Week 7 - Immunity, ocular surface immunology Flashcards
What are the functions of monocytes and macrophages?
- Generally the 1st phagocytic cell to sense an invading microbe
- Orchestrate the response to infection. Recruit neutrophils and other leukocytes to area
- the major cells in chronic inflammation
What are neutrophils?
WBC - 70% - involved in killing pyogenic bacteria and fungi
No mitochondria
Granules - myeloperoxidase, lysozyme, acid hydrolases
Major cells in acute inflammation
How does phagocytosis occur?
What is the role of eosinophils?
Eosinophils release granule content to kill large pathogens that cannot be engulfed by phagocytes.
Also play a role in allergic disease - release histamines
Basophils and Mast cells
Stimulated to release granule contents upon
- when allergens cross-link IgE molecules on surface (i.e. specific immunity)
- binding to complement factors C3a and C5a
Granules contain hisamine and heparin
- cause adverse symptoms of allergy
- Immunity against parasites by enhancing acute inflammation: attraction of neutrophils and eosinophils
Natural killer cells
non-phagocytic
Target virally infected and tumour cells
Secreted products include?
1) complement
2) opsonins - complement (and antibody for adaptive)
3) acute phase proteins
4) cytokines - interferons, cytokines
Mediating protection before the development of adaptive immunity
What are complement?
- Synthesised by hepatocytes
- Circulate in plasma and place of activation to set up an enzymatic cascade
- system is controlled to protect the host
Functions of complement system
Initiate acute inflammation - by direct activation of mast cells
Chemotaxis - attraction of neutrophils
Opsonisation - enhancement of attachment of the microbe to the phagocyte
Killing - of the microbe by activating the membrane attack complex
Acute phase proteins
Produced in liver
macrophages and neutrophils produce cytokines in response to tissue injury/infection, which leads to stimulus to produce more APP.
Maximise activation of the complement system
Cytokines
Small molecules secreted by cells in response to a stimulus
Induce growth, differentiation, chemotaxis, activation, enhanced cytotoxicity
Same cytokine can be produced by different cell populations, or can induce different functions in different cell types
Other proteins of the Innate System
Fibronectin
Lysozome
Lactoferrin
Signs of inflammation
Redness
Swelling
Heat
Pain
Acute inflammation
Onset is rapid and short duration
Characterised by presence of oedema and neutrophils
Chronic inflmmation
Prolonged duration
Associated with the presence of lymphocytes and macrophages
Process in which acute inflmmation, tissue destruction and attempts to repair are all occuring at the same time
e.g.
TB, RA, chronic lung disease,
The 3 step process for acute inflammation
1) Alterations in vascular calibre
- increase blood flow to affected area
2) Increased vascular permeability
- enables plasma proteins and leukocytes to leave circulation
3) Leukocytes accumulate at injury site and become activated
- enables the offending agent to be eliminated
Vascular change - Acute inflammation
Transient vasoconstriction
Vasodilation
Increased blood flow causes heat and redness and oedema
Maximise movement of plasma proteins and cells to site of injury
Mediators include:
- histamine
- nitric oxide (NO) on smooth muscle
Increased vascular permeability - Acute Inflammation
Caused by:
1) formation of endothelial gaps in post-capillary venules by contraction of the cells and separation of inercellular junctions
2) Direct endothelial injury
3) Leukocytes - dependent injury
4) leakage from new blood vessels
- Decreased intravascular osmotic pressure
- increased fluid osmotic pressure
therefore –> oedema
Leukocyte extravasation - acute inflammation
Leukocytes at site of injury -
- kill microbes
- Get rid of necrotic tissue
- ingest offensive agents
What leukocytes are involved?
