module 7: immunology Flashcards
define immunity
the ability to resist infectious disease
what is the immune system comprised of?
(i) Cells – white blood cells (leukocytes), and other cells resident in the tissues e.g. macrophages
(ii) Organs – e.g. spleen and lymph nodes
(iii) Secreted factors – e.g. antibodies
summarise the key barriers of innate immunity
surface barriers - physical and chemical barriers
- skin
- mucous membranes
can be breached by injury, insect bites, and invasive pathogens.
internal defences
- phagocytes
- natural killer cells
- inflammation
- anti-microbial proteins
summarise the innate immune response
Acts within minutes to days of infection.
* Important for control until acquired response develops.
* If innate immunity rapidly clears the infection, an acquired immune response will not develop.
* Responds similarly each time a specific organism is encountered – no “memory”
Initiates inflammation = redness, heat, swelling, pain – influx and activation of immune cells
summarise the adaptive/ acquired immune response
humoral immunity
- B cells - antibodies
cellular immunity
- T cells
Effective from about 4-5 days after an initial infection.
* Has specificity for recognizing particular pathogen molecules, and memory of previous infections – hence is essential for long-lived
immunity and vaccines.
what is the complement system?
several dozen secreted proteins that can directly attack bacteria by making
pores in the bacterial membrane leading to lysis, or alternatively by “marking” bacteria for
phagocytosis.
what are the innate cells
neutrophils, macrophages, dendritic cells (DC), natural killer (NK) cells, basophils, mast cells
what are phagocytes and what cells are phagocytes?
play a major role in the early response to pathogens. Phagocytes include macrophages, neutrophils, and dendritic cells (DC).
phagocytosis!
what are the 5 steps of phagocytosis?
- Recognition of organism by phagocyte receptors
- Extension of membrane around organism, fusion of membrane to form phagosome
- Fusion of phagosome with a lysosome, an organelle containing degradative enzymes. Then, acidification of the phago-lysosome.
- Bacteria are killed and degraded by the generation of reactive free radicals – molecules with an upaired electron (e.g. superoxide O2.-) and enzymes activated by low pH.
- Bacteria may evade phagocytosis e.g. through having a capsule, and evade killing, e.g. by preventing acidification
what are neutrophils?
- Multi-lobed nucleus and cytoplasmic “granules”. Granules are membrane-bound vesicles containing
antimicrobial peptides, lysozyme enzyme that attacks bacterial cell wall, and degradative enzymes. - The first cell type to migrate to sites of infection or tissue damage
- Phagocytose and kill invaders.
- Short-lived, and many die at the site of infection, contributing to the formation of pus. In the process of dying they can release DNA and anti-bacterial proteins which together trap and kill organisms.
what are monocytes?
phagocytes resident in tissues –involved in immunity as well as wound healing and tissue remodelling
* Monocytes are the blood precursors of macrophages
what are macrophages?
In an infection, tissue resident macrophages play a role in phagocytosing pathogens, but there is also recruitment of monocytes from blood which differentiate into macrophages, and then phagocytose and kill pathogens
what are dendritic cells?
phagocytic innate immune cells closely related to macrophages, but are more specialised for activating T cells and the acquired immune response
what is inflammation?
- The body’s early response to infection or injury – swelling, redness, pain, heat
- Inflammation helps to attract and activate immune cells, and prevent the spread of infection
- Chronic inflammation that doesn’t get switched off causes tissue damage
- Systemic (body-wide) inflammation can cause septic shock and death
Inflammatory processes are also involved in the pathology of a huge
range of non-infectious diseases, such as atherosclerosis, Alzheimer’s
disease, diabetes, cancer….any disease with tissue damage.
how is inflammation initiated?
Inflammation can be initiated by:
(i) Cell damage - release of molecules
from damaged cells – “danger signals”
(ii) Recognition of pathogen molecules – PAMPs
- Circulating neutrophils (and later
monocytes) bind to inflamed vessel wall. - Cells traffic out of the capillaries
- Chemotaxis towards source of infection
- Phagocytosis of invading organisms
what are PAMPs?
How innate immune cells recognise pathogens
Innate immune cells recognise characteristic molecules that are conserved amongst classes of
pathogens - Pathogen Associated Molecular Patterns (PAMPs)
bind to receptors on innate immune cell cell surface or in the cytoplasm.
what are the responses to PAMPs
- Secretion of cytokines and chemokines – enhanced inflammation
- Recognition of organisms for phagocytosis
- Enhanced killing by phagocytes
- Maturation of dendritic cells, so they can activate T cells
where and how do immune cells develop?
primary lymphoid organs - bone marrow and thymus.
