Immune System Components and Pathogen Recognition

Immune System Overview

• The immune system comprises various tissues and organs.
• This lecture serves as an introduction; subsequent lectures will detail the function of different components.

Primary Lymphoid Organs

• Immune cells develop here.
• Bone marrow: Immune cells develop.
• Thymus: T cells further develop.

Secondary Lymphoid Organs

• Adaptive immune responses are generated or initiated here.
• Spleen: Important for blood-borne antigens.
• Lymph nodes: Important for tissue antigens.
• Mucosal and Cutaneous Lymphoid Tissues: Examples include tonsils and Peyer's patches.

Lymphatic System

• A network of vessels connects lymph nodes.
• Important for draining lymph from tissues into lymph nodes.
• Lymphatic vessels drain interstitial fluid from tissues into lymph nodes, carrying antigens.
• Antigens in blood are taken to the spleen.
• Lymphocytes (T and B cells) meet antigens in lymph nodes.
• Lymph nodes are where lymphocytes encounter antigens.

Immune Cells Overview

• All immune cells develop in the bone marrow from a multipotent hematopoietic stem cell progenitor.
• Immune cells are collectively called white blood cells or leukocytes.

Innate Immune Cells

• Can come from the lymphoid progenitor or from the myeloid progenitor.
• Examples: NK cells, dendritic cells, neutrophils.

Adaptive Immune System

• B and T cells are derived from the lymphoid progenitor.
• Different cells are found in different places, depending on how pathogens infect us.

Key Innate Immune Cells

• Macrophage
• Neutrophil
• Dendritic cell
• Basophil
• Natural killer cell
• Mast cell
• Eosinophils
• Neutrophils, basophils, and eosinophils are granulocytes with granules in their cytoplasm and multi-lobed nuclei, sometimes called polymorphonuclear leukocytes.
• Macrophages, neutrophils, and dendritic cells are phagocytes that engulf particles and pathogens.
• Macrophages and dendritic cells are found in tissues.
• Mast cells are also found in tissues.
• Eosinophils, basophils, neutrophils, and natural killer cells are found in blood.
• Monocytes (precursors to macrophages) are found in blood.
• They have different morphological characteristics and different functions.

Adaptive Immune Cells

• Derived from the lymphoid lineage.
• Lymphocytes: B and T cells.
• B cells develop in the bone marrow.
• T cells begin to develop in the bone marrow, but then they move to the thymus to finalize their development.
• Two types of T cells:
  • Helper T cells (CD4 positive T cells)
  • Cytotoxic T cells (CD8 positive T cells)
• B and T cells have specific antigen receptors for distinct recognition of pathogens.
• B cells produce antibodies, important for the humoral immune response.
• T cells contribute to cell-mediated immunity.

Molecules of the Immune System

• Signaling molecules: cytokines and chemokines.
• Receptors and accessory proteins: important in signaling and directing a cell's response.
• Effector molecules: antimicrobial proteins (defensins), complement, and antibodies which eliminate microbes.

Recognition of Pathogens

• To have an immune response, pathogens need to be recognized.
• Innate immune system: Is it a virus or a bacteria?
• Adaptive immune system: What exactly is it? (e.g., flu or SARS CoV-2).
• Cells are constantly sensing their environment and responding accordingly, such as through insulin receptors.

Generic Signaling Cascade

• Extracellular signaling molecule binds to a receptor on a cell.
• Signaling cascade happens.
• There is an outcome, a response to that original response.
• Immune cells need to recognize pathogens and differentiate them from self.
• Recognition is mediated by different types of receptors; some molecular components also need to recognize pathogens like complement and antibodies.

Innate Immune Cells: Pattern Recognition Receptors (PRRs)

• Recognize pathogens using pattern recognition receptors (PRRs).
• Types of PRRs: Toll-like receptors, Nod-like receptors, C-type lectin receptors.
• Germline encoded: expressed on the cell (one macrophage and another macrophage will have the same type of pattern recognition receptors).
• PRRs are expressed in various locations (cell surface, endosomes, cytosol) to recognize pathogens regardless of entry point.
• PRRs recognize molecules called pathogen-associated molecular patterns (PAMPs).
• PAMPs are conserved structures shared by different classes of microbes.
• PAMPs are critical for their survival, so they are not mutated, and they are not found in mammalian cells.
• Examples of PAMPs: lipopolysaccharide (gram-negative bacteria), double-stranded RNA (certain viruses), and flagellin (motile bacteria).
• PRRs can also recognize damage-associated molecular patterns (DAMPs) from damaged or dying host cells, which initiates repair.

Adaptive Immune Cells: Antigen Receptors

• Adaptive immune cells use antigen receptors.
• B cells express a B cell receptor (BCR) which is a membrane-bound antibody comprised of two light chains and two heavy chains. It has a constant region and a variable region.
• T cells express a T cell receptor (TCR), very different to a B cell receptor but also with a constant region and a variable region.
• Antigen receptors are specific for their cognate antigen.

Antigen Definition

• A molecule recognized by an antigen receptor.
• The exact part of the antigen recognized by the antigen receptor is called the epitope.

B and T Cell Antigen Recognition

• B cells and antibodies recognize whole antigens (proteins, carbohydrates, lipids, and nucleic acids).
• B cells can recognize the conformational portion or linear epitopes of the antigen.
• Antigens can be associated with a cell or can be soluble antigens such as toxins.
• T cells recognize peptide antigens presented on major histocompatibility complex (MHC) molecules.
• T cells only see protein antigens and those linear epitopes in the context of MHC.
• T cell antigens can only be associated with cells.

Specificity and Diversity

• Antigen receptors confer specificity and diversity to the adaptive immune system.
• T and B cell populations consist of clones with different antigen receptors.
• Each clone has a different antigen receptor and is specific for one type of antigen.
• Antigen receptors are generated randomly by somatic recombination of gene segments.
• Billions of specificities exist, and we are prepared for almost anything.

Summary of Recognition of Pathogens

Immune Cell Activation

• After pathogen recognition, cells are activated to eliminate the microbe.
• Innate cells: one signal through the pattern recognition receptor to activate.
• Adaptive immune cells: Two signals are needed to be activated.
  • Signal 1: Through the antigen receptor (BCR or TCR); what is the pathogen?
  • Signal 2: Innate immune system provides a confirmatory danger signal.

Take-Home Messages

• The immune system is not just our defense mechanism. Dysregulation or absence of system is associated with disease.
• We can use our knowledge of the immune system for our advantage to treat or prevent disease or to use in research and diagnostics.
• Our immune system needs to be prepared with any potential pathogen, so we have lots of different cells and molecules to do that.
• Our innate immune response is very broadly specific to classes and works to prevent or contain an infection and then eliminate pathogens. We need that innate immune system to, activate our adaptive immune system, which is very highly specific. So, that adaptive immune system takes time, but it's very effective because it gives us a tailored response.
• Memory is a key property of the adaptive immune response, so it allows us to give an even better response the next time we see that pathogen.
• They recognize, microbes in different ways.