Immunology Flashcards
What does the immune system do?
It identifies and eliminates microorganisms and other harmful substances as well as abnormal cancer cells.
It does this by distinguishing ‘self’ molecules from ‘non-self’ molecules, by identifying danger signals (eg inflammation) or by a combination of the two
What does it mean to have a balanced immune system?
Where the immune system is at optimal effectiveness and has found a balance between protecting from the pathogen and not rejecting donor tissues
What happens when the immune system goes wrong?
Immune over-reactions lead to autoimmunity diseases, allergies, asthma, eczema, sepsis
Immune under-reactions lead to cancers, HIV,
How do we help the immune system prevent or treat diseases?
Immunisations
Anti-inflammatory markers and immunosuppressant drugs (eg ibuprofen, aspirin, cortisol)
Cancer immunotherapy -enables immune system to recognise, target and eliminate cancer cells. (genetic engineering also used)
What are the defences used towards foreign bodies in the immune system?
Natural/ physical barriers Soluble factors (innate and acquired) Immune cells (innate and acquired)
What are the innate soluble factors?
Cytokines
Acute phase proteins
Inflammatory mediators
Complement proteins
What are the types of innate immune cells?
Macrophages
Mast cells
Natural killer cells
Neutrophils
What are the types of adaptive soluble factors?
Cytokines and antibodies
What are the types of adaptive immune cells?
B and T cells
What is innate immunity?
Immunity that is present continuously and is generally non specific (the same response occurs to many types of material). Rapid response and no immunological memory.
Works closely with acquired immunity
What is acquired immunity?
Immunity induced by the presence of foreign or non-self material, the response is usually unique and specific to the pathogen. Slower response with immunological memory. Self regulating through regulatory T cells
Works closely with innate immunity.
What are the points of entry for pathogens to infect the body?
Digestive system
Respiratory system
Urogenital system
Skin damage
What are the routes of attack of pathogens
Circulatory system and lymphatic system
Why is skin such an effective barrier to infection?
It is a physical barrier composed of tightly packed, highly keratinised, multi layered cells which are constantly undergoing renewal and replacement
physiological factors such as a low pH (bacteria don’t like acidic conditions) and low oxygen tension
Ut has sebaceous glands which secrete hydrophobic oils, lysozymes, ammonia and antimicrobial peptides
How does mucus act as a barrier to infection?
Mucus membranes line all body cavities that come into contact with the environment (respiratory, GI, urogenital) so is a physical barrier
Secretory igA prevents bacteria and viruses attaching to and penetrating epithelial cells
Contains enzymes lysozyme, defensins and antimicrobial peptides which directly kill pathogens.
The mucus traps the bacteria which are subsequently removed by ciliated cells.
What is commensal bacteria?
Helpful bacteria which is in a symbiotic relationship with the host. The compete for scarce resources and produce byproducts which inhibit the growth of many pathogens
How can physical barriers be bypassed?
Burns, bites, injections, breaks of the skin.
What are the functions of macrophages?
Phagocytosis, pro/anti inflammatory markers, bacteria killing mechanism, antigen presentation, wound healing
What are the functions of mast cells?
Pro-inflammatory, parasite killing mechanisms, linked to allergy and asthma
What are the modes of ingestion by macrophages?
- pinocytosis = ingestion of fluids surrounding cells
- receptor-mediated endocytosis
- phagocytosis = intact particles are internalised whole (facilitated by opsonisation)
What is opsonisation?
The coating of a pathogen by soluble factors (opsonins) to enhance phagocytosis. (by c3b, CRP, igG/igM)
How do mast cells destroy large parasites?
1- degranulation = release of pre-formed pro-imflammatory substances
2- gene expression = production of new pro-inflammatory substances
Leads to localised, acute inflammation
Describe the process of phagocytosis
Macrophages express a set of pattern recognition receptors (PRPs) > bind to PAMPs (pathogen associated molecular patterns) >plasma membrane extends and surrounds bound pathogen (cup) > membrane pinches off and internalises microbe forming a phagosome > fuses with a lysosome to form phagolysosome which kills off pathogens > debris released into extracellular fluid> pathogen deprived peptides are expressed on cell surface receptors (MHC2) > pro inflammatory mediators released
What are the types of phagocyte?
Monocytes, macrophage, neutrophil and dendritic cells
What does the complement system do when activated ?
Creates a cascade of chemical reactions that promote opsonisation of pathogens, direct pathogen killing, acute inflammation or leukocyte recruitment
What are the three pathways of the complement system ?
Classical pathway, mannose binding lectin pathway, alternative pathway
They convert C3 to C3a and C3b
What happens in the mannose binding lectin pathway?
Mannose-binding lectin binds to mannose on the bacterium and causes a conformational change triggering a wave of changes. This makes an enzyme which cleaves C3 into C3a and C3b
(This is specific as mannose is specific to certain pathogens)
Describe C3b in the mannose-binding lectin pathway.
