Lecture 16 - Mucosal Immunity I Flashcards
List the various body surfaces that are exposed to the external environment
Outer:
• Skin
Inner (mucosal sites):
• Respiratory tract
• GIT
• UGT
What are the functions of mucosal surfaces?
How does this represent vulnerability?
Functions:
• Absorption
• Thermoregulation
• Gas exchange
To perform these functions, the tissue needs to have a very great surface area, be permeable and thin
This makes it more vulnerable to pathogens
Implication: we need an immune system in the skin and the mucosa
List the various functions of the skin
Protection: • Chemical • Physical • Microbiological • Mechanicam
Thermoregulation
• From blood
• Perspiration
Sensation
• Mechanosensation
• Heat
H2O exchange
Energy storage
Describe the basic tissue structure of the skin
Epidermis
• Keratin
• Keratinocytes
Dermis • Vasculature • Hair follicles • Sweat glands • Lymphatics
Hypodermis (Panniculus)
• Fat
Describe the defence endowed by the epidermis
Keratinocytes produce:
• Cytokines
• Anti-microbial peptides
Antimicrobial peptides:
• β-defensins
• Cathelicidins
These are packaged into Lamellar bodies
Lamellar bodies are located in the keratinocyte network and form a watertight anti-microbial network
Describe what happens when there is a breach in the skin
Loss of the antimicrobial epidermis
Microbes have access to dermis
- Oedema
- Necrosis
- Haematoma
- Wound pockets
Compare the components of the immune system present in the various regions of the skin
Epidermis:
• Langerhans cells
• Intra-epithelial CD8+ T cells
Dermis: • Mast cells • Plasma cells • Dermal DCs • Dermal CD4+ T cells • Macrophages
Describe the important features of Langerhans cells
Located in the epidermis
‘DC of the epidermis’
Drain through lymphatics to lymph nodes, where they activate T cells, inducing the adaptive immune response
Immunity vs. tolerance ?**
What are the predominant T cells in the epidermis?
Describe the features of these cells
γδ-T cells
Tissue resident, non-migratory
Invariant γδ TCR (role in innate immunity?)
Role:
• Wound healing
• Epidermal homeostasis
Which T cells are present in the epidermis?
γδ-T cells
T(RM)
CD4 memory cells
Tregs
Describe the features of T(RM)
A type of memory T cell Located in the epidermis Non-migratory (resident cells) Lodged during local infection / trauma ↑ effector function
Describe the features of mast cells, and their role in skin immunity
What brings about their activation?
What happens after they are activated?
Abundant in barrier tissues
Located in the dermis, non-recirculating
Role:
• Sentinels: trigger inflammation
• Role in wound healing **
• Closely associated with blood vessels and nerves
Activation:
• Microbial products (through bound IgE and IgG, or TLRs)
• Inflammatory mediators (cytokines, complement)
• Physical stimuli (heat, cold)
Degranulation: • Occurs in a matter of seconds • Pre-formed mediators: - Histamine - TNF • Metabolism of phospholipids: - Arachidonic acid metabolites - PAF - Leukotrienes - Prostaglandins • Cytokine synthesis (TNF, IL-4, IL-6, IL-10, IL-13, TGF-β)
Sentinel function:
• Mast cells are the early responders to invading pathogens
• By release of inflammatory mediators (histamine, TNF, leukotrienes, prostaglandin) the mast cells set up the inflammation
• Recruits cells to the area of invasion:
- TNF induces expression of adhesion molecules (P-selectin, E-selectin, VCAM-1, ICAM-1)
- Histamine and leukotrienes increase vascular permeability of vessels
- Lipid mediators and chemokines recruit cells
What is the role of memory CD4 T cells in the skin?
