Regional and Mucosal Immunity

Regional Immunity

• The body interacts with its environment through epithelial tissues.
• The immune system at epithelial surfaces has unique properties for protection against microbial challenges.
• Specialized properties ensure tolerance to nonpathogenic commensal organisms on epithelia and in mucosal lumens.
• A regional immune system is a collection of components serving specialized functions at a specific anatomical location.

Mucosal Immune System

• Protects internal body surfaces like the GI tract, urogenital tract, respiratory tract, and exocrine glands.
• Forms the largest part of the body's immune tissues, containing a quarter of lymphocytes and most immunoglobulin.
• Produces a lot of IgA in the gut.
• Most bacteria try to evade protection at the mucosal surfaces
• Requires immune tolerance to non-pathogenic foreign antigens (food, environmental factors) and the microorganisms in the healthy large intestine.
• Gut bacteria provide enzymes for digestion, develop the immune system, promote proper immune system development, and prevent pathogen colonization

Immune Response Challenge

• The immune system will need to eliminate pathogenic organisms, limit growth of commensal organisms, and remain harmless to food and environmental antigens

Intestinal Epithelium

• Forms a physical barrier to the external environment.
• The lamina propria contains connective tissue with blood vessels, lymphatic vessels, and lymphoid tissues.
  • It also contains immune cells
• Crypts create epithelial cells that shed in the intestinal lumen.
• The intestinal epithelium is the first defense for the mucosal immune system in the gut.

Immune Components with Intestinal Epithelium

• Intestinal epithelial cell barrier includes tight junctions and antimicrobial proteins
• Innate lymphoid cells secrete IL-17 for neutrophil recruitment, and IL-22 to enhance the mucosa barrier function.

Defensin / Cathelicidins

• Two mucus layers, the 1st layer is inhabited by bacteria , pushing bacteria out through the motion of peristalsis
• The 2nd layer contains antimicrobial proteins such as cathelicidins and defensin which prevent bacterial growth
• Goblet cells produce mucin
• IgA is essential for maintaining luminal compartmentalization.
• IgA binds to and neutralizes toxins

Symbiotic Bacteria

• IgA deficiency can lead to increased penetration of symbiotic bacteria into the host tissue.
• ɣδ intestinal epithelial lymphocytes (like T cells) act like innate immune cells by secreting growth, antimicrobial, and pro-inflammatory factors
• These lymphocytes don't recognize MHC-associated peptide antigens, aren't MHC-restricted, and exhibit limited diversity, recognizing conserved ligands like PRRs.
• Macrophages phagocytose bacteria that pass across the barrier of mucosal origin

Intestinal Epithelial Cells

• Express PRRs (pattern recognition receptors) with adaptations for tolerance.
• No PRRs are on the luminal side
• Express little/no cell surface TLRs, minimizing recognition of microbes
• Basolateral and intracellular PRR localization engages only pathogenic bacteria that invade the epithelial cell barrier.

Small Intestines

• Contain specialized epithelial Paneth cells at the base of crypts.
• The crypt lumen is maintained sterile in contrast to the intestinal lumen, preventing injury to nearby epithelial stem cells.
• Bacteria in infected crypts activate pattern recognition receptors on Paneth cells.
• After activation through PRRs, Paneth cells produce anti-microbial proteins like defensins that lyse bacterial membranes to keep the crypt lumen free of bacteria

Adaptive Immune Response

• Intestinal adaptive immune response activation and effector functions happens in the mucosa-associated lymphoid tissue (MALT) located in specific gut (GALT) compartments.
  • GALT include Peyer's patches (ilium), solitary lymphoid follicles in the intestine, appendix, tonsils, adenoids, mesenteric lymph nodes.
• GALT can be divided into scattered lymphoid cells for effector sites, and organized tissues for induction sites with activation sites

Organized Tissues for Gut Antigens

• Peyer's Patches are aggregates of lymphoid cells built into the intestinal wall with large B cell follicles, T cell regions, and macrophages/dendritic cells
• M cells uptake pathogens from the intestinal lumen, and transcytose them into the lymphoid tissue, handing them off to dendritic cells

M Cells

• Do not secrete digestive enzymes or mucus, and lack thick glycocalyx, enabling microorganism and particulate antigen uptake from the gut lumen.
• Continuously sample luminal antigens, which are taken up by dendritic cells on the basal surface
• Dendritic cells then present to naive T and B cells in Peyer's patches or mesenteric lymph nodes

Dendritic Cells in Lamina Propria

• Captures luminal antigens and then move into T-cell area of a mesenteric lymph node to stimulate antigen specific T cells
• DCs extend processes between the cells of the epithelium
• Loaded DCs traffic to T cell areas of the mLN to interact with naïve lymphocytes
• Effector DCs (CXC3R+) capture luminal antigens (independently of M cells) and move into the mesenteric lymph node's T-cell area to stimulate effector T cell responses, and then activate the response
• Activated intestinal CD4 T cells differentiate into IFN-gamma or IL-17 producing cells.
• Mesenteric lymph nodes are isolated lymphoid follicles with effector sites of activated lymphocytes scattered throughout the epithelium and lamina propria of mucosa

