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Immunology and Thermoregulation summary - Immunology part
This is a summary covering only the immunology lectures and the theory explained during the practical from the course Immunology and Thermoregulation.
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IMMUNOLOGY AND THERMOREGULATIONIMMUNOLOGY PART
Introduction
Health is the ability to adapt.
Definition of immunology: study of cells, tissues, organs and molecules involved in the recognition,
inactivation, removal and protection to foreign or dangerous materials (that can come both from the
environment (non-self) and from inside the animal (self)).
Immune surveillance is the recognition and removal of cells originating in the animal (self), e.g.
cancer (oncogenic) cells.
Antigen: (Antibody generator) it is a compound that stimulates an immune response in the animal, so the
antigen is produced by the pathogen. The animal fights antigens by producing specific antibodies.
Knowledge of veterinary immunology is important because:
- health and welfare are a right of animals
- it allows to have a healthy animal population and lower medical costs
- it allows to increase longevity of animals
- it allows to optimise production
- animals and humans share many immune characteristics
- 60-70% of infectious diseases in humans originate from animals zoonoses. It is facilitated
because we keep animals near cities (so near humans), and because we consume or have contacts
with wild animals (e.g. SARS or Corona). In addition, a large part of our DNA consists of DNA of
viruses (proviral DNA). There is also an important relationship between our intestinal microbiota
and the immune system. There is also risk that microbe resistance caused by high use of antibiotics
is transferred from animals to humans (e.g. via food) and vice versa, and this is bad.
Examples of zoonoses: influenza, tuberculosis, hepatitis, BSE, hypersensitivity, many parasites, Salmonella,
E. coli etc.
Two types of immunity:
- Innate/natural: it is fast and acute so it works to eliminate the pathogen within minutes/hours; it is
non-specific against pathogens, because it has no “memory” so it means that every infection is
treated in the same way; it precedes specific immunity. Innate immunity prevents infections
because it consists of cells that degrade microbes such as macrophages and killer cells, and of
physical and anatomical barriers that prevent the entrance of pathogens, e.g. the skin, “self-
cleaning” processes like coughing, production of mucus, diarrhea, vomiting, urine.
- Specific/adaptive: it is slow so it becomes effective in days or weeks; it is acquired/adaptive; it is
specific towards pathogens, so each pathogen carries certain antigens on its body that are
recognised by specific antibodies produced by the immune system. Specific immunity can be:
o Self-acquired, thanks to active vaccination or because the body had previous infections by
the same pathogen so it has “memory” and it knows what to do to fight that pathogen. It
means that the immune response to that pathogen can improve with time.
o Passively acquired, thanks to passive vaccination (=e.g. the serum of an immune individual
is injected in you, so you also become immune because it contains the right antibodies),
maternal immunity because antibodies of the mother are transferred to the baby via milk
or the placenta. In this case, the body has no “memory”.
NB: immunity is not always equivalent to relevant protective disease resistance.
,Types of immune responses:
- Protective: 1) concomitant, when the pathogen is present and active in the body (it helps to
maintain memory); 2) sterilising, when pathogen is completely removed; 3) modulating, when the
pathogen is present in the body but inactivated.
- Counter-protective, when the immune response “protects” the pathogen, e.g. HIV virus, and it is
bad.
- Irrelevant
- Harmful, when immune response causes inflammation or hypersensitivity when fighting the
pathogen.
CELLS OF THE IMMUNE SYSTEM
They originate from bone marrow in a process called hematopoiesis. Hematopoiesis produces
hematopoietic stem cells, and from these originate all other cells of the immune system:
- Common lymphoid progenitor, from which
originate B-cells and T-cells
- Myeloid progenitor, from which originate
leukocytes (basophils, neutrophils,
monocytes)
- Megakaryocytes, from which originate
Platelets
- Erythroblasts, from which originate
erythrocytes
NB: the names, levels and frequency of cells and cell
types in tissues and blood differ between animal species and between individuals, and also depending on
their health status.
Cells of the innate immune system are phagocytes, granulocytes, platelets, antigen-presenting
cells/dendritic cells, natural killer cells.
Cells of the specific immune system are T-cells and B-cells.
Phagocytes/macrophages (innate response)
They originate from monocytes in blood; there are different types of macrophages e.g. Kupffercells in liver,
osteoclasts in bone, alveolar macrophages (dust cells) in alveoli, mesangium cells in kidneys.
Main characteristics:
- they are very easy to isolate because they attach to glass and plastic;
- they contain a lot of RER;
- they have receptors for immunoglobulins (antibodies) called Fc receptors, so antibodies bound to
antigens attach to the Fc receptor on macrophages and they engulf the antigen to destroy it;
receptors for complement systems; for y-interferon and MAF; for antigens (produced by microbes)
called Toll-like receptors (TLR), which recognise specific antigens; receptors for MHC class II
molecules (these molecules bind antigens and display them on the cell surface so they can be
recognised by T-cells and destroyed).
