Immunology Flashcards
B lymphocyte cell marker
CD20
T lymphocyte cell marker
CD3+
CD4: Th1
involved with dealing to bacterial/viral
CD4: Th2
Promote some antibody classes (IgE)
Promote allergic responses
Immunity against extracellular organisms in particular helmtiths
CD4: Tregs
regulating suppressive T cells
Natural Killer cells marker
CD3-
Linked recognition
CD40 binds to receptor
MHC II binds to CD4 and TCR
Cytokines release
B cell activation (movement)
Antigen activated B cells proliferate and migrate to border
Antigen specific T-helper cells migrate to border
Linked recognition
B cell proliferation and migration back to follicle to form germinal centres
Generation of plasma cells and memory cells
Antibody effector functions
Neutralisation of specific molecular interactions
Antibody enhancing phagocytosis
Antibody causing complement cytolysis
Antibody driving ADCC (anitbody-dependent, cellular cytotoxicity)
Internal innate factors
Chemokines Phagocytosis The complement system Pattern recognition receptors Other acute phase proteins
Phagocytosis steps
Adherence -> membrane activation -> phagosome formation -> fusion and digestion and release of degraded products
Phagocytosis - receptors
Pattern recognition receptors
TLRs and CLRs, detect a broad array of molecular patterns from bacteria
Systemic effects of inflammation
Pyrexia (fever): mediated by release of IL-1 by monocytes and macrophages
Acute phase proteins: Increased production of liver proteins involved in limiting tissue damage and resolving infection and inflammation (e.g fibrinogen and complement proteins)
Leukocytosis: Increased production and release of polymorphonuclear leukocytes (neutrophils) and monocytes from the bone marrow
Endocrine changes: Increased production of glucocorticoid steroid hormones as a response to stress. Other endocrine organs may also be affected when physiological stress is severe or sustained
PALE
Cardinal signs of inflammation
Redness Swelling Heat Pain Loss of function
Exotoxins: secretion of electrolytes
important in pathogens causing diarrhora, cholera
Exotoxins: necrosis
Death of host cells e.g leukocidin produced by Staph. aureus
Exotoxins: apoptosis
Triggered by Shiga toxins produced by some E.coli strains
Exotoxins: nerve synapse inhibition
Inhibition of release of compounds which transmit signals across nerve synapses e.g Clostridium species causing tetanus and botulims
Exotoxins: superantigens
Trigger cytokine release e.g toxic shock syndrome toxin produced by Staph. aureus
Endotoxin
LPS in cell wall of most Gram negative bacteria causes an inflammatory cascade
Other cell wall fragments
Lipotechoic acid occurring in gram positive bacteria causes an inflammatory cascade
Hydrolytic enzymes
Enable bacteria to spread through tissues e.g hyaluronidase and proteases produced by Staph. aureus
Inhibition of secretory products
Inhibition of stomach acid secretion e.g Helicobacter pylori. Inhibition and degradation of digestive enzmyes e.g Giardia lamblia (protozoan)
Invasion and intracellular multiplication
Viruses, some parasites and bacteria
Cross reactive antibodies
immune damage to host tissue e.g rheumatic fever by strep. pyogenes
Mutation
Some viruses carry oncogenes
Obstruction
Occurs particularly with parasites which form large masses e.g hydatid cysts of the parasite Echinococcus
Suppuration
If injury occurs in solid tissue and the causal agent is pyogenic (pus forming) organism
Abscess
Localised by a fibroblastic boundary and has a necrotic puss filled centre
Ulcer
Inflammatory lesion in epithelial surfaces
Cellulitis
Inflammatory reaction spreading through connective tissue planes
Requirements for Autoimmune disease
- Escape of autoreactive clones from thymus or bone marrow
- Autoreactive clones encounter self-antigens
- Peripheral tolerance failure
- Autoreactive tissue damage
General Mechanism for Autoimmune Disease
Genetic susceptibility - susceptibility genes disrupt self tolerance mechanisms
Injection or injury - infections or tissue injury alter the way self antigens are displayed
Influx self reactive lymphocytes - infection or injury induces inflammation
Activation of self reactive lymphocytes - Autoreactive lymphocytes response must cause clinical damage
Exposure of antigens at immune privileged sites due to trauma, example
Sympathetic opthalamia - damage to eye after trauma or surgery releases sequestered antigen
Molecular Mimicry
Component of pathogen has an epitope that resembles a self epitope. T and B cells think they look the same. The antigens/proteins on pathogen and self are NOT the same, but they have stretches of sequence that ARE the same
Acute Rheumatic Fever
Group A Streptococcal post-infection complication
GAS cell wall protein (M protein) share epitopes with proteins in the heart muscle and valve (myosin and collagen)
Autoimmune mediated tissue damage and inflammation
Long-term low dose antibiotics required to prevent further attacks
Multiple Sclerosis
Affects the brain and spinal cord. Autoimmune attack is directed against myelin sheath that surrounds nerve fibres of the brain and spinal cord
Some cases of MS maybe caused by mimicry between viral proteins (EBV) and myelin
Immune response causes gradual destruction of myelin and damage to nerve axis
Symptoms: changes in sensation, visual problems, muscle weakness or paralysis
Type 1 Diabetes
Immune system attacks the B-islet cells of the pancreas
Islets destroyed leading to failure to produce insulin
Have normal levels of Tregs but function of Tregs is decreased
Treated by daily injection of insulin
Rheumatoid athritis
Autoimmune attack on the synovial tissue and cartilage in the joints
Symptoms: ligaments, tendons and bone degradation, pain
Levels of Tregs are increased but functionality is decreased
Distinctive feature is the presence of rheumatoid factor in patient serum. RF are autoantibodies that bind patients own IgG
Coeliac Disease
Abnormal reaction to gliadin
Inflammatory reaction flattens villi of intestine. This intereferes with nutrient absorption and frequently leads to anemeia
Removal of gluten from diet leads to recovery of intestinal mucosa
Genetic Predisposition
Certain individuals are genetically susceptible to developing autoimmune disease
Susceptibility is most cases is polymorphic
Multiple polymorphisms are inherited that can contribute to disease
But highly susceptible individuals may be not develop disease suggesting environmental factors are likely involved
Susceptibility genes, polymorphic
Each polymorphism makes a small contribution to a particular autoimmune disease Antigen presentation genes Antigen receptor genes Complement genes Regulatory genes
Gender predisposition
Many autoimmune diseases have a higher incidence in females than males
Eg. RA is 3x more common in females than males
Treatment of Autoimmunity: 3 things
Replacement: replace the lost secretions or inhibit endocrine function. E.g Type 1 diabetes = insulin injection
Infection treatment: Use appropriate antibiotics to control infection, e.g monthly penicllin injections for rheumatic fever
Remove trigger: For food-induced autoimmunity like coeliac disease.