Effector CD4+ T Cells

• Different subsets of these cells are induced in the gastrointestinal tract and protect against different microbial species
• Th17 cells maintain the epithelial barrier with IL-22 (and IL-17 to recruit neutrophils), and induce mucin and defensin production
• Th2 cells eliminate parasitic worms with IL-4 and IL-13 signaling and IgE class switching and IL-5 recruits eosinophils
• Regulatory DCs (CD103+) induce regulatory T cell responses to suppress immunity and are conditioned by mucosal epithelial cells to secrete TGF-beta and retinoic acid

Treg Differentiation Factor

• Tregs suppress inflammation through the production of IL-10 and TGF-beta
• Proportion of FoxP3+ Tregs among CD4+ cells is doubled in intestines than in other tissues
  • No FoxP3= IPEX immunodeficiency disease, which is therefore no Tregs, and massive anti-inflammation
• Humoral immunity in the gut is dominated by production of IgA in GALT and transport across the mucosal epithelium into the lumen.
• IgA is a neutralizer that binds to microbes and toxins to prevent binding to host cell receptors.
• Antibody responses to ingestion exposure are IgA and secretory immunity, which is shown with examples of oral vaccines like live-attenuated polio vaccine

Dominance of IgA

• Dominance comes from intestinal plasma cells due to selective induction of IgA isotype switching in GALT-activated B cells and mesenteric lymph nodes
• It can occur through mechanisms dependent on T cell and mechanisms independent of T cells.
• The T cell dependent pathway of IgA class switching involves transport of luminal antigen by M cells.
• It then presents in CD4 T cells
• Interaction happens with CD40-Ligand and CD40 interaction between activated CD4 T cells and B cells engaging antigen - A 2nd cytokine signal for this pathway is: TGF-beta for follicular B cells which signal for IgA switch class
• This yields high affinity IgA (dimer) against pathogens and toxins

T Cell Independent Pathway of IgA Class Switching

• This pathway involves B-1 B cells (responds more to polysaccharide/lipid antigens) TLR activated DCs of this pathway secrete factors that induce IgA class switching, including BAFF, APRIL, and TGF-beta, which yield low affinity IgA to intestinal bacteria by lamina propria

Release of IgA

• IgA mechanisms involves IgA protection from secretion due to the binding fragment of poly-lg receptor
• Poly - lg receptor protects secreted IgA from broken or degraded components in the intestinal lumen

Actions of IgA

• Intestinal IgA neutralizes on gut surfaces and it can be secreted
• IgA internalizes binds of antigens
• Secreted IgA can export toxins and pathogens from the lamina

Priming Outcome in GALT

• It yields intestinal antigens that can result into different outcomes Antigen from invasive bacteria creates protective immunity with specific antibodies
• Food proteins and commensal bacteria creates immunological unresponsiveness by oral tolerance and IgA

GALT Differentiation

• How it differentiates from common bacteria with harmless commensal bacteria with food
  • It activates from the innate system with mechanisms of tissue from pathogens and production of inflammatory cytokines
  • Commensal bacteria lacks the ability to trigger response that the innate immunity system possesses

Intestinal Epithelium Cont.

• They lack the ability to penetrate the intact intestinal epithelium
• Do not trigger TLRS

Pathogenic GI Organism

• Salmonela and Shigella can use either M or DC cells infecting into the epithelium
• Bind in epithelium of intestinal lining to create response

GALT and Mesenteric Lymph Nodes

• The GALT have selective integrin cells and chemokine to home circulation
• Have acquire phenotype that acquire through gut

MadCAM

• GALT allows restricted tissues within vascular blood flow with mucosal surfaces
• Provides immune responses

Lymphocytes Compartments

• 3 Types B, CD4 and C D8 create epithelium in the mucosa layer
• Lymphocytes can migrate into the epithelium CD4 = mostly active to effector system CD8= high in cytotoxity Immunocompetence
• General features of immunity with infectious disease
• Defense with bacteria that mediates effector that adapts and causes innate-specific microbes

Host Evasion of Microbes

• Pathogenicity and microvesicles affects effector
• Some microbes has repsonse that are eliminated with no issue • The inherited host for acquired defects can affects the susceptibility of infections

Extracellular

Examples:

1. Staphylococcus
2. Vibrio
3. Streptococcus

Indude through 2 mechanisms:

1. Inductions of destruction
2. Production such as bacterial endotoxins

Adaptive System

• PAMPs will help generate cells with activation during PRRs

Immunity

• The primary and effector cells that help lamina create the epithelium
• MAdCAm that occurs with tissues
• CD4 and CD 8 causes the adaptive of most infectious responses