Some present in the epidermis, as well as the dermis
Many types: • Th1 • Th2 • Th17 • Treg
Immune surveillance, part of the adaptive immune response
Describe the various types of DCs found in the skin
A. Epidermis:
1. Langerhans cells:
• Drain to LNs to initiate adaptive immune responses or tolerance
B. Dermis 1. Dermal DCs • Drain to LNs to initiate adaptive immune responses or tolerance • CD103+Langerin+ • CD11b+Langerin- • Present in steady state
- iDCs
• Present in inflammatory state
• Differentiate from monocytes - pDCs
• Present in inflammatory state
What is the role of NK cells in the skin immune system?
Present in the dermis
Role in innate immunity
(Detection of infected cells through inhibitory and stimulatory receptors)
Production of IFN-γ
What is the role of ‘unconventional’ T cells in the skin immune system?
NKT cells
γδ-T cells
Located in dermis
Role in innate immunity
What is the role of macrophages in the skin immune system?
Present in the dermis
Role:
• Phagocytosis of pathogens
• Antigen presentation?*
How does mast cell activation lead to expression of adhesion molecules in blood vessels?
TNF in synthesised in activated mast cells
TNF acts on endothelium to increase the expression of:
• P-selectin
• E-selectin
• ICAM-1
• VCAM-1
Describe how mast cells can lead to immunopathology
- Urticaria
• Vascular reaction
• Localised oedema in skin - ‘wheals’
• Severe itching and stinging
Pathogenesis:
• Triggering factors (food, drugs, dermatographia, heat, cold, stress, sunlight, pressure, infection)
• Acute mast cell degranulation
2. Angioedema • Subcutaneous swelling • Causes systemic complaints: - Abdominal pain - Airway obstruction, asthma - Coryza
- Anaphylactic shock
Widespread hypotension
What is angioedema?
Subcutaneous swelling
What is coryza?
aka Rhinitis
Inflammation and irritation of the mucous membrane in the nasal cavity
Describe how skin DCs activate the adaptive immune response
- Resident DCs in the skin capture viral Ag / become infected
- DCs maturate and migrate to the local LNs
- Skin DCs transfer Ag to LN resident DCs
- LN resident DCs present the viral Ag to naïve T cells
- DCs induce the expression of ‘skin homing molecules’ on the T cells:
• PSGL1 (ligand for P-selectin)
• CD43 (ligand for E-selectin)
• CCR4, CCR10 (receptors for CCL17 and CCL7)
• LFA-1 (ligand for ICAM-1)
• VLA-4 (ligand for VCAM-1)
Describe how activated T cells are recruited to the infected skin
1. Infection in skin triggers release of TNF-α and IFN-γ, which up-regulate adhesion molecules on the endothelium: • P-selectin • E-selectin • ICAM-1 • VCAM-1
Also, chemokines are released:
• CCL17
• CCL27
- T cells activated by DCs from the skin are imprinted with molecules that allow them to home to the skin
a. Rolling:
• PSGL1 - P-selectin
• CD43 - E-selectin
b. Activation:
• CCR4 - CCL17
• CCR10 - CCL27
c. Adhesion;
• LFA-1 - ICAM-1
• VLA-4 - VCAM-1
- T cells extravasate and move into the infected tissue
Describe the presence of memory T cells in the skin post-infection
CD8+ T memory cells: epidermis
CD4+ T memory cells: dermis
Compare cell surface marker expression of the following cells:
• T(CM)
• T(EM)
• T(RM)
T(CM):
• CCR7+
• CD62L+
T(EM):
• CCR7-
• CD62L-
T(RM): • CCR7- • CD62L- • CD103+ • CD69+
Where are T(RM) located after a skin infection?
In the epidermis of the region of skin where the infection occurred
Describe the differentiation leading to T(RM)
- Naïve T cells are activated during the infection and differentiate into effector T cells
- Effector T cells migrate to various regions, some into the skin
3. T cells that migrate into the skin receive local signals that guide their differentiation into T(RM): • TGF-β • IL-15 • IL-33 • TNF-α
4. Differentiation into T(RM): ↑ CD69 ↑ CD103 ↑ β7 ↓ CCR7 ↓ CD62L ↓ S1P1
How do activated T cells know whether to migrate to the skin or the gut?