Treatment of Autoimmunity: Immunity
Suppress immunity - Corticosteroids to reduce inflammation
NSAIDS (non-steroidal anti-inflammatory drugs) - to block pain and swelling. eg ibuprofen
DMARDS (disease-modifying antirheumatic drugs) - slow acting immune suppressants e.g methotrexate
Treatment of Autoimmunity: Biologics
Rheumatoid arthritis - TNF drive inflammation
TNF antagonists inhibit TNF signalling and leukocyte migration to site of inflammation
Drawbacks: interfere with normal immune function
Long COVID
Long term sequelae and a range of symptoms - fatigue, muscle weakness, cognitive dysfunction, intestinal disorders)
Women 2x as likely as men to get Long COVID
Long COVID: Possible mechanisms
Organ damage caused by excessive inflammatory response activated by the virus
An autoimmune reaction unmasked by the virus itself (loss of tolerance)
Autoantibodies in patient sera
Has been described as “polyautoimmunity” - more than one autoimmune disease in a single patient
Type 1 Hypersensitivity
Due to IgE, IgE used for defence against parasites. IgE binds allergy causing substance triggering mast cell degranulation. Mast cells can bind empty IgE, ‘armed’
Mast cell mediators: Pre-formed
Biogenic amines (histamines) Enzymes
Mast cell mediators: Synthesised after activation
Lipid mediators
Cytokines
Common causes of allergies
Rhinitis (hay fever) = house dust, pollens, animal dander
Insect stings = proteins in venom
Food allergies = wheat protein, milk proteins, peanuts, strawberries
Small molecules = penicillin, codeine, morphine
Common sites of allergies
Respiratory tract: allergic rhinitis, sinusitis, asthma
Skin: urticaria (hives)
Gut: food allergy (diarrhoea, abdominal cramps, vomiting)
Multiple organs: anaphylaxis
Treatment of allergies
Avoidance: often difficult
Anti-histamines: common for mild forms. block histamine receptor
Corticosteroids: essential for chronic conditions such as asthma
Epinephrine: adrenaline for anaphylaxis
Desensitisation - gradually increasing doses of allergen to induce high affinity. IgG, memory IgG response, competes with IgE for allergen
Only works for some allergens, usually not for serious illness
Allergy testing
Immunoassay (inaccurate): tests for presence of antibodies to allergens in blood. Safe but often IgE bound to mast cells so go undetected
Skin prick (best): skin pricked with needles coated in dilute antigen, strong positive reaction is diagnostic
Type 2 Hypersensitivity
Antibodies bind directly to antigens on the surface of cells causing lysis. Antibodies are IgG and IgM. In some cases the antibodies attack mobile cells (blood), in other cases antibodies bind fixed/solid tissue
Type 2 Hypersensitivity: Phagocytosis: haemolytic anemia
Individual makes antibodies to their own red blood cell
IgG coated RBC are cleared from circulation via uptake by Fc receptor bearing macrophages. IgM coated RBC are fixed by complement and directly lysed (MAC)
Type 2 Hypersensitivity: Anti-tissue antibodies: Good posture syndrome
Antibodies against type IV collagen in glomerular basement membrane. Affects the kidney glomeruli and alveoli in lungs. Antibodies trigger component activation that damages epithelial cells. Patient present with transient kidney dysfunction and bleeding in the lungs
Type 3 Hypersensitivity
Normal: antibody binds antigen, complement C1q binds the constant region of the antibody. Immune complex is cleared.
Type 3 HS: Antibody complex is not cleared, complex becomes large, insoluble. Complexes lodge in sites and provoke immune response
Type 3 Hypersensitivity: Serum sickness
Develops after injection of foreign antigen that can’t be processed. 7-10 days after serum injection (time needed to mount IgG response the sickness occurs). Eventually complexes clear and the sickness is self limiting
Type 3 Hypersensitivity: Rheumatoid arthritis
Antibodies that bind patients own IgG found in circulation. Leads to deposition of immune complexes systematically. IgM rheumatoid factor binds IgG
Type 4 hypersensitivity
After antigen is injected, T-helper cell recognises antigen and releases cytokines, acting on vascular endothelium. Recruitment of phagocytes and plasma to site of antigen injection causes visible lesion. *see notes
After antigen exposure, an initial local immune and inflammatory response occurs that attracts leukocytes. The antigen engulfed by the macrophages and monocytes is presented to T cells, which then becomes sensitized and activated. These cells then release cytokines and chemokines, which can cause tissue damage and may result in illnesses.
Mantoux test
same as Mtb, local T-cell inflammatory reaction
Contact sensitivity
Very similar mechanism observed in allergic contact dermatitis. Causes by direct contact with certain antigens. Urushiol oil in poison ivy. Nickel in jewellry.
