Lecture 2- cells and the anatomy of the immune system Flashcards
what are the 3 levels of defence against infections?
1 - Anatomical and physiological barriers.
2 - Innate responses (non-specific).
3 - Adaptive responses (specific).
what is a defence system? with a castle analogy
anatomical = structural defences
innate = the look out
innate = the foot soldiers
adaptive = commanding officers
adaptive = training for the troops
what are the anatomical and physiological barriers?
This barrier is always present - i.e., its there before an infection occurs.
The part of the body that is in contact with the environment is called the epithelium. This includes the skin, the tubular structures in your body (i.e., respiratory tract, digestive tract, urinary tract).
Intact skin - skin is very tough, most pathogens cannot get through. Skin is also covered with secretions that make the pH acidic, high in salt, and small molecular weight proteins called defensins that can kill bacteria. The tubular structures are covered with mucous which traps the pathogens and prevents them from making contact with the epithelium.
Stomach acid kills most pathogens. Lysozyme in tears and saliva also kills many pathogens.
what are innate responses?
Sometimes, something happens that damages the anatomical or physiological barriers, and pathogens can enter the body.
For example, a break in the skin (cut, puncture wound), or something that reduces stomach acidity, or inhalation into the body.
(Some pathogens have special abilities to infect the body - for example, they may secrete enzymes that damages the host so that they can enter the body. )
Innate responses take over when the 1st barrier has been breached. There are some responses that are cellular based, and some that are protein based.
Non-specific i.e., the same events, cells and proteins are involved for different types of bacterial infections.
There are some responses that occur within minutes, and others that take a few hours to develop.
what are examples of innate immunity in action?
induced: hours
Mast cells cause changes in the blood vessel wall that make it “sticky and leaky”. This allows more fluids and proteins like complement to enter the tissue.
recruitment of more phagocytic cells - neutrophils and monocytes - to engulf and kill the pathogen. The changes in the blood vessel allow these cells to leave the blood and enter the tissue.
the complement cascade
what are adaptive responses?
The adaptive responses are something that take about 7 - 10 days to fully develop. The cells that are involved are already present in the body, but they need to be activated/mature, they need to proliferate and they need to differentiate into effectors and memory cells - these processes take about 7 - 10 days to complete.
This is one of the reason why your innate responses are so important in controlling the infection.
Adaptive responses are slower, but specific and more effective.
Adaptive responses are initiated by dendritic cells and mediated by
B cells, that secrete antibodies (Ab response)
T cells, that release cytokines and toxic molecules (cell-mediated response).
how does the immune system get to different places?
Through the circulation: blood and lymph
The circulatory system takes blood around the body.
Lymph fluid drains from the tissues into lymphatic capillaries and then into lymph nodes.
The blood and the lymph are connected
what are the differences between 1 and 2 degree lymphoid organs?
1
- where all immune cells develop
- where lymphocytes develop and mature
- bone marrow = b cells and thymus = T cells
2
- where mature lymphocytes encounter foreign pathogens / molecules
- where adaptive immune responses begin
- spleen, lymph nodes
where do leukocytes come from?
Hematopoietic Stem Cells are produced in the bone marrow
what are hematopoietic stem cells?
- HSCs can be isolated because they express a unique combination of proteins on their cell surface
-they give rise to red blood cells and all immune cells
-HSCs are already successfully used in many clinical situations - to treat cancers of the immune system, to treat immunodeficiencies, to treat genetic diseases
what are leukocytes? - white blood cells
Monocyte : Dendritic cell and Macrophage
precursor
Lymphocyte : Key component of the Adaptive immune response
granulocytes : basophil, neutrophil, eosinophil
Patient blood smear showing all different blood cells
Further stores of white blood cells in your bone marrow ready to be released.
During infection bone marrow production of white blood cells, particularly granulocytes and monocytes is enhanced
Each cell has different properties and thus deals with pathogens in slightly different ways. This makes the innate immune system flexible and takes into account the variety of pathogens and diversity of tissues in the body.
what are the cells that are part of the innate immune responses?
mast cells - raise the alarm, release toxic molecules
neutrophil - release toxic molecules, engulf and bacteria
macrophage - engulf and kill bacteria, alert the immune system of the presence of an
infection, tissue repair and wound healing
dendrite cell - engulf and kill bacteria/viruses, migrate to lymph node and activate adaptive responses
Dendritic cells are especially important in the immune system - they bridge the innate and adaptive responses.
what are the cells that are part of the adaptive immune responses?
b cells - secrete antibodies into body fluids - antibodies:
1) kill bacteria (in the presence of complement),
2) opsonsize pathogens (makes phagocytosis more efficient), and
3) neutralize pathogens (prevent pathogens from binding/infecting cells).
cytotoxic t lymphocyte - kill viral infected cells (helps to prevent spread of viral infection)
t helper cells - provide cytokines and other stimulatory signals to B cells, CTLs and macrophages.
what happens when the barriers are breached?
