What are the 5 main ways that the Innate Immune System can be Activated?
1. Breaching of the innate barriers
2. Complement + macrophage activation,
3. Histamine + kinins + TNF- causing vasodilation, chemoattraction of neutrophils and monocytes,
4. Macrophage release of IL1 + IL6- acute phase response and fever,
5. Local Inflammation.
What are PAMPs?
They are Pathogen Associated Molecular Patterns, that recognise specific epitopes on pathogens e.g. Toll Like Receptors and Opsonin Receptors.
What is the First Line of Defence of Innate Immunity?
Mechanical barriers e.g. mucous membrane, skin, bronchial cilia, and chemical barriers e.g. lysozymes, mucous production, gastric acid and pepsin, IgA of saliva and tears. They help to limit the entry and growth of bacteria.
What is the Second Line of Defence of Innate Immunity?
Phagocytosis, Cytokines + Chemokines, and activation of the Alternative Pathway.
What is the purpose of IL-8?
Attraction of neutrophils.
What is the purpose of IL1 + IL6?
Is part of the acute phase response leading to fever.
What is the purpose of TNF?
Activation of vasomodulation and phagocytosis.
Which Toll Like Receptors recognise bacterial pathogens?
TLR2, TLR4 and TLR5.
Recognises the peptidoglycan of gram-positive bacteria.
Recognises the LPS of gram-negative bacteria.
Recognises flagellin from bacterial flagella.
What Toll Like Receptors recognise viral pathogens?
TLR3, TLR7, TLR9.
Recognises double-stranded RNA viruses.
Recognises single-stranded RNA viruses.
Recognises double-stranded DNA viruses.
Why are gram-negative bacteria resistant to the actions of complement?
They have a LPS cell wall.
What are the 3 pathways that can activate complement?
Classical pathway, Leptin pathway and Alternative pathway.
Describe the Classical Pathway
It is antibody dependent as it requires IgM or IgG to produce C3 convertase. The antibody-antigen complexes bind to C1q + activate the C1qrs complex.
Describe the Leptin Pathway
Mannose binding leptin binds to the mannose on organisms leading to the activation of C4 and C2 which go on to join the complement pathway.
Describe the Alternative Pathway
It is antibody independent. When microbes are in contact with bodily fluids they produce a small amount of activated C3 (C3b) which leads to the activation of C4 + C2 which join the pathway.
How does the activation of Complement kill organisms?
The form a membrane attach complex (MAC) which produces a pore complex in the cell membrane leading to cell lysis. C3b complemen also opsonises pathogens 'marking' them for phagocytosis.
How does the Innate Immune System respond to viral infection?
Production of anti-viral proteins, release of type 1 interferons (IFN alpha and beta) and release of NK cells.
How does the release of type 1 interferons by the innate immune system, protect against viral infection?
IFN alpha + beta are recognise by toll like recepots 3, 7 +9. This causes the production of an:
1. Anti-viral state= inhibition of viral replication, and protection of infected cells.
2. Infected cell recognition= increase in antigen presentation + MHC1, with the activation of APCs of the adaptive immune system.
3. Infected cell killing= activation of NK cells.
How do Natural Killer cells produce by the Innate immune system help protect against viral infection?
They cause the lysis of virally infected cells and tumour cells releasing TFN gamma promoting cell-mediated immune response. They cause the relase of perforin and granzymes activating apoptosis.
Leukocyte Adhesion Defect
A deficiency in B-integrins molecule CD18 affecting neutrophils ability to migrate and phagocytose.
Chronic Granulomatous Disease
A defect in an enzyme needed to produce the reacitve O2 species in neutrophils. Affects the respiratory burst.
Autosomal Dominant deficiency of C1inhibitor causing activation of the classical pathway and production of bradykinin. There is increased vascular permeability and tissue oedema.
What is the humoral Response of Adaptive Immunity?
It is the release of antibodies from B-cells.
Define the Polyclonal Response
Each B-cell only produces one type of antibod, but there are lots of different types of B cells and specificities.
What stimulates further development of B-cells?
The release of IL-4 and IL-5 from T-cells.
How is the survival of B-cells conferred?
They reelase of Bcl-xL from T-cells.
What are the 2 different light chains of B-cells?
Lambda and Kappa.
What are the 5 types of antibodies produced by B-cells?