All immune cells develop from bone marrow stem cells. T cell progenitors move to the thymus in the embryo and early life, where they
mature.
what do naive T and B cells do
circulate through the blood and lymph and secondary lymphoid tissues in a surveillance pattern, looking for foreign
define antigen
molecules to which T and B cells mount a very specific response
where are B and T cell response to foreign antigens initiated?
secondary lymphoid tissues. These are the spleen, lymph nodes and mucosal associated lymphoid tissues (MALT)
summarise the lymphatic system and its importance for immunity
Some blood plasma (and a few leukocytes but no red cells) leaves the capillaries and enters tissues.
* Fluid drains out of the tissues into the lymphatic capillaries and vessels.
* Lymph fluid returns to the blood stream via the thoracic duct.
* Lymph nodes are filled with immune cells, and act as filters which capture pathogens, antigens and
particulate material.
*Drainage of fluid from the peripheral tissues into lymph nodes allows surveillance for foreign molecules in the lymph node
what are lymphocytes?
T cells and B cells
what are the receptors for foreign antigens?
B cell receptor (BCR) and T cell receptor (TCR).
what are the steps in clonal expansion?
- Progenitor cell
- Lymphocyte pool with different Ag specificity
- Removal of self-reactive lymphocytes during their development in bone marrow (B cells) and thymus (T cells) leads to self tolerance
- Recognition of foreign antigen by mature naïve lymphocytes and clonal expansion
what are antibodies and how are they formed?
Activated B cells become plasma cells that secrete antibodies- also called immunoglobulin (Ig).
* Antibodies are soluble proteins which can bind with high affinity to foreign antigens.
what are the 5 antibody classes and what does each class do?
- IgM - first type of antibody made in an immune response. Specific IgM detected in plasma indicates a recent/ongoing infection.
- IgG - the major class found in blood, comes up later than IgM. It crosses the placenta, and protects the newborn for several months.
- IgA - Present in tears, saliva, mucus, milk as well as blood. Protects mucous membranes.
- IgE – Activation of mast cells and basophils. Involved in allergy and anti-helminth (worm parasite)
responses
explain ways that antibodies act
- Neutralisation - antibody binding to virus can block entry into cells. Antibody can also neutralise bacterial toxins (e.g. tetanus toxin) and prevent effects on cells
- Opsonisation (coating of organisms) to promote phagocytosis via receptors for antibodies on phagocytes.
- Activation of the complement system – leading to bacterial lysis and inflammation
- IgE binds to mast cells. When it recognises antigen (frequently allergens) the mast cells release histamine (inflammatory small molecule).
how do B and T cells recognise antigens?
- T cells recognise antigen through the TCR which is evolutionarily related to the BCR, but has no secreted form. It has two chains (a and b), with variable and constant regions like BCR. The two chains together form one variable antigen-binding site.
- Each B cell makes one specific BCR/antibody and each T cell makes one specific TCR.
- Antibodies/BCR and TCR recognise a small region of a whole protein antigen
- BCR/antibody can recognise an intact protein antigen, whereas the TCR requires the antigen to be
processed by proteases into short peptides (8-13 amino acids) that are bound on the surface of an antigen presenting cell (APC) on MHC molecules.
what are the consequences of antigen recognition by T and B cells
- Proliferation
* Particular B cells and T cells recognising antigen will proliferate = clonal selection or clonal expansion. - Differentiation
* B and T cells develop mature “effector” cell function.
* B cells become antibody-secreting cells (“plasma cells”)
* T cells become cytotoxic T lymphocytes (CTL) or T helper cells
* Some T and B cells become long-lived memory cells
When a T cell is activated, what are the 2 T cells it could be?
(i) T helper cells that either:-
- release cytokines that help promote B cell antibody production
- release cytokines that help activate macrophages to kill phagocytosed organisms
(ii) Cytotoxic T lymphocytes - “CTL”
- Effective against tumour cells and virally infected cells.
- They do not directly attack pathogens themselves.
- Recognition of antigen causes secretion of granules containing proteins which induce apoptosis (cell death) in target cells
what are MHC cells?
Proteins involved in display of Antigen to T cells are MHC (major histocompatibility complex)
why does the process
of DC activation control the
whole acquired immune
response
The major antigen-presenting cell (APC) involved in activation of naïve* T cells
* Immature DC reside in tissues and blood as sentinels, looking out for infection
* DCs take up soluble antigens and whole pathogens
* Upon pathogen encounter, they are activated to mature and migrate to the lymph node (or if they are in the blood they exit into the spleen). There they activate T cells which recognise peptides on MHC.
