Immunology Notes

Immunity

• Immunology is the study of how the body distinguishes itself from everything else.

• All multicellular organisms have some type of recognition system.

  • Animals, such as sponge colonies.

  • Plants, such as pollen.

• The immune system is a vertebrate development from older recognition systems.

Historical Context

• 430 BC: Evidence of understanding immunity.

• 1500-1802: Early observations and experiments.

• 1805: Questioning if the chickenpox vaccine would provide protection against smallpox.

• 2021: Coronavirus vaccine candidates developed using various methods.

  • Nucleic acid vaccines

  • Viral vector vaccines

  • Protein-based vaccines

Host Defense

• Steps of infection:

  • Adherence

  • Multiplication

  • Evasion of host defense

  • Cause damage

• Host defense relies on disrupting one or more of these steps.

• No defense layer is perfect.

Components of Immune Response

• First line of defense: Innate Immunity

  • Intact skin

  • Mucous membranes and their secretions

  • Normal microbiota

• Second line of defense:

  • Phagocytes (neutrophils, eosinophils, dendritic cells, and macrophages)

  • Inflammation

  • Fever

  • Antimicrobial substances

• Third line of defense: Adaptive Immunity

  • Specialized lymphocytes: T cells and B cells

  • Antibodies

Physical and Chemical Barriers to Infection

• Physical barriers: Epithelial layers of skin and mucosal/glandular tissues.

• Chemical barriers: Acidic pH and antimicrobial proteins and peptides.

Cellular Responses to Infection

• Phagocytosis and degradation by macrophages and dendritic cells.

• Cell activation

• NK cell activation

• Release of cytokines and chemokines, leading to inflammation.

• Production of antimicrobial substances.

• Pathogen elimination.

Lymphoid Tissues

• Nasal-associated lymphoid tissue (NALT)

• Tonsils and Adenoids

• Bronchus-associated lymphoid tissue (BALT)

• Skin-associated lymphoid tissue (SALT)

• One of many lymph nodes that comprise the Axillary lymph nodes

• Mesenteric lymph nodes

• Gut-associated lymphoid tissue (GALT)

• Isolated lymphoid follicles

• Reproductive tract-associated lymphoid tissue

• Peyer's patches

• Inguinal lymph nodes

• Para-aortic lymph nodes

Cells

• Granulocytes:

  • Neutrophils

  • Eosinophils: deal w/parasitic infections

  • Basophils

  • Mast cells: release histamine

• Monocytes

• Macrophages: Phagocitize

• Dendritic cells: present samples

• Megakaryocytes: Laquire antiboties

Phagocytosis

• Process:

  • Chemotaxis: Phagocyte is attracted to the microbe.

  • Adherence: Phagocyte attaches to microbe (PAMPs binding to TLRs).

  • Ingestion: Microbe is ingested forming a phagosome.

  • Formation of phagolysosome: Phagosome fuses with a lysosome.

  • Digestion: Microbe is digested by enzymes.

  • Discharge: Waste materials are discharged.

Inflammation

• Symptoms:

  • Redness

  • Swelling (edema)

  • Pain

  • Heat

Steps of Inflammation

• Tissue damage causes release of vasoactive and chemotactic factors, increasing blood flow and capillary permeability.

• Permeable capillaries allow influx of fluid (exudate) and cells.

• Phagocytes migrate to the site of inflammation (chemotaxis).

Inflammation Pathways

• Prostaglandins lead to fever via the hypothalamus.

• IL-1, TNF-α, IL-6 influence the hypothalamus and pituitary, resulting in the release of ACTH and corticosteroids from the adrenal cortex.

• Cytokines (IL-1, TNF-α) stimulate the liver to produce acute-phase proteins (C-reactive protein, serum amyloid A, fibrinogen, mannose-binding protein, complement components).

• IL-6 and TNF-0 act on the bone marrow, leading to leukocytosis.

Complement Cascade

• Classical pathway: Initiated by antigen-antibody complexes.

• Lectin pathway: Activated by microbial cell walls.

• Alternative pathway: Triggered by microbial surfaces.

