Skin and Mucosal Immunity: Extracellular vs Intracellular
Extracellular Pathogens – Skin
When an extracellular pathogen enters through the skin, the innate immune system activates several responses to detect and eliminate it:
- Pathogen Recognition: Pattern Recognition Receptors (PRRs) like TLR2 and TLR4 detect Pathogen-Associated Molecular Patterns (PAMPs) on the pathogen’s surface.
- Inflammation: Macrophages and keratinocytes release pro-inflammatory cytokines (IL-1β, TNF-α) to recruit immune cells.
- Phagocytosis and Antigen Presentation: Macrophages and Dendritic Cells (DCs) phagocytize pathogens and present antigens to T cells in lymph nodes.
- Type I Interferon Response: Plasmacytoid DCs produce IFN-I, activating Natural Killer (NK) cells and promoting an antiviral state.
- NK Cells: Release perforin and granzymes to kill infected cells.
- Complement and Mast Cells: Opsonize pathogens and release histamine to increase vascular permeability.
- Effector Cells: Macrophages and eosinophils eliminate additional pathogens through cytotoxicity.
Intracellular Pathogens
When pathogens are intracellular:
- Pathogen Recognition: Infected cells detect PAMPs via cytoplasmic PRRs like NOD-like receptors, RIG-I-like receptors, and the cGAS-STING pathway.
- Type I Interferon (IFN-I) Response: Infected cells secrete IFN-α/β, which:
- Induces inflammation, recruiting NK cells and macrophages.
- Establishes an antiviral state by inhibiting viral replication, degrading RNA, blocking translation, and increasing antigen presentation.
- Plasmacytoid DCs: Boost IFN-I production (100–1000x more) upon recognizing viruses, enhancing NK cell activation.
- NK Cells: Detect infected cells via activatory/inhibitory signals and HLA. Induce apoptosis using perforin and granzymes. Work synergistically with macrophages.
- Conventional DCs: Phagocytose apoptotic bodies and migrate to lymph nodes to present antigens, bridging innate and adaptive immunity.
- Macrophages: Engulf pathogens, release pro-inflammatory cytokines, and enhance NK cytotoxicity.
This coordinated response ensures rapid containment of intracellular pathogens while activating adaptive immunity.
Extracellular Pathogens – Mucosal Barrier
When extracellular bacteria penetrate the mucosal barrier, they are detected by dendritic cells (Antigen-Presenting Cells – APCs), which capture their antigens and migrate to lymph nodes or mucosa-associated lymphoid tissue (MALT) to present them to naive CD4+ T cells. Activated CD4+ T cells differentiate into Th1 and Th17 cells.
Th17 cells dominate the mucosal response, recruiting neutrophils to enhance phagocytosis and stimulating epithelial cells to produce antimicrobial peptides, while Th1 cells activate macrophages to boost phagocytic activity.
B cells, with T cell help, differentiate into plasma cells and produce antibodies:
- IgA: Neutralizes bacteria in the mucosal lumen and prevents adhesion.
- IgG: Opsonizes bacteria and activates complement, leading to enhanced bacterial destruction.
These antibodies neutralize pathogens, promote opsonization, and trigger complement activation, ultimately eliminating the bacteria. Memory T and B cells are generated to ensure a faster and more robust immune response upon re-exposure.
T Regulatory Cells (Treg)
- Tolerogenic Mucosal Microenvironment: Controlled inflammation with TGF-β and IL-10 promoting Treg differentiation. Antigen presentation by tolerogenic dendritic cells (DCs) with low co-stimulatory signals.
- Tolerogenic DC Activation: Recognition of commensal antigens via PRRs without triggering excessive pro-inflammatory responses.
- Role of Gut-Associated Lymphoid Tissue (GALT): GALT provides a tolerogenic environment with TGF-β, retinoic acid, and metabolites like short-chain fatty acids (SCFAs), enhancing Treg generation.
- Helminth Interactions: Helminths induce an anti-inflammatory environment with IL-10 and TGF-β, indirectly supporting iTreg development and mucosal tolerance.
- Effector Balance: iTregs suppress excessive immune responses, preventing inflammation from mast cells and eosinophils, while maintaining tolerance to commensals.