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Questions and Answers
What role do TLR2 receptors have in maintaining gut homeostasis?
What role do TLR2 receptors have in maintaining gut homeostasis?
How do germ-free mice differ in their immune response compared to normal mice?
How do germ-free mice differ in their immune response compared to normal mice?
What happens to enterocytes' responses under steady conditions when they interact with commensals?
What happens to enterocytes' responses under steady conditions when they interact with commensals?
What is the effect of activated phagocytes producing nitric oxide?
What is the effect of activated phagocytes producing nitric oxide?
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In which mucosal tissue is the role of TLR9 particularly important for antimicrobial peptide secretion?
In which mucosal tissue is the role of TLR9 particularly important for antimicrobial peptide secretion?
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What is the primary consequence of PRR engagement by PAMPs/DAMPs during an immune response?
What is the primary consequence of PRR engagement by PAMPs/DAMPs during an immune response?
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What do NKT cells do in mucosal immunity?
What do NKT cells do in mucosal immunity?
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What impact does the microbiota have on the mucosal immune response?
What impact does the microbiota have on the mucosal immune response?
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What enzyme do DCs express upon TLR5 engagement that influences B cell differentiation?
What enzyme do DCs express upon TLR5 engagement that influences B cell differentiation?
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What is the primary antibody produced by plasma cells in mucosal effector sites?
What is the primary antibody produced by plasma cells in mucosal effector sites?
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How do activated B cells homes to mucosal effector sites after their activation?
How do activated B cells homes to mucosal effector sites after their activation?
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Which is NOT a characteristic role of mucosal IgD antibodies?
Which is NOT a characteristic role of mucosal IgD antibodies?
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What type of T cell response is generally needed when an aggressive pathogen attacks a mucosal surface?
What type of T cell response is generally needed when an aggressive pathogen attacks a mucosal surface?
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What cytokine do interfollicular DCs produce that helps activate Th1 effectors?
What cytokine do interfollicular DCs produce that helps activate Th1 effectors?
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What is a significant effect of the microbiota on the immune response in the gut?
What is a significant effect of the microbiota on the immune response in the gut?
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What method does polymeric IgA use to reach mucosal surfaces?
What method does polymeric IgA use to reach mucosal surfaces?
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What is the primary integrin expressed by mucosal B cells for homing to effector sites?
What is the primary integrin expressed by mucosal B cells for homing to effector sites?
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What influences the expression of CCR9 on mucosal T cells?
What influences the expression of CCR9 on mucosal T cells?
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Which of the following statements regarding immune responses in different mucosal sites is true?
Which of the following statements regarding immune responses in different mucosal sites is true?
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During mucosal defense, which chemokine does CCR9 bind to specifically?
During mucosal defense, which chemokine does CCR9 bind to specifically?
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How do responses to infections in one inductive site affect responses to other pathogens?
How do responses to infections in one inductive site affect responses to other pathogens?
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What distinguishes the microbiota in the urogenital tract from that of the gut?
What distinguishes the microbiota in the urogenital tract from that of the gut?
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What mechanism allows conventional T and B cells to bind to sites of inflammation?
What mechanism allows conventional T and B cells to bind to sites of inflammation?
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Why might some individuals infected with Mycobacterium tuberculosis not develop active disease?
Why might some individuals infected with Mycobacterium tuberculosis not develop active disease?
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What is a primary function of TLRs in enterocytes during steady conditions?
What is a primary function of TLRs in enterocytes during steady conditions?
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Which immune cells are primarily recruited to an infection site during an innate immune response?
Which immune cells are primarily recruited to an infection site during an innate immune response?
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What happens when enterocytes' PRRs engage with PAMPs during an immune attack?
What happens when enterocytes' PRRs engage with PAMPs during an immune attack?
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How do germ-free mice differ from normal mice concerning T cell populations in GALT?
How do germ-free mice differ from normal mice concerning T cell populations in GALT?
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What molecule is produced by activated phagocytes to inhibit viral replication?
What molecule is produced by activated phagocytes to inhibit viral replication?
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What is the main role of retinoic acid in the immune response?
What is the main role of retinoic acid in the immune response?
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Which antibodies can mucosal B cells switch to produce in response to pathogen exposure?
Which antibodies can mucosal B cells switch to produce in response to pathogen exposure?
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What is the function of mucosal IgD antibodies under steady state conditions?
What is the function of mucosal IgD antibodies under steady state conditions?
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What cytokines do activated intestinal Th17 cells primarily produce?
What cytokines do activated intestinal Th17 cells primarily produce?
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What happens to polymeric IgA when secreted into mucosal sites?