Neutrophils
- first 6-24 hours
Monocytes/macrophages
- recruited later 24-48 hours
Chemotaxis
Leukocytes migrate to site of injury along a chemotactic gradient
Chemoattractants
- exogenous bacterial products
- endogenous chemical mediators
Leukocyte activation
Leukocytes express a number of receptors that are involved in their activation
- toll-like recceptors
- 7-transmembrane G-protein coupled receptors
- Cytokine receptos
- opsonin receptors
effects of mediators
Role of mediators in inflammation
Outcomes of Acute inflammation
Features of chronic inflammation
1) infiltration of monocellular cells
- macrophages, lymphocytes and plasma cells
2) tissue destruction: induced by persistent agent or by inflammatory cells
Granulomatous inflammation
A special type of chronic inflammation
Collection of macrophages, epitheloid cells and giant cells
- Uveitis
Innate vs adaptive immunity
What are the two branches of the adaptive immune response?
1) Humoral (antibody M mediated) immune responses
- a specific defense provided by B cells secreting antibodies
- targets bacteria, viruses, parasites and fungi
2) Cell mediated immune response
- Response mounted by T cells
- Targets pathogens infected cells and cancers
Monocytes/macrophages
Monocytes leave the blood and become macrophages
Macrophages are large phagocytic cells that engulf:
- Antigens
- remove dead and dying cells
Dendritic cells are?
Dendritic cells are sentinel cells: present antigen to T cells
Activate naive T cells
Mature dendritic cells
Antigen presenting cells
Reduced capacity for antigen uptake
increased antigen presentation and T cell stimulation
Redistribution of MHC II from intracellular compartments to cell surface
MHC I (endogenous antigen) versus MHC II (exogenous antigen)
The MHCEI and MHCEII molecules show preferential restriction to T cells bearing CD8 or CD4 respectively
This is related to the observation that CD8 binds to the polymorphic a3 domain of MHCEI,
whilst CD4 interacts with the b2 domain of MHCEII
Lymphocytes
The most common types of lymphocytes are
B lymphocytes (B cells): responsible for making antibodies
Differentiate into plasma cells
Present antigen
Lymphocyte - T cells
Helper T cells enhance the production of antibodies by B cells
Cytotoxic T lymphocyte (CTL) that kill virus and tumour cells
Regulatory T cells - required for immunological tolerance, they shut down T cell mediated immunity towards the end of a reaction to restore homeostasis
Residence of B and T cells
Both B and T cells also take up residence in lymph nodes, the spleen and other tissues where they:
- encounter antigens
- continue to divide
- mature into fully functional cells
Adaptive immunity in the eye - HSV keratitis
Herpes simplex virus keratitis
- vision loss due to corneal scarring and neovascularisation caused by inflammation
Virus can replicate in the corneal epithelium, stroma and endothelium and can result in inflammation, ulceration, vascularisation and oedema
Overview of the innate and the adaptive immunity system
Overview of the B and T cells
Eye Associated Lymphoid Tissue
IgA positive lymphoid tissue in lacrimal gland
Includes conjunctival ALT — diffuse and follocular lymphocyte accumulations (B and T cells)
Lacrimal drainage ALTs — canaliculae and lacrimal mucosa – diffuse and follocular accumulation (T and B cells)
CALT clinical distribution
CALT concentrated across cornea during eyelid closure
Cornea has relatively low concentration of immune cells in structure
CALTS situated to support corneal immune protection
CALTs - clinical manifestations
Process of CALT movement
LDALTS
Demonstrate diffuse and follicular accumulations of immune cells
Secretory form of IgA throughout mucosal epithelium
Diffuse layer of sub-epithelial igA-positive plasma cells
LDALTs - follicular accumulations
follicular lymphocyte accumulations probably larger in drainage system than conjunctiva
Central mass of B-cells, surrounded and infiltrated by T cells, germinal centre apparently less dense
What is the function of the corneal barrier function
Squamous epithelial cells a very effective, renewable barrier, tight junctions form barrier
Effective secondary protection through tight packing of basal epithelium
Other protective biological agents
Antimicrobial - lysozyme, lactoferrin, mucin, small antimicrobial proteins
Immune modulators – complement, interleukins, surfactant protein
Some produced and secreted in lacrimal gland, others by conjunctiva and lacrimal mucosa
Immune and pro-inflammatory mediators - higher concentrations in closed eye
Summary of tear movement and immunity
