Mucosal Immunity Flashcards
What are the key anatomical features of the mucosal immune system
Intimate interactions between mucosal epithelia and lymphoid tissues
Discrete compartments of diffuse lymphoid tissue and more organised structures such as Peyer’s patches, isolated lymphoid follicles, and tonsils
Specialised antigen-uptake mechanisms, e.g. M cells in Peyer’s patches, adenoids and tonsils
What are the effector mechanisms of the mucosal immune system
Activated/memory T cells predominate even in the absence of infection
Non-specifically activated ‘natural’ effector/regulatory T cells present
What is the immunoregulatory environment of the immune system?
Active downregulation of immune responses (e.g. to food and other innocuous antigens) predominates
Inhibitory macrophages and tolerance-inducing dendritic cells
What lymphoid tissue is associated with mucosa and what types of tissues are they composed of?
GALT (GI tract)
BALT (bronchial)
NALT (nasopharyngeal)
- Organised e.g. Peyer's patches - Diffuse e.g. lamina propria
What are the key components of GALT?
Peyer’s patches
- Organised follicles, found in small intestine - inductive site
- Found below follicular associated epithelium (FAE) - induction site
Lamina propria lymphocytes:
- Scattered throughout intestinal lamina propria (CD4+) - Effector site
Intraepithelial lymphocytes (IELs):
- Located between epithelial cells of mucous membranes (CD8+) - effector site
How is the immune response induced in the Peyer’s patch?
M cells transport antigens from the gut lumen to dendritic cells, which present them to T and B cells.
Activated T cells and B cells (producing IgA) migrate to the gut, where they mediate mucosal immunity and maintain gut homeostasis
What is the process of antigen uptake and presentation and T cell activation in M cells
Epithelial cells differentiate into M cells after interactions with T and B lymphocytes
M-cells continuously sample molecules, particles and microbes from the lumen of the gut
Involved in uptake, transport, processing, presentation of microbial antigens
Local DCs take up and present antigen to lymphocytes
Targeting of microbes to mucosal APC via M-cells gives a vigorous mucosal immune response and is a focus of vaccine development
T-cells enter Peyer’s patches from blood vessels, directed by the homing receptors CCr7 and L-selectin
T-cells in the Peyer’s patch encounter antigen transported across M cells and become activated by dendritic cells
Activated T cells drain via mesenteric lymph nodes to the thoracic duct and return to the gut via the bloodstream
How are B cells activated
Naïve B cells are activated in:
- Peyer’s patches
- Mesenteric lymph nodes
Class switching of naïve B lymphocytes from IgM to IgA occurs under the control of transforming growth factor B (TGF-b) and IL-10 in peyer’s patch
Activation and differentiation lead to expression of a4:b7 mucosal homing integrin
Allows localisation of IgA producing plasma cells to lamina propria - effector site
What does the lamina propria consist of?
Contains a heterogeneous mix of:
- IgA producing plasma cells
- Lymphocytes (memory)
- CD4 and CD8 effector T cells but CD4 T cells predominate
- Dendritic cells
- Macrophages
- Mast cells
What are the characteristics of Intra-epithelial lymphocytes (IEL)
Large granular lymphocyte morphology
CD3+ CD8+
aE, b7 integrin expression
yd TCR most common
Produce IL2, IFN-y
Function - cytotoxic, immunoregulatory
What is the movement of the lymphocytes of the mucosal immune system
Originate in the bone marrow and thymus and migrate to Peyer’s patches and recirculate to mucosal sites
Circulation is controlled by tissue specific adhesion molecules and chemokine receptors
What is the role of adhesion molecules and chemokine receptors in the lymphocyte cirulation?
Entry of naïve cells to peyers patches controlled by CCL21 and CCL19 and the expression of CCR7 on lymphocytes and occurs via high endothelial venules
If they do not encounter their antigen they exit via efferent lymphatics and enter bloodstream
If they encounter their antigen - expression of CCR7 is lost and they can no longer re-enter via high endothelial venules but can do so via small blood vessels in lamina propria - selectively home to mucosal tissue
During T cell activation and under control of DCs, T-cells lose L-selectin expression and gain expression of CCR9 and integrin a4:b7
Cells exit Peyer’s patch and enter lymphatics, pass through mesenteric lymph nodes and enter thoracic duct, which empties into bloodstream allowing circulation and return to lamina propria of gut
What is lymphocyte homing facilitated by?
Integrin expression - a4:b7
Vascular addressin - MAdCAM-1
Chemokines by the gut epithelial cells - CCL25 (gut)/CCL28(colon/salivary gland)
What happens following memory T cells accumulation in the GALT?
CD8+ memory T cells accumulate in the lamina propria to await antigenic challenge
These T cells do not express CCr7 and are ‘effector memory’ calls (as opposed to central memory cells)
They express CCR9 and bind its ligand CCL25 (thymocyte-expressed chemokine) - CCL25 found in villous crypts in mice
Dual expression of intestinal homing receptor (a4b7) and CCR9 allows selective homing of memory T cells to the lamina propria
This allows rapid responses of GALT
How can priming of responses in one mucosal compartment induce protection at other surfaces
MAdCAM-1 not entirely restricted to blood vessels of intestine
Lymphocytes primed in GALT can recirculate to resp tract, urinary tract and lactating breast
Mucosal immune system - common mucosal immune system
Potential for vaccination development, vaccinate at one surface - protection obtained at another
How is IgA secreted?
Binding of IgA to receptor on basolateral face of epithelial cell
Endocytosis
Transcytosis to apical face of epithelial cell
Release of IgA dimer at apical face of epithelial cell
What is the role of IgA in mucosal immunity?
Secreted IgA on the gut surface can bind and neutralise pathogens and toxins
IgA is able to bind and neutralise antigens internalised in endosomes
IgA can export toxins and pathogens from the lamina propria while being secreted
What are the differences between priming and oral tolerance
PROTECTIVE IMMUNITY
Antigen: invasive bacteria, viruses, toxins
Ig production: intestinal IgA, specific Ab present in serum
T-cell response: local and systemic effector and memory T cells
Response to antigen re-exposure: enhanced (memory) response
ORAL TOLERANCE
Antigen: food proteins, commensal bacteria
Ig production: some local IgA, Low or no Ab in serum
T-cell response: No local effector T-cell response
Response to antigen re-exposure: low or no response
What are the characteristics of oral tolerance
Necessary to prevent excessive responses to normal flora and food antigens
May be cause of poor or absent immune response to most antigens administered by oral route
Several forms: tolerance for all Ig classes systemic tolerance, IgA immunity
Numerous factors contribute to determining the tolerance or response to antigen
How is the GALT tone anti-inflammatory
Inflammation is generally suppressed in GALT
sIgA
Constitutive activation of COX2 to secrete PGE2 is a phenotype unique to intestinal lamina propria
Intestinal epithelial cells DO express TLR - may upregulate responses to pathogens
Dendritic cells may be able to distinguish between pathogenic and commensal bacteria
What is the response to pathogenic bacteria in the mucosal epithelium
Many pathogens transported into Peyer’s patch through M cells - require rapid host innate immune response
PAMPs bind to TLRs on macrophages and dendritic cells and intracellularly
Many PAMPs also expressed by commensals - but most commensals do not gain access to peyers patch - remain trapped in mucus
Lamina propria contain many B cells with sIgA specific for commensal antigens - T cell independent pathway for IgA
