Lecture 15- Clocks and Immunity I Flashcards
(28 cards)
Innate immunity
First line of defense; non-specific and rapid, same response on each encounter with antigen
E.g. external barriers, receptors that recognise a broad spectrum of pathogens
Adaptive immunity
Acquired immunity; creates immunological memory; pathogen specific; i.e lifelong immunity after measles infection (basis of vaccinations)
Cells involved in innate immunity
Macrophages, mast cells
dendritic cell, granulocytes, natural killer cells
Cells involved in adaptive immunity
B cell, T cell
Cells involved in both kinds of immune response
γδ T cell, natural killer T cell
Macrophages (overview)
Phagocytic cells;
Detect, engulf and destroy pathogens; Antigen presenting cells; Initiate inflammation via release of cytokines (e.g. tumour necrosis factor alpha, TNF⍺) that activate other cells
LPS into peritoneal cavity of rat, collecting peritoneal macrophages (2hrs) and performing RNA analysis shows…
… time of day affects macrophage responses to LPS (IL6 + IL2 higher at CT12 than CT0)
LPS into peritoneal cavity of rat, collecting blood sample (4hrs) and performing ELISA…
…quantifies cytokine response in serum –> time of day affects systemic responses to LPS (again IL6 + IL2 higher at CT12)
Using Cre-lox system to specifically delete clocks in macrophages (LysM-Bmal1-/-)…
…renders mice macrophages arhythmic while mice remain behaviourally rhythmic
Deletion of the macrophage clock…
…abolishes time of day response
Endotoxin dosing
The same dose of endotoxin survived by most animals in the middle of subjective night is highly lethal if given 8-12 hours earlier or later
Rev-erb alpha -/-
No rhythm in IL6 response –> mediates circadian regulation of macrophage responses
Mast cell overview
Type of granulocyte, full of granules which contain inflammatory mediators, such as histamine; Histamine is a vasoactive amine, increasing blood vessel diameter; Important in defense against parasitic infection and allergic reactions
Mast cell activates…
Histamine, cytokines (IL4, IL13, TNF alpha) and lipid mediators (leukotrienes, prostaglandins)
Histamine (blood vessels and smooth muscle contraction)
Increases vascular permeability; Smooth muscle contraction
IL4 + IL13
Promotes Th2 differentiation; Promotes IgE production
Leukotrienes and prostaglandins
Increases vascular permeability; Causes smooth muscle contraction; Stimulates mucus secretion; Chemoattractant for T cells, eosinophils, mast cells and basophils
Histamine release in Clock delta 19 mice vs WT
Is generally lower and lacks the rhythm that remains consistent +/- serum shock in WT (though obvs raised + shock) –> histamine release from mast cells in circadian
How can the clock be disrupted?
Environmental: lighting, feeding, jet lag, shift work
Genetic (via targeting): deletion of core clock genes (Bmal1 deletion in macrophages, Clock mutation in mast cells)
Jet-lag protocol in mice
6 hour phase advance by shortening dark period once/week;
Show increased pro-inflammatory response to LPS challenge
Shiftwork and disease risk
Circadian misalignment;
Increased risk of cancer, metabolic disease and obesity, chronic inflammatory disease, cardio vascular disease, gastro-intestinalproblems
IL6 in circadian misalignment
Increased circulating IL6 in human volunteers
Immune homeostasis
Natural turnover of immune cells and searching for pathogens
Lymphocyte trafficking (immune homeostasis)
Lymphocytes (white blood cells) T cells and B cells; Survey antigen by circulating through blood
and lymph;
In mouse, lymphocyte numbers peak ZT13 (start of active phase) (previously thought to be continuous release)
