Effective Communication Strategies

Immunity and Immunity Based Points

• Immunity is impacted by factors like genotype, diet, exercise, microbiota, stress, and antibiotics.
• Symbiosis, a state of harmonious coexistence between bacteria and the body, promotes barrier integrity and gut/brain immune homeostasis. It also leads to proper metabolism and immune function.
• Dysbiosis, the opposite of symbiosis, is associated with chronic inflammation (a factor in IBD) and metabolic dysregulation (a factor in T2D).

Immune Cell Travel

• The presentation will cover primary versus secondary lymphoid organs.
• It will discuss how immune cells travel throughout the body, including the lymphatic system and blood vessels.
• Myeloid cells (innate), like dendritic cells and macrophages, and lymphoid cells (adaptive, B and T cells) will be in the presentation

Immune Response Magnitude

• The presentation will illustrate the differences in the magnitude of primary and secondary immune responses.

Additional Immune System Concepts

• Innate cells have microbial sensors, namely Toll-like receptors (TLRs).
• Dendritic cells recognize, destroy, and present pathogens to T cells.
• Helper T cells play a part in helping develop and supporting an immune response.

Overview/Responsibilities of the Immune System and Vaccination

• The presentation will cover an overview of the immune system
• It will also discuss various vaccination topics including:
  • Relevant diseases like H1N1 and H5N1
  • Historical development of vaccines, and usage of vaccines in past diseases like smallpox, mumps and the most recent one SARS-CoV-2.
  • Recent issues related to vaccination

Important Terms

• The immune system is a network of cells, tissues, and organs working together to recognize and defend against foreign substances, microbes and cancer.
• It has a capacity to recognize self and non-self, tolerating healthy self, commensal organisms and microbes, while also neutralizing or destroying foreign substances or altered self tissues.
• The immune system also has a capacity to clean up old cells.
• Immunity is the host's overall response to combat a particular disease or infection.
• Immunology is the study of immune responses.

Recognition and Response (Tolerance)

• The immune system distinguishes self from altered self and foreign invaders.
• The system also has the capacity to promote interactions with beneficial microbes.
• The immune system differentiates between various pathogens.

Effector Response and Vaccinations

• Recognition of pathogens leads to an effector response aiming to neutralize or remove the invader.
• Secondary exposure results in a more rapid immune response due to immunological memory.
• Vaccination involves building a robust immune response in preparation for a real-life encounter with an antigen.

Influenza Vaccine Targets

• Hemagglutinin allows influenza to enter cells.
• Neuraminidase allows the virus to exit cells thus making them infectious.
• Neuraminidase inhibitors are used to treat influenza. (e.g., Oseltamivir, Zanamavir, peramivir)

Historical Development of Vaccines

• Thucydides in 430 BC observed immunity to plague.
• 15th-century variolation (dried smallpox crusts) was used - although a method was discovered, effective medical application developed slowly (it took 2000 years)
• Edward Jenner developed the first vaccine in 1798 using cowpox to protect against smallpox.
• Pasteur also made significant contributions to vaccination, specifically with attenuated vaccines, by identifying bacteria causing cholera in chicken, and further experimenting in sheep and immunizing them against anthrax; where he successfully immunized the sheep by weakening the bacteria or introducing a very small dose, resulting in survival upon infection.

Overview of Pathogens/Pathogenesis

• Pathogens are organisms that cause diseases, including viruses, bacteria, fungi, and parasites.
• Pathogenesis refers to the mechanisms pathogens use to cause disease.
• Opportunistic infections are often caused by ubiquitous organisms (Candida albicans and Herpes simplex virus).

Types of Pathogens

• Viruses, bacteria, fungi, and parasites cause various diseases.
• Polio, smallpox, influenza, measles, and AIDS are examples of diseases caused by pathogens.

Super Fungus Scare (1980's)

• An increased number of opportunistic fungal infections, were primarily caused by a lack of immune regulation, i.e, lack of functioning CD4+ cells, which is an indication of acquired immunodeficiency syndrome (AIDS)
• This is caused by the human immunodeficiency virus (HIV).

Early Studies - Serum vs. Cells

• Blood serum can transfer immunity between unimmunized animals.
• Antibodies (gamma globulin) can neutralize toxins.
• Antisera (e.g., from horses) were used before antibiotics for treatments (e.g., snake/scorpion anti-venom, diphtheria anti-toxins).
• Ilya Metchnikov discovered phagocytosis (ingesting microorganisms).
• Chase demonstrated the transfer of tuberculosis immunity between guinea pigs using white blood cells

Innate and Adaptive Immunity Overview

• Innate immunity acts fast and initially, and is largely the same for repeated infections. Adaptive immunity is "tailor-made" to specifically target pathogens and has a stronger magnitude with repeated exposure.
• Adaptive immunity includes:
  • Antigens
  • B cells (humoral)
  • T cells (cell-mediated), including: -Cytotoxic T lymphocytes (CTLs)
• Innate immunity includes:
  • Physical barriers (skin and mucous membranes)
  • Physiological defenses (fever)
  • Phago-endocytic activity
  • Non-specific chemicals -inflammatory response

Monocytes and Macrophages (MACs)

• Monocytes circulate in blood and mature into tissue macrophages.
• Macrophages have various surface receptors, named depending on tissue location (e.g. alveolar macrophage in lungs, kupffer cells in liver, microglial cells in brain).
• Activated macrophages have heightened phagocytic ability, killing mechanisms (cytotoxic proteins), and display elevated MHC II levels.