IgM, IgG, IgA, IgE, IgD
What are the actions of IgM?
It is the primary antibody response seen in the blood and tissues. Causes agglutination and complement activation.
What are the actions of IgG?
It is the secondary response seen in the blood and tissues. Transplacental transfer. Activation of NK cells, neutralisation, complement and opsonin.
What are the actions of IgA?
They prevent attachment to mucouse membrane. They are present in the blood and breast milk.
What are the actions of IgE?
They cause mast cell degranulation and activation of eosinophils.
What are the actions of IgD?
They are the B-cell antigen receptors.
What are the 6 main actions of antibodies?
1.) Opsonisation for phagocytosis and complement mediated killing.
2.) Neutralisation of toxins.
3.) Agglutination of bacteria for phagocytosis.
4.) Preventing bacteria binding to mucous membranes.
5.) Eosinophilic parasite activation.
6.) Complement activation.
Define Combinatorial Diversity
It is the different combinations of light and heavy chains, variable and joining regions. Not all variable regions are equally utilised and not all heavy and ligh chains go together.
Define Junctional Diversity
Insertion of a nucleotide into the 3rd hypervariable region.
Define Somatic Hypermutation
It is a point mutation increasing the affinity then maturation of an antibody.
What are the 2 types of antibodies produced by the Adaptive immune system in response to viral infection?
Neutralising antibody- binds to the virus and blocks its entry and binding to the host cells.
Virus specific antibody- act as opsonins increasing phagocytosis.
How do CD8+ cells react to viral infection?
They release cytotoxic granules containing perforin, producing pore formation and granzymes e.g. caspases that induce apoptosis. They also activate the FAS-FAS ligand pathway which signals to the cell to induce apoptosis.
How do CD4+ cells react to viral infection?
They contribute to the humoral reponse by the release of IL4 and IL5 promoting B-cell growth and differentiation, isotype switching, affinity maturation and enhances bacterial elimination.
Also, CD8+ cells promote macrophage activation and NK cell activity.
What is the Th1 response?
Release of IL2, TNF + TFN gamma from CD4+ cells. Causes B-cell proliferation, macrophage activation, NK cells and APCS.
What is the Th2 response?
Release of IL4, IL5 and IL13 from CD4+ cells. Causes class-switching to IgE + eosinophilic activation.
What types of cells are APCs (Antigen Presenting cells)?
Dendrites, B-cells and macrophages.
T-cell antigen receptors (TcRs) require 2 lots of stimulation: they recognise the MHC-antigen complexes and they also bind to APCs.
What MHC is activated in intracellular infection (viruses)?
MHC1 causing the activation of CD8+ cytotoxicT cells.
What MHC is activated in extracellular infections (bacteria)?
MHC2 causing the activation of CD4+ helper T cells.
What are the 4 steps in T-cell Maturation?
Induction, Activation, Effector phase and Resolution.
What happens in the Induction phase of T-cell Maturation?
Antigens are transported to lymph and activate T-cells by costimulation.
What happens in the Activation phase of T-cell maturation?
Antigen-specific T-cells undergo clonal expansion + differentiation + activation. Memory cells develop.
What happens in the Effector phase of T-cell maturation?
Activated cells migrate to the site of infection. CD4+ cells release cytokins ad CD8+ cells enhance NK cells and macrophages.
What happens in the Resolution phase of T-cell maturation?
Phagocytic celle e.g. macrophages + fibroblasts resolve damage and promote healing.
Define Positive Selection
It is the selection of T-cells which recognise MHC molecules and foreign antigens and stimulates differentiation.
Define Negative Selection
It is the selection of T and B-cells that recoginse MHC/self-antigens with high affinity. If these were left in the periphery then they would lead to autoimmunity.
What mnemonic helps to determine whether a patient has an immunodeficiency?
S- severe, life-threatening infections,
P- perisistent despite appropriate treatment,
U- unusual e.g. opportunistic infections,
R- recurrent episodic infections.
An absence of antibodies.
Low levels of antibodies.
It causes the absence of mature B-cells due to a lack of tyrosine kinase.
Common Variable Immunodeficiency
B-cells do not differentiate into plasma cells.
If isolates is due to a lack of thymus gland, which occurs when there is a failure in development of the 3rd and 4th branchial pouches. Is associated with Di George syndrome.