What happens to polymeric IgA when secreted into mucosal sites?
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What is the primary role of TLR9 in enterocytes during an immune response?
What is the primary role of TLR9 in enterocytes during an immune response?
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Which type of immune response is typically activated when a host experiences significant injury from a pathogen?
Which type of immune response is typically activated when a host experiences significant injury from a pathogen?
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Germ-free mice exhibit a significant increase in which type of T cells compared to normal mice?
Germ-free mice exhibit a significant increase in which type of T cells compared to normal mice?
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What consequence arises from the engagement of enterocytes’ PRRs when the host is under attack?
What consequence arises from the engagement of enterocytes’ PRRs when the host is under attack?
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Which molecules are recognized by enterocytes’ pattern recognition receptors (PRRs) during an immune response?
Which molecules are recognized by enterocytes’ pattern recognition receptors (PRRs) during an immune response?
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What is a primary feature of secretory IgA (sIgA) that enhances its effectiveness in mucosal defense?
What is a primary feature of secretory IgA (sIgA) that enhances its effectiveness in mucosal defense?
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How does the production of sIgA maintain homeostasis in the gut?
How does the production of sIgA maintain homeostasis in the gut?
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What role do enterocytes play in the production of sIgA?
What role do enterocytes play in the production of sIgA?
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Which statement best describes the specificity of sIgA antibodies in mucosal defense?
Which statement best describes the specificity of sIgA antibodies in mucosal defense?
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What is one reason sIgA is not an efficient activator of complement?
What is one reason sIgA is not an efficient activator of complement?
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Study Notes
Mucosal and Cutaneous Immunity
- Mucosal immune responses are studied primarily in GALT, NALT, and BALT.
- Similar principles apply in other mucosal sites.
- Microbiota contribute to GALT responses. Enterocytes express PRRs interacting with commensals and pathogens.
- Under steady conditions, TLR engagement by commensals dampens inflammation and adaptive responses to innocuous antigens.
- TLR2, TLR5, TLR9, and NOD2 play crucial roles in gut homeostasis.
- Germ-free mice show decreased GALT, elevated Th2 cells, and reduced Th1 and Th17 cells.
- TLR2 engagement by enterocytes induces Tregs.
- Oral tolerance and gut integrity are maintained via Tregs.
Innate Responses to Pathogens
- If a host's steady state is disrupted by injury, pathogen, or toxin, innate responses are activated by the engagement of enterocyte PRRs.
- PRRs recognize PAMPs, DAMPs, and PRMs, triggering the production of pro-inflammatory cytokines and chemokines.
- Complement activation (lectin pathway) may occur.
- Activated phagocytes produce nitric oxide, inhibiting viral replication.
- Antimicrobial peptides (defensins and lactoferrin) secreted by Paneth cells target enteric viruses and bacteria.
- Neutrophils and mast cells are recruited to infection sites, along with αβ and γδ T cells.
- NK and NKT cells are stimulated by cytokines.
- Leukocytes with PRRs and/or Ag receptors are activated, leading to effector actions.
- Neutrophils produce IL-18, which combines with DC-produced IL-12 to stimulate NK cells and IFN-γ release.
- IFN-γ activates DCs and macrophages, increasing their production of inflammatory cytokines.
Adaptive Responses to Pathogens
- Mucosae (e.g., gut and lungs) are fragile, so immunity relies primarily on secretory antibodies like sIgA.
- sIgA protects against pathogens and toxins without extensive inflammation.
- sIgA abundance in secretions, constitutive localization in mucus, and independent of antigenic specificity, make it useful.
- Most sIgA is cross-reactive, effectively dealing with a broader range of threats.
- sIgA's limited complement activation capability reduces the risk of damaging inflammation.
- sIgA is highly resistant to proteases.
- The body produces substantial amounts of sIgA (2-3 grams per day).
- sIgA-producing plasma cells are frequently present in mucosal surfaces, under steady-state conditions.
- Enterocytes play a key role in sIgA production.
- BAFF, APRIL, and IL-10 from enterocytes prompt IgA isotype switching in B cells in the lamina propria.
- DCs utilize TLR5 activation by flagellin, converting vitamin A to retinoic acid for mucosal B cell differentiation into IgA-producing plasma cells.
- Activated B cells circulate in lymph and blood, home to effector sites, and extravasate to their targets.
Other Mucosal Antibodies
- IgG antibodies access body secretions through antibody transporter proteins (in need)
- IgG responses are robust, inducing inflammation and activating complement.
- Tissue damage can occur, but pathogens are destroyed.
