Theme 2: The immune system in health and disease Flashcards
What factors does the response to bacterial infection depend on
-The nature of the pathogen
-The inoculation dose (level of the antigen exposed to)
-Its route of transmission (adaptive needed if innate overcome)
-host factors (age, nutrition, lifestyle, health, meds)
-amount of tissue destruction
-the tissues involved
What are the main immune responses to bacterial infection, from breaching defences to adaptive immunity and clearing the pathogen
INNATE:
-Adherance
-Penetration of epithelium. Breaching physical and chemical barriers
-Local infection.
-Colonisation.
-Recruitemnt of effector cells
-Recognition of PAMPs
-Activation of phagocytes, complement system (AMP) and inflammatory response to destroy invading pathogens.
[Phagocytes, NK cells, chemokine, cytokine action]
ADAPTIVE:
-Dendritic cells migrate to lymph nodes to present antigens to T cells which activate adaptive.
-Clonal expansion and differentiation of T cells.
-B cells make antibodies to clear infection
-Memory
How extracellular and intracellular pathogens spread
-Obligate intracellular pathogens spread cell to cell
-Extracellular bacteria spread in blood and lymphatics
What are immunodeficiencies. What is the difference between primary and secondary immunodeficiency. Give examples of causes and diseases
-component(s) of the immune system are defective.
1-Primary= inherited mutations in genes that control immune responses (defects in TLR signalling, T/B cell development etc.) Rare.
eg. SCID, Bruton’s X linked agammaglobulinemia, combined variable, hyper IgE syndrome
2-Secondary= acquired due to environmental factors. More common (due to immunosuppressive meds, malnutrition, chemotherapy, asplenia, major surgery, HIV infection, severe burns)
eg. AIDs, leukaemia
naive CD4 cells secrete cytokines which mediates specialised helped function by differentiating into different types of T cell. What are their different roles (Th1, Th2, Th17, Tfh, Treg)
-Th1= macrophage recruitment. Respond when an abundance of MHC.
-Th2= allergy cells at mucosal surfaces. Respond when limited MHC
-Th17= neutrophil & AMP. Reinforcing innate. Protection against candida.
-Tfh= B cells
-Treg= supress T cell
What are the roles of interleukin 1,2,4,8,6,12,10
IL-1 = inflammatory response
IL-2= T cell division and proliferation (growth stimulating factor)
IL 4= allergy cells and enhance barrier function at mucosal surfaces
IL8 = Neutrophil chemotaxis
IL6= B cell activation, by T helper cells
IL12= T cell activation
IL10- suppress T cell activity, prevent autoimmunity
What are the indirect and direct links between innate and B cells
-Indirect links: dendritic cells and T cells
-Direct links: Complement proteins can regulate B cell activation.
- B cells can be activated by bacterial antigens and cytokines without T cell help
The role of Th1 T cells in clearing bacterial infection. What are the different molecules it secretes. What happens if it fails to destroy pathogen.
-TH1 cells activate macrophages, inducing fusion of phagosome and lysosome and degradation by antimicrobials and lysozymes.
-TH1 cells also produce IFNɣ, CD40L, chemokine and cytokines to enhance macrophage function.
-If bacteria are resistant to intracellular digestion, the TH1 cells produce Fas ligand and LTβ to induce apoptosis of cell to release the pathogen to be destroyed by fresh macrophages
What is plasticity of T cells
T cells can shift between different subtypes (TH1, 2 etc), due to the adapting environment, to carry out different effector functions, to allow an effective and dynamic immune response.
-A single CD4+T cell can take on characteristics of many T cell subsets simultaneously, by transitioning.
Eg. Infection with Mycobacterium leprae can result in different clinical forms of leprosy
How the different responses to mycobacterium leprosy infection can result in different clinical forms of leprosy (tuberculoid and lepromatous leprosy)
- T leprosy:
-low level of organism
-pathogen is restrained by Th1 cells but not cleared, causing localized effects - L leprosy:
-high infectivity with uncontrolled and widespread damage
-TH1 ineffective at restraining so get a TH2 response. Lots of antibodies which cause problems as attach to host cells
Why are mucosal tissues prone to bacterial infection. How is it protected by the immune system (5 points)
-surfaces are thin and permeable so prone to infection.
1-Immune system distinguishes between commensals and pathogens. Surveillance of what’s good and bad
2-Areas with organized secondary lymphoid tissue (Peyer’s patches & GALT in gut) close to mucosal surfaces. Epithelium have T cells ready to respond, and B cells that secrete IgA into mucous.
3- Downregulates immune responses, to food and commensals
4-Commensals stimulate epithelial cells to make AMPs to protect epithelial surface. Outcompete pathogens.
