Partridge L15-21 Flashcards
What is the immune system?
Integrated system of cells and molecules that defends against disease. Reacts against infectious pathogens. Type of response is dependant on the pathogen.
What are the two types of immunity?
Innate and adaptive.
What is innate immunity?
The one you are born with. It is present in almost all organisms and has a broad specificity, not affected by prior contact and has a rapid response.
What is adaptive immunity?
The acquired one. It is highly specific, enhanced by prior contact and has a slower response. As adaptive requires previous contact, babies require the immunity from the mother either from milk or the placenta.
What does the innate immune system consist of?
Barrier. Leukocytes (Phagocytes, NK cells). Soluble proteins (Complement, Interferons). Local and system responses (Fever, inflammation).
How are barriers part of the innate immune system?
Keratinised skin is an effective barrier unless breached by wounds or cuts which are exploited by pathogens. Some pathogens explicitly infect the skin such as Papilloma.
Most infections are caused by infections of mucosal surfaces.
What are the mucosal surfaces that can be infected in the body?
- Gastro-Intestinal Tract (300m2). = Salmonella, Shigella, Listeria, E.coli, Campylobacter. Poliovirus, Rotavirus, Norovirus
- Respiratory Tract (100m2) = Strep pneumoniae, Haemophilus influenza, Neisseria meningitides, Mycobacterium tuberculosis, Adenoviridae, influenza virus, SARS-Cov-2
- Genito-urinary tract = small surface area, but close contact for transmission of pathogens. Urinary tract infections are caused by E.coli and others that enter the genito-urinary tract and travel to the kidneys. Sexually transmitted include Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, HIV, HSV.
How do leukocytes affect the innate immune system?
These are derived from pluripotent stem cells which give rise to two main lineages one for myeloid cells and one for lymphoid cells.
1. Phagocytes are particularly important in extracellular bacterial/fungal infections. Two main types: neutrophils, mononuclear phagocytes.
Neutrophils = Main phagocyte in blood. Short-lived, fast-moving. Specialised lysosomes release enzymes, H2O2 etc.
Mononuclear phagocytes = Long-lived (months). Help initiate adaptive responses. Brain - microglial cells. Lungs - alveolar macrophages. Liver - Kupfer cells. In the blood called monocytes in the tissues called macrophage.
2. NK cells are a type of lymphocyte. Distinct cytoplasmic granules. Kill infected host cells. Important in viral (e.g. Herpes) and certain intracellular bacterial (e.g. Listeria monocytogenes) and protozoal (e.g. Leishmania) infections. Help keep viral infections in check until adaptive immunity develops
What does soluble proteins consist of in the innate immune system?
Defensins = positively charged peptides made by neutrophils. Disrupt bacterial membranes causing lysis.
Interferons = important in viral infections
Complement = important in extracellular infections
INTERFERONS (IFNalpha and IFNbeta) induced by viral infection make several contributions to host defence.
What is complement?
20 serum proteins, normally inert but can be activated in response to pathogens by innate mechanisms or when antibody binds to antigen (classical pathway). C1, 4, 2, 3, 5, 6, 7, 8, 9 is the classical pathway. C3 is the most important part of the pathway. Many components have enzyme (protease) activity. Central event of complement activation is the cleavage of C3 protein to generate peptide fragments C3a + C3b by C3 convertase.
What are the three major biological activities of complement?
- Recruitment of inflammatory cells = C5a (C3a) chemo-attractants to induce inflammatory mediator release. S.aureus chemotaxis inhibitor protein (CHIPS) binds C5a receptor to combat complement action.
- Opsonisation = C3b increases binding and phagocytosis. Important in killing gram +ve bacteria. Some bacteria evade opsonisation by producing a thick capsule that envelopes C3b (S. pneumonia, N. meningitides).
- Cell lysis = Membrane attack complex (C5b – C9). C9 polymerises to form hollow cylinders creating pores in bacterial membranes. Important in defence against gram -ve bacteria (gram +ves are resistant to MAC killing)
How do local and systemic responses affect the innate immune system?