Granulocytes

• Neutrophils, basophils, eosinophils, and mast cells are granulocytes part of innate immunity.
• These cells contain multilobed nuclei and cytoplasmic granules involved in direct pathogen damage, immune cell regulation, and tissue remodeling.

Neutrophils

• Neutrophils (PMNs) are the most abundant leukocytes in blood.
• They migrate to sites of tissue damage and are recruited to inflammatory/chemokine sites.
• They kill pathogens by releasing enzymes and reactive oxygen metabolites.
• Leukocytosis is an increase in circulating neutrophils that is a marker of infection.

Eosinophils

• Eosinophils are granulocytes stained red.
• They provide protection against parasites.
• They also release cationic proteins and reactive oxygen metabolites; and play a role in allergic reactions.

Basophils and Mast Cells

• Basophils and mast cells are granulocytes involved in allergic reactions and hypersensitivities.
• Their granules contain histamine.
• These cells are less phagocytic than neutrophils, macrophages and eosinophils.

Dendritic Cells (DCs)

• DCs act as "sentinels" by detecting pathogens and presenting them to T cells.
• During maturation, phagocytosis is decreased, and MHC I and MHC II presentation increases.
• Different types of DCs (e.g., Langerhans cells, interstitial DCs) exist, specialized for different locations.

Cluster of Differentiation (CD)

• Cluster of Differentiation (CD) markers are cell surface proteins that distinguish different immune cell types or stages of maturation .

Follicular Dendritic Cells (FDCs)

• FDCs are not derived from bone marrow and do not have MHC II receptors.
• They have high levels of antibodies and play a role in B cell maturation.
• They are found in B cell follicles.

Natural Killer (NK) Cells

• NK cells are large granular lymphocytes that kill malignant and infected cells.
• Recognition of target cells occurs through antibody-dependent or non-peptide mechanisms.
• NK cells use perforins and granzymes for killing.

CD4+ T Cells

• These are helper T cells that have a T cell receptor (TCR) and need activation via signals 1,2,3.
• They help in antibody production and B cell maturation.
• They also aid macrophage maturation and CD8+ T cell enhancement. Important to note the activation signals involved (MHC + antigen; and B7/CD28 protein interaction).

CD8+ T Cells

• These are cytotoxic T cells (CTLs) involved in killing virus-infected or cancerous cells; they have a role in recognizing these diseased cells in the context of MHC I.
• They require activation signals (similarly to CD4+ T cells) and differentiate into memory or cytolytic T lymphocytes (CTLs or CD8+) upon activation.

Cytolytic T Lymphocytes (CTLs)

• CTLs are effector cells responsible for eliminating cells carrying foreign antigens via MHC complexes.
• CTLs use mechanisms such as Fas/FasL interaction and the release of perforins/granzymes to directly kill target cells.

Immunological Memory

• The hallmark of adaptive immunity is immunological memory.
• The primary response occurs upon initial antigen exposure.
• Subsequent exposure triggers a faster and more robust secondary response due to memory cells and a shorter lag period.

Key Recognition Molecules (PRRs)

• The immune system recognizes pathogens through germline receptors (PRRs).
• PRRs bind to pathogen-associated molecular patterns (PAMPs) found on various pathogens.
• These receptors are expressed widely on various immune cells.

Key Recognition Molecules (B- and T-Cell Receptors)

• B cell and T cell receptors recognize unique specific antigens.
• These receptors are generated via genome rearrangement, making them highly diverse.
• B cells produce antibodies with the same specificity as their receptors.
• T cell receptors bind to displayed peptides along with MHC proteins found on other cell types for recognition.

Tolerance

• Tolerance is crucial to prevent the immune system from destroying host cells.
• The immune system eliminates cells with self-reactive receptors.
• Maintaining self-tolerance ensures that future responses are directed only towards foreign antigens.

Hematopoiesis Overview

• Hematopoiesis is the formation of blood cells (red blood cells (RBCs), and white blood cells (WBCs)).
• Specific genetic regulation is required for proper hematopoiesis, which also involves regulation of programmed cell death and different growth signals.

Hematopoiesis: Genetic Regulation

• Correct gene expression is needed during development of HSCs into different blood cell types.
• Several transcription factors (e.g. GATA-1, GATA-2, PU.1) are involved for blood cells development and function.

Hematopoietic Homeostasis

• A dynamic equilibrium is maintained in the bloodstream involving the cells lifespan, and replacement.
• Many factors, including cytokines, contribute to hematopoietic homeostasis.

Apoptosis

• Apoptosis is programmed cell death; critical for homeostasis in the body.
• Improper control can lead to uncontrolled cell growth or accumulation of damage.

HSC Isolation, Enrichment

• Specific surface markers distinguish HSCs from other cells (mature cells).
• Antibodies targeting these markers are used in methods like panning or FACS to isolate HSCs.
• Small amounts of enriched HSCs can reconstitute hematopoiesis in lethally irradiated mice.

Stem Cells Types

• Totipotent, pluripotent, multipotent, and unipotent stem cells have different differentiation potential (to create an entire organism; various cell types, a limited number, and themselves respectively).

Stem Cell Transplantation

• Different transplant options exist, with autologous, syngeneic, and allogenic transplantation differing based on the donor.
• Graft-versus-host disease (GVHD) can arise in allogeneic transplants and requires immunosuppression in patients.

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