There are 2 main types of macrophages: 1) M1, involved in inflammation and defence against infection, and
2) M2, involved in tissue repair when they are activated by IL4, IL10, IL13 (interleukins: messenger
molecules produced e.g. by T-cells that stimulate immune responses by other cells of the immune system).
,Macrophages “eat” foreign particles or bacteria via phagocytosis. Phases of phagocytosis:
1. the macrophage detects the bacterium via chemotaxis thanks to a density gradient (it goes in a
region where there are antigens)
2. the macrophage attaches to the bacterium via carbohydrates, fibronectin or hydrophobic fusion
3. the macrophage is activated and forms a sort of vesicle called phagosome, in which the bacterium
is contained, and the bacterium is engulfed in the macrophage.
4. the phagosome fuses with the lysosome (an organelle that contains enzymes for digestion of
molecules in the cell), so the bacterium is killed and digested thanks to substances produced by the
lysosomes so it is degraded.
5. The residual parts of the bacterium are expelled by the macrophage
Opsonisation means that the microbe is “coated” with fibronectin or antibodies to facilitate phagocytosis.
These substances are then detected by the receptors on the macrophage so they attach to the microbe
more easily and engulf it.
Granulocytes (innate response)
There are 4 types of granulocytes, and are classified based on their staining properties: 3 types are found in
blood, i.e. neutrophils (do not get stained), eosinophils (get stained by acidic dyes), basophils (get stained
by basic dyes), and 1 is found in tissues i.e. mast cells (they actually correspond to basophils).
Characteristics:
- Their cytoplasm is filled with granules
- Their nucleus is irregular and with lobes so they are called polymorphonuclear, vedere una figura
- They have no antigen specificity but they can do opsonisation to attach to specific antigens on
microbes
- They do not present antigens
- They make phagocytosis and pinocytosis, but also exocytosis to expel the content of their granules
in tissues, but these substances cause tissue damage and inflammation
Neutrophils: are the most diffused leukocytes in blood. They travel through blood and go into tissues when
they detect a microbe or an immune complex (immune complex=antigen bound to an antibody ), and cause
inflammation to fight it. They have a short life because they also die during inflammation. When they die,
they are phagocyted by macrophages.
Eosinophils: their number rises a lot in blood and tissues during parasitic worm infections and acute
hypersensitivity reactions (allergy). NB: they do not kill the worm, but they make it leave the intestine. They
are also attracted by immune complexes, which they degrade. They do not make phagocytosis but expel
their granules. They contain a lot of histaminase, which inactivates histamine (histamine is a molecule
released by mast cells when there are allergens). Eosinophils are highly present in the intestine of animals,
because here is where parasitic worms go and there are many immune complexes.
Mast cells (tissues) and basophils (blood): there are 2 types of mast cells: 1) connective tissue mast cells
(CTCM), present in all connective tissues, 2) mucosal mast cell (MMC), they are only present during
parasitic infections especially in the gut after they are activated by T-cells. They have receptors for
immunoglobulins E, G, M, C5a, IL4, IL5. The granules of mast cells contain several biological active
components like heparin (prevents coagulation), histamine/serotonin (involved in
vasodilation/constriction), fatty acids (e.g. prostaglandin), they activate platelets and produce EFCA which
attracts eosinophils to fight parasites.
,Platelets (innate system)
They have no nucleus, but have the MHC class I receptor on their surface, receptors for immunoglobulins,
for immune complexes and for fibrinogen. Functions of platelets is to heal wounds by aggregating with
other platelets and coagulation factors (e.g. fibrinogen), and to transport immune complexes to the spleen
to degrade them.
Dendritic cells (or antigen presenting cells, innate system)
They are one of the most important cells in the immune system because they are involved in the initiation
of the specific immune response. Characteristics:
- They form networks in lymph nodes, thymus, bone marrow, skin, gut.
- They express many MHC class II molecules (these molecules bind antigens and display them on the
cell surface so they can be recognised by T-cells and destroyed), so dendritic cells are involved in
antigen presentation.
- They do not make phagocytosis.
- They have receptors for immunoglobulins and toll-like receptors
Their important function is to present antigens that can then bound to T-cells and B-cells of the specific
immune system, that degrade them. In this way, they also maintain memory for antigens.