*see lecture
Primary immune deficiencies
Born with a genetic mutation that results in a defective immune response
Secondary immune deficiencies
Individual is born with a normal immune is born with a normal immune response but experiences an event that damages the immune system
Defects in phagocyte responses: Leukocyte adhesion deficiencies
Defects in LFA1 which prevent migration of leukocytes by blocking ability of cells to adhere to endothelium
White cell trafficking problems, particularly of neutrophils
Recurrent severe pyogenic bacterial and fungal infections with compromised wound healing
Absence of pus formation at the sites of infection (no neutrophils)
Defects in phagocyte responses: Chronic granulomatous disease
Very rare, 1:200,000
Mutation in NADPH oxidase
Phagocytes can’t produce reaction oxygen species, failure to kill ingested bacteria
Life-threatening bacterial and fungal infections of skin, airways, lymph nodes, liver, brain and bones
Complement deficiencies: classical pathway
Increased susceptibility to bacteria that require opsonisation via antibody and/nor complement binding for clearance
Complement deficiencies: C3b deposition
Defects in activation of C3b and C3 itself are associated with increased susceptibility to a range of pyogenic bacteria and Neisseria species
Complement deficiencies: MAC
Defects membrane attack (MAC) have more limited effects, really limited to Neisseria species for which MAC is primary means of pathogen elimination
B-cell primary immunodeficiency: Agammaglobulinemias (congenital)
Defects in B-cells and antibody production. Characterised by recurrent infection with pyogenic bacteria
Symptoms first occur at 7-9 months after birth, no more maternal antibodies
Wiskott-Aldrich syndrome
Defect in WAS gene. WAS regulates lymphocyte development via its role in immune synapse (T cell and APC) formation. In WAS patients T-cell don’t respond to T-cell receptor cross-linking
Severe combined immunodeficiency (SCID)
Mutations that result in compromised T and B cells arms. 1:50,000 people. Diagnosed after 5 months. Lymphocyte numbers low in blood and lymphoid tissue. Present with chronic diarrhea, failure to thrive and severe infections
Examples of SCID defiencies
Defects in nucleotide metabolism - most common cause is deficiency in adenosine deaminase (ADA) leading to increased dATP. Accumulation is toxic to developing B and T cells causing profound reduction in lymphocytes
X-linked SCID, mutations in genes encoding gamma chain of interleukin receptors:
x linked = more common in males (boy in the bubble)
T cells can’t mature
SCID symptoms
Prolonged diarrhea due to rotavirus or bacterial infection
Ear infections, persistent respiratory infleunza with respiratory syncytial virus of parainfluenza viruses. Pneumonia due to fungal Pneumocystis jirovecii
Oral skin and gut candida infections common
Normally die within 1 to 2 years of birth
SCID treatment
Compatible bone marrow transplant
Gene therapy to restore correct gene
Improved testing methods means SCID can now be diagnosed from minute amount of blood collected. Added to panel of other conditions that are screened for part of standard new born screening (heel prick) in 2017
Aplastic anemia
Stem cells in bone marrow are destroyed.
Leads to deficiency in: red blood cells (anemia), white blood cells (leukopenia) and platelets
(thrombocytopenia)
Aplastic anemia symptoms
Fatigue, pale skin, infections, bruises, nose bleeds
Causes of aplastic anemia
Exposure to chemicals, drugs, radiation (Marie Curie), infection
Aplastic anemia developing infections
Bacterial infections, invasive fungal infections, viral infections
Aplastic anemia modern treatment
blood tranfusions, bone marrow transplantation, antibiotics (when a bacterial infections has caused aplastic anemia)
Latent virus reactivation
Reactivation when host immune response is deficient from chemotherapy or immunosuppressive drugs, bacterial infection, stress, age, hormone changes
Maintain genome within nucleus of cells without replicating
Examples of latent virus reactivatino
Epstein-Barr virus (glandular fever)
Herpes simplex virus (cold sores)
Varicella Zoster (chicken pox/ shingles)
Herpes simplex virus reactivation
Initially infects epithelial cells, then spreads to sensory neurons servings infected area. Virus persists in latent state in sensory neurons - have low levels of MHC 1
During reactivation the epithelial cells are reinfected (cold sore)
Varicella-Zoster Virus
Causes chicken pox, remains dormant in dorsal root ganglia (nerve cells). Reactivation by stress or immunosuppression (common in elderly). Spreads down nerves to cause shingles (varicella rash). Shingles vaccine (Zostavax) recommended for >60 yr olds
Immunologically deficient sites: infective endocarditis
No dedicated blood supply to heart valve tissue. Poor access for immune effectors. Occurs in patients with altered/abnormal valve architecture in combination with bacterial exposure. High mortality rate, treated with IV antibiotics
Other immunologically deficient sites
Coronary stents, joint replacements, breast implants, cochlear implants, intraocular lenses
Biofilms
Biofilms are densely packed communities of microbial cells growing on living or inert surfaces. Produce matrix or extracellular polymeric substances (EPS) that act as a protective slime layer, which is resistant to immune attack. Surgery is only effective means of removing/disrupting a biofilm
Virus: general info
Cannot make energy or proteins independently of a hose cell. Obligate parasites. Are assembled and do not replicate by division. Filterable. RNA or DNA. Naked capsid or envelope morphology
Virus: consequences of viral properties
Not living, must be infectious to endure in nature, must be able to use cell processes, encode any required proteins not provided by the host cell, must self-assemble
Virus: size
Small
Virus: Classification
Structure: size, morphology, nucleic acid (picornavirus)
Biochemical characteristic: structure, mode of replication
(coronavirus)
Disease: (hepatitis virus)
Mode of transmission: (arbovirus)
Host cell (host range): animal, plant, bacteria (bacteriophage)
Tissue or organ (tropism): (adenovirus, enterovirus)
Members of a particular family: (papovavirus)
Location of first isolation: (Marburg virus)
Virus: basic structure
Nucleic acid (RNA or DNA) Capsid (protective proteins coat) Capsids are made of capsomers Envelope is an outermembranous layer made of lipids and proteins, stolen from host Not all viruses have envelops
Virus: capsid morphology
- nucleic acid genome
- Capsomer (bind to DNA or RNA)
- Capsid (protection, host cell attachment)
different shapes, eg. icosahedron, helical, spherical, bacteriophage
Viruses: naked or enveloped
Can be either or but not both
Virus: spikes
Protein structures used to host cell binding Very specific (narrow host cell spectrum)
