🛡️Immunobiology Unit 1 – Immunobiology: Intro to Innate Immunity

Key Concepts and Terminology

• Innate immunity provides immediate, non-specific defense against pathogens and foreign substances
• Comprises physical barriers (skin, mucous membranes), chemical barriers (enzymes, pH), and cellular components (neutrophils, macrophages, dendritic cells)
• Pathogen-associated molecular patterns (PAMPs) are conserved molecular structures found on pathogens recognized by pattern recognition receptors (PRRs) on innate immune cells
• Toll-like receptors (TLRs) are a major class of PRRs that detect various PAMPs and initiate innate immune responses
• Complement system consists of plasma proteins that enhance phagocytosis, recruit inflammatory cells, and directly lyse pathogens
  • Three pathways of complement activation: classical, alternative, and lectin pathways
• Cytokines are small signaling proteins secreted by immune cells that regulate immune responses (interleukins, interferons, tumor necrosis factors)
• Chemokines are a subclass of cytokines that attract immune cells to sites of infection or inflammation

Components of the Innate Immune System

• Physical barriers include skin, mucous membranes, and epithelial cells lining respiratory, gastrointestinal, and urogenital tracts
  • Skin provides a mechanical barrier and produces antimicrobial peptides (defensins, cathelicidins)
  • Mucous membranes secrete mucus that traps pathogens and contains antimicrobial enzymes (lysozyme)
• Chemical barriers consist of enzymes (lysozyme, defensins), pH (acidic environment in stomach), and antimicrobial peptides
• Cellular components include phagocytic cells (neutrophils, macrophages), dendritic cells, natural killer (NK) cells, and innate lymphoid cells (ILCs)
• Humoral components include complement proteins, acute phase proteins (C-reactive protein), and cytokines
• Innate immune system is evolutionarily ancient and found in all multicellular organisms
• Provides rapid response to pathogens within minutes to hours of exposure

Cellular Players in Innate Immunity

• Neutrophils are the most abundant white blood cells and first responders to infection
  • Phagocytose and kill pathogens through oxidative burst and release of granules containing antimicrobial enzymes
• Macrophages are long-lived phagocytic cells that reside in tissues and engulf pathogens, debris, and apoptotic cells
  • Secrete cytokines and present antigens to T cells, linking innate and adaptive immunity
• Dendritic cells are professional antigen-presenting cells that capture, process, and present antigens to T cells
  • Mature upon encountering pathogens and migrate to lymph nodes to initiate adaptive immune responses
• Natural killer (NK) cells are cytotoxic lymphocytes that recognize and kill virus-infected and tumor cells
  • Secrete cytokines (interferon-gamma) that activate macrophages and enhance antiviral responses
• Innate lymphoid cells (ILCs) are tissue-resident cells that secrete cytokines and regulate mucosal immunity
  • Three main subsets: ILC1 (produce interferon-gamma), ILC2 (produce IL-5 and IL-13), and ILC3 (produce IL-17 and IL-22)
• Eosinophils and basophils are granulocytes involved in allergic reactions and defense against parasites
• Mast cells are tissue-resident cells that release histamine and other mediators in allergic responses

Recognition of Pathogens

• Innate immune cells express pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs)
• PAMPs are conserved molecular structures essential for pathogen survival and absent in host cells (lipopolysaccharide, peptidoglycan, double-stranded RNA)
• Toll-like receptors (TLRs) are a major class of PRRs expressed on cell surface or in endosomes
  • Different TLRs recognize specific PAMPs: TLR4 (lipopolysaccharide), TLR3 (double-stranded RNA), TLR9 (CpG DNA)
• Other PRRs include C-type lectin receptors (CLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs)
• PRR engagement activates signaling cascades that lead to production of cytokines, chemokines, and antimicrobial molecules
• Innate immune cells also express receptors for opsonins (complement, antibodies) that enhance phagocytosis
• Natural killer (NK) cells express activating and inhibitory receptors that regulate their cytotoxic activity
  • Activating receptors (NKG2D) recognize stress-induced ligands on infected or tumor cells
  • Inhibitory receptors (KIRs) recognize self MHC class I molecules and prevent NK cell activation

Innate Immune Responses

• Phagocytosis is the process by which phagocytic cells (neutrophils, macrophages) engulf and destroy pathogens
  • Involves recognition of PAMPs or opsonized pathogens, actin polymerization, and formation of a phagosome
  • Phagosome fuses with lysosomes containing antimicrobial enzymes and reactive oxygen species
• Neutrophils undergo oxidative burst, generating reactive oxygen species (superoxide, hydrogen peroxide) that kill pathogens
• Neutrophils and other granulocytes release granules containing antimicrobial enzymes (myeloperoxidase, defensins) and proteases
• Natural killer (NK) cells release cytotoxic granules containing perforin and granzymes that induce apoptosis in target cells
• Innate immune cells secrete cytokines and chemokines that regulate immune responses and recruit additional immune cells
  • Macrophages and dendritic cells produce IL-1, IL-6, IL-12, and TNF-alpha
  • Neutrophils and epithelial cells produce IL-8, a potent neutrophil chemoattractant
• Complement system enhances phagocytosis (opsonization), recruits inflammatory cells (anaphylatoxins), and directly lyses pathogens (membrane attack complex)
• Interferons (type I and II) are cytokines that induce an antiviral state in infected and neighboring cells
  • Type I interferons (IFN-alpha, IFN-beta) are produced by most cells in response to viral infection
  • Type II interferon (IFN-gamma) is produced by NK cells and T cells and activates macrophages

