5.2 Innate and adaptive immune responses to the microbiome

The immune system's response to the microbiome involves both innate and adaptive mechanisms. Innate immunity provides quick, non-specific defense, while adaptive immunity offers targeted, memory-based protection. These systems work together to maintain a delicate balance between tolerance and protection.

Pattern recognition receptors play a crucial role in detecting microbial components and triggering immune responses. The gut-associated lymphoid tissue, the largest component of mucosa-associated lymphoid tissue, is key in shaping immune responses to the microbiome and maintaining homeostasis in the gut.

Innate vs Adaptive Immunity

Characteristics and Components

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• Innate immunity provides rapid, non-specific defense against microbes
• Adaptive immunity offers specific, memory-based protection developing over time
• Innate immune system includes physical barriers (skin, mucous membranes), antimicrobial peptides (defensins, cathelicidins), complement proteins, and phagocytic cells (neutrophils, macrophages)
• Adaptive immunity involves T and B lymphocytes recognizing specific antigens
  • B cells produce antibodies
  • T cells mediate cellular immunity
• Adaptive immunity provides long-lasting immunological memory
  • Memory B and T cells respond quickly to subsequent exposures

Microbiome Interactions

• Microbiome shapes both innate and adaptive immune responses through continuous interactions with host immune cells
• Innate immune responses to microbiome involve activation of pattern recognition receptors
• Adaptive responses include generation of microbiome-specific antibodies and T cells
• Balance between pro-inflammatory and regulatory immune responses maintains homeostasis with microbiome
  • Pro-inflammatory responses protect against pathogens
  • Regulatory responses prevent excessive inflammation and tissue damage

Pattern Recognition Receptors for Microbes

Types and Functions

• Pattern recognition receptors (PRRs) recognize conserved microbial structures called pathogen-associated molecular patterns (PAMPs)
• Toll-like receptors (TLRs) detect various microbial components
  • TLR4 recognizes lipopolysaccharides from gram-negative bacteria
  • TLR2 detects peptidoglycan from gram-positive bacteria
  • TLR3, TLR7, and TLR9 recognize different types of microbial nucleic acids
• NOD-like receptors (NLRs) recognize intracellular microbial products
  • NOD1 and NOD2 detect peptidoglycan fragments
  • NLRP3 forms inflammasomes in response to various stimuli
• C-type lectin receptors (CLRs) detect carbohydrate structures on microbes
  • Dectin-1 recognizes β-glucans on fungal cell walls
  • Mannose receptor binds to mannose-rich structures on pathogens
• RIG-I-like receptors (RLRs) detect viral nucleic acids
  • RIG-I recognizes short double-stranded RNA
  • MDA5 detects longer double-stranded RNA

Signaling and Responses

• PRR activation triggers signaling cascades leading to production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines, and antimicrobial peptides
• PRRs maintain balance between tolerance to commensals and responses against potential pathogens
  • Commensals induce low-level PRR activation promoting immune homeostasis
  • Pathogens trigger strong PRR activation leading to inflammation

Gut-Associated Lymphoid Tissue (GALT)

Structure and Development

• GALT largest component of mucosa-associated lymphoid tissue (MALT)
• Development begins prenatally and continues postnatally, influenced by colonizing microbiome
• GALT consists of organized lymphoid structures
  • Peyer's patches clustered in small intestine
  • Isolated lymphoid follicles scattered throughout intestinal mucosa
  • Mesenteric lymph nodes draining intestinal tissue
• M cells in follicle-associated epithelium of Peyer's patches facilitate antigen sampling from gut lumen
  • Transcytose antigens to underlying immune cells

Functions and Interactions

• Dendritic cells in GALT present antigens to T cells, shaping adaptive immune response
  • CD103+ dendritic cells promote regulatory T cell differentiation
  • CX3CR1+ macrophages sample luminal antigens and maintain tolerance
• GALT generates IgA-producing plasma cells
  • Secrete antibodies into gut lumen maintaining microbial homeostasis
• Bidirectional interaction between GALT and microbiome
  • Microbiome influences GALT development and function
  • GALT shapes microbial composition through selective IgA coating

Immune Tolerance and the Microbiome

Mechanisms of Tolerance

• Immune tolerance prevents inappropriate responses against commensal microbes
• Central tolerance eliminates self-reactive T and B cells during development
  • Occurs in thymus for T cells and bone marrow for B cells
• Peripheral tolerance maintains non-responsiveness to commensal microbes
  • Regulatory T cells (Tregs) suppress excessive immune responses
  • Tolerogenic dendritic cells promote Treg differentiation
  • Anergy induction in self-reactive T cells

Microbiome Influence on Tolerance

• Microbiome induces and maintains immune tolerance through metabolites and interactions with host immune cells
• Short-chain fatty acids (SCFAs) produced by commensal bacteria promote Treg differentiation
  • Butyrate enhances Foxp3 expression in T cells
  • Propionate modulates dendritic cell function
• SCFAs maintain integrity of intestinal epithelial barrier
  • Enhance tight junction protein expression
  • Promote mucus production by goblet cells
• Dysregulation of immune tolerance can lead to inflammatory bowel diseases (Crohn's disease, ulcerative colitis) and other autoimmune disorders
• Therapeutic approaches exploring promotion of immune tolerance
  • Probiotics (Lactobacillus, Bifidobacterium) to enhance Treg function
  • Prebiotics (inulin, fructo-oligosaccharides) to promote SCFA production