Severe Combined Immunodeficiency (SCID)
Severe impairement of T-cell development, both cell mediated and humoral immunity. Presents in the first few months of life with failure to thrive, infections, diarrhoea and hepatosplenomegally. Live vaccines should be avoided and all blood products should be screened to be CMV negative.
It is an immune response against self-antigen/pathogens that leads to tissue damage or disturbed physiological function.
What is the purpose of B1 cells?
They produce 'natural antibodies' which are a type of IgM. They do not exhibit affinity maturation and are independent of T cells.
Define Central Tolerance
It is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self.
Define Peripheral Tolerance
It is immunological tolerance that develops after T and B cells enter the periphery.
Describe a Type 1 Hypersensitivity Reaction
APCs digest antigen + present to T-cells. T-cells differentiate into Th2 cells. They release IL-4 + stimulate B-cells to manture + release IgE. IgE binds to mast cells + basophils completing sensitization. An allergic response occurs with a 2nd encounter as the antigen binds + cross-links to IgE antibodies of mast cells + basophils. This causes cells to degranulate, releasing histamine and inflammatory mediators.
Describe a Type 2 Hypersensitivity Reaction
IgG binds to antigens on the host's own cells. This gets recognised by APCs as 'foreign' causing B-cell activation, complement-mediated lysis + phagocytosis. Can also stimulate ADCC as foregn antigens are 'tagged' by IgG and are recognised by NK cells.
Describe a Type 3 Hypersensitivity Reaction
Igs + antigens cause extensive cross-linking + formation of insoluble antigen-antibody complexes. These complexes insert themselves into small blood vessel, joints and glomeruli leading to an intense inflammatory response and cell-mediated lysis.
Describe a Type 4 Hypersenstivity Reaction
Delayed reaction. It is mediated by CD4+ cells and the activation of macrophages secreting IL-12 and CD8+ cells. Occurs 2/3 days after exposure and causes the release of Th1 cytokines.
What are the 5 different ways in which Self-Tolerance can be broken down in autoimmunity?
Defective Immunoregulation, Cytokine Disregulation, Molecular Mimicry, T-cell Bypass, and 'Hidden' self antigens.
Describe Defective Immunoregulation in terms of its role in the breakdown of self-tolerance.
There are normally suppressor/regulatory T-cells e.g. CD25+ which act to inhibit autoimmunity. Therefore a reduction in numbers leads to autoimmunity.
Describe Cytokine Disregulation in terms of its role in the breakdown of self-tolerance.
Cytokines have a role in the suppression and regulation of T-cell responses. They are released from regulatory T-cells and help to maintain peripheral tolerance.
Describe Molecular Mimicry in terms of its role in the breakdown of self-tolerance.
It is when foreign antigens resemble self-antigens. Occurs when epiopes of a self-antigen resemble those of a foreign antigen, antibodies made against the foreign antigen can therefore cross-react with the self-antigen e.g. rheumatic fever.
Describe T-cell Bypass in terms of its role in the breakdown of self-tolerance.
B-cells no longer require T-cells to produce antibodies.
Describe 'Hidden' Self-antigens in terms of their role in the breakdown of self-tolerance.
The release of Self-antigens that are not normally seen by the immune system as it does not normally have access e.g. within the CNS, testicular tissue. Does not normally evoke an immune response.
What is the structure of gram-positive bacteria?
Made up of 2 layers- a thick peptidoglycan layer and a plasma membrane.
What is the structure of gram-negative bacteria?
Made up of 3 layers- outer LPS, thin peptidoglycan layer and a plasma membrane.
They are release from microbes and can cause damage to the host cell by killing cells or disrupting normal cellular metabolism.
How do bacteria multiple?
It is the inactivation of all self-propagating biological entities.
It is the reduction of pathogenic organisms to a level which no longer constitutes a risk.
It is disinfection applied to human tissue.
What are the 3 ways in which antibiotic resistance can be transferred between bacteria?
Transduction, Transformation and Conjugation.
Define Inherent/Intrinsic Bacterial Resistance
Organisms are deemed clinicall resistant of the concentration of the antibiotic needed to produce inhibition is beyond what is safe to use, or if the bacteria does not contain the appropriate target for the antibiotic resistance.
What are the 4 mechanisms of bacterial antibiotic resistance?