C3b is unstable and rapidly degrades unless it binds to cell surfaces so binding to a pathogen stabilises it. This allows activation of downstream events of the complement system and it results in the production of C5 convertase.
C3b generates an amplification loop and stimulates more C3 cleavage.
(Powerful opsonins)
What does C5 convertase do?
Cleaves inactive C5 into active C5a and C5b.
What does active C5b do?
Goes on to associate with other complement system proteins to produce the membrane attack protein (MAC).
What is the MAC?
(Membrane attack complex)
A pore forming channel which inserts into the pathogen membrane.
It causes extracellular salts and water to enter the pathogen via the pore, causing the pathogen to swell and burst.
What are anaphylatoxins?
C3a and C5a
They promote changes by activating mast cells (which degranulate and release histamine and other pro inflammatory mediators) and by directly acting on local blood vessels.
What are the physiological signs of acute inflammation?
Dilation of blood vessels, increased blood flow, cell accumulation, increased cell metabolism, increased permeability of post capillary venules, fluid accumulation, stimulation of nerve endings, swelling + pain
What are mast cells?
Large granular cells that release highly inflammatory substances when activated. They are tissue resident and important in defence against large antibody coated pathogens that cannot be phagocytosed.
What are the differences between healthy tissues and inflamed tissues?
- in healthy tissues there are no inflammatory mediators and normal vasculature whereas inflamed tissues have inflammatory mediators and vascular changes (increased blood flow and permeability)
- neutrophils in healthy tissues are circulating and in inflamed tissues they are recruited and activated.
Describe the process of endothelial migration
1 - loss of intravascular fluid in blood vessels and increase plasma viscosity slows blood allowing neutrophils to move towards the post-capillary venules walls -this is MARGINATION
2- pro-inflammatory cytokines cause the expression of adhesion molecules on neutrophils
3- neutrophils translocations across the endothelial gap to extravascular spaces- DIAPEDESIS (induced by chemokines)
4- neutrophils move towards site of infection along conc. gradient called chemist is (induced by chemokines and microbial products)
5- PAMPs on pathogens activate neutrophil killing mechanism
What do neutrophils do?
Phagocytosis, degranulation and NETs (neutrophil extracellular traps)
They are short lived
What are the two ways in which neutrophils can cause phagocytosis?
Phagolysosomal killing and ROS-dependant killing
What is neutrophil degranulation?
Release of anti-bacterial proteins from neutrophil granules directly into the extracellular space. This directly kills extracellular pathogens, bacteria and fungi. It also Can cause tissue damage and potentially systemic inflammation.
What is NETs ?
(Neutrophil extracellular traps)
A method whereby neutrophils kill extracellular pathogens while minimising damage to host cells. NETs immobilise pathogens and then induced phagocytosis.
Where are neutrophils produced and immobalised?
Bone marrow
What role does the liver play in acute inflammation?
Liver hepatocytes produce a variety of acute phase proteins (C3, MBL,CRP)
What is CRP?
(C reactive protein)
It primes certain bacteria for destruction by the complement system and has a role in determining the severity and duration of inflammation.
What are inferons?
Small proteins produced by virally infected cells which play a role in immune protection against viruses. -they prevent the replication if viruses, signal cells to produce anti-viral factors that protect the cell from viral infection and act as signalling molecules to warn nearby cells of a viral presence.
What do natural killer cells do?
They are lymphocytes that can Kill infected and abnormal cancer cells and ignore healthy tissues and cells. They do this by releasing cytotoxic molecules that cause apoptosis. They respond to lower levels of class 1 MHC molecules on cell surface.
Describe B cells
Mature in the bone marrow
Responsible for humoral (body fluids) immune responses. They produce antibodies that attack pathogens circulating in the blood and lymph.
Play a key role in defence against pathogens
Use membrane bound antibodies as a receptor to recognise and bing to antigens.
Describe T cells
Mature in the thymus
Responsible for cellular immune responses
Key role in defence against intracellular pathogens
What do CD4+ T cells do?
Regulate the entire immune system
What do CD8+ T cells do?
Kill virally infected body cells
What are the different classes of antibodies and why are they different?
IgM, IgG, IgA, IgE, IgD
They have different heavy chains so present different antibodies
Where do adaptive immune responses occur?
Secondary lymphoid tissues
Mature B and T cells constantly re-circulate between the blood, secondary lymphoid tissues (lymph nodes, spleen, mucosal associated lymphoid tissues) and lymphatic vessels
Where is the key site of pathogen detection by B and T cells?
Lymph nodes
Describe how B and T cells search for antigens in the lymph nodes
B and T cells enter lymph nodes through high endothelial venule (HEV) and separate off into their distinct areas. B cells are stationed in the lymphoid follicle and T cells go to the T-cell area.
Lymph comes in through the afferent lymphatic into the lymphoid follicle where they will bind with specific B cells and if not they move on to the T cell area where they bind with T cells, then move out via the efferent lymphatic
How is the acquired immune response mediated by B cells?
B cells produce specific antibody IgM which binds to target antigens activating B cells. The B cells then globally proliferate and differentiate into plasma cells (secrete antibodys specific to the antigen) or memory B cells
How do B cells encounter antigens?
