Lecture 17 AI Notes

Immunology Study Notes

Course: HSCI 3540
Lecture: #17
Textbook: Kuby Immunology, Eighth Edition
© 2019 W. H. Freeman and Company

Today's Plan

  • Intestinal Epithelium

  • Immunological Interactions

  • Other Barrier Interactions

Barrier Immunity

  • Definition: Barrier immunity encompasses the immune systems associated with the skin and mucosal tissues.

  • Components:

    • Gut or mucosal-associated lymphoid tissue (GALT or MALT).

    • Microbes coexisting peacefully at barrier surfaces are referred to as commensal organisms.

    • Homeostasis is preserved by mechanisms that inhibit inflammation and promote tolerance.

Epithelial Cells and Their Functions

  • Physical Barrier: Epithelial cells serve as a primary physical barrier and are actively involved in responses to the microbiome.

  • Protective Functions:

    • Some epithelial cells produce a protective mucus layer.

    • Some secrete antimicrobial peptides (AMPs) that can kill or inactivate bacteria.

    • Cells with cilia act to sweep pathogens away from epithelial surfaces.

  • Response to Damage:

    • Damaged epithelial cells release specific signals to immune cells to initiate an inflammatory immune response against microbial invasion.

Intestinal Anatomy

  • Organization: The gut is organized into various anatomical sections and tissue layers:

    • Lumen: The interior of the gastrointestinal (GI) tract.

    • Mucosa: Comprising epithelial cells and lamina propria.

      • Lamina Propria: Home to resident and migrating immune cells.

      • Isolated Lymphoid Follicles (ILFs): Sites for generation of IgA-producing B cells and plasma cells.

    • Submucosa: The connective tissue layer between the mucosa and muscular wall.

Epithelial Cell Types and Functions

  • Phenotype and Functionality: Gut epithelial cells exhibit variability in both phenotype and function.

  • Cell Polarization:

    • Epithelial cells are polarized.

    • Apical Surface: Faces the lumen.

    • Basolateral Surface: Contains polymeric Ig receptors that capture and internalize IgA produced in the lamina propria.

  • Types of Epithelial Cells:

    • Enterocytes: Uptake epithelial cells recognizing microbial pattern recognition receptors (PRRs) and alerting the immune system via internal TLR4.

    • Goblet Cells: Secrete mucus and AMPs, transporting antigens and microbes to antigen-presenting cells (APCs) in the lamina propria, and secreting regulatory cytokines.

    • Tuft Cells: Secrete cytokines that initiate immune responses specifically targeting parasitic worms.

Specialized Gut Cells

  • Microfold (M) Cells:

    • Specialized for transcytosis of antigens across the epithelium to dendritic cells located in Peyer’s patches and ILFs.

  • Paneth Cells:

    • Reside in intestinal crypts and produce secretory factors that sustain stem cells.

    • Secrete antimicrobial peptides (AMPs).

  • Intraepithelial Lymphocytes (IELs):

    • Express CD8 and function as resident memory cells.

Immunological Interactions

  • Defensive Strategies: Three strategies help maintain barriers between microbiota and the epithelium to prevent microbial penetration:

    • Mucus Production: By goblet cells, which inhibits bacterial motility.

    • AMP Production: By Paneth and goblet cells, producing defensins, lysozyme, and REG3.

      • Defensins: Create pores in bacterial membranes.

      • Lysozyme: Destroys bacterial cell walls.

      • REG3: Is lethal for gram-positive bacteria.

    • Antibody Secretion: Plasma cells in the lamina propria secrete IgA that neutralizes microbiota adhesins.

      • IgA Transcytosis: Adds secretory components that stabilize the dimeric form.

Mucosal-Associated Lymphoid Tissue

  • Local Lymph Nodes: Barrier tissues are supported by local lymph nodes.

    • Mesenteric Lymph Nodes: Specifically drain the intestine.

  • Cellular Composition: Barrier organs are populated with innate and adaptive immune cells, including dendritic cells, macrophages, innate lymphoid cells, and B and T lymphocytes.