- IgD is observed in tears, saliva, nasal and lung secretions (in lesser amounts compared to other body secretions)
- Mucosal IgD is produced by B cell lineage cells with IgD+IgM+ plasmablast phenotype and J-chain synthesis ability.
- IgD binds to commensals in steady state to keep them from penetrating deeply into tissue.
- IgD reacts with pathogens (when necessary) to activate basophils, which release antimicrobial proteins and cytokines.
Th1 and Th17 Responses
- Th1 and Th17 responses combat pathogens attacking mucosal surfaces.
- Interfollicular DCs produce IL-12, causing locally activated T cells to differentiate into Th1 effectors.
- Some interfollicular DCs migrate to lymph nodes to activate naïve T cells and encourage Th1 effects.
- Microbiota presence raises Th17 levels in the gut lamina propria, crucial for bacterial and fungal defense in mucosa.
- Activated intestinal Th17 cells generate IL-17 and IL-21, causing nearby cells to release inflammatory molecules for gut protection.
- IL-17 signaling in the lung is vital for bacteria.
- Pulmonary Th17 and γδ T cells are crucial sources of IL-17.
CTL Responses
- Phagocytic APCs capture pathogens that evade mucus and Abs.
- These APCs activate naïve Tc cells in mucosal inductive sites (e.g., PPs or interfollicular areas of the gut).
- Nearby mucosal DCs acquire pathogen antigens from infected, dying, or apoptotic epithelial cells (or M cells).
- These DCs then present processed antigens to Tc cells, activating them.
- Activated Tc cells differentiate into Ag-specific CTLs, migrating to multiple effector sites.
Common Mucosal Immune System
- A pathogen invading one mucosal region (potentially the gut) can induce sIgA production in other mucosal regions.
- sIgA in saliva, tonsils, trachea, lungs, and gut can react to infectious Ag exposure.
- This disseminated protective function is called the common mucosal immune system (CMIS).
- Mucosal T and B cells from an inductive site migrate through blood and lymphatics to various effector sites.
- This migration is guided by shared mucosal homing receptors (differing from general T cells and B cells).
- Specifically, a conventional B cell will use α4β1 to bind to VCAM-1 to deal with inflammatory sites. Mucosal B cells express α4β7 and bind to MAdCAM-1 on effector sites in mucosa.
- Mucosal T cells express CCR9, which binds to TECK produced by mucosal epithelial cells, at effector sites.
- Immune response strength at different mucosal effector sites is variable; sites nearest inductive sites or sharing lymph drainage are the strongest.
- A strong reaction, for example, will be detected in the intestine region closest to lymphoid tissue, but distant regions will show lesser responses if the source pathogen was located in a different region.
- The reaction to a pathogen at one mucosal surface can influence reactions to a foreign pathogen at a different inductive site.
MALT in the Urogenital Tract
- Female and male urogenital tracts have distinct mucosae.
- Urogenital tract microbiota composition differs from the gut and respiratory tract's microbiota.
- Vaginas are type II mucosae that often lack organized lymphoid structures typically seen in MALT inductive sites.
- Vaginal tissue responsiveness to pathogens is low for evolutionary reasons—sperm entry protection.
- Mucus in the vagina is less acidic than in other locations, allowing sperm penetration.
- Vaginal microbiota composition includes Lactobacillus species offering pathogen protection.
- The penile urethra serves as both inductive and effector sites.
- Penile urethra's lamina propria contains IgM- and IgA-secreting plasma cells, as well as some IgG producers.
MALT in the Ear
- The middle ear is lined with mucus that is transported to the nasopharynx by cilia beating.
- This helps keep the middle ear sterile.
- The mucus also contains antimicrobial proteins.
- Middle ears have few organized lymphoid structures, thus not considered an inductive site, but infection converts it into a mucosal effector site with locally produced sIgA.
MALT in the Eye
- Eyes are immune-privilege sites.
- Immune responses and inflammatory actions are suppressed in the eye.
- Cells and macromolecules cannot readily travel from the eye's blood vessels to the lymph nodes.
- Intraocular APCs capture pathogens and may have T2 development encouraged by TGF-β in the aqueous humor.
- Intraocular APCs migrate to blood and spleen for later immune responses.
- Effector Th2 cells return to the eye and support non-inflammatory humoral responses.
Cutaneous Immunity
- The skin protects against infection and injury damage.
- Skin-associated lymphoid tissue (SALT) comprises immune elements underlying the skin.
- The epidermis, dermis, and hypodermis make up the skin.
- The epidermis, lacking vasculature, is separated from the dermis by the basement membrane.
- The dermis contains lymphatic and blood vessels.
- The hypodermis, a fat layer, facilitates a passive barrier function and serves as an energy source.
