Immune System: Innate and Adaptive Responses

Immune System Responses

• The immune system is divided into innate and adaptive responses, which cooperate with each other
• Innate responses provide an intitial, rapid, non-specific response to microbes, lacking memory, but can stimulate adaptive responses
• Adaptive responses are slow, specific, acquired, and use memory cells

Innate Host Defenses

• Innate host defenses use anatomical barriers with physical components, including:
  • Mechanical barriers like skin, desquamation, tears, saliva, coughing, and sneezing
  • Chemical barriers through fatty acids, lysozymes, phospholipids, low pH, defensins, cathelicidins, surfactants, lactoferrin, and transferrin
  • Biological barriers using normal microflora to prevent pathogen colonization

Cellular Components

• Granulocytes (neutrophils, basophils, and eosinophils)
• Monocytes and macrophages (macrophages derived from monocytes)
• NK cells
• Mast cells
• Dendritic cells
• NKT cells
• Lim B1 and Lim Τγδ

Humoral Components

• Complements
• Plasma proteins
• Cytokines

Pathogen Recognition in Innate Immunity

• Pathogen-associated molecular patterns (PAMPs) are microbial substances essential for survival that stimulate immunity
• Innate immunity recognizes pathogens via pathogen recognition receptors (PRRs) on cell surfaces

Tod-Like Receptor Signaling

• Engagement by bacterial or viral molecules
• Recruitment of adaptor proteins
• Activation of transcription factors (NF-kẞ and IRFs)
  • NF-kẞ leads to increased expression of cytokines, adhesion molecules, and costimulatory molecules, causing acute inflammation or stimulation of adaptive immunity
  • IRFs lead to production of type 1 interferon (IFN a/B), causing an antiviral effect

Phagocytosis of Neutrophils

• Neutrophils are short-lived cells, making up 60-70% of circulating WBCs to mediate early inflammation
• Recognition, ingestion, and destruction of microbes via phagocytosis happens through either oxygen-dependent or independent processes

Cytoplasm Granules

• Cytoplasm granules contain myeloperoxidase, defensins, lysozymes, and lactoferrin for expression of receptors
• PAMPs, chemokines, complement, IgG (Fcy R), DAMPS, and adhesion molecules are what receptors express

Neutrophil Extracellular Traps (NETs)

• NETs are released by neutrophils
• NETs trap and kill pathogens like bacteria and fungi, but excessive NET formation leads to inflammatory diseases and tissue damage

Monocytes

• Monocytes are 2-10% of total WBC; they migrate to tissues and differentiate into macrophages
• Inflammatory cells rapidly recruited from the blood to infection sites expressing CD14, PRRs, Fcy R, adhesion molecules, and CR

Macrophages

• Macrophages are derived from circulating blood monocytes, residing in tissues with long lifespans
• Macrophages recognize, engulf, digest, and destroy germs via phagocytosis that generates enzymatic digestion and ROS
• Macrophages act as APCs to regulate inflammatory processes and initiate angiogenesis, and fibrosis to remodel tisse repair
• Activated macrophages secrete cytokines such as IL-1, IL-6, TNF-a, IL-12, IL- 15, IL-18, INF-a Iẞ, IL-10, TGF-β, and CXCL8

Classically Activated Macrophages (M1)

• Monocytes activate in the blood and differentiate into macrophages
• Macrophages reach tissues and start expressing either ROS, NO, and lysosomal enzymes for antimicrobial actions, or IL-1, IL-12, IL-23, and chemokines to mediate inflammation

Eosinophils

• Eosinophils make up 2-5% of WBC's to damage parasites, with degranulation by direct contact, cytokine induced, Fcy RII or Fce RII
• Cytoplasmic granules contain perforin, major basic protein , eosinophil cationic proteinand eosinophil-derived neurotoxin
• Eosinophils cause inflammation and type I hypersensitivity
  • IL-5 promotes eosinophil maturation from myeloid precursors

Basophils and Mast Cells

• Basophils are rare (0.02% of WBCs)
• Mast cells reside in numerous tissues and mucosal epithelium near blood vessels
• Basophils and Mast cells express receptors via IgE(Fce RI- high affinity). complement componentsC3aR, C5aR and PAMPS(PRRs)
• They release inflammatory mediators(histamine, PGD2, LTC4, IL-1, IL-6, TNF) and anaphylaxis mediators

Natural Killer (NK) Cells

• NK cells make up 5-10% of WBCs, distinct from T and B cells, which don't require expansion or differentiation to kill
• Their phenotype is CD16+, CD56+, CD3-
• The target of NK cells include cells infected with viruses and cancer cells, which include:
  • FasL-Fas interaction
  • Exocytosis of granules (perforin and granzymes)
  • ADDC(antibody-dependent cell-mediated cytotoxicity)
• Cytokines secreted by NK cells include INF-y and TNF-α
  • IL-2 → activate NK, IL-12 → increase Cytoxicity, IL-15 → release INF-gamma, IL-18
• Granule-associated killing mechanisms involve perforin to create holes, allowing entry of granzymes that initiate a signalling event to cause apoptosis

