Text Analysis Techniques Quiz

Point of Immunity

• Immunity is affected by genotype, diet, exercise, microbiota, stress, and antibiotics.
• Symbiosis (healthy bacteria) promotes barrier integrity, gut/brain immune homeostasis, proper immune function, and proper metabolism.
• Dysbiosis (unhealthy bacteria) results in chronic inflammation (IBD) and metabolic deregulation (T2D).

Things We Will Address

• Primary vs. secondary lymphoid organs
• How immune cells travel through the body (lymphatic system and blood vessels)
• Types of immune cells (myeloid - innate, dendritic cells/macrophages, lymphoid - adaptive, B cells, and T cells)
• Humoral vs. cell-mediated immunity
• Magnitude of immune response (primary vs. secondary)

Additional Concepts

• Innate immune cells have microbial sensors (TLRs - pattern recognition receptors).
• Dendritic cells identify, destroy pathogens, and present them to T cells.
• Helper T cells aid the overall immune response.

Outline

• Overview/Responsibilities of the immune system
• Vaccination
  • Relevant diseases (H1N1, H5N1)
  • Historical development
  • Use in smallpox, mumps, SARS-CoV-2
  • Recent issues (anti-vax movement)
• Nobel Prize Winners in Immunology
• Overview of Pathogens/Pathogenesis
  • Types of pathogens
  • Super fungus scare
  • Early studies - serum vs. cells

Important Terms

• Immune system: composed of cells, tissues, and organs that recognize self, foreign substances, microbes.
• It tolerates healthy self and commensals/mutualistic organisms.
• Neutralizes or destroys foreign substances, altered self (cancer), and harmful microorganisms.
• Cleans up old cells.
• Immunity: the general ability of the host to resist a particular disease or infection.
• Immunology: the science concerned with immune responses.

Recognition versus Response (Tolerance)

• The immune system distinguishes between self and altered self.
• It distinguishes between self and foreign invaders.
• It promotes mutualistic microorganism interactions.
• It distinguishes between different foreign pathogens.

Effector Response and Vaccinations

• Recognition of a pathogen triggers an effector response to eliminate or neutralize the invader.
• Subsequent exposures result in a more rapid immune response due to immunological memory.
• Vaccination develops a robust immune response prior to antigen exposure.

Vaccination Example: H1N1 (Swine Flu) - 2009

• FluMist: attenuated virus
• Intramuscular injections (protein antigen)
• Inactivated virus
• Zoonotic disease/reservoir

Influenza Vaccine Targets

• Hemagglutinin allows influenza to fuse into cells.
• Neuraminidase allows it to exit cells (infectivity).
• Treatment: Neuraminidase inhibitors (oseltamivir, zanamivir, peramivir).
• Immunology driven by economics.

Historical Development of Vaccines

• Latin term immunis means "exempt".
• Thucydides (430 BC) noted that those who recovered from the plague could care for the sick without contracting the disease.
• Variolation (15th century): Using dried smallpox pustules for vaccination.
• Jenner (1798): Observed cowpox immunity to smallpox.

Historical Development: Attenuated Vaccines

• Pasteur identified cholera-causing bacteria in chickens.
• Old bacterial cultures were injected, making chickens sick yet surviving.
• Re-injection with fresh culture did not make them sick.
• Heat-attenuated Bacillus anthracis was used in sheep, proving immunity against lethal anthrax.

Did the Treatment for Rabies Use by Pasteur Confer Active or Passive Immunity to the Rabies Virus?

• [Answer needed].

Cases of Selected Infectious Disease Before and After the Introduction of Effective Vaccines

• Diseases like smallpox, diphtheria, measles, mumps, pertussis, paralytic polio, rubella, tetanus, and invasive hemophilus influenzae greatly decreased post-vaccination.

Overview of Pathogens/Pathogenesis

• Pathogens are organisms that cause disease.
• Pathogenesis is the method of attack.
• Opportunistic infections are ubiquitous organisms (ex: Candida albicans, Herpes simplex virus).

Types of Pathogens

• Major groups of human pathogens (ex: viruses, bacteria, fungi, and parasites).
• Examples of diseases caused by these pathogens (e.g., polio, smallpox, influenza, tuberculosis, tetanus, thrush, ringworm, and malaria).

Example: The "Super Fungus" Scare of the 1980s

• Opportunistic fungal infections were killing many.
• Lack of immune regulation, specifically a lack of CD4+ cells (acquired immunodeficiency syndrome - AIDS), caused by the human immunodeficiency virus (HIV).