Specialised cells within B cells express opsonin receptors which trap opsonised antigens
What signals do B cells need to become fully activated and clonally proliferate?
They need specific antigens and ‘helping’ signals (only happens due to pathogenic infection)
What happens to B cells after receiving both signals required?
It clonally proliferates resulting in daughter cells which express BCRs with the same antigen specificity as the parent B cell . They then form a follicle within the germinal centre.
- then they differentiate into antibody secreting plasma cells
What happens after B cells have become plasma cells?
- they secrete low affinity IgM antibodies and are short lived
- T helper cells help produce better antibodies which are of a higher affinity
- There is a switch from producing IgM to IgG antibodies
- B cells differentiate into long-lives plasma cells
- stimulates the production of memory B cells
How do antibodies help kill and eliminate antigens (pathogens) ?
The antibodies have variable region sites which allow them to recognise complementary antigens.
The heavy chain constant region interacts with effector molecules complement and fc receptors to inactive/eliminate the microbe
What are the functions of IgM?
-b cell activation
-agglutination
-complement system activation
(Present in plasma and secretory fluids as a pentamer)
What is agglutination?
The action of an antibody when it cross links multiple antigens producing clumps of antigens
Describe the process of agglutination
- mediated by specific antigens binding to IgM and IgG antibodies
- results in the increase of efficacy of pathogen elimination via phagocytosis
- can also prevent viruses from binding to and infection host cells.
How is the classical complement system activated?
By the Fc region of IgM and IgG antibodies binding to antigens which induces a conformational change in the Fc regions, exposing multiple binding sites for C1, the first component of the classical activation pathway of the complement system.
Describe IgG
- most abundant and longest lived of the immunoglobulin classes
- produced during secondary immune response
- functions are agglutination, complement system activation, foetal immune protection (maternal IgGs help protect the baby until it’s own immune system develops), neutralisation, opsonisation, natural killer cell activation
Describe neutralisation
High affinity antibodies IgG and secretory IgA bind to antigens. This prevents viruses from infecting host cells and microbial toxins from disrupting normal cell function.
What does IgG do ?
- the best opsonins
- a good activator of natural killer cells
Describe IgD
-function is not well understood (found at very low concentrations)
B cell activation
Describe IgA
Monomeric form -present in serum
-helps neutralisation
Dimerise form -present in secretory fluids (sIgA)
- neonatal defence
- neutralisation
- primary defence mechanism at mucosal surfaces
What does colostrum do?
It’s a form of milk produced in late pregnancy which contains sIgA antibodies to protect newborns from disease (eg hypogammaglobulinaemia)
What do IgE antibodies do?
Can trigger allergic responses (allergy, asthma, anaphylaxis)
What are TCRs?
T cell receptors which expresses thousands of copies of a single antigen receptor. (T cells can only recognise peptide antigens)
A hyper variable region at the tips of the alpha/beta TCR is involved in antigen binding and is unique to each T cell
What does the MHC (major histocompatibility complex) do?
Process and present broken down peptides from pathogens to T cell receptors.
(B cells do not require this)
They are encoded by highly polymorphic genes and are able to present many different peptides
What are the classes of MHC molecules?
Class 1- expressed on all uncleared cells and present peptide antigens to CD8+T cells
Class 2- express only on professional antigen presenting cells (dendritic cells, macrophages, B cells) present peptide antigens to CD4+ cells
What do dendritic cells do?
They are in an immature state in non-inflamed tissues.
When tissues are inflamed they recognise and phagocytise antigenic debris and become mature in the presence of pro inflammatory mediator TNFalpha. They then ingest proteins and display small peptides derived from then on their surface in complex with MHC proteins.
What other signals do T cells need to respond to antigens and fully activate?
Co-stimulators molecules expressed by the dendritic cell.
What do CD4+ T cells do?
Differentiate into different types of effector helper T cells which remain in lymphoid tissues or migrate to site of infection to help B cells CD8+ cells or macrophages.
Describe CD4+ and IL-2
1-Antigen activated CD4+ T cells start to secrete a cell growth factor, interleukin 2 (IL-2) and also express the IL-2 receptor which leads to autocrine mediated cell proliferation.
2-proloferating cells are know as Th0 cells and the induce autocrine/paraautocrine mediated proliferation of CD4+ and CD8+ cells due to large productions of IL-2
3- IL-2 is used by antigen activated CD4+ and CD8+ cells for them to proliferate and differentiate
What do CD8+s become when affected by IL-2?
Cytotoxic T cells
What do Th1 cells do?
Effector Th1 cells migrate out of secondary lymph nodes and enter sites of inflammation/infection
They become re-activated by infected, tissue resident macrophages
This makes them release pro-inflammatory cytokines which enhance macrophage mediated killing of pathogens by stimulating production of reactive oxygen species (ROR)
Macrophages respond to signal by becoming super killers like neutrophils and kills pathogens before they leave the phagosomal compartment