Barrier Immunity Responses

  • Tolerogenic vs. Inflammatory Responses:

    • A healthy barrier balances tolerance and inflammation; the immune system is predominantly tolerogenic.

    • Constant exposure to the microbiota trains sampling dendritic cells to tolerate their presence.

  • Effects of Dysbiosis:

    • Dysbiosis, resulting from antibiotics or infections, can enhance inflammation.

  • Cytokine Production:

    • Cell-microbe interactions can trigger the production of anti-inflammatory molecules and cytokines, such as TGF-β and IL-10, which enhance production of TREG cells and IgA-secreting B cells.

  • Role of IgA:

    • IgA interacts with commensal microbes to prevent their penetration across epithelial barriers, thwarting potential inflammatory responses.

Anti-Inflammatory Cytokines

  • Examples of Anti-Inflammatory Cytokines:

    • IL-10

    • TGF-β

  • Question: Which of the following are anti-inflammatory cytokines?

    • A. IFN-gamma

    • B. IL-2

    • C. IL-10

    • D. TGF-beta

T Cell Differentiation

  • Cytokine Influence: The nature of cytokines detected influences how T helper (TH) cells differentiate.

  • Master Regulators: These biomolecules commit T cells to specific subsets, leading to the production of cytokines that guide the immune response.

TREG Cells and Tolerance

  • Dendritic Cell (DC) Function: When encountering antigens in a tolerogenic environment, DCs promote T-cell differentiation toward the TREG lineage.

  • TREG Cell Population: TREG cells constitute approximately 30% of all T cells in the lamina propria and play a critical role in maintaining tolerance.

  • Cytokine Production: TREG cells secrete cytokines such as IL-10 and TGF-β that reinforce tolerance.

  • B Cell Activation: Conventional B cells activated in Peyer’s patches or by mesenteric lymph nodes lead to IgA class switching stimulated by the cytokine environment established by intestinal immune cells.

IgA Production

  • Mechanism:

    • Antigens from the GI tract are presented to naïve T cells within Peyer’s patches.

    • Activated T cells stimulate T follicular helper (TFH) cell activity.

    • Follicular dendritic cells (FDCs) also activate naïve B cells by binding antigens.

    • TGF-β is involved not only in anti-inflammatory signaling but also stimulates class switching to IgA and expression of tissue-homing receptors (CCR9 and α4β7).

TH1 Inflammatory Cytokines

  • Examples of TH1 Inflammatory Cytokines:

    • IFN-gamma

    • IL-17

  • Question: Which of these are TH1 inflammatory cytokines?

    • A. IFN-gamma

    • B. IL-4

    • C. IL-5

    • D. IL-17

Inflammatory Responses

  • Activation Impact: Inflammatory conditions can activate DCs, leading to typical immune responses.

    • This includes activating inflammatory TH1 or TH17 cells that produce pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17).

  • Response Determinants: The balance between inflammatory and anti-inflammatory cytokines ultimately dictates the nature of the immune response.

Intestinal Antigen Sampling

  • Antigen Transfer Mechanisms: Antigen delivery from intestinal epithelium to APCs occurs through various mechanisms:

    • Cells like M cells sample antigens in the lumen and transfer them to the lamina propria.

    • Fc receptors (FcR) carry IgA-antigen complexes from the lumen to the lamina propria.

    • Goblet cells also convey soluble antigens from the lumen to the lamina propria.

    • Resident APCs extend their processes between epithelial cells to sample antigens directly from the lumen.

Microbiota Functions

  • Role in Health: The GI tract plays a critical role in maintaining the well-being of the commensal microbiome and regulating local and systemic immune responses.

  • Effects on Immunity:

    • Commensal microbes maintain a tolerogenic tone in the intestine and the wider immune system, particularly effective at stimulating TREG tolerance.

    • Firmicutes: Ferment dietary fibers to produce short-chain fatty acids (SCFAs) that influence APCs and enhance the development of TREG cells, boosting IgA production and TH17 development.

    • Bacteroides fragilis: Produces polysaccharide A (PSA) which helps maintain the systemic TREG pool.