5-Resident microbiota are essential for immune system development and training it
What are the 5 signs of inflammation
Redness, swelling, heat, pain, loss of function
What causes acute inflammation (lots)
microbial infection, foreign agents, physical trauma, ionizing radiation, heat, cold, irritant/ corrosive chemicals (acids, alkalis, oxidizing agents) Tissue necrosis (lack of oxygen/ nutrients due to inadequate blood flow)
What is involved in the 3 interlinking steps in the acute response: vasodilation, increased vascular permeability and immune cell activation
1-Small blood vessels adjacent to site of infection dilate to increase blood flow into tissues. Causes swelling.
2-Endothelial cells relax and vessels become leaky to allow the passage of exudate through tight junctions into tissues (exudation). Causes extracellular expansion and swelling = oedema
3-Promoted adhesion molecules on endothelial cells bind to and recruit circulating immune cells in the blood
-Immune cells then pass through capillary wall (diapedesis) and migrate into tissues (chemotaxis)
-Monocytes differentiate into macrophages
What is exudate. What it contains and their functions
-When endothelium becomes permeable, the fluid passes out of the vessels into the tissues, causing swelling/ oedema.
-it provides the following to tissues:
-Water and salts= dilutes toxins in tissues. Allows diffusion of mediators
-Glucose and oxygen= support immune cells that have high metabolic activity
-Complement proteins and antibodies= for opsonisation and phagocytosis
-Fibrin= provide scaffold entrapping microbes and assist immune cell migration
How does inflammation cause pain
-Stretching of tissues due to oedema
-Immune cells release inflammatory mediators (cytokines), mast cells release histamine, and prostaglandins are made which all act on receptors on primary afferent neutrons causing pain
What are 3 main complications of dental abscesses (cellulitis etc)
1.Cellulitis= abscess cannot establish drainage so spreads through fascial planes
2.Ludwig’s angina= infection of the floor of the mouth. Causing swelling of neck and tissues of the submandibular and sublingual spaces. Can lead to dysphagia (difficulty swallowing) and possibly airway obstruction
3.Sepsis= infection in blood stream with endotoxin producing gram negative bacteria, causing overreactive systemic inflammation and potential death.
What is suppuration. Causes
-formation of pus/ abscess in infected/ inflamed area
-Usually due to pyogenic (pus-forming) bacteria. It is the accumulation of bacteria and dead/ dying neutrophils. Once pus accumulates, it is surrounded by a pyogenic membrane to prevent spreading
What is the difference between non-specific and specific chronic inflammation and how they arise
1.Non-specific chronic inflammation:
-Failure to resolve acute inflammation and eradicate the stimulus, or persistent bouts of acute inflammation - a dynamic balance between tissue destruction and repair
2.Specific/ primary chronic inflammation:
-Induced by persistent exposure to agent, as it cannot be cleared.
- Can be non-granulomatous or granulomatous
- due to pathogens resistant to phagocytosis, foreign body in tissues, infective viruses growing in cells, autoimmune reactions, hypersensitivity reactions
What is a granulomatous disease. What are the predominant cell types. Give examples diseases. How granulomas form and their conequences
-Characterised by the presence of granulomas.
-The predominant cell types are epithelioid macrophages and giant cells
-IL2 and IFNY involved.
-Granuloma- a small area of inflammation, usually benign.
-Macrophages phagocytose and present antigens to Th1 cells. T cells induce formation of epithelioid macrophages. They fuse to form giant cells which engulf and present more foreign material. Inflammation
-The granuloma can cut off blood supply, causing anoxia, cell death and caseation necrosis, where tissue appears like cottage-cheese
-Dead macrophages release lytic enzymes causing damage to tissues
eg. TB, orofacial granulomatosis/ Crohn’s
What is orofacial granulomatosis (OFG) or oral Crohn’s
-Granulomas in soft tissue (mainly buccal and lips) causing swelling.
-Diagnosed as OFG if patient doesn’t have crohn’s. Dietary restriction can be effective treatment.
-60% of pediatric patients that have it go on to develop crohn’s
What is an autoimmune disease. Give examples
-unwanted inflammatory response to otherwise well tolerated commensal bacteria/ self antigens.
-Loss of self-tolerance due to checkpoints being breached (e.g. T cells that have high affinity for self antigens not killed, Treg suppressed)
-Mediated by Autoreactive T cells or autoantibodies.
-Sustained immune response because self antigens cannot be destroyed, causing tissue destruction.
-eg. Crohn’s, grave’s disease, rheumatoid arthritis, multiple sclerosis, type 1 diabetes [Collectively found in 5% of western populations]
Describe the 3 main systemic effects of inflammation (fever, acute phase response, and shock)
- Fever: pyrogenic cytokines (IL1,6 TNFa) act on temperature control sites in hypothalamus
- Acute phase response: cytokines made by macrophages (IL6) act on hepatocytes to induce synthesis of acute-phase proteins which activates complement
- Shock: Systemic oedema, decreased blood volume, hypoperfusion, collapse of vessels, coagulation, septic shock due to sepsis
Key steps in the Immune response to viral infection (TLR, IFN, NK cells, MHC, T cells, antibodies)
-Most controlled by innate response but if not then adaptive is activated.