Early Studies - Serum vs. Cells

• Serum can transfer immune state to unimmunized animals.
• Serum can neutralize, precipitate, and agglutinate toxins.
• Gamma-globulin immunoglobulin (antibodies) were found to be responsible.
• Antisera (from horses) was used in treatment prior to antibiotics.
• Snake, scorpion anti-venom, and diphtheria anti-toxin are still in use.
• Metchnikoff (1883): Certain white blood cells (WBCs) phagocytize microorganisms and foreign materials.
• Chase (1940s): Transfer of immunity to tuberculosis between guinea pigs using WBCs (passive vs. active immunity).

Innate and Adaptive Immunity Overview

• Innate immunity: Rapid response active before infection; essentially the same response to repeat infections; response in hours; important in adaptive response activation.
• Adaptive immunity: Tailor-made immune responses; response increases in magnitude with subsequent exposures; response in days; T cells and B cells are major players.

Innate Immunity

• Physical barriers (skin, mucous membranes)
• Physiological barriers(fever)
• Phagocytosis/endocytosis (engulfing of material)
• Non-specific chemicals
• Inflammatory response

Skin

• Strong mechanical barrier to microbial invasion.
• Inhospitable environment for microbes; organisms shed in skin cells.
• Slightly acidic pH.
• High NaCl concentration.
• Subject to periodic drying.
• Non-specific chemicals (e.g., psoriasin).

Mucous Membranes

• Form protective coverings that resist penetration and trap microbes.
• Often bathed in antimicrobial secretions containing antimicrobial substances.
• Mucosa-associated lymphoid tissue (MALT).

Physical Barriers in Innate (Nonspecific) Resistance

• Effectiveness is affected by direct factors (nutrition, physiology, fever, age, and genetics) and indirect factors (personal hygiene, socioeconomic status, and living conditions.)

Physiological (Fever)

• Macrophages release proinflammatory cytokines (IL-1, IL-6, TNF-α) to cause fever.
• Some viruses are less stable at high temperatures.
• Macrophages can be further activated by fever.

Phagocytosis

• Process for phagocytic cells (monocytes, tissue macrophages, dendritic cells, and neutrophils) to recognize, ingest, and kill extracellular microbes.
• Often occurs via recognition of pathogen-associated molecular patterns (PAMPs) like cell wall components, mannan, B-glucan, LPS, peptidoglycans, and proteins.
• Phagocytic cells have receptors for PAMPS.
• Dead cells (damage-associated molecular patterns - DAMPS) can be phagocytosed.
• Phagocytosis is increased by opsonization (binding molecules to microbes).

Mechanisms of Phagocytic Recognition

• Opsonin-independent recognition.
• Opsonin-dependent recognition (opsonins bind to microbes).
• Opsonins include complement, mannose-binding lectin, C-reactive protein, and antibodies.

Endocytosis

• Ingestion of extracellular particulate matter (phagocytosis) or liquid (pinocytosis by DCs)
• Involves tissue macrophages, blood monocytes, neutrophils, eosinophils, and dendritic cells.
• Receptor-mediated endocytosis.

Non-Specific Chemicals

• Lysozyme (hydrolyzes peptidoglycan)
• Lactoferrin/transferrin (binds iron)
• Calprotectin (chelates zinc/manganese of S. aureus)
• Psoriasin (produced by human skin/tongue against Escherichia coli)
• Cationic peptides (disrupt cell membranes, interfere with transport)
• Bacteriocins (produced by microbiota, lethal to related bacterial species).

The Complement System

• Composed of >30 serum proteins.
• Augments the antibacterial activity of antibodies.
• Defends against bacterial infections.
• Bridges innate and adaptive immunity.
• Disposes of wastes.

Complement Activation Pathways

• Complement activation begins in different ways (with specific proteins), resulting in the same outcomes (opsonization, stimulation of inflammatory mediators, lysis of microbes)
• Pathways are activated as a cascade.

Interferons (IFNs)

• IFN categories: Type I, Type II, and Type III.
• Induce an antiviral state.
• Type I IFNs are produced by virally infected cells.
• Type II IFN (IFN-γ) is produced by NK and T cells.

Inflammatory Response

• Usually triggered by foreign substances.
• Capillaries expand to increase blood flow (reddening).
• Permeability of microvascular structure increases.
• Facilitates the exit of leukocytes and plasma protein—causing edema (swelling).