Complement Functions

• Activation of inflammatory response

• Lysis

• Opsonization

• Clearance of immune complexes

Mechanism of IFN α and IFN β

• Virus-infected host cells produce interferon mRNA (IFN-mRNA).

• Translation of IFN-mRNA leads to the production of alpha and beta interferons.

• Interferons alert neighboring cells.

• Neighboring cells transcribe antiviral protein genes.

• Translation produces antiviral proteins (AVPs) that interfere with viral replication.

Acquired Immunity

• Specific for a particular antigen.

• Developed by contact with antigen.

• Has memory: More potent on subsequent exposures.

• Basis for vaccination.

• Discriminates between self and non-self.

• Based on the action of lymphocytes.

  • Humoral response (B lymphocytes)

  • Cell-mediated response (T lymphocytes)

Lymphocytes

• B lymphocytes (B cells): involved in the humoral response

• T lymphocytes (T cells): involved in cell-mediated response.

Generation of Diversity

• Selection (positive selection)

  • Keep ones that bind to foreign invaders

• Deletion

  • delete anything "that binds to me" (own body)

B Cells

• Antigen-binding receptor: antibody

Antibodies

• Surface antibody

• Soluble antibody

• Antigen-binding site

• Disulfide bonds

• Light chain and Heavy chain

Antibody Types

• IgG: most common, can cross the placenta

• IgD: ignore!

• IgE: binds to mast cells and deals with parasites and allergies

• IgA (dimer): secretions, respiratory, digestive mucus, breast milk, etc. -bind virus in mucus

• IgM (pentamer): first antibody, activates complement

Antibody Protection Mechanisms

• Virus and toxin neutralization: Prevents pathogen-host binding.

• Opsonization: Enhances phagocytosis.

• Complement fixation: Leads to formation of the membrane attack complex (MAC).

• Antibody-Dependent Cell-mediated Cytotoxicity (ADCC): NK-induced apoptosis.

T Cells

• Tc cell : Class I MHC with CD8 receptors

• TH cell : Class II MHC with CD4 receptors

Cytotoxic T Cells

• Delete themselves

• Cell-mediated immunity

T Helper Cells

• Antigen presenting cells:

  • MHC class II - exogenous, external threats

  • MHC class I - endogenous, found inside cell

T Helper Cells types

• Naïve -> TH1: Bacteria

  • IFN-γ, IL-12

• Naïve -> TH17: Fungi

  • IL-6, IL-23

• Naïve -> TH2: Helminth, Allergies

  • IL-4, IL-5, IL-13

• Naïve -> Treg: Autoimmunity

  • IL-10, TGF-β

Humoral vs. Cell-Mediated Response

• Humoral: B lymphocytes

• Cell-mediated: T lymphocytes (T-helper cells and Cytotoxic T-cells)

Antigen Presentation

• Foreign proteins, viruses, bacteria, parasites, fungi.

• Internalized antigen digested by cell

• Altered self cell presents antigen

• Class II MHC: TH cell

• Class I MHC: Tc cell

• Activated T cell secretes cytokines that contribute to the activation of B cells, Tc cells, and other cells.

Vaccines

• Pasteur's Rabies Vaccine

Vaccine Statistics

Vaccine Development

• Clinical trials:

  • Phase I: 20-80 participants

  • Phase II: 100-300 participants

  • Phase III: 1000--3000 participants

  • Phase IV: 1000+ participants: To confirm safety and effectiveness

Immunologic Memory

• The immunological memory lasts about 12 months

Herd Immunity

• Herd immunity occurs when a large portion of the community (the herd) becomes immune to a disease, making spread from person to person unlikely.

R0 of Contagious Diseases

Monitoring Vaccine Safety

• Active surveillance: DoD VAECS, NHSN, VSD, PRISM, BEST Initiative

• Passive surveillance: VAERS

• Case consults: CISA Project

Vaccine Efficacy

• Greater risk of disease, hospitalization, and death among unvaccinated vs. vaccinated people.

  • 8-fold reduction in disease incidence

  • 25-fold reduction in hospitalization incidence

  • 25-fold reduction in death incidence