Activation of naïve T cells needs activated DCs - The DC must recognize that there is “danger” (e.g. PAMP recognition) to be competent for T cell activation.
what is a naive T or B cell?
those that have never responded to their cognate antigen
what 2 things so vaccines need to work
an antigen and an innate immune stimulus (means of activating DC)
Vaccines made with purified proteins use “adjuvants” to provide the innate immune stimulus normally given by a PAMP in an infection
“Live” virus vaccines like measles vaccine intrinsically generate their own PAMP activity and so do
not need an adjuvant.
what are the 6 different approaches to vaccination?
Live attenuated organisms: The pathogen has become non-virulent through mutations. Examples of
attenuated viral vaccines - yellow fever; measles/mumps/rubella; chicken pox.
Live vectored vaccines: e.g. Adenovirus engineered to express SARS-CoV2 spike protein - AstraZeneca vaccine
Inactivated (killed) pathogens: Pathogen killed by chemical treatment, detergent or heat. Examples for viruses - influenza, inactivated polio vaccine; bacteria- Vibrio cholerae (cholera), Yersinia pestis (plague). Effect can often be improved with adjuvants.
Subunit vaccines: Purified single antigen or group of antigens used as vaccine. Good safety profile.
Examples – hepatitis B, Bordetella pertussis – whooping cough, human papilloma virus. Needs adjuvant.
Toxoid vaccines: Vaccinate with a toxin secreted by the pathogen. Example – tetanus, diptheria
mRNA vaccines: Administer mRNA that needs to get into host cells to be translated into the pathogen
protein. Pfizer and Moderna SARS-CoV2 vaccines. RNA itself can act as an adjuvant.
what do vaccines aim to do?
- Vaccination aims to prime the acquired/adaptive immune system to the antigens of a particular microbe
so that a first infection induces a secondary response. - Ideally a vaccine would prevent infection completely and stop disease spread. But, if it just makes the
infection much less severe, and prevents disease, it has done its job.
what is herd immunity?
- If a high enough proportion of the community are vaccinated, the infection cannot maintain transmission
- Some immunocompromised people can’t be vaccinated, but they can be protected by community
vaccination
what is R0 (R-nought)?
average number of people who will be infected by one infectious person in a completely susceptible population. (i.e. assuming no vaccination or prior immunity).
- R0 for a particular disease is not a constant in all circumstances – it can vary between places,
because it depends on things like population density and temperature.
what is Reff (R-effective)?
the “effective” R value for a population, that changes with time due to changing levels of susceptibility (i.e. depending on vaccination levels or numbers already infected), and behaviour that reduces or increases transmission (i.e. social distancing, mask-wearing, rioting).
- The aim is to reduce Reff below 1, so that incidence gradually declines.
how do you calculate what proportion of the population need to be vaccinated to achieve herd immunity?
Critical Immunisation Threshold
qc = 1 – 1/R0
describe SARS-CoV-2 Immunology and Evolution
- SARS-CoV2 infects and replicates in airway epithelial cells
- Also non-productively infects monocytes, and resulting excessive inflammatory response seems to be
the key to severe disease - Immune responses to SARS-CoV2 seem fairly typical for viral infection – there is reasonable activation of T helper, CTL and B cell immunity
- 20-50% of people not exposed to SARS-CoV2 have pre-existing CTL or T helper responses that crossreact with SARS-CoV2. This may represent memory cells from common cold coronaviruses.
- The virus naturally evolved to become more infectious (e.g. delta and omicron strains) because faster
replicating and transmitting viruses will be selected for. But as the pandemic progresses, the virus has
to accumulate mutations to evade antibody neutralization. Current strains have numerous mutations
that change the amino acid sequence of the spike protein relative to the original Wuhan strain.
what is immunodeficiency
- Immunodeficiency can be genetic, or due to exposure to chemical or biological agents e.g. human
immunodeficiency virus (HIV). Stress can also lower immune function. - Immunodeficient people are subject to recurring infections and cancer
how do genetic deficiencies impact the acquired immune system?
- Defects in B cell production/function cause susceptibility to extracellular bacterial infections and gut viruses, but many other infections are cleared, as T cell responses are intact.
- T cell deficiency is more severe than B cell deficiency, as T helper cells are required for most B cell activation and antibody production.
T cell deficiency causes “Severe Combined Immunodeficiency” (SCID)
what is AIDs and how does it affect the immune system?