Immune cells are numerous in barrier tissues providing an impressive degree of coverage
These immune cells reside in the barrier tissues.
They are numerous and provide enormous breadth of coverage.
They monitor the health and infection status of barrier tissues and other tissues
Proximity to the blood vessels is also an important factor
Tissue resident macrophages would be similarly abundant
what are Mast cells: Granules, the look out
Have a granular appearance. These granules are bags full of potent substances who’s release will act as a sophisticated alarm signal.
The granules can contain:
Histamine
Leukotriene B4 (LTB4)
Cytokines
Chemokines
This is not an exhaustive list of granule contents.
Each one of these substances has a complementary function that act in concert to orchestrate the immune response
This is not an exhaustive list of granule contents.
Each one of these substances has a complementary function that act in concert to orchestrate the immune response
what is Histamine and LTB4: and what is the Response of the blood vessels?
-Blood vessels dilate: consequently there is more fluid passing through this area.
-Vessels become leaky: anti-microbial chemicals and proteins in blood arrive at site of infection.
-Vessels become stickier for immune cells present in the blood e.g. neutrophils
what are neutrophils? - the foot soliders
-Short-lived
-Segmented nucleus
-A granulocyte AND a phagocyte
-Can kill one bacteria by phagocytosis
-Granules containing an array of preformed anti-pathogen mediators to kill and digest.
-in humans, 50–70% of circulating leukocytes are neutrophils, whereas only 10–25% in mice
what are neutrophils swarms
Neutrophils are incredibly active. Highly motile, sensitive to pathogens and capable of producing microbe destroying substances.
Static pictures of neutrophils do not do justice to these very active cells.
what are macrophages? - sentry guards
-Long-lived
-Expert phagocytes (kill hundreds of bacteria)
-6% of circulating leukocytes are macrophages
-Phagosomes merge with lysosomes to digest foreign material
innate vs adaptive?
- Innate response is sufficient for clearing ~ 95% of infections
- For the others, we have the adaptive response- b cells make antibodies and T cells make cytokines and kill
- The cell that links the two systems is the DENDRITIC CELL
macrophages stay and eat; dendritic cells eat and run
DC move to the lymph node, where they activate T and B cells
what are the key players of adaptive immunity?
dendritic cells, T cells, b cells
Dendritic cells, antigen presenting cells, link innate and adaptive, dendrite = tree (Greek)
B & T cells high nuclear ratio to cytoplasm – LYMPHOCYTES as produced in lymph nodes
How do they recognise pathogens and neutralise them? - Signs of a bacterium
Unusual things about microbes-
-Cell wall components (LPS, peptidoglycan)
-Flagella(flagellin)
-Nucleic acids(Bacterial DNA, dsRNA in viruses)
Evolutionary stable structures
“Pathogen-Associated Molecular Patterns (PAMPs)”
Has to be features that we don’t express so our body is not attacked
PAMPs: what makes microbes look different from host cells?
Viruses:
Double stranded RNA
Viral DNA
Glycoproteins
Bacteria:
Bacterial DNA
Cell wall components
Fungus:
Polysaccharides
Zymosan
Protozoa:
Glycolipids
DNA
RNA
what are features of a PAMP?
1 - not found in multi-cellular hosts
2 - present on numerous groups of pathogens
3 - not frequently mutated
4 - recognised by pattern recognition receptors
what is phagocytosis?
Initial binding and recognition of pathogen or particle triggers a phagocytosis programme
Neutrophils are efficient phagocytes and engulf microbes into phagosomes that rapidly fuse with the granules, creating an inhospitable environment. There, microbes are exposed to many enzymes, including lysozyme, which breaks the bacterial wall; proteases; and phospholipases. Also, very cationic peptides, like bactericidal permeability–increasing protein (BPI), defensins, and cathelicidins, are discharged into the phagolysosome. Simultaneously, reactive oxygen species (ROS), like superoxide and hydrogen peroxide, are generated by the NADPH oxidase complex at the phagosomal membrane and released into its lumen.
what are pattern recognition receptors?
-Can be soluble (eg. LPS binding protein) or on the surface of innate immune cells, the phagocytes: macrophages and neutrophils
What happens when a PRR
binds a PAMP?
Phagocytosis or cytokine production
what is The progeny of HSCs
HSC also produce red blood cells and platelets but we’ll focus on white blood cells
Other cells eosinophils and basophils
the key players of innate immunity?
-There are other cells of the innate immune system but we are going to focus of three key players.
-Each cell performs a specific function.
-Micrographs and schematics to start familiarising you with what we would see in the lab