Adaptive Immunity

• Humoral immunity (B cells) and cellular immunity (T cells).
• Antibodies.
• Other cell types (Mast cells, Basophils, Eosinophils, etc.).

Antigen

• Anything that elicits an immune response—originally defined as a substance that binds to a specific antibody.
• Very similar compounds generate very distinct antibodies.

Humoral Response - B cells

• B cells mediate humoral immunity.
• Create antibodies.
• Have BCRs (B-cell receptors) on their surface.
• BCR is essentially an antibody with a transmembrane domain.
• B cells recognize various molecules (including proteins).
• Express MHC-II to present antigens to CD4 T cells.

Cell-Mediated Immune Response - T cells

• Cytotoxic T cells (Tc) with T cell receptor (TCR) and CD8 marker.
• Helper T cells (Th) with T cell receptor (TCR) and CD4 marker.
• Viruses infected cells have viral antigens along with MHC I on their surface.
• Antigen-presenting cells (APCs) process antigens and present them with MHC II molecules on their surface.

Antigen Presentation

• Class I MHC-infected cells.
• Class II MHC-APCs.
• MHC molecules (complexes) present to T-cell receptors (TCRs).
• CD4 and CD8 markers (T-cell co-receptors).

Major Histocompatibility Complex (MHC)

• MHC class I is on virtually every nucleated cell.
• MHC class II is normally limited to macrophages, B cells, and dendritic cells.
• MHC molecules recognize and present foreign antigens to T cells.

Dendritic Cells (DCs)

• Sentinels that detect, capture, and present pathogens to T cells.
• Immature DCs phagocytose pathogens.
• Mature DCs present pathogens to T cells while promoting activation and differentiation.
• Essential in adaptive immunity.

Cluster of Differentiation (CD)

• Cell surface molecules used to identify cell types.
• Differentiate leukocyte lineages.
• Recognized by monoclonal antibodies.

Follicular Dendritic Cells

• Derived from non-bone marrow sources.
• Do not express MHC-II membrane receptors.
• High levels of membrane receptors for antibodies.
• Vital for B-cell maturation.
• Located within B cell follicles.

Natural Killer (NK) Cells

• Large, non-phagocytic granular lymphocytes that kill malignant and pathogen-infected cells.
• Two ways to recognize target cells: - Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) - Recognize/kill cells that have lost MHC I expression.
• Killing mechanisms similar to cytotoxic T lymphocytes (CTLs).
• Always express cytotoxic granules.

CD4+ T Cells (Helper T Cells)

• Possess a T-cell receptor (TCR).
• Activation requires signals 1, 2, and 3.
• Help B cells in isotype switching and antibody production; mature macrophages.
• Support/enhance cytolytic properties of CD8+ T lymphocytes.

CD8+ T Cells (Cytotoxic T Cells)

• Play role in recognizing cancerous and viral antigens on cells presented on MHC-I.
• Activated by antigen-presenting cells (APCs), requiring signals 1, 2, and 3.
• CD4+ help is usually required for maturation.
• Upon activation, they become memory or cytolytic T lymphocytes (CTLs).

Cytolytic T Lymphocytes (CTLs)

• Eliminate cells bearing MHC complexes with foreign antigens.
• CTLs form conjugates with target cells, attack the membrane, and dissociate as target dies.
• Utilize Fas (on target cell)/ Fas ligand (FasL, on CTL) interactions.
• Inject perforins and granzymes (serine proteases) to kill target cells; not in naïve CD8s.

Use of Cells/Interferons across a Viral Infection

• Time-dependent changes, showing the involvement of NK cells and CTLs through a viral infection.

Immunological Memory

• hallmark of adaptive immunity.
• Primary response (initiated upon first exposure and yields memory cells), vs. secondary response (yields a faster/stronger reaction to second exposure).

Key Recognition Molecules: PRRs

• Immune responses rely on recognition molecules.
• Germ-line-encoded pattern-recognition receptors (PRRs) bind to pathogen-associated molecular patterns (PAMPs), found on different pathogens.
• PRRs are expressed in various cells.

Key Recognition Molecules: B- and T-Cell Receptors

• Humoral and cell-mediated immune responses rely on cell-surface B- and T-cell receptors.
• Receptors bind to highly specific antigens rather than generic molecules.
• Ligands can be whole pathogens, fragments of pathogens, or secreted molecules.
• Receptors are randomly generated.
• B cells produce antibodies during antigen encounter.
• T-cell receptors bind to specific peptides presented by MHC molecules.