Alteration of the antibiotic binding site, prevention of access of the antibiotic to its site of action, enzyme inactivation of the antibiotic and metabolic bypass.
It is the natural habitat for the organism to which it must propagate.
Define Immediate Source
It is where the organism is transferred and survives, may/may not propagate.
What are the physical means fo sterilisation?
Heat, ionizing radiation, and filtration.
What are the chemical means of sterilisation?
Alkylating agents, phenolics, hydrochlorite, alcohol, chorhexidine and iodine.
It is the relative capacity of a microbe to cause disease.
Name some virulence factors
LPS/endotoxins, polysacharide capsule, flagella, chemotactic factors, adhesions, receptor-binding exotoxins, pore-forming haemolysins, antigenic variations, serum resistance factors, antimicrobial resistance, iron uptake mechanisms.
Define Endogenous Infections
They are caused by the normal flora of the body and result from the disruption of normal defences.
Define Exogenous Infections
Organisms are acquired from an external source and elad to infection.
How does the normal flora of the body help protect against infection?
They compete with pathogens for colonisation sites and produce antibiotic substances that suppress competing organisms.
Name some routes of transmission
Faecal-oral, mucosal, respiratory, transcutaneous and vertical.
It is the ability of fungi to pass the protective mechanisms of humans/animals and cause infection. They are classified depending on the degree of tissue involvement and mode of entry into the host.
They cause infection of the skin and gain their nutrients from keratinised skin. Cause diseases such as 'ringworm' and tinea.
It is a yeast which causes candidiasis or thrush. Is a superficial mycosis and typically infects the mouth or vagina. During ill health, impaired immunity or on antibiotic treatment allows its multiplication . Also, forms on the the surface of implants and medical devices.
Caused by the mould most commonly aspergillus fumigates. Causes systemic infection in immunocomprised patients. Can form an aspergilloma in a cavity produced by another disease e.g. TB. Some also produce aflotoxin- a carinogenic.
Is caused by the yeast cryptococcus neoformans and can cause a subacute or chronic form of meningitis resulting from the inhalation of the organism.
Caused by pneumocystis carinii/ jiroveci. Causes severe penumonia in immunosupressed patients.
What are the 5 different types of antifungal agents?
Polyenes, Flucytosine, Azoles, Allylamines and Caspofingin.
How do polyene antifungals act?
They bind to ergosterols on fungal cell membranes cuasing leakage of intracelullar contents e.g. amphoteric B and nystatin.
How do Azole antifungals act?
They inhibit the synthesis of cells walls and CYP450. E.g. Fluconazole used to treat candida and cryptococcus.
How does Flucytosine (5FC) antifungal act?
It inhibits thymidylate synthase and is incorporated into RNA so disrupts protein synthesis, treats candida and cryptococcus and candida.
How does Caspofingin antifungal act?
It inhibits glucan synthesis. Is used in the treatment of systemic aspergillosis.
They are the simplest form of protozoa and are characterised by a feeding and dividing trophozoite stage that extends pseudopodia.
Causes amoebic dysentery. Infections comes from consuming a cyst, which then hatches in the intestines.
They are protozoa with flagella for locomtion and food gathering. Have a complex structure and set of microtubules in 9+2 formation.
Causes trichomoniasis a sexually transmitted parasite. Females produce an offensive discharge, itching and inflammation.
Causes GI disturbance Giardiasis. Transmitted by tha faecal-oral route.
They are protozoans that are intracellular and their life cycles compose sexual and asexual reproduction. E.g. Malaria.
What are the 2 forms of malaria?
Plasmodium Falciparum and Plasmodium Vivax.
What type of mosquito spreads malaria?
The female anopheles mosquito.
What are the signs and symptoms of malaria?
Shaking chills, fever, profuse sweating, anaemia and jaundice due to erythrocyte destruction, dark pigmented urine, hepatosplenomegally and renal failure.
It is a microbe that has the capacity to cause host damage.
Define Obligate Pathogen
They are only found in humans in association with disease e.g. mycobacterium tuberculosis and Hep. B.
Define Typical Pathogen
They are highly pathogenic organisms that are frequently associated with disease but can be present as part of the normal microbiota in many individuals. E.g streptococcus pneumoniae, staph aureus.
Define Opportunistic Pathogen
They only cuase disease in patients who are immunosuppressed e.g. staph epidermis and pseudomonas aerugnosa.