Respiratory Immunology 4: Hypersensitivity and Autoimmunity Flashcards
Immune system functions?
Provide a robust defense against a wide variety of aggressive external agents
Provide a robust defense against internal aggressive agents, e.g: cancer
Consequences of immune recognition?
Intended destruction of the antigen
Incidental tissue damage (BYSTANDER DAMAGE/collateral)
Definition of hypersensitivity reactions?
Immune response that results in BYSTANDER DAMAGE TO SELF
Normally, an exaggeration of the normal immune response and is the basis of many disease (allergic, autoimmune)
Hypersensitivity reaction types?
Type 1: Immediate hypersensitivity (allergic)
Type II: Direct cell killing
Type II: Immune complex mediated
Type IV: Delayed type hypersensitivity
Key features of Type II hypersensitivity?
Direct cell killing that is ANTIBODY-MEDIATED (bind to targets on CELL SURFACE)
Pathophysiology of Type II reactions?
Antibody binds to cell-surface antigen resulting in:
Activation of complement - can cause cell lysis and also opsonisation (facilitates antibody-mediated phagocytosis)
Antibody functions?
Opsonisation
Activation of complement
Virus and toxin neutralisation - can achieve this alone
Antibody-dependent cell cytotoxicity - mediated by NK cells
Direct anti-microbial activity
Reduced damage to host from inflammatory response
Immunomodulation
Mechanism of direct cell killing (Type II reactions)?
B cells produce IgM/IgG antibody directed against cell membrane protein
Binding of IgM/IgG to cells surface results in COMPLEMENT ACTIVATION (osmotic cell lysis, phagocytosis by macrophages)
Describe the complement system
> 20 tightly regulated, linked proteins produced in the liver and present in circulation as inactive molecules
Triggering enzymatically activates other proteins in a biological cascade - causes rapid, HIGHLY AMPLIFIED RESPONSE
Complement activation pathways?
Classical (C1, C2, C4)
Lectin (mannose-binding lectin)
Alternative
…all activate C3
Effects of C3 complement activation?
Opsonisation - of antigen-antibody complexes enhances phagocytosis by macrophages and neutrophils
Direct killing - of encapsulated bacteria (punch holes in bacterial cell membranes to cause fluid entry and osmotic lysis), by involvement with MEMBRANE ATTACK COMPLEX formation
Solubilisation - of immune complexes
Chemotaxis (increase in VASCULAR PERMEABILITY and cell trafficking) - stimulate migration of macrophages and neutrophils to site of inflammation
How does opsonisation facilitate pathogen uptake and how do complements do this?
Opsonins act as a bridge between the pathogen and phagocyte receptors:
Acute phase proteins like C REACTIVE PROTEIN (CRP)
Antibodies
Complement (fragments of complement activation bind to micro-organisms and also bind to receptors on phagocytes, bridging between phagocyte and bugs)
Describe complements increasing vascular permeability
Fragments of complement proteins (ANAPHYLOTOXINS) released after activation increase blood vessel permeability
Increases traffic of cells to sites of infection
How do complements act to solubilise immune complexes?
Complement activation triggered by immune complexes and fragments can dissolve complexes which triggered them, switching OFF process of complement activation (NEGATIVE FEEDBACK regulates pathway)
What is autoimmune haemolytic anaemia?
Type II hypersensitivity reactions
Phagocytosis of opsonised red cell (both complement and antibody can act as opsonin)
Phagocytosis of lysed rbcs
What are transfusion reaction?
Type II hypersensitivity reactions
AKA ABO reactions to target donor rbcs
Anti-blood group antibodies bind to surfaces of donor erythrocytes and form antigen-antibody complexes
Activates complement and stimulates phagocytosis
Give an example of when transfusion reactions may occur
Giving a patient with blood group A (rbcs express A and their serum contains naturally occurring anti-B antibodies)
Donor blood is blood group, rbcs express B, and there is an instant reaction
Symptoms of haemolytic transfusion reaction?
Overwhelming systemic inflammatory response: Pyrexia and rigors Tachycardia/tachypnoea Hypotension/dizziness Headaches/chest or lumbar pain May be fatal
Other examples of Type II hypersensitivity reactions?
Idiopathic thrombocytopaenic purpura - antibodies bind to platelets
Goodpasture’s syndrome - antibodies bind to lung and kidney (glomerular) basement membrane, causing bleeding from lungs and kidney failure
Proving that a disease is mediated by antibodies?
Demonstrate that serum causes disease when transferred into another host, e.g: mouse
Diseases which may be transferred to neonates?
Myasthenia gravis (autoimmune condition where antibodies attack communication system between the brain and your muscles, causing weakness)
Idiopathic thrombocytopaenic purpura
Rhesus disease
What is a neonate with a bright red rash likely to have?
Neonatal lupus (antibodies clear after a while) Mother with no/mild symptoms of autoimmune disease may be at substantial risk for development of overt autoimmune disorder, e.g: Sjorgen's syndrome, systemic lupus erythematosus
Managing Type II hypersensitivity reactions?
Plasmapheresis - removal of pathogenic antibody by patient blood removal via cell separator (separates cells from plasma); cells returned but plasma replaced by plasma from someone else (Fresh Frozen Plasma) or pooled immunoglobulin
Approx. 50% plasma removed each time
Immunosuppression - rebound antibody production (B cells producing more antibodies) limirs efficacy of plasmapheresis; given potent immunosuppressive agent to switch off B cell antibody production
What is a type III hypersensitivity reactions and how do they occur?
Immune-complex mediated
Antigen is free (not on cell surface); autoantibodies bind to circulating antigen to form immune-complexes
Where type III hypersensitivity reactions?
