Immune Mechanism of Action

Mechanisms of Immune Activation

• The mechanisms of the immune system detail how the body recognizes and responds to threats

General Principles of the Innate Immune Response

• A pathogen enters the body, where it is recognized by a sensor or effector, leading to a response
• Macrophages recognize the pathogen, triggering phagocytosis
• Macrophage recognition can lead to the release of first-order cytokines like IL-8
• IL-8 activates neutrophils, initiating phagocytosis of the pathogen

General Principles of the Immune Response

• A pathogen enters the body and is recognized by a sensor
• This leads to the release of first-order cytokines like IL-21
• IL-21 activates lymphocytes (ILC or T cells), which then release second-order cytokines like IFN-γ
• IFN-γ activates macrophages, resulting in phagocytosis of the pathogen

Innate and Adaptive Immunity

• Innate immunity involves physical barriers, macrophages and neutrophils for phagocytosis
• Adaptive immunity involves antigen-specific antibodies, T and B cell activation, and antigen presentation

Activation of the Immune System: PAMPs

• Pathogen-Associated Molecular Patterns (PAMPs) activate the immune system
• Pattern Recognition Receptors (PRRs) recognize PAMPs
• TLR2 recognizes lipopeptides
• TLR5 recognizes flagellin
• Pathogen recognition causes activation of Professional phagocytes, production, secretion of antiviral interferons and other cytokines

PAMPs and DAMPs

• Signalling pathway include Gram-negative bacteria releasing LPS
• Pattern recognition receptors (PRR) bind to the signaling pathway macrophage
• Binding causes activation of a signalling pathway
• This leads to NF-kB transcription factor entering the nucleus
• Subsequent transcription results in secretion of cytokines IL-8, IL-1, and TNFα

Danger Signals: DAMPs

• Examples of PAMPs include nucleic acids (ssRNA, dsRNA, CpG)
  • Their microbes include virus and bacteria types
• Proteins (Pilin, Flagellin) come from Bacteria
• Cell wall lipids: LPS comes from Gram-negative bacteria
• Lipoteichoic acid comes from Gram-positive bacteria
• Carbohydrates Mannan and Glucans from fungi bacteria
• Damage-Associated Molecular Patterns include stress-induced proteins (HSPs), crystals (Monosodium urate), and nuclear proteins (HMGB1)

Pattern Recognition Receptors

• Types include Cell-Associated receptors plus Soluble receptors
• Cell-Associated receptors: Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and Cytosolic DNA sensors (CDSs)
• Toll-like receptors (TLRs) are on plasma membrane and endosomal membranes of dendritic cells, phagocytes, B cells, endothelial cells, and more
• C-type lectin-like receptors (CLRs), Scavenger receptors, and N-Formyl met-leu-phe receptors on Plasma membranes of phagocytes
• NOD-like receptors (NLRs) are in Cytosol of phagocytes, epithelial cells, and other cells.
• RIG-like receptors (RLRs) are in Cytosol of phagocytes and other cells
• Cytosolic DNA sensors (CDSs) are in Cytosol of many cell types

The Targets of Adaptive Immunity: Antigens

• Antigens trigger an immune response and can be specifically targeted by antibodies

The Players: Cells and Humoral Factors

• Lymphoid stem cells differentiate into T cell progenitors, B cell progenitors, and natural killer (NK) cells
  • T cell progenitors become T helper 1 (Th1) lymphocytes, T helper 2 (Th2) lymphocytes, and cytotoxic T cells
  • B cell progenitors become memory cells and plasma cells
  • NK cells also become killer lymphocytes without antigen receptors
• Myeloid progenitors differentiate into various cells
  • Neutrophils are phagocytic cells migrating to sites of ingesting invading microorganisms releasing toxins
  • Eosinophils are phagocytic cells that release toxins to kill parasites and bacteria.
  • Basophils are non-phagocytic cells for defense against parasites
  • Mast cells are granulated cells that degranulate and initiate inflammatory reactions
  • Monocytes migrate to inflammation sites to mature into macrophages and dendritic cells
  • Dendritic cells are professional antigen-presenting cells display antigens to activate naïve T lymphocytes
  • Macrophages are phagocytic cells that ingest extracellular debris or invaders to stimulate immune cells

Innate Immune Cells - First Responders

• Macrophages and neutrophils are the first responders of the innate immune system

Macrophages

• Macrophages originate as white blood cells playing an important role in immune system
• They engulf and digest microorganisms for clearing debris, dead cells and to stimulate other cells involved
• M1 macrophages detect, engulf and destroy bacteria, promoting inflammation to invading cells
• M2 macrophages regenerate connective tissue, produce VEGF and TGF-β1, and secrete growth factors.