Virus: properties of the naked capsid
Stable to: temperature, acid, proteases, detergents, drying
Virus: consequences of naked capsid
Can be spread easy (dust, hand-to-hand)
Can dry out and still contain infectivity
Can survive the adverse conditions of the gut
Can be resistant to poor sewage treatment
Virus: properties of the envelope
Stable to: acid, detergent, drying, heat
Virus: consequences of the envelope
must stay wet
cannot survive in gastrointestinal tract
spread in large droplets, bodily fluids (blood, saliva, breast milk, transplants, blood transfusion)
Virus: replication
See slides
Host cell can survive if they are not that many. naked viruses, cell always die by replicating so much causing bursting
Virus: single cycle growth curve
See slides
Virus: nucleic acid and protein synthesis in viruses
Complex concept, refer to slides
Virus: Steps for replication
Attachment: binding to a receptor on host cell
Penetration: entire virus enters cell
Uncoating: viral genome escapes from the capsid
Biosynthesis: viral genes are expressed, genome replicated
Assembly: viral parts are assembled
Release: virus escapes by cell lysis or budding
APUBAR
Bacteriophage: Steps for replication
Attachment: binding to a receptor on bacterial cell
Penetration: injection of DNA into cell
Biosynthesis: phage genes are expressed genome replicated
Assembly: phage parts are assembled
Release: phage escapes by cell lysis
Virus: progression of viral disease
- Acquisition (entry into the body)
- Initiation of infection (at primary site)
- Incubation period (virus amplifies and spreads)
- Replication in target tissue (disease symptoms)
- Immune responses (limit and contribute to disease)
- Virus production in tissue, release, contagion
- Resolution or persistent infection/ chronic disase
Arrogant Infants Inhaled Rabies In-Vitro Readily
Viral transmission
Aerosols: influenza virus, SARS
Food, water: Enteric virus, such as reovirus (cruise ships)
Fomites (tissues, clothes): e.g rhinovirus
Direct contact with secretion (saliva, semen): e.g cytomegalovirus, Epstein Barr virus (kissing virus)
Sexual contact: e.g herpes simplex virus, papilloma virus
Maternal-neonatal: e.g rubella virus, herpes simplex virus
Blood transfusion, organ transplant: e.g HIV, hepatitis
Zoonoses (animals, insects): rabies, influenza
Latent virus infections
Persistent infection
Virus does not reproduce (no clinical symptoms)
Virus can occasionally activate and produce symptoms
Latent infections are limited by immune response
Latent virus infection: Herpes virus
Latent in neurons (nucleic acid integrated in genome)
Activated by fever, stress, sun light
Causing cold sores
Latent virus infection: chickenpox virus
Resurfaces when immune system
Weakens by disease or old age
Causes shingles
Latent virus infection: HIV
Latent in T cells, macrophages (integrated in genome)
Causes AIDS
Oncogenic viruses
Viruses that can cause cancer
Integrate into host genome close to proto-oncogen
activation of virus also activated proto-oncogen. Viral promoter drives host genes which can activate proto-oncogene.
Examples of oncogenic viruses
Epstein-Barr virus: Burkitt’s lymphoma
Human Papillomaviruses: cervical cancer
Human Herpesvirus 8: Karposi sarcoma (common in AIDS)
Viroids and Prions
Even smaller and less complex than viruses
Viroid: short naked fragments of ssRNA, infects plants
Prion: small infection proteins, cause aggregation, when encountered they cause other to aggregate. Cause neurological disease
Examples of disease associated with viroids and prions
Scrapie (sheep)
Bovine spongiform encephalopathy (mad cow disease)
Creutzfeld-Jakob disease (CJD, humans)
Drugs against viruses
Antibiotics are not effective against viruses
Activity of most antiviral drugs is limited to certain virus family
Resistance to antiviral drugs is becoming more of a problem
See slides
Examples of Herpes Viruses
Chicken pox, Glandular fever, cold sores
Chicken pox: General information
Once gotten never leaves your body. Can cause shingles later in life. Easy to diagnose, not many complications. Initially clear fluid, then white or colourless, bigger ones can cause scars
Herpes simplex 1: where
Effects the lips and mouth area, vermillion border or at mucous membranes between nose and skin. Can sometimes affect genitalia.
Herpes simplex 2: where
Effects the penis or female genitalia. Can sometimes effect mouth
Herpes virus: General information
Cause persistent latent infection of nerve cells, skin, lymphocytes. Intermittent shedding - lots of chances to spread.
Herpes virus: Structure
Outer envelope derived from host cell membrane wrapped around a nucleocapsid containing the DNA genome
Herpes virus: Diagnostic tests
Syndrome, immunofluorescence (inject rabbit, sheep, goat with HSV, remove antibodies later and use for agglutination test) culture, serology, PCR
Herpes virus: Treatment
Acyclovir (or related drugs)
Herpes virus: Replication
Attachment to herpes envelope glycoproteins to cell surface molecules
Entry into cell cytoplasm
Transport of viral DNA to cell nucleus
Synthesis of viral proteins (approx 80) in cell cytoplasm
Transport of viral proteins into cell nucleus
Packaging of viral DNA in capsid and exit nucleus taking nuclear membrane with glycoproteins inserted
Death of cell
Herpes simplex type 1: General information
Infection via contact with contaminated saliva
Replication of virus in cells of skin and oral membranes
Latent infection of trigeminal ganglion, moves back to original site of infection in times of vulnerability.
Reactivation causing cold sores
First infection worst, severe clusters of lesions inside the mouth, lasting 7-10 days. Herpes simplex travels via the axons to and from nerve cells
Rare, severe diseases caused by Herpes simplex: Neonatal Herpes
Pregnant woman is last stages of pregnancy gets first infection of herpes, resulting in lesion in the birth canal. Upon birth baby gets high doses of herpes, there are no maternal antibodies. Affects CNS, liver, brain lungs. Can cause encephalitis or meningitis (not too fatal). Can be treated with drugs but will still cause brain damage due to uncontrollable replication
Rare, severe diseases caused by Herpes simplex: Progressive or disseminated disease in immunocompromised patients
Adults can sometimes get the virus move into the temporal lobe causing encephalitis in the brain, causing massive reactions
Varicella Zoster Virus: General information
Infection via contact with contaminated saliva, skin
Replication of virus in cells of skin and mucous membranes.
Latent infection of dorsal root ganglia. Reactivation causing shingles.
VZV: Dorsal root ganglia
Dorsal root ganglia are on all parts of the spinal cord. The dorsal root ganglia is the site of latent infection following chicken pox. Reactivation of infection at this site leads to shingles.