Often settle in glomerulus and can cause complement activation (do all their functions) and infiltration of macrophages and neutrophils
Example of a type III hypersensitivity reactions?
Farmer’s lung - inhaled fungal particles (from mouldy hay) deposited in lung stimulates antibody formation and these form immune complexes with antigen
Results in complement activation, inflammation and recruitment of other cells
Causes wheezing and malaise after exposure to antigen
Bird fancier’s lung - source is avian excreta, feathers and organism/agent is Avian serum proteins
What is acute hypersensitivity pneumonitis?
Type III hypersensitivity response
Immune complexes deposited in walls of alveoli and bronchioles so cell accumulation and inflammation within alveoli, causing symptoms within 4-8 hours after exposure
Explain the clinical features of acute hypersensitivity pneumonitis
Wheeze - inflammation of terminal bronchioles and alveoli caused by activated phagocytes and complement
Breathlessness - alveolitis (inflamed alveoli have reduced gas exchange efficiency), caused by activated phagocytes and complement - results in decreased efficiency of gas transfer
Malaise, pyrexia - systemic manifestation of inflammatory response
Give an example of systemic type III hypersensitivity
Systemic Lupus Erythematous (SLE):
Antibodies produced against contents of cell nuclei
Form immune complexes with antigen
Deposited in small vessels of skin, joints, kidneys
Result in complement activation, inflammation, recruitment of other cells
Problems with immune complex deposition?
Small vessel vasculitis and systemic antigen causes systemic disease:
Fever
Renal impairment (deposition of IgG immune complexes in glomeruli)
Vasculitis skin rash/vasculitis purpura (deposition in skin)
Arthralgias (immune complex deposition in joint)
Diagnosis of Type III hypersensitivity reactions?
Specific IgG to putative antigen:
Anti-DNA binding antibodies (in SLE); when cells die, DNA can be released
Antibodies to aspergillus (in Farmers’ lung)
Does the immune response consume complement?
Managing Type III hypersensitivity reactions?
Avoidance
Decrease inflammation - corticosteroids
Decrease antibody production - immunosuppression
Respiratory disease that can be treated with corticosteroids?
Obstructive lung diseases - asthma and COPD
Restrictive lung diseases - sarcoid, pulmonary fibrosis
Infective lung disease - if evidence of severe inflammation
Some type of cancer
Corticosteroids are not used to treat these respiratory diseases?
Sleep apnoea
Uncomplicated infection
What are Type IV hypersensitivity reactions?
AKA DELAYED type hypersensitivity
T-cell mediated hypersensitivity
Mechanism of Type IV hypersensitivity reactions?
Initial sensitisation to antigen - generation of “primed” T cells (memory)
Subsequent exposure - activation of previously “primed” T cells (CD4+ and CD8) causes recruitment of macrophages, other lymphocytes, neutrophils and releases of proteolytic enzymes and persistent inflammation
Example of Type IV hypersensitivity?
Nickel hypersensitivity:
Infiltration of activated T cells - CD4+ cells (produce cytokine, recruit and activate macrophages, help for CD8+ lymphocytes and involved with granuloma formation) and CD8 cells (mediate direct cell killing)
Recruitment of macrophages - leads to phagocytosis and production of inflammatory cytokines
Collection of activated macrophages and lymphocytes = GRANULOMA
Persistent inflammatory response is earring not removed as too big
Diseases associated with delayed type hypersensitivity reactions?
Autoimmune:
Type I diabetes
Psoriasis
Rheumatoid arthritis
Non-autoimmune:
Nickel hypersensitivity
TB
Leprosy (some forms)
Sarcoidosis
Berylliosis, silicosis and other dust diseases
Chronic stage of hypersensitivity pneumonitis
Cellular rejection of solid organ transplant
What is sarcoidosis?
Multi-system granulomatous disease of unknown aetiology and characterised by the presence of granulomas (non-specific)
Type IV delayed type hypersensitivity response to unknown antigen
What is a granuloma?
Organised collection of ACTIVATED MACROPHAGES AND LYMPHOCYTES
How do granulomas form?
Non-specific inflammatory response triggered by diverse antigenic agents/inert foreign materials
Activation of T lymphocytes and macrophages
Failure of removal of stimulus results in persistent production of activated cytokines
End result - organised collection of persistently activated cells
Mechanism of sarcoidosis affecting lungs?
Inhalation of unknown antigen
Stimulates alveolar mecrophages (secrete IL-12 which stimulates T cells) and CD4 and CD8 T cells (release gIFN which stimulates macrophage production of TNF and free radicals for effective killing) and, also, B cells within lung parenchyma
Failure of to clear the antigen results in persistent stimulation and granuloma formation
Persistent immune activation leads to tissue damage and fibrosis
Sarcoid management?
Watchful waiting - many patients undergo SPONTANEOUS REMISSION
NSAIDs for acute onset of disease
Systemic corticosteroids (most often used) - block T cell activation and block macrophage activation
Type I hypersensitivity reaction example and key immune system components involved?
Allergic disease
Mast cells, IgE, antibody (B lymphocytes and T lymphocytes)
Type II hypersensitivity reaction example and key immune system components involved?
Autoimmune haemolytic anaemia, blood transfusion reaction
Antibody to cell surface protein (B lymphocytes, T lymphocytes)
Type III hypersensitivity reaction example and key immune system components involved?
SLE, Farmer’s lung
Antigen-antibody immune complexes (B lymphocytes, T lymphocytes)
Type IV hypersensitivity reaction example and key immune system components involved?
Type I diabetes, Sarcoid, TB
Activated T cells and macrophages