Inflammation: Vasoactive amines, complement. Includes dilation of blood vessels, increases capillary permeability and phagocytes to migrate into tissues. Causes heat, redness, swelling and pain.
Fever response: Cytokines, LPS. Induces synthesis of prostaglandin E2 acting on the hypothalamus.
Inflammation and the fever response are examples of integrated response to infection
How is pathogen recognition done by phagocytes?
- Antibody bound to pathogen ( via Fc receptors)
- Complement components bound to pathogen (via C3b receptors)
- Innate mechanisms – Pattern recognition receptors (PRRs) recognise microbe associated molecular patterns (MAMPs).
What are pathogen recognition receptors?
Receptor binding may initiate phagocytosis, chemotaxis or signalling. Chemotactic receptors recognise chemo-attractants = C5a receptor binds C5a or f-met-leu-phe receptor recognises N formylated polypeptides (produced by bacteria). Toll like receptors or TLRs are sensors that signal the presence of microbes.
Toll like receptors are an ancient pathogen recognition system. There are 11 in humans, each recognising distinct MAMP. They can be cell surface receptors or endosomal. TLRs usually function as dimers. Signalling induces expression of inflammatory cytokines and interferons.
What are the mechanisms for phagocytosis?
Acidification, toxic nitrogen oxides, enzymes, competitors etc. These are short lived and contained in the phagosome.
How do neutrophils work?
They “throw” neutrophil extracellular traps (NETs) around bacteria. This occurs following NETosis. The net is a DNA (chromatin) impregnated with antimicrobial compounds.
How do NK cells work?
Natural Killer cells recognise “altered self.” Killing regulated by opposing activating or inhibitory receptors Inhibitory receptors recognise MHCI (“self”) proteins present on all nucleated cells Alterations in MHCI expression prevents inhibitory signalling.
Activated NK cells produce perforin, which inserts into the membrane of the target cell. Granule contents (“granzymes”) are released into the target cell. Target cells undergo apoptosis. A recently discovered granzyme can enter intracellular bacteria, killing them directly.
How do cytokines work?
These are the “hormones” of the immune system. They are a diverse group of small soluble proteins that bind to cytokine receptors on target cells, regulating their behaviour during immune responses. Regulate immune responses by changing cell behaviour or gene expression 5-20kD; >100 identified Most act locally, but can have systemic effects Can be produced by many cell types in response to immune activation Act on cells bearing specific cytokine receptors. Main groups of cytokines include:
- Interleukins (IL-1, IL-38?) – usually made by T cells
- Interferons (IFNs) viral infections e.g. IFNα, IFNβ; cell activation (IFN γ)
- Chemokines - cell movement or chemotaxis e.g. IL-8
- Tumour necrosis factors (TNFs) – pro-inflammatory, can kill some cells
What is humoral (adaptive) immunity?
B lymphocytes recognise antigen. Differentiates into plasma cells that secrete soluble antibody that labels antigen.
What is cell mediated (adaptive) immunity?
T lymphocytes recognise antigen. Differentiates into cytotoxic T cells that kill infected host cells or helper T cells that control immune response.
What is an antigen?
A molecule that induces production of antibodies. It is an ANTibody GENerating material. A single antibody molecule is specific in that it normally binds to only one antigen
Where do B and T cells acquire their specific antigen receptors?
In bone marrow and thymus respectively.
What is the structure of an antibody?
Light (L) chain = 25kD Heavy (H) chain = 50kD Immunoglobulin G = L2H2 = 150kD. Antigen recognition is at the top and the Fab part of the chain. Antigen elimination is at the bottom and the Fc part of the chain. Antibodies act as “adaptors.” Important in extracellular bacterial infections, but also activity against intracellular pathogens. Antibodies may be DIAGNOSTIC of infections.
Variable (V) regions bind to the antigen. These differ between antibodies with different specificities. Constant (C) regions are the same for antibodies of a given H chain class or L chain type. VARIABLE and CONSTANT regions are encoded by separate exons. Multiple V region exons in the genome can RECOMBINE during early B cell differentiation (SOMATIC RECOMBINATION).