Expression of markers on their cell surface:
Skin-tropic T cells:
• CCR4+
• CLA+
Gut-tropic T cell:
• CCR9+
• α4β7+
What is CLA?
Cutaneous leukocyte antigen
A ligand for E-selectin
Expressed by skin-tropic memory T cells
What is Fixed Drug Eruption?
Skin hypersensitivity reaction triggered by certain drugs
The lesions occurs in the same location despite many years gap between eruptions (‘resident memory’)
The predilection sites are often those that were previously exposed to infection or trauma
T(RM) persist in these eruption sites
Pathogenesis:
1. Sensitisation phase:
• Drug-specific effector T cells lodge in the epidermis
• Differentiate into T(RM) and remain localised
- Resting phase
• T(RM) still present but inactive - Rechallenge with drug
• T(RM) become rapidly activated
• T(RM) produce vast amounts of IFN-γ (after 3 hrs) - IFN-γ brings about inflammation; inflammatory cell infiltrate into the skin region
- Formation of a lesion in the skin
Describe the main features of psoriasis
Chronic inflammatory skin condition that affects 1-3% of the population
Erythematous lesion with silvery scales (plaques)
When therapy is stopped, the lesions recur in the same location
Histopathology: • Epidermal thickening • Inflammatory infiltrate in epidermis - T cells - DCs
What is thought to be the underlying cause of psoriasis?
Predisposition determined by interaction between genes and environment
- Genotype
Dysregulated skin immune system:
• IL-21 / Th17 axis
• NFκB system
2. Environmental triggers: • Smoking • Stress • Drugs • Microorganisms • Trauma
Describe the simplified immunopathogenesis of psoriasis
- Predisposing factors
• Genes, environmental triggers
Keratinocytes become stressed
– Initiation of disease –
- Stressed epidermal cells release self DNA
- Formation of self-DNA LL-37 complexes
- DCs activate naïve T cells in LNs
• Specificity of these responses is still completely unknown
• Must be some skin-derived self-Ag - T cells activated and migrate back to skin, into epidermis
• Th1
• Th17 - T cell effector function brings about harm in the skin:
• Cytokines
• Chemokines
• Inflammatory cell infiltrate
- Th17 recruits neutrophils which cause microlesions - Keratinocyte dysfunction
Describe the experiment in which healed skin from an individual with psoriasis was transplanted into a mouse
- Individual with psoriasis took treatment and the lesion healed
- Skin that was affected, but is now healed, was grafted onto a mouse w/o an immune system
- In the absence of treatment, the transplanted skin relapsed to form an active lesion
Implication:
• The resident immune cells in the healed skin mediate the pathogenesis:
- pDCs
- T cells
Which type of hypersensitivity reaction can mast cells cause?
Type I hypersensitivity
What is the effect of chemokines on T cells homing to the skin?
Result in a conformational change in the integrins on the surface of the T cells, such that they can now strongly bind to adhesion markers on the endothelium (ICAM-1, VCAM-1)
Describe the effector function of T cells that home to the skin
CD8 T cells:
• IFN-gamma production
• In the epidermis
CD4 T cells:
• IFN-gamma production
• In the dermis, often clustered around hair follicles
Describe the function of T(RM)
Remain localised in the skin, and are able to rapidly respond to subsequent invasions
Produce sterilising immunity very rapidly
Compare the migratory patterns of CD8 and CD4 T cells in the skin
CD8 T cells:
• Located in the epidermis
• Very low migration
• Reside permanently in the epidermis
CD4 T cells:
• Found in the dermis
• Can be either resident of the dermis, or be recirculating around the body
What is the implication of lesions occurring at the same sites in diseases like Psoriasis and FDE?
Implies some sort of localised memory in these areas
Which cells constitute the inflammatory infiltrates in psoriatic skin?
- Neutrophils
- CD8 T cells
- DCs
Describe the evidence for the autonomous function of the skin immune system
Psoriatic skin grafts into mice w/o immune system provide evidence for this