1- Virus recognised by TLRs.
2- IFN a & b released
3- NK cells activated (by IFN 1, IL 12 & TNF a)
4- If they recognise cells with lots of MHC class I, they are presented to CD8 for destruction. CD8 release perforin & granzyme.
- NK can kill infected cells by releasing cytotoxic granules and activating apoptosis.
5- NK inhibit death of cells with little MHC class I
6- NK release IFN y to activate T cells, macrophages and antibodies.
The role of interferons in inhibiting viral replication
- switch on expression of antiviral proteins in cells to inhibit replication.
-Activate NK cells to kill infected cells
-Increase surface expression of MHC class I which targets infected cells for destruction by CD8 T cells
-Initiate apoptosis by activating FADD
What activates NK cells
- IFN a & B ( type 1)
-IL 12 & TNF a (released by infected cells)
How do antibodies destroy viruses
-Antibodies neutralise the virus
- cause agglutination of infected cells so easier targets for immune cells
-inhibit adhesion
-induce phagocytosis by opsonisation
-damage the envelope.
What is AIDs. How the virus infects cells and immunodeficiency is caused.
-Caused by HIV 1 and 2 virus. Transmitted via sexual contact and via blood
-Severe depletion in CD4 T cells
-Flu like symptoms or asymptomatic
-RNA virus binds to CD4 receptor (on T cells, macrophages and dendritic) via envelope. Enters the cell and the RNA virus is reverse transcribed into cDNA
-DNA integrated into host genome
-Virus originally infects macrophages and dendritic cells but because they are short lived, they then go on to infect CD4 T cells.
-If HIV has high mutation rate, it can evade host immunity. Persistent viral replication in CD4 T cells so CD8 kill these infected T cells.
-Rate of T cell depletion overtakes replacement and HIV progresses into AIDs.
-Memory T cells lie dormant and harbor the viral genome so cannot be eradicated. Virus only replicates when the cells become activated.
What receptors are involved in SARS CoV 2 infection. Symptoms
-Envelope with spike proteins that bind to ACE2 receptors in airways. TMPRSS2 allows slight modification of ACE so it can recognize spike protein. Virus enters cell.
-SARS-CoV-2 infection causes COVID-19 which is usually mild however it can result in life threatening systemic inflammatory response syndrome (SIRS). Shortness of breath, chronic inflammation, fluid in lungs, cytokine storm, shock and multiple organ shut down.
Give examples of superficial and systemic fungal infections
-Most fungal infections are superficial. Eg. Athletes foot, ring worm, pseudomembranous candida. Don’t cause high mortality but costly so burden for healthcare
-However some can be more serious. Eg. opportunistic candida species and pneumocystis species. Candida albicans is one of the most significant invasive fungal pathogens. High mortality rate. Candidaemis
Candida: how many species reside in the mouth, most abundant, disease of diseased, how it is recognised by the immune system
-around 12 species in the mouth.
-80% are Candida albicans
-candida commensals on skin, GI tract, vagina as like warm moist conditions. -Opportunistic when host is compromised.
-recognised by TLR. PAMPs recognised are carbohydrates in cell wall, chitin & B glucan.
-infection usually is mild but only becomes severe when patient is immunosuppressed/ diseased.- disease of the diseased.
-candidemia (blood infection) and systemic candiasis (spread to organs)
Risk factors for oral c. albicans - for mild infection and severe infection.
-Risk factors: impaired local & systemic defence mechanisms, decreased saliva, smoking, decreased blood supply, poor oral hygiene, dental prostheses, altered oral flora, immunosupression (HIV, corticosteroids), malnutrition, malignancies, broad spectrum antibiotic therapy.
-More severe: immunosupression (HIV, corticosteroids), antibiotics, catheters, GI or cardiac surgery, prolonged hospital stay, burns.
What is involved in the immune response to Candida albicans (innate, T cells, and antibody response)
-Innate= AMP, IgA. NK cells to directly kill and also release cytokines to promote innate defences. Phagocytosis of yeast cells but not hyphae. Macrophages struggle when candida accumulates so need support
-Cell mediated defences: T cell activation to support macrophage function (Th1) and reinforce innate system (Th17).
-Humoral responses: IgA, IgM and IgG antibodies specific to cell wall components of fungi. Antibodies inhibit candida adhesion to mucosal surfaces, opsonise to allow phagocytosis, activate complement, target germ tube, inhibit hyphen growth
What properties makes candida a potential killer
-It can undergo phenotypic switching (yeast cells to hyphae) - long filamentous hyphae form allows it to invade epithelial cells.
-forms biofilms, adapted to survive in extremes (lack of nutrients)