- Human Immunodeficiency Virus-1 (HIV-1) is a retrovirus – a virus with an RNA genome which is reverse transcribed into double-stranded DNA. This DNA integrates into the genome of infected cells.
- HIV-1 infects cells with the surface molecule CD4 including T helper cells
- HIV-1 leads to the death of T helper cells, resulting in immunodeficiency and the development of AIDS.
- AIDS patients are subject to many infections (e.g. tuberculosis, fungal pneumonia, Candida yeast
infections) and cancers.
what is tolerance and autoimmunity?
Tolerance involves the deletion (killing) or control of T and B cells which attack “self” molecules.
Failure of tolerance leads to autoimmunity.
what causes autoimmunity?
Generation of autoimmunity involves:
(1) genetic factors
(2) environmental factors - e.g. infections. Infections can provide “molecular mimicry” where a
foreign antigen has similarity to a self protein. Alternatively they could also provide excessive
inflammation promoting responses to self antigens
what is type 1 diabetes and how does it impact the immune system?
- An organ-specific autoimmune condition
- Pancreatic islet b-cells that are responsible for insulin production are specifically destroyed by CTL
- Loss of insulin production = loss of control of blood glucose levels
- Islet-specific T helper cells and CTL recognise a range of b-cell specific antigens, including insulin
itself
what is multiple sclerosis and how does it impact the immune system?
- Affects nerves of central nervous system - problems with sensation, movement, vision
- Myelin sheath surrounding nerve axons is attacked, which disrupts the transmission of nerve signals
- Both T and B cells are important in this disease
what is multiple narcolepsy and how does it impact the immune system?
- Daytime sleepiness, with sometimes sudden onset of sleep
- Inability to regulate sleep-wake cycle
- Loss of neurons in the hypothalamus which make hypocretin neuropeptide hormones that regulate wakefulness
- Thought to be due to T cell-mediated autoimmune attack on
neurons
define allergy and allergen
- Allergy is an inappropriate immune response to environmental or food molecules.
- The antigens eliciting allergic responses are called allergens (pollen grains, house dust mite allergen,
peanut allergen, bee venom)
what do allergies involve?
(i) Prior sensitization to allergen by activation of acquired immune responses, resulting in production
of IgE antibody specific for the allergen. The IgE binds to receptors on mast cells
(ii) Allergen binding to the IgE on Mast Cells leading to “degranulation”- release of histamine which increases blood vessel permeability and smooth muscle contraction and causes symptoms of allergy
(iii) Severe responses can lead to anaphylactic shock - large scale mast cell degranulation causing dangerous drop in blood pressure
what are the 6 steps of sensitisation and triggering an allergic response?
- antigen (allergen) invades body
- plasma cells produce large amounts of class IgE antibodies against allergen
- IgE antibodies attach to mast cells in body tissues (and to circulating basophils)
- more of same antigen invades body
- antigen combines with IgE attached to mast cells (and basophils), which triggers degranulation and release of histamine (and other chemicals)
- histamine causes blood vessels to dilate and become leaky, which promotes edema; stimulates secretion of large amounts of mucus; and causes smooth muslces to contract. (if respiratory system is site of antigen entry, asthma may ensue.)
explain the Old Friends Hypothesis for host dependence on microbiome
Organisms we have co-evolved with may need to be encountered, for normal development or regulation of the immune system – the “Old Friends Hypothesis” or “Microflora Hypothesis”.
We have evolved along with commensal bacteria, bacteriophages, resident fungi, common viruses
and parasitic worms. Some of these are good for us, some neutral, and some detrimental, but our body expects to encounter them and they affect the development of the immune system.
What modern lifestyle factors might alter the microbiome?
- caesarian birth, and bottle-feeding
- antibiotic use
- household cleanliness, and parents preventing kids eating dirt
- antibacterial products – cleaning products, pillows, cutting boards, dish cloths, toothpaste (triclosan –
a surgical “scrub” antiseptic until recently in Colgate Total.) - urban and indoor lifestyle – lack of contact with nature and soil
- exposure to animals, particularly on traditional farms, is protective against allergy
- diet and obesity modify gut flora extensively
- dietary fibre is especially important….
why is dietary fibre important for our microbiome?
- High fibre diet changes the gut flora, and is metabolised by the beneficial bacteria in the colon to make short chain fatty acids (acetate, propionate, butyrate).
- These are anti-inflammatory. They act on receptors on immune cells and prevent excessive immune activation.
- Apart from recent work on immunity, fibre is known to reduce cholesterol, control blood glucose, reduce colon cancer