Dysbiosis

  • Definition: Dysbiosis refers to the disruption of the healthy microbiome balance, allowing pathobionts (potentially pathogenic bacteria) to proliferate.

  • Causes:

    • Conditions leading to dysbiosis include past infections, antibiotic treatments, stress, poor diet, pollutants, and genetic predispositions.

Response to Pathogens

  • Two Phases of Immune Response:

    • Inductive Phase: Activates the immune response initiated by epithelial cells and APCs that recognize PRRs and TLRs.

      • Example: Salmonella can invade epithelial cells or pass through M cells.

      • Activated APCs can polarize naïve T cells to TH1/TH17 or TH2/TH9 depending on the pathogen type.

    • Effector Phase: Aims to clear or expel invading organisms.

      • Type 1 response: ILC3 and TH17 cells recruit neutrophils, especially with intracellular pathogens like Salmonella.

      • ILCs secrete IL-22 that prompts epithelial AMPs, enhancing barrier function.

      • End result: Recruitment of phagocytic neutrophils and activation of APCs.

Pathogen Specificity

  • Type 2 Response to Worms: The intestinal immune system mounts a type 2 response targeting worms.

    • Sensed by tuft cells in the epithelium that produce alarmins and cytokines such as IL-25, triggering the type 2 response.

    • This response leads to the production of cytokines (IL-4, IL-5, IL-13) by ILC2 and TH2 cells, resulting in IgE production and eosinophil degranulation to eliminate the worm.

Intestinal Autoimmunity

  • Dysbiosis Impact: Disruption of a healthy microbiome contributes to the development of Inflammatory Bowel Disease (IBD).

    • Crohn’s Disease: Linked with inappropriate TH1 response.

    • Ulcerative Colitis: Associated with inappropriate TH2 response.

    • Celiac Disease: An autoimmune disorder triggered by an immune response to gluten, leading to IL-15 production that activates intraepithelial lymphocytes (IELs), resulting in epithelial cell death.

Respiratory Epithelia

  • Functions: Epithelial cells possess cilia to clear microbes from the airway.

    • Alveolar macrophages, known as dust cells, help manage tolerogenic and inflammatory responses.

    • Tonsils and adenoids serve as nasal-associated lymphoid tissue (NALT), akin to Peyer’s patches.

Immune Response in Respiratory Epithelium

  • Microbial Interactions: Invading microbes trigger events in the respiratory system that parallel intestinal responses.

    • Alveolar macrophages receive anti-inflammatory signals from epithelial cells (e.g., CD200 and αvβ6).

    • Upon engaging with microbes through PRRs, they initiate a cascade of pro-inflammatory signals and cytokines.

    • Ag-specific lymphocytes target respiratory tissues, whilst worms and allergens prompt epithelial cells to release alarmins, stimulating a type 2 immune response.

Skin Barrier

  • Characteristics: The skin represents a unique barrier, with keratinocytes forming the first waterproof line against infection.

    • Keratinocytes act as innate immune cells producing antimicrobial molecules and recognizing pathogen-associated molecular patterns (PAMPs).

    • Langerhans Cells: Skin-resident dendritic cells in the epidermis, communicating with immune cells in the dermis.

    • Resident Memory T Cells: Located in the epidermis, integrating within the skin's immune architecture.

    • The dermis contains the majority of immune cells along with lymphatic vessels to transport antigens to lymph nodes.

Learning Objectives

  • Identify the cells and tissues of the gastric epithelium and their role in creating an antimicrobial barrier.

  • Understand how the gastric epithelium establishes an anti-inflammatory, tolerogenic state, including IgA generation.

  • Analyze how inflammation disrupts this anti-inflammatory state.

  • Understand the mechanisms employed to sample lumen antigens.

  • Investigate the microbiota's role in establishing a healthy gut immune system and the impact of dysbiosis.

  • Understand the immune system's inductive and effective phases when combating pathogens, including intracellular versus extracellular pathogen responses.

  • Identify autoimmune disorders linked to gastrointestinal immunity.

  • Grasp the construction of the respiratory epithelium immune system and its pathogen response mechanisms.

  • Understand how the skin immunological barrier is formed.