Activating and Inhibitory Receptors of NK Cells

• A locked inhibitory receptor prevents activation of NK cells
• When inhibitory receptor is not engaged on a virus infected host activation ensues
• B- Inhibitory receptor not engaged

Dendritic Cells

• Dendritic cells capture and transport pathogens to lymph nodes, displaying antigen to naive T cells, cross presenting via MHC I and MHC II
• Dendritic cells express co-stimulatory molecules (CD40, CD80/CD86), MHC II, receptors for PAMPs, chemokine, and adhesion molecules linking innate to adaptive immunity
• Dendritic cells are the link between innate and adoptive immunity and release IL-6, IL-12, TNF-α, and type l interferon

Follicular Dendritic Cells

• Reside in B cell follicles in lymph nodes, spleen and mucosal lymphoid tissues, but they don't present antigen to helper T cells
• Follicular dentritic cells trap antigens to antibodies or complement products and show them so B cells can recognize them

NKT Cells

• NKT cells are a small T cell population that recognize non-protein antigens (lipids and glycolipids) presented by CD1 and express limited diversity α / β TCRs
• NKT cells Produce: INF-y and IL-4 in epithelial tissue (GIT and respiratory)

Τγδ Cells

• Consist of less than 5% of all T cells to initiate immune response at epithelial (gut) tissue
• Has varied antigen recognition and are abundant in epithelial tissue

B1 Cells

• B1 cells develop from feotal liver derived stem cells and separate from the majority (B2) of lymphocytes
• B1 cells differentiate into plasma cells secreting IgM antibodies
• These cells are defined by their expression of CD5 and BCRs

Inflammatory Response

• Prevents infection spread and recruits effector cells, with clinical signs:
  • Redness, swelling, heat, pain, and increased mucus production

Inflammatory Mediators

• C3a and C5a facilitate smooth muscle contraction, mast cell and basophil degranulation, and chemotaxis; Histamine increases endothelial cell contraction
• IL- 1 increase vascular permeability, neutrophil chemotaxis
• TNF prothrombotic activator, promotes leukocyte adhesion and migration for regulation and macrophages activation

Chemokines and Adhesion Molecules

• Chemokines stimulate leukocyte movement towards secreted protein, like CXCL8 and CCL2
• Selectins initiate low-affinity adhesion of circulating leukocytes to endothelial cells
• Integrins mediate cell adhesion to other cells or ECM

Leukocyte-Endothelial Interaction

• TNF and IL-1 activate endothelial cells, producing selectins and integrin ligand
• They stimulate formation of chemokines increase neutrophil production and induce IL- 6

Complement System

• It has the ability to clear pathogens by:
  • Opsonizing cells to attract antibodies to promote phagocytosis
  • Trigger inflammatory cells to recruit
  • Tag them for destruction
• Puncturing holes in the targets plasma membrane causing its death
• Activating a series of plasma proteins that trigger proteolytic cascades

Complement Activation Pathways

• The classical pathway is initiated by antibodies
• The alternative pathway is initiated by a microbe
• The lectin pathway starts via mannose binding lectin

Alternative Pathway Details

• C3 is continuously cleaved at a low rate
• If it is not bound, C3b is quickly hydrolized
• They activate upon meeting a foreign structure

Lectin Pathway Details

• Start on the surface of a microbe with the interaction of Mannose-Binding Lectin to mannose
• Once initated MASP1 and MASP2 connect to the former to activate the pathway
• MASP1 and MASP2 cleave C4 and C2, and no, no antibodies are involved

Classical Pathway Details

• This pathway is linked to adTopitve pathways and the antigens display epitopes on the surface
• Immunoglobulins can activate C1, but only with 1fc
• They are IgM, IgG1, IgG2, and 3 but NOT IgG4

Late-Stage Complement Activation

• The membrane attack complex is activated at the end, leading to cell killing
• Thick walls prevent this pathway from efficiently killing cells

Functions of Complement Components

• Increasing vascular permeability is C2a
• Anaphylatoxins are C5a, C3a, and C4a
• C5a stimulates phagocytic cells
• C3b acts as an opsonization factor
• C5b-9 is a membrane-attack protein

Complement Protein Receptors

• CR1 (promotes phagocytosis by binding to C3b and C4b) and clearance of immune circulating complexes.
• CR2→ (stimulate humoral responses enhancing b cell activation by binding C3d) and is part of the B cell co-receptor.