Epidermis
- The keratin layer, an outer skin layer, resists penetration from inert stimuli and microbes due to the resilience of keratin fibers produced by epidermal keratinocytes.
- Keratinocytes are linked together with desmosomes.
- Keratinocyte turnover prevents microbial entrenchment.
- Skin microbiota compete with pathogenic microbes, and antimicrobial substances (e.g., lipases, altering pH) discourage pathogen replication. Sebum maintains acidity.
Lower Epidermis
- Lower epidermis contains small amounts of αβ and γδ epidermal T cells, immature DCs (Langerhans cells).
- B cells are not prominently found in skin.
- Langerhans cells capture antigens penetrating the keratin layer.
- Keratinocyte cytokine secretion and growth factors maintain Langerhans cell and epidermal T cell survival and activity.
Cutaneous Immunity (Lower Epidermis Cont'd)
- Keratinocytes are constantly producing TLRs, releasing inflammatory cytokines and chemokines.
- The response to inflammatory cytokines promotes LC maturation.
- Langerhans cells present peptides to αβ epidermal T cells; they also present glycolipid antigens to γδ epidermal T cells.
Basement Membrane & Dermis
- The basement membrane separates the epidermis from the dermis.
- Epidermal leukocytes secrete enzymes, dissolving small regions of the basement membrane, and allowing leukocyte passage.
- The dermis contains fibers, neurons, blood vessels, lymphatics, hair follicles, fibroblasts, and immune cells.
- Most common dermal leukocytes are macrophages, mast cells, dermal DCs, and αβ memory T cells.
Innate Responses in SALT
- When pathogens penetrate the epidermis, they release PAMPs, and keratinocyte damage releases DAMPs.
- γδ T cells recognize these, triggering TCR activation.
- Damaged keratinocytes release IL-1 and TNF.
- Inflammatory cytokines induce additional keratinocyte chemokine and growth factor secretion
Innate Responses in SALT (Cont'd)
- A diffusion gradient forms, penetrating the basement membrane and reaching the dermis.
- Dermal fibroblasts and macrophages respond by releasing inflammatory cytokines and chemokines.
- Cytokines affect endothelial cells in dermal blood vessels, increasing vasodilation and selectin expression.
- Extravasation of additional leukocytes, particularly neutrophils and other granulocytes, occurs.
- Neutrophils produce hydrolyses that degrade the basement membrane to enable other leukocytes' entry into the epidermis.
Innate Responses in SALT (Cont'd)
- Neutrophils and macrophages in the skin respond to pathogens, infection, and trauma by increasing PRR and phagocytic receptor expression and internalizing/killing pathogens.
- Complement activation amplifies phagocytosis.
- Mast cell degranulation is prompted by complement activation.
- NK cells and plasmacytoid DCs (pDCs) are recruited to infection and injury sites.
- pDCs support antiviral activity with strong IFN-α and -β production, promoting wound healing.
Adaptive Responses in SALT
- Adaptive responses in SALT begin when APCs (like Langerhans cells) engulf Ags from dying keratinocytes or pathogens.
- Ripe Langerhans cells migrate and present antigens to αβ Th cells and Tc cells in the epidermis.
- Rapid response is characteristic of these memory cells that differentiate into CTLs and Th effectors.
- Infected cells expressing Ag are eliminated by CTLs.
Adaptive Responses in SALT (Cont'd)
- If IL-12 concentration is high at the infection site, Th1 and Th17 differentiation of T cells is promoted.
- Skin tolerance to Th1 and Th17 is high.
- IL-17 influences other inflammatory cytokines and fosters CTL-mediated cytotoxicity toward infected cells.
- Epidermal Th0 cells can interact with Langerhans cells, leading to Th22 differentiation and IL-22 production.
- IL-22 promotes or stimulates keratinocyte proliferation, injury repair, and prevents terminal keratinocyte differentiation.
Adaptive Responses in SALT (Cont'd)
- Activated epidermal T cells release IFN-γ and microbial products, stimulating dermal macrophages and DCs and increasing migration.
- LCs may enter the dermis, reaching the immediate lymph node.
- Naïve T cells in the lymph node develop into Th effectors and CTLs, expressing cutaneous lymphocyte antigen (CTA) for directing their return to the inflammatory dermis.
- Humoral responses can be elicited in the skin if required.
Next Lecture
- Chapter 13: Immunity to infection.
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Explore the critical roles of TLR receptors and immune responses in maintaining gut homeostasis through this quiz. Delve into the differences between germ-free and normal mice, and understand the interactions between enterocytes and commensals. Test your knowledge on mucosal immunity, the microbiota's impact, and the functions of various immune cells.