Shingles: Presentation
Last 1 week. Red bumpy rash with dermatome representation, band of skin that goes around half of the body. The dorsal root ganglia can be inflammed leading to hypersensitivity in normal skin. Not across midline. When at worst point can give antiviral drugs.
Epstein-Barr Virus
Infection via contact with infected saliva (‘Kissing Disease). Infection of B-lymphocytes in tonsils. Spread of infection to B lymphocytes in other lymphoid tissue - lymph nodes, spleen etc. Cytotoxic T lymphocytes attack infection B-lymphocytes- killing most of these cells.This results in swollen lymph nodes and spleen, fever, unwellness. Some cells will becomes latent for rest of life. Persistent infection of B lymphocytes and excretion of virus in saliva. Persons saliva will always carry virus.
Glandular Fever more info
Onset about 30 days after exposure. Lethargy, anorexia. Recovery over weeks to months, can cause chronic fatigue. Immune response gives person illness. Severity can vary a lot.
EBV: Immortalises
EBV infection potentially results in B lymphocytes entering and remaining in growth cycle. Infected cells are usually effectively killed by cytotoxic T lymphocytes but some escape killing and are the reservoir for persistent infection. Inadequate killing of infected B lymphocytes can result in B cell lymphomas ( in AIDS)
EBV: Diagnosis
- Detection of antibodies to EBV: heterophile antibodies that agglutinate sheep erythrocytes (Paul Bunnell Test = Monospot test). Specific antibodies to EBV antigens
- Detection of abnormal cytotoxic lymphocytes in blood - clue not definitive
- Detection of EBV DINA in sample (PCR)
Treatment of Herpes Viruses
HSV - acyclovir tables, cream, IV (neonates and encepholitis)
VZV - acyclovir or valacyclovir
EBV - no effective treatment
Herpes viruses: Vaccination
No vaccine for HSV or EBV. Vaccines to prevent chickenpox or to prevent shingles: Live attenuated vaccine (Zostavax) will not cause latent infection.
Surface protein vaccine (Shingrix) to protect people who have had chicken pox to prevent shingles
Cholecystitis
Infection of the gall bladder
Cholangitis
Infection of the bile duct
Hepatitis A: Source of infection
Faeces after a person swallowing contaminated food. Excreted in bile -> intestine -> faeces. Contaminates food/water
Hepatitis A: Mortality of acute infection
<1%
Hepatitis A: Risk of chronic infection
Nil
Hepatitis A: Vaccine available?
Yes
Hepatitis A: Symptoms
loss of appetite
yellow skin - jaundice
liver pain
Hepatitis B: Source of infection
Contact with blood or sexual interaction (genital excretions), mucous of vagina, male ejaculate
Excreted from liver in blood not bile ducts, also excretion found in genital excretions
Hepatitis B: Mortality of acute infection
5-10%, can die from both acute and chronic infections
Hepatitis B: Risk of chronic infection
Variable
Hepatitis B: vaccine available
Yes
Hepatitis C: source of infection
Blood, usually in people who inject drugs through needle
Hepatitis C: Mortality of acute infection
<0.1%
Hepatitis C: Risk of chronic infection
70%
Hepatitis C: Vaccine available
No
Hepatitis B: Most prevalent in which ethnicity
Maori and Pacific Islander
Hepatitis B: Which people did it originate from
Originated from people who left Africa.
Hepatitis B: Ways in which people are infected
Mother to child transmission at birth
Child to child transmission in pre-school years
Persistent infection following acquisition in infancy or childhood
Hepatitis B: Laboratory diagnosis of infection
Detect parts of micro-organism by a chemical test (blood test)
Hepatitis B: Part of virus that is detected
Hepatitis B surface antigen = HBsAg
Hepatitis B: Structure of virus
Outer envelope = surface antigen = HBsAg, (lost)
Central shell = core antigen = HBcAg
DNA = HBV DNA
Hepatitis B: Clumps
Once liver cell has been infected it produces excessive amount of surface antigen more than virus it’s making needs, which form HBsAg tubules.
Hepatitis B: Diagnosis
Detect HBsAg in blood
HBsAg +ve = infected and infectious
HBsAg-ve = not infected (and non-infectious)
Hepatitis B: infectivity
The concentration of HBV in the blood or genital secretion determines the risk of transmission
HBV concentration can be: as low as 1HBV per ml of blood or as high as 100 million HBV per ml of blood
Hepatitis B: HBeAG
Presence of HBeAg means large amount of HBV in blood, (10^5 - 10^9). Dramatically increasing risk of transmission
Hepatitis B: Damage
The outcome depends on immune responses. Killing of virus infected cells by cytotoxic lymphocytes is responsible for: clearing infection, liver cell damage, illness
Hepatitis B: In adults
Usually gets cleared within months due to cytotoxic lymphocyte killing of infected liver cells. Antibodies also produced which will be there for rest of life. Eradication of infection. Immunity to repeat infection
Hepatitis B: symptoms
Loss of weight, Jaundice, liver pain, anoxeria. If liver fails to detoxify, potentially leads towards death
Hepatitis B: In infants
Minimal cytotoxic lymphocyte killing of liver cells, no symptomatic illness, lots of scarring, development of cirrhosis and liver cancer damage over decades, number of infected liver cells stays constant for many years.
Hepatitis B: Prevention
Antibody to HBsAg prevents infection, by covering the surface of the virus and preventing it attaching to liver cells. Put on pills that block virus replication, reduce number of virus for pregnant woman in early pregnancy. Boost by injecting antibodies to baby just after birth.
- Vaccinate those at risk of infection with HBsAg
- In emergency give serum containing antibodies to HBsAg
Hepatitis B: Vaccine
Older cheap vaccine = serum derived from HBsAG - from blood of someone with chronic infection
New vaccine = recombinant yeast derived HBsAg. 3 doses give lifelong immunity in approx 90%
HIV: stands for
Human Immunodeficiency Virus, infection with HIV leads to AIDS
AIDS: stands for
Acquired Immune Deficiency Syndrome
Collection of illnesses
HIV: Oral Candidas
Caused by candida albicans - effects oesphagus -> loss of weight. Colonisation of soft palate. Treated in 2-3 days. Everyone has candida albicans
HIV: Kaposi’s sarcoma
A rare cancer caused by human herpes virus 8 in people with HIV infection. Removed by radiotherapy on surface
Purplish lump, no pain, does not bleed
HIV: Toxoplasma brain abscesses
Dead brain tissue, cysts in the brain. Headache, fever, confusion, hard to speak, pain in one arm or leg. 10 days after tablet, then gone.