Acute-Phase Proteins

• Produced by the liver due to acute infeciton
• Examples:C-reactive protein, amyloid, fibrinogen, mannose-binding lectin, SP-A, and SP-D
• They clear infections by: acting as opsinons that bind to pathogens to activate the complement system and promote phagocytosis

Cytokines

• Secreted proteins mediating immune and infalmmatory functions, which trigger several other processes:
  • TNF/IL-1 (adhesion proteins with inflammation)
  • IL-8 is a chemokine (CXCL-8)
  • TNF/IL-1/IL-6 affect both the brain and the liver
  • TNF/IL-1/IL-6 affect bone marrow
• Activation of dendritic cells, macrophages and NK cells, microbes attach to the complex of macrophages and dendritic cells to produce IL-12
  • IL-12 triggers NK cells that excretes the inflammatory cytokines, like TNF to attract inflammation response

Role of Type I Interferons

• Produced whenever viruses infect host cells, causing them to produce Type I interferons
• Uninfected cells have Interferon (IFN) receptors which then enter an antiviral state
  • Which causes degradation of viral RNA or hinders its synthesis and the expression of its gene

Pathogens That Resist Immune Responses

• Pneumococci produces polysaccharides on their capsule that stops phagocytosis from occurring
• Staphylocci use catalase to do the same with phagocytosis
• Neisseria express sialic acid that inhibits certain C3/C5 convertases that hinder activation of the entire complement system

Adaptive Immune Stimulation

• T-call proliferation and differentiation (cell mediated immunity)
• B cell proliferation and differentiation (humoral immunity)
• Macrophage-dendritic complex produces cytokines, costimulatory, and then creates Naive T-cells that mature in the lymph nodes
• Polysaccharides expressed by microbes that contain C3d binds to in the in B lymphocytes receptors to trigger an immune response

Adaptive Immunity

• Adaptive immunity is characterised by: specificity, diversity, memory, and specialisation
• Contraction and homeostasis allow the immune sytem to adapt to threats whilst not becoming autoimmune using non-reactivity
• Unlike adaptive immunity innate immunity response lacks specificity and memory

Humoral or Cell-Mediated Adaptive Immunity

• Humoral immunity uses extacellular microbes with antibodies secreted from B lymphocytes with cellular microbe elimination
• Cell-mediated immunity occurs in microphages to kill with T helper lymphocyte cytokines or can enter inside cells to cause T-cytotoxic lymphocyte

Active and Passive Immunity

• Active immunity develops by getting the disease from a vaccine and develops a defence on the new microbe
• Passive immunity is serum injections that temporarily fight a threat
  • Active immunity develops a specialised memory whereas passive has none

Lymphocyte-Mediated Adaptive Immunity

• B cells (antibodies) can also neutralise microbes and phagocitize as part of the innate response
• T cells can kill with cytokines and also release cytokines from infected cells
• Antigen-presenting cells and effector cells trigger antigen elimination

Types of B Lymphocytes

• B-1a (CD5+) and B-1b (CD5) trigger the production oh IgM for innate repsosne
• Also known as breg cells that release TGF to regulate immunal function

T Helper and Cytotoxic Lymphocytes

• Differ in their cytokine profile, with all types having the same CD profile
• TH1 cells create IL-2 using INF (MAC) for help complement/ IgG activation
• TH2 produce IL-4,5,10 and 13 which help differiation of IgA and E (mucosal immunity)
• TH17 stimulate inflammatory response by helping with IgM, IgG, and IgA production
• With certain subtypes deviating and controlled via INF and and IL-10

Thymocyte Cells

• TH1 (intracellular) and TH2 (parasites) lead to to autoimmunity if hindered in job
• Disruptions of the Thymocyte cycle can prevent the immune system collapsing

Regulatory Lymphocytes

• Squelsh immune response, releasing Treg 1, 3, and 2 with IL-10
• Gut tolerance to gut antigen, hyper sensitivity reduction, and protection of the fetus

Cytotoxic Lymphocytes

• Alpha and delta are key components of the innate response to clear viruses, tumours, and block the latters replication

Humoral vs Active Lymphocytes

• Adult Cells dont contact contact antigen whilst immature ones can, those that do and survive stimulate cell populations Differentiated cells lead to Th for CD4 and plasma cells, with an increase in CTLS (which have CD8)
• Can survive after stimulation because memory T cells develop Surface CD's to adapt

Cytokines and Antiogens

• Short term synthesidation by varying gene expressions that affect an immune response
• Antigens and Immunagens are substances bound by various antibodies to trigger TCR

Explore the cooperation between innate (rapid, non-specific) and adaptive (slow, specific) immune responses. Learn about anatomical, chemical, and biological barriers in innate host defenses. Understand cellular and humoral components involved in immunity.