The Mechanics of Phagocytosis

• The phagocyte recognizes and binds to the pathogen via specific surface receptors
• It engulfs the pathogen by extending its plasma membrane, forming a phagosome
• The phagosome fuses with a lysosome to create a phagolysosome, containing hydrolytic enzymes and acidic components
• Enzymes degrade the pathogen into molecular components
• The phagocyte assimilates components and expels debris via exocytosis, making them available for other immune cells

Neutrophils

• They are the most abundant type of white blood cell and deemed "shock troops" of innate immune system
• They are mobile and recruit to inflammation sites
• They release toxins combat bacteria/fungi
• They are more aggressive than macrophages but have a shorter lifespan

Neutrophils Action

• Mechanisms of an attack involve Phagocytosis, Granule release and Neutrophil Extracellular Traps (NETs)

Cytokines and Chemokines

• TReg releases CCL17
• B cell releases BAFF, APRIL and IL-21
• DC releases CCL2, CCL4, CCL18, CCL19 and CCL20
• TH17 releases CCL2
• T1 releases CXCL9, CXCL10, and CXCL11

T-Cell Activation and Antigen Presentation

• Memory T- Cells, T-Cell Activation and Native T-Cells are all factors
• IFN-Y and GM-CSF are also part of T-Cell Activation and Antigen Presentation

Inflammation

• Inflammation is caused by damage or perceived danger
• Five key characteristics of inflammation include Redness, Heat, Swelling, Pain and Loss of function

Special Forces: Natural Killer (NK) Cells

• NK cells can recognize injured cells or virus-infected cells
• Inhibitory receptors prevent activation
• Activating receptors will kill of injured cells

Special Forces: Dendritic Cells

• Continuously sample the surrounding environment through macropinocytosis
• Detect PAMPS, DAMPS and Cyrokine signals
• They cease routine fluid sampling when detecting foreign antigens and initiate antigen capture
• Captured antigens are processed and presented via major histocompatibility complex (MHC) molecules
• Activated dendritic cells migrate to lymph nodes through system to initiate and regulate adaptive response

Adaptive Immunity and Dendritic Cells

• Virus Infects, Dendritic Cell Activation occurs, the T and B cell priming occur in the lymph node, adaptive immunity is activated

Immature vs Mature Dendritic Cells

• Immature cells include Pathogens, Cytokines, PAMPS and DAMPS
• Include a Co-stimulatory Molecule
• High Presence of MHC II Expression, secretion and Pro-Inflammatory Cytokines
• Capacity for phagocytosis & Glycolysis.

Adaptive Immune Cells

• B Lymphocytes (B cells) function to produce antibodies for humoral immunity
• T Lymphocytes (T cells) perform cell-mediated immunity.

T Cell Career

• Pre T Cell goes through training
• Becomes virgin or regulatory T Cell
• If regulatory T cell, activation through MHC1
• If virgin T Cell, then activation through MHC 2 and the becomes a Helper T Cell
• Both cells can get an infection activating them into Tissue Memory Cell, Effector Memory Cell, and Central Memory Cell

B Cell Career

• Pre B Cell undergoes Bone Marrow Training
• Activation 1 of the activated bone marrow gives a cell called Vrigin B Cell
• Activation happens when exposed to to an antigen
• When activation #2 occurs through another T cell
• An Infection will turn the cell into either a Plasma cell, Memory B Cell or a long-lived plasma cell

Structure of T and B cell receptors

• Key receptor parts include light/heavy chains, variable/constant regions and antigen binding site
• Alpha and beta chains are key

Activation of T-Cells

• Activation requires 2 signals from APC (Antigen-presenting cell) -Signal 1 is when T-Cell receptor (TCR) engages with the Antigen-MHC Complex on the APC -Signal 2 gives Co-Stimulatory a additional Activation Signal only and occurs when both signals
• Co-Stimulatory molecules provide an additional activation signal and successful activation occurs when both signals are present

T-Cell Activation and Differentiation

• Naive CD4+ T cells recognize presented antigen by APCs via MHC-II signals and they receive co-stimulatory signals
• Based on cytokine signals, CD4+ T cells differentiate into Th subsets
• Effector functions release characteristic cytokines

Two Signals of T-Cell Activation

• Signal 1 is for structural stimulation on MHC
• Signal 2 is for activation (B7-1 & B7-2 with CD28 & CD80, CD86)
• Similarities occur for both inhibitory and stimulatory molecules (ie, CTLA-4)

B-Cell Activation

• T-helper and B cells interact if the B-cell presents the correct peptide-MHC complex
• B-cell antigen presentation to activated T leads to CD40-CD40L dependent co-stimulation
• CD40L on the T-helper cells binds to CD40 on the B
• Essential for cells that secrete IL-4, promote B-cell class switching, clonal expansion and more in adaptive immunity
• This interaction is critical for B cell activation and antibody production in adaptive immunity