AIDS defining illness: In order of most common
Pneumocystitis carinii (jiroveci) pneumonia (PCP, PJP) Toxoplasma gondii brain abscesses Candida albicans oesophagitis Cryptococcus neoformans meningitis Mycobacterium tuberculosis disease Kaposi's sarcoma CNS lymphoma Cytomegalovirus retinitis etc.
AIDS: sexual links
Man to man (gay), Bi man to woman, woman to baby (birth)
AIDS due to transmissible agent
AIDS in sexual partners of MSM
AIDS in injecting drug users
AIDS in infants born to injecting drug users
Origins of HIV
HIV is a retrovirus closely related to the simian immunodeficiency viruses (SIV) which infect African apes
Humans got blood from apes (hunting), into injuries of person.Humans in central Africa.
Global spread of HIV
Origins in central Africa in early 1900s
Spread from rural to urban Africa in 1950s
Spread to Haiti in 1960s then to US and Europe etc, 1970s
Epidemic spread affected by:
prevalence of infection, rate of sexual partner change and condom use, rate of unsafe injecting drug use. Africa, has high rate of sexual partner change and gay, explains.
HIV structure
HIV Is an enveloped retrovirus. It has a protein core encasing the genetic material. Two strands of RNA. Retro-transcriptase, RNA -> DNA. Virus budding from helper T-cell doesn’t damage cell.
HIV replication
Check Folder
HIV Pathogenesis
- 10^9 T helper lymphocytes produced each day
- HIV infects T helper lymphocytes
- Infected cells produced 10^9 HIV per day
- Productively infected cells are killed by cytotoxic lymphocytes
CD4 cells wait and are latent, waits for particular infection then activated and produced HIV. Only then it is detected.
HIV: Rapid evolution
Continuous production of HIV (10^9 HIV / day)
Highly error-prone copying of HIV RNA by reverse transcriptase
No ‘proof-reading’ for errors
Generation of a very wide range of mutant viruses every day. HIV continually evolving. Virus due to mutation will be slightly different to original infecting virus
HIV: Time course of untreated HIV infection
Check folder
HIV: Diagnosis
- Detect antibodies to HIV in blood
a) screening test = ELISA
b) confirmatory test = Western blot - Detect HIV genome in blood, PCR
Test had a 1 week, 1 month, take about a month for antibodies to be produced.
HIV replication cycle, targets for drug treatment
Reverse transcriptase, 3 e.g AZT, 3TC, tenofovir, efavirenz
DNA integration -5->6 dolutegravir
Protease 11->12 darunavir, atazanavir
HIV binding ,1, maraviroc
HIV: Time course of treated HIV infection
Check folder
HIV: Vaccines
Some exposed by uninfected people have immune responses for HIV. Cytotoxic lymphocyte responses appear to be more protective than antibody responses. No clearly effective vaccine in sight.
HIV risk of transmission of HIV per unprotected episode
Man to Man - 1% - frail surface area, more likely trauma
Man to Woman - 0.1%
Woman to Man - 0.1%
Mother to infant - 25% at delivery
- 12% with breastfeeding
Not during pregnancy, cannot cross placenta.
Protozoa
Single celled eukaryotes (membrane bound nucleus), cell like animals, more complex than bacteria and fungi. May be mobile
Important Protozoal Disease
Plasmodium falciparum = malaria
Toxoplasma gondii = toxoplasmosis
Giarda lamblia = giardiasis
Trichomonas vaginalis = trichomoniasis (vagina, urethra, treated with antibodies, microscope diagnosis)
Entamoeba histolytica = amoebiasis (intestines, liver)
Leishmania donovani = leishmaniasis (liver, spleen, bone marrow)
Giardia lamblia: General information
Infects the gut of many mammals but doesn’t invade.
Acquired in contaminated water
Surface infection of enterocytes = small intestine cells causing reduced absorption of fluids
Watery diarrhoea, minimal systemic upset.
Shit out organism, contaminates water. 5-6 bowel movements a day
Giardia lamblia: Replication cycle
Giardia lamblia cysts are ingested, trophohoziotes excyst, graze and replicate, then cysts are excreted in faeces.
Cysts allow survival, just waiting for opportunity to be swallowed. Trophoziotes eat at villi, eating intestinal contents. No strong immune response as stays in lumen
Cysts form as moves through bowel or as enters environment
Giardia lamblia: Diagnosis and Treatment
Cysts are seen in faeces under microscope
Metronidazole used for giardia and amoeba, active against anaerobic bacteria
500mg TDS (three times daily), orally for 7 days.
Can’t see trophoziotes under microscope.
Toxoplasma gondii: Replication cycle
Infects the gut of various cat species
Oocysts excreted in cat faeces
Oocysts ingested and cause tissue infection with bradyzoites and tachyzoites.
Cat are infected by eating tissues with bradyzoites or tachyzoites. Humans can be infected by eating oocysts in cat faeces or uncooked infected tissues containing bradyzoites or tachyzoites.
Moves from intestine into blood and spreads. Immune system is able to control them at a microscopic focus, most cells survive.
Toxoplasma gondii: Symptoms
Swollen lymph nodes, fever. Cooking kills organism.
Toxoplasma gondii: In humans
Infection in approx 30% pop, as get older, more people infected
Usually acquired in childhood
Usually minor symptoms
Persistent lifelong infection - controlled till you die
Reactivation if immuno-suppression
May cause severe infection in fetus if primary maternal infection in pregnancy.
Toxoplasma gondii: Retinal toxoplasmosis
Congential infection, from mother being infected. Greater ability to replicate in CNS including eye.
Toxoplasma gondii: Diagnosis
Serology: IgM positive = acute infection IgG positive = chronic infection PCR for DNA in CSF Radiology Opthalmoscopy appearances
Toxoplasmosis treatment
Usually none for acute infection in immune competent person.