There are different types of dendritic cells:
- Dendritic cells in lymphoid tissues: 1) IDC, that present antigens to T-cells and 2) FDC, that present
antigens to B-cells
- Dendritic cells in skin and gut are called Langerhans cells
- Dendritic cells in blood and lymph fluid are called Veiled cells
- Dendritic cells in the paracortex of lymph nodes are IDC, and in the germinal centre of lymph
nodes are FDC
B and T lymphocytes (specific system)
They recognise specific antigens thanks to receptors they have on their surface: TCR receptor on T-cells and
BCR receptors for B-cells. They have different functions: T cells help or regulate immune responses (helper
T-cells TH and regulation T-cells Treg), they kill cells infected with viruses (cytotoxic T-cells Tcyt); B cells
produce immunoglobulins.
NB: 109 lymphocytes are produced every day, but then 90% of them is killed because only the best of them
is chosen; indeed, many of them are auto-immune lymphocytes that would attack healthy cells and you
want to avoid it.
T-cells and B-cells are hard to distinguish, but can be distinguished:
- using serological methods and monoclonal antibodies (antibodies that recognise only one type of
molecule): monoclonal antibodies recognise one specific molecule found on T cells called CD
molecules, so if they recognise it you know that is a T-cell. E.g. CD2, CD3 (T-cell receptor complex),
CD4 (on T-helper cells, it can bind to MHC class II molecules), CD8 (on T-cytotoxic cells, it can bind
MHC class I molecules) (questi sono da sapere)
- Cytokine production is different in T and B cells. Cytokines are messenger molecules produced by T
and B-cells to regulate immune function.
- Cytokine mRNA expression is different in T and B cells
,T-cells have TCR receptors on their surface and they can be 1) TCR1 (γ/δ) or 2) TCR2 (α/β), which can be
Th1 or Th2 depending on the cytokine profile (?). Both TCR1 and TCR2 are found in the CD3 receptor
complex.
T-cells regulate the immune response by producing many messenger molecules called interleukins that
activate/inactivate/recruit other cell types. They also produce e.g. Macrophage Arming Factors (MAF),
Colony Stimulating Factors (CSF), y-interferon.
B-cells produce immunoglobulins (antibodies). When B-cells are activated, they become plasma cells and
produce antibodies. They have also MHC class II and Fc receptors for
antibodies on their surface.
There are some cells that look like T-cells and are called Null cells, which
include natural killer cells that kill infected cells. Null cells do not have TCR
receptors.
Antigen presentation
Viruses and bacteria produce molecules called antigens, that are
recognised by the immune system. When microbes are phagocytosed, they
are degraded into antigens (short peptide chains) that are then presented
on the surface of the immune cell that degraded the microbe (macrophage, dendritic cells or B-cells). These
antigens are presented via MHC class II or MHC class I molecules on the surface of immune cells, then each
antigen is recognised by a specific TCR receptor of T-cells. The T-cell then produces cytokines that activate
B-cells, which produce antibodies specific for the antigens.
THE COMPLEMENT SYSTEM
It is a part of the immune system that enhances the ability of antibodies and phagocytic cells to remove
microbes, immune complexes and damaged cells from the organism. It is based on cascades, meaning that
there are several proteins/enzymes that get activated by other proteins/enzymes (so these enzymes are
first found in the inactive form called zymogen), e.g. enzyme A activates enzyme B, that activates enzyme C
etc. These cascades cause some molecules to bind to pathogens and mark them for destruction.
Complement system characteristics/functions:
- It is thought to be the oldest type of immunity
- It is both related to the innate and specific immune response
- It directs the recognition and lysis (breakdown) of particles like cells, bacteria (alternative and MBL
cascades)
- It marks microorganisms for destruction via opsonisation (vedi sopra definizione) and phagocytosis
- It indirectly binds to particles via immunoglobulins (classical cascade, related to specific immunity)
- It has chemotaxis of phagocytes and leucocytes (it attracts them), so it is involved in the start of
inflammations
- It is involved in the transport and destruction of immune complexes in the spleen
- It keeps immune complex soluble (they do not precipitate, if they do they can cause problems in
organs), so it prevents type-III hypersensitivity
- It is heat sensitive: incubation at 56°C for one hour destroys activity of the complement system
NB: the complement system must be regulated properly because it can also attack healthy cells of our
body, and it is not good.
4 types of cascades:
- Classical: based on C3 activation
, - Alternative: based on C3 activation
- MBL: based on C3 activation
- Terminal: it is activated after one of the other cascades “finished” its work, and consists in the
formation of the MAC Membrane Attack Complex, it attacks cell membranes to destroy them.
Components of cascades: (these are the proteins that form the complement system)
- Classical: C1q, C1r, C1s, C2, C3, C4
- Alternative: C3, B, D, P, H, I
- MBL: MASP-2, C4, C2, C3
- Terminal: C5, C6, C7, C8, C9
Other components of the complement system are e.g. macrophages, fibroblasts, liver cells, kidney cells, T-
cells.
