goal - heal + restoration functions, structural change + regulation In the molecular, it heals imflamed mucosa via cytokines + structures.

Lecture 08: Allergens

• Allergens come from pollen, fungi, insects, domestic animals, and food sources.
• High IgE test results indicate an allergy with allergens tested in skin and serum.
• Grass pollen grains (hay fever) are windborned and inhaled, Aerodynamic properties of allergens,Protein epitopes are main target for IgE antibodies while allergens D1 is airborne at all times.
• Senitisation = Immunisation doesnt require persistne IgE response
• Allergy specific reactions incls trouble breathing, itching, headache
• Grass pollen (LOLL 1)= pollen allergens, Dust mites.
• Main properties, wide range of substances to Innate + Inflammatory response.
• Anaphylaxis (life threatening) via rapid responses, exposure and trandserma

Sensitisation and responses

• Allergens cause immune reaction with CD2, ligands
• Th2 can lead to hyper activity
• Microbes Inhibit allergen induced Th2

The qualties and T ell respones

• There are muliple factors and responses, dose/ pathwas
• Tolerances can be made in responses
• This causes a hetergenous in nature & respons
• This mean site, exposure is important
• In genmoies -> the DC activation can influcene
• These all need inbalacne to occur

Influence

Site and dose are important, but DC central Common sites are skins, respiratory, mouth and gut For example, there haigh prevalence in eczema in asthma patients But in short they need inbalacne to occur

Lecture 09: Immune System Disorders

• Microorganism is pathogens, Commensals live but cause no damage; and host is infections and causes transmissions.
• Pathogens have varying types: food, contact etc
• Human have three types of defebse, physcial barrier, adaption/ inante and daptive immunity
• Tests are needed to identify/ diagnose: Full blood count [FBC] Packed cell vol [PCV[ Total protein [PT[
• WBC disorder are due to not functioning or right and not functioning
• There are several syndromes incl di georges yndrome( low Tcells) and agammaglobulinemia ( BCell lack)
• The EBV virus causes: Virus first infects epithelial cell in pharnyx causing pharyngitis, followed by infection in B cells B cells proliferate/ activate t cell/

types of immune system disorrer

1. Primary immune deficiency = born with weak immune system
2. Acquire immune deficiency = getting a disease that weakens your immune system
3. Allergic reaction = immune system being too active
4. autoimmune disease = immune system fighting against you

• SCID - Rare inherited disrder that has great risk
• It needs treatmemt/ can cue, 3 Lymphocyte: T, B, N
• It comes from inherited mutations and diagnosis for babys usually after infection (There is no treatment)

HIV & Innitate & Cellular Immune Response

• Causes AIDS from retrovirus reducing Tcells ->
• monocytes reduce ingesting and presentation to T cells, DC -> anti pre
• It has early prevention cell activities with activation to protect
• Cell meidated activated (T-Cell receptor + MHC1) inhibiting infection.

Humoral/ Faliure

• There system happens later with binding proetins. & GP41
• Immunity falliure -> repsonse

Lecture 10: Autoimmunity - Transplantation

• Transplant is the transfer where it requires damage. This needs donor + host relationship

Types of transplants

1. Autograft: tissue from self to self
2. Allograft: tissue to someone else. (Risks genetic rejection
3. Xenograft. From specie risk, Rejection.

• Trans plants needs immunosupessives
• The major compatiblity is between donor and recipient to avoid rejection
• MHC allow lyphocite detect - macrophages engage for response In short HLa gene determines and can havel multiple of these copies PRA-> predict respones limits

AutoImmune

• Where body doesnt recognizes self - > launches, Auptreacyuve needed clears to prevent Immuen respnse hapeen

stages post transplant - immune respnse

• Hyperacute rejection:* Very rapid response - minutes to hours - due to pre-existing antibodies against the donor tissue.

• Accelerated rejection:* Occurs within days of transplantation, often due to previous sensitization to donor antigens.

• Acute rejection:* Develops within the first few weeks to months after transplantation. - Involves intense activation of T lymphocytes - damage the transplanted organ.

• Chronic rejection:* Develops over a longer time - months to years.

• In medication. Inflammtroy, supressive etc Reductions does not elimination miHA

• This occurs over all levels of the cells as the side product occurs Stem cells are infused with regular testing and the risks must be taken with the organs Why is fetus not rejected? Progesterone Hormone: Acts as an immunosuppressive agent to Redux maternal immune response against the fetus + regulators

Lecture 11: Manipulating the immune response to fight infections

• Preexisiting required for protectice measure with anti targeting
• effective vaccines lead to GENERATION CONSTRAINTS -SAFE, PROTECT T CELL RECEPTORS The vaccination program reduces to those to trasmitter
• effective vaccines leads to: Generation of antibodies T cells direct to correct epitopes of infectoR

vaccine program

• Conjugaged Vaccine: T cell independent, harvest for own

• Solution: Chemically

• Adjuvants : stimulate, alum with cells bactera

• Mechanism of action: act: Direct/indierect/ Activate rec and agents

• Synthetic protect : TCell

• Reverse immuengeics

• Live VACC, RECOM AND ATTENUATES

• Has inactivated/live attenuated viruses Advantages: Safe - unable to given in huge number, few can get infected Protective - able to produce protective immunity in majority of people given Long terms - protection against illness able to last several years Cheap - able to be cost effective if given large population Effective vaccination program provides herd immunity

• Can also boost with therapy. with schisorm and lesh

• Two immunological approaches

1. Boost pattern of host immune response with use to cytokine therapy
2. Attempting therapeutic vaccination -> whether host immune response can be enhanced by immunisation

• Cytokinetherapy is the injection directly into the lesion. Has not had succes.

DEFINITION FOR LECTURE:

schistose + lesion + leprosy. Granuloma,TAP, Leis + eo + hellminth

Questions about innate immunity's mechanisms, including physical barriers, antimicrobial peptides, phagocytosis, and pattern recognition receptors. Explore how these components protect against pathogens.