Sulphadiazine + pyramethamine for 6 weeks for CNS abscess in aids. Blocks production of sulfates.
Uncertainty about efficacy of treatment of acute infection in pregnancy. Can check women by taking blood samples and checking regularly for presence of IgM antibodies
Malaria: Common organisms
Plasmodium falciparum - potentially fatal
Plasmodium vivax - relatively benign
Malaria: Rare organisms
Plasmodium ovale
Plasmodium malariae
Malaria: Mosquitoes
Anopheles - forest dwelling, night feeding. Never found in NZ. Females and males feed on nectar, but females need blood meal for egg development. Not present in Pacific to east of Vanuatu.
Malaria: Highest incidence where?
Africa, rates slowly decreasing worldwide
Malaria: replication cycle
Infected female anopheles mosquito feeds on blood and injects saliva containing sporozoites. Squirts anti-coagulants down probiscus, parasites in probiscus infect human. Sporozoites invade liver cells and replicate. Merozoites are released from liver and invade erythrocytes. Multiplication in liver causes no damage.
Merozoites replicate in erythrocytes and rupture erythrocytes causing fever. Some merozoites mature into female gametocytes which are the source of sexual replication in mosquito salivary gland. Immune system only kicks in after ruptures
Malaria: rigor
A sudden feeling of cold with shivering accompanied by a rise in temperature, often with copious sweating, espcially at the onset or height of a fever.
Malaria: RBC
8-10 merozoites in an RBC cause rupture. Can die from rupturing of lots and lots of RBC.
Malaria: Blood Film examination
Finger prick, take blood. Microscopy, add stain and look. Can see merazoites inside RBC. And signet ring seen.
Malaria: Synchrony
Process of infection in RBC is synchronous causing synchronous fever.
Malaria: Diagnosis
Residence in malarious area
Fever, rigors, malaise, headache, coma (days before death)
Blood film examination
Antigen detection in blood.
Malaria: Difference between organisms
P.falciparum
High parasite load >1% erythrocytes.
Sticks to endothelial cells and stop flowing causing blockage of capillaries espcially in brain and kidney. Can cause coma. (sequesteration) After 10 days release of all merozoites from liver, no reoccurence unless bitten again.
P.vivax
Low parasite load <1%
Relapse from liver hypnozoites - sleeping in liver, for years doing nothing. Some organisms leave and some stay behind in liver.
Malaria: Treatment
P.falciparum
Quinine (bark of cinchona tree)
Doxycycline
Artemether - to kill merozoites in erythrocytes
P.vivax
Chloroquine
To kill merozoites in erythrocytes
Then primaquine to kill hypnozoites in liver, to prevent relapse.
Malaria: Prevention
Avoid malarious area
Mosquito control
Bed nets, long sleeved shirts, long pants etc
Insect repelent
Doxycycline, mefloquine, other drugs to kills as soon as they enter.
What is nosocomial infection?
Infections acquired in hospital. Infections diagnosed more than 48 hours after admission and within 30 days after discharge from hospital
Examples of nosocomial infections?
Surgical wound infections Gastroenteritis Urinary catheter-associated infections IV Tube down throat
Steps for prevention of wound infection
Avoid contamination Clean to remove contamination Prevent further contamination Remove dead tissue Avoid creation of fluid collections Antibiotics prophylaxis (antibiotic active against those bacteria most likely to contaminate the wound given shortly before and during surgery.
Factors predisposing to nosocomial infections
Acute illness/injury in patient
Underlying illness in patient
Exposure to large numbers of new organisms to which patient may have little immunity
Insertion of foreign bodies
Inability to maintain normal hygienic practices
Prevention of nosocomial infection
Sterilisation, Disinfection, cleaning, isolation
Sterilisation methods
Autoclave
Gas sterilisation - ethylene oxide
Chemical sterilisation - glutaraldehyde (2%) or H202 (6%)
Irradiation - ionizing or ultraviolet or microwave
Autoclaving
Steam at 121 (103kPA) for 30min or 134 (203kPa) for 4min
Disinfection - what
Kills all vegetative bacteria including TB, plus all fungi and most viruses but not all bacterial spores
Disinfection methods
Alcohols Hypochlorites Formaldehyde, glutaraldehyde H202 Phenols Quaternary ammonium compounds
Respiratory Virus Infections: Where do they occur?
The middle ear and sinuses of the head. Air spaces that have mucous draining from them that when blocked can cause infection. Respiratory epithelium
Respiratory Virus Infections: Repiratory Epithelium
Virus attaches and moves in, CD8 cells move in and kill epithelium leading to no cilia. Infection won’t disseminate through out body.
Respiratory Virus Pathogenesis
Attach to and enter respiratory epithelial cells
Replicate inside cells
Death of infected cells, due to viral replication and release and/or immune responses
Impaired function of respiratory tract
Death or recovery
Respiratory Virus: result from damage to epithelium
Narrowed airways due to swollen tissues
Obstructed airways due to loss of cilia, viscous mucous, shed cells.
Respiratory Virus: result from inflammation
fever, achiness, malaise, anorexia
Respiratory Virus: More severe for?
In very young infants, narrow airways before illness
Very old people, damaged illness before illness, may include bacterial infection of affected tissues
Common causes of respiratory viruses
Rhinoviruses, coronaviruses, RSV, influenza virus
Which infections are almost always due to viruses?
Colds, bronchitis, pharyngitis, influenza + others
Respiratory infections: Antibiotics
Most respiratory infections don’t need an antibiotic
Concentrations of SARS-CoV-2 virus
Concentrations of SARS-CoV-2 virus in respiratory secretions fall to low levels by day 9 in most patients
SARS-CoV-2 virus: Antibodies
Antibodies to SARS-CoV-2 are present in blood within 8-14 days in almost all patients
Influenza A: HA
Haemogluttinin - sticks to surface of human respiratory epithelium. Name comes from sticking to RBC causing coagulation of RBC, not in humans. Trimer
Influenza A: NA
Neurominidase: like scissors, prevents sticking of haemogluttinin binding to cell as it buds off. Tetramer
Influenza A: Genome
Segmented Genome: 8 RNA molecules, 2 RNA molecules code HA and NA
Change in influenza viruses: Antigenic drift
Gradual accumulation of mutations in genes with minor changes in HA and NA. Small change in RNA leading to small change in HA.