Tolerance

• Ensures immune system avoids destroying host tissue.
• Tolerance must be established.
• Many random B and T-cell receptor rearrangements could be anti-self.
• Cells with anti-self recognition are eliminated before bloodstream entry.

Tolerance, Continued

• Tolerance must be maintained.
• Immunity system assesses the "danger" and "damage" of any encounter.
• "Good deaths", like apoptosis, do not trigger immune responses.
• "Bad deaths", like damage or infection, elicit an immune response.

Hematopoiesis Overview

• Formation of RBCs and WBCs (leukocytes).
• Hematopoietic stem cells (HSCs) are rare and difficult to study.
• Self-renewal with rapid division in response to stress (e.g., lethal radiation).

Hematopoietic Activity Over Time

• Hematopoietic activity changes with development.
• Stages (yolk sac, liver/spleen, and bone marrow) and locations (yolk sac, liver, spleen, bone marrow) are distinguished and displayed throughout development.

Location of Hematopoiesis: The Bone Marrow Niche

• Specialized microenvironment (niche) for HSCs.
• Stromal cells regulate HSC survival, proliferation, differentiation, and trafficking within the niche.

Classical Hematopoiesis Overview

• Hematopoiesis.
• Cytokines (signals generated by macrophages, stromal cells, and activated T cells) regulate development.
• Different lineages arise from common myeloid and lymphoid progenitors (ex: erythrocytes, platelets, basophils, eosinophils, neutrophils, monocytes).

Hematopoiesis of NK, IL Cells

• Origination from a common lymphoid progenitor (CLP).
• NK and ILC lineages arise during hematopoiesis; different lineages are regulated by distinct cytokines during and after development.

Hematopoiesis: Regulation at the Genetic Level

• Development of HSC into cell type requires gene expression regulation.
• Regulation is assisted through transcription factors (TFs).
• Insight into TF functions is gained through knockout (KO) mice studies.

Hematopoiesis: Essential Transcription Factors

• Various transcription factors (e.g., GATA-1, GATA-2, PU.1, Bmi-1, Ikaros, Oct-2) regulate distinct developmental lineages in hematopoiesis.

Hematopoietic Homeostasis (HH)

• Dynamic equilibrium between cell production and destruction.
• Lifespan of different cells (RBCs, neutrophils, and T lymphocytes) is distinguished from each other.
• Number of WBCs produced per day in humans.
• Many factors (cytokines) influence HH maintenance, regulating hematopoiesis.

Maintaining Homeostasis: Programmed Cell Death (PCD)

• Apoptosis (programmed cell death) involves morphological changes (nuclear fragmentation, blebbing, and apoptotic body release).
• Apoptosis prevents the release of intracellular contents, thus curtailing erratic danger signals.
• Leukocytes (e.g. neutrophils) have a fixed lifespan and undergo apoptosis.
• Apoptosis is used for cells targeted by CTLs/NK cells.
• Necrosis is the unplanned process of cell swelling and bursting.

Apoptosis in Lymphocyte Populations

• Lymphocyte counts increase during infection to combat pathogens.
• Transcription factor Bcl-2 inhibits apoptosis during infection.
• Excess lymphocytes need to be eliminated—activated lymphocytes have decreased Bcl-2 levels, rendering them more susceptible to apoptosis.
• Antigen presence can block apoptotic signaling.

Apoptosis: Regulation via Genes

• Various genes control the regulation of apoptosis through inhibitory vs. promoting signaling pathways (e.g., bcl-2, bax., bcl-X₁/Xₗ, caspases.. Fas).

Example: Thymocyte Apoptosis

• Light and SEM.

HSC Isolation, Enrichment

• Unique surface proteins distinguish different cell types from one another.
• HSC selection through the use of specific antibodies, followed by panning or FACS, occurs through negative selection.
• Antibodies to various differentiation cell markers (e.g., RBCs, WBCs) are used to isolate HSCs through the negative selection technique.
• Remaining, enriched cells can be used in mouse reconstitution.

Panning

• Procedure for isolating HSCs based on their lack of surface proteins unique to differentiated cells (negative selection).

Reconstitution

• Process of restoring hematopoiesis in a lethally irradiated mouse.
• Enriched or wholly enriched HSC inject to restore blood lineages (e.g., cell types - B cells, T cells, neutrophils).

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