Inflammation and Its Role

• Inflammation is a protective response to infection, injury, or tissue damage that involves recruitment of immune cells and release of soluble mediators
• Cardinal signs of inflammation: redness (rubor), heat (calor), swelling (tumor), pain (dolor), and loss of function (functio laesa)
• Acute inflammation is a rapid, short-lived response that aims to eliminate the triggering stimulus and initiate tissue repair
  • Mediated by vasodilation, increased vascular permeability, and recruitment of neutrophils
  • Triggered by PAMPs, DAMPs (damage-associated molecular patterns), and pro-inflammatory cytokines (IL-1, TNF-alpha)
• Chronic inflammation is a prolonged response that can lead to tissue damage and contribute to various diseases (atherosclerosis, cancer, autoimmunity)
  • Mediated by macrophages, lymphocytes, and fibroblasts
  • Characterized by simultaneous destruction and healing of tissue, formation of granulomas or tertiary lymphoid structures
• Inflammatory mediators include cytokines (IL-1, IL-6, TNF-alpha), chemokines (IL-8), lipid mediators (prostaglandins, leukotrienes), and vasoactive amines (histamine)
• Resolution of inflammation involves clearance of pathogens, apoptotic cells, and debris, followed by tissue repair and restoration of homeostasis
  • Mediated by specialized pro-resolving mediators (resolvins, protectins) and anti-inflammatory cytokines (IL-10, TGF-beta)
• Dysregulated inflammation underlies many chronic diseases, making it a target for therapeutic intervention

Connection to Adaptive Immunity

• Innate immune responses provide the first line of defense against pathogens and initiate adaptive immune responses
• Dendritic cells are the key link between innate and adaptive immunity
  • Capture, process, and present antigens to naive T cells in lymph nodes
  • Provide costimulatory signals (CD80/86) and cytokines (IL-12) necessary for T cell activation and differentiation
• Macrophages also present antigens to T cells and secrete cytokines that shape adaptive immune responses
  • M1 macrophages produce IL-12 and promote Th1 responses
  • M2 macrophages produce IL-10 and promote Th2 and regulatory T cell responses
• Innate immune cells express cytokine receptors and respond to cytokines produced by T cells
  • IFN-gamma activates macrophages and enhances their microbicidal activity
  • IL-4 and IL-13 promote alternative activation of macrophages and wound healing
• Complement system enhances antibody-mediated effector functions (opsonization, phagocytosis, antibody-dependent cell-mediated cytotoxicity)
• Innate lymphoid cells (ILCs) secrete cytokines that regulate T cell responses and maintain tissue homeostasis
  • ILC2s produce IL-5 and IL-13, which promote Th2 responses and allergic inflammation
  • ILC3s produce IL-17 and IL-22, which maintain intestinal barrier integrity and protect against extracellular bacteria
• Adjuvants used in vaccines often stimulate innate immune responses (TLR agonists) to enhance adaptive immunity

Clinical Relevance and Applications

• Defects in innate immunity can lead to increased susceptibility to infections
  • Neutropenia (low neutrophil count) is associated with bacterial and fungal infections
  • Chronic granulomatous disease (defective oxidative burst) leads to recurrent infections with catalase-positive bacteria and fungi
• Excessive or dysregulated innate immune responses contribute to inflammatory and autoimmune diseases
  • Sepsis is a life-threatening condition caused by an overwhelming systemic inflammatory response to infection
  • Rheumatoid arthritis is characterized by chronic inflammation of synovial joints mediated by macrophages and fibroblasts
• Targeting innate immune pathways is a promising strategy for treating inflammatory diseases and cancer
  • Monoclonal antibodies against TNF-alpha (infliximab) are used to treat rheumatoid arthritis and inflammatory bowel disease
  • Small molecule inhibitors of JAK kinases (tofacitinib) block cytokine signaling and are effective in treating rheumatoid arthritis and ulcerative colitis
• Harnessing innate immunity is a goal of vaccine development and cancer immunotherapy
  • Adjuvants that stimulate TLRs (monophosphoryl lipid A) are used in vaccines to enhance immunogenicity
  • Chimeric antigen receptor (CAR) NK cells are being developed as an "off-the-shelf" cancer immunotherapy
• Understanding the role of innate immunity in health and disease is crucial for developing new diagnostic tools and therapeutic interventions
  • Biomarkers of innate immune activation (C-reactive protein, IL-6) are used to monitor disease activity and response to treatment
  • Modulating the innate immune system holds promise for treating a wide range of diseases, from infections to cancer to autoimmunity