The key component of these pathways is C3b, a molecule that binds to sugars and proteins (on the surface
of bacteria/cells) that must be generated after activation of the other components. Indeed, C3 protein is
present in the first 3 cascades, and it needs to be cleaved into C3a and C3b by the other components. “a”
refers to a small fragment, “b” to a large fragment (except for C2a and C2b, it is reversed).
Classical
It was the first discovered. It is usually activated by the presence of clusters of antibodies on the surface of
a pathogen. Steps:
1. The first component of the classical cascade is a protein complex C1, consisting of three proteins
C1q, C1r and C1s. When C1q binds to the Fc part of IgG or IgM antibodies on the surface of the
pathogen, the C1 complex is activated.
2. The activated C1s protein cleaves C4 into C4a and C4b, then C4b binds to C2 to form C4bC2.
3. C1s then splits it into C2a and an active C4bC2b.
4. C4bC2b cleaves C3 into C3a and C3b. C3b is the fundamental protein of the pathway.
5. C3b convertase binds to sugars and proteins on the microbe surface, then there are reactions that
lead to the formation of the terminal cascade (C5/6/7/8/9) that lead to the killing of the pathogen
because the Membrane Attack Complex (MAC) is formed and attacks the membrane of pathogens.
(knowing the sequence C1-C4-C2-C3-C5 etc. is enough, and that C1 is the first to activate and C3b binds to
the cell)
NB: the presence of Ca2+ and Mg2+ must be present to make the classical cascade work
Alternative
It is activated when cell walls of pathogens interact with components of the complement system in the
blood. the most important protein of this cascade is again C3, because it has a thioester side chain that,
when active, binds to the surface of microbes and marks them for destruction by immune cells. NB: C3
activation must be carefully regulated because there is risk that it binds to normal cells/tissues and marks
them for destruction.
1. C3 breaks down spontaneously and continuously in C3a and C3b, and C3b exposes the thioester
side chain. The thioester generates a carbonyl group that binds the C3b irreversibly to
carbohydrates and proteins on surfaces of nearby cells.
2. Breakdown of C3 also exposes a binding site for protein H; when it binds to C3, a protein I degrades
C3b and generates fragments iC3b and C3c. iC3b binds receptors on leukocytes to stimulate them
to engulf pathogens and activate inflammatory cells.
, 3. The final breakdown product of C3 is C3dg, which targets pathogens to surface receptors on B-cells
to promote production of antibodies.
4. The degradation of C3b depends on the binding of protein H; protein H can to C3b bind only when
sialic acid is present on the cell, so protein I is activated and C3b can be destroyed. However,
bacterial cells do not have sialic acid so when C3b is on this type of surface, H cannot bind to it and
C3b is not degraded. Therefore, protein B binds to it and forms C3bB. The B part of this complex is
then cleaved by protein D, and C3bBb forms (C3 convertase). If protein P is present, it binds to the
complex and forms C3bBbP, which can act on C3 to generate more C3b and so on.
5. The terminal cascade is also active to destroy cells.
(it is enough to know the sequence C3-H-I-B-D-P, that C3 is the first to activate, that C3 activates
continuously without antibodies being present unlike the classical cascade)
MBL
MBL stays for mannose-binding lecitin.
1. MBL binds to microbes because they recognise certain sugars on their surface (e.g. mannose), and
activate proteases that activate the complement system.
2. When bound to the microbe, MBL activates a protease called MASP-2, which splits the factor C4
into C4a and C4b.
3. C4b has a thioester group that binds to the microbe, then C2 binds C4b and forms C4b2.
4. C2 is cleaved by MASP-2 and C4b2b is formed. This complex splits C3 into Ca and C3b and exposes
the thioester of C3b.
5. C3b binds to microbes. Then, the terminal cascade is activated to destroy the pathogen.
(it is enough to know the sequence MASP2-C4-C2-C3)
Terminal cascade
It is the final step of all other cascades.
1. C3b activated in the other cascades splits C5 into C5b and C5a.
2. C5b binds to C6, C7, and C8 and they deposit on the surface of the microbe.
3. They also bind to C9, so the MAC complex (membrane attack complex) is formed to destroy the
microbe
---
C3b can bind also to proteins and sugars on our cells, and it is dangerous because they might be destroyed.
Protection against this is provided by the Complement Control Proteins (CCP), which degrade the
components of the cascades to stop them. Regulation of complement system by CCPs:
- They inhibit binding of C2 and C4
- Regulate catabolism of C4b and C3b by factor I
- Inactivation of C1r and C1s
- Destabilisation of C4bC2b and C3bBb
If C3b manages to bind to our healthy cells, then complement system is regulated in this way:
- You have More C3bBb amplification, or
- Catabolism by Factor I is stimulated by factor H, or
- Binding to receptor for C3b
Microbes have mechanisms to protect themselves from being attacked by the complement system:
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