Change in influenza viruses: Antigenic shift
Abrupt reassortment of genes between two strains with major changes in HA and NA. Two influenza viruses infect the same cell, causing mixing. Producing a progeny virus
Influenza A: origination
Virus originates from duck, geese gut where mixing occurs. Shit out influenzas. From water birds, found in china.
Influenza: After infection
Illness lasting 5-6 days
3-4 days in bed, off work
Morbidity and mortality, esp in young and elderly
Episodes of illness approx every 7 years
Influenza: Symptoms
Abrupt onset
Fever, chills, headaches, myalgia, malaise
Dry cough, pharyngeal pain and nasal discharge
Recovery with immunity.
Death is from replication in lungs. Lungs cause large secretions, person drowns
Influenza: Diagnosis
Clinical presentation
virus isolation on cell cultures - slow, expensive, rare
Detection of influenza antigens
PCR of influenza RNA
Serology - just show antibodies produced, useless
Influenza: Immunity
Antibodies to surface proteins: appear at 10-14 days post infection. Enhances if previous infection with similar strain. Persist lifelong, protect against recurrent infection with same strain.
Influenza: Treatment and prevention
Oseltamivir - Tamiflu - modestly effective treatment
Moderately effective vaccine - changed annually to anticipate drift in circulating strains
Rhinovirus: which family
Picornaviruses -> enteroviruses -> Rhinoviruses
Rhinovirus: general info
Very small RNA viruses
99 Serotypes
Replicates in cells at 33-35 degrees, nose not lungs
Rhinovirus: Spreading and Symptoms
Transmitted by respiratory droplets and contaminated surfaces. Incubation period 1-4 days. Infection of nose and sinuses. Nasal mucous, sneezing, cough, sore throat. Minor fever, muscle aches etc. Recovery in 1-2 weeks.
Rhinovirus: Treatment
Recovery with long-lasting immunity to that serotype
Symptomatic treatment
No effective antiviral treatment
No effective vaccine
Discovery of vaccinee
Edward Jenner recognized that milkmaids exposed to bovine virus (cowpox) were protected from small pox
An effective vaccine will generally elicit?
- Elicit a protective antibody response. Antibodies are secreted by B-cells
- Elicit a memory T-cell response
T-cell response is needed to maintain a strong B-cell response, and generate memory B-cells
Examples of whole live organism vaccines
Cowpox (cross-reactive)
Measles, Mumps, Rubella
MMR (attenuated)
BCG (attenuated)
Examples of whole killed organisms
‘old’ whopping cough (pertussis)
Cholera, typhoid
Components of organisms (subunit)
Tetanus toxoid Hepatitis B (HBsAg) Hemophilus Influenze type B (HiB)
Characteristics of whole live organism vaccines
Establish infection in vaccinated person - very mild
Immune responses clear infection after 1-2 weeks
Prolonged exposure to organism
Single dose usually - effective at stimulating lifelong immunity
Characteristics of whole killed or component vaccines
Briefly expose vaccinated person to antigens of organism
Immune response clear antigens within a few days
Three (or more) doses to stimulate good immunity
Polysaccharide vaccines
Eg. First generation HiB, Typhoid
Very weak antibody responses to polysaccharide antigens
Polysaccharides are T-cell independent antigens
Little immunological memory - because peptide always presented by MHC are proteins not polysaccharides
Conjugate vaccines
Bacterial polysaccharide component attached to a good antigenic protein carrier. Taken up by B cells. Protein digested and antigen presented. T cells stimulated and provide help. Converts into a T cell dependent antigen. Good immunogenicity. Eg. Tetanus toxoid protein presented on MHC
Causes of vaccine hesitancy
No personal experience of once common diseases
Emphasis on vaccine risks in media
Too many vaccines at once might weaken or overwhelm the immune system
Lack of empathy can alienate people around vaccines
We need to be totally transparent for COVID and all future vaccines.
Central tolerance: General mechanism
Occurs in primary lymph organs. Self-reactive immature cells are deleted, change their specificity (B cells only), or (CD4+ T cells) develop into regulatory lymphocytes
Peripheral tolerance: General mechanism
Some self-reactive lymphocytes mature and enter peripheral tissues. There they may be inactivated or deleted by encounter with self antigens in these tissues, or are suppressed by the regulatory T cells.
Central tolerance: Non-selection (neglect)
Thymocytes bear TCRs that fail to bind to self pMHC or do so very weakly (about 80%)
Central tolerance: Negative selection
Thymocytes with TCRs than bind strongly to self pMHC peptides are removed (about 20%)
Central tolerance: Positive selection
Preserves approximately 1-2% of thymocytes whose TCR recognise self MHC neither to strongly or too weakly and will display non-self peptides in the periphery.
How do T-cells encounter self-antigens in the thymus?
Thymic epithelial cells (TECs) express extra-thymic antigens. Extra thymic antigens are normally expressed in other tissues or organs (eg insulin in the pancreas, saliva proteins in salivary glands). Lymphocytes are negatively slected when their affinity of interaction with self-antigen MHC complexes presented thymic epithelial cells is very high. These cells will undergo apoptotic death.
Central tolerance: Tregs and Affinity model
Some self-reactive thymocytes are NOT deleted but instead differentiate into Tregs. Affinity model suggests those cells receiving signals slightly weaker than those inducing negative selection become Tregs.
Central tolerance in B cells
- Immature B-cells recognise self antigens present at high concentration then B-cells edit sequence of BCR.
- If editing fails B cells maybe deleted
- If self antigen recognition is weak the B cells become unresponsive and exit bone marrow in an unresponsive state (anergic)
Mechanisms of Peripheral Tolerance
Clonal anergy - self-reactive lymphocytes still exit but are inactive and are resistant to antigen stimulation
Supression - self reactive lymphocytes are present and potentially active, but are continually kept in check by Tregs
Immunological ignorance - self-reactive lymphocytes are present but do not mount a pathological response.
Antigens are sequestered in immunologically privileged sites.
B cells lacking adequate T cell help
Lack co-stimulation by other molecules
