When the immune system goes wrong Flashcards
What does the immune system protect us from?
-Bacteria
-Viruses
-Parasites
-Cancer
What is hypersensitivity?
-Immune response to a harmless molecule, ignored by the immune systems of the majority
-But in some people it initiates a response that leads to tissue damage and even death
What is an immediate hypersensitivity reaction?
Allergy
-Mediated by IgE, mast cells and Th2 responses
-Harmless molecule is called allergen
What is atopy?
-An inherited tendency to make immediate hypersensitivity
responses
-30-50% of the population suffer
What causes immediate hypersensitivity response?
-Mast cell degranulation and histamine release
-When it happens in the skin there is a wheal and flare
What causes allergy and allergic response?
Th2 response
-Pollen grains taken up by APCs
-Presented as peptides to CD4+ T cells
-Activation of CD4+ T cells causes release of IL-4, IL-5 , IL-13 which activate B cell
-B cells differentiate to plasma cell which produces IgE antibody
-IgE binds to surface of mast cells in skin, nose etc
-Pollen binds to multiple IgE molecules (cross linking) causing mast cell to degranulate and release inflammatory mediators
What are the symptoms of allergy or atopy?
-Sneezing
-Wheal and flare
Common and rare immediate hypersensitivity diseases
Common:
-Asthma
-Perennial rhinitis (hay fever)
-Allergic eczema
Rare:
-Anaphylaxis (bee/wasp stings)
Common and rare immediate hypersensitivity therapies
Common:
-Anti-histamines
-B2-adrenoceptor agonist
-Corticosteroids
Rare:
-Desensitisation
-Monoclonal antibody
against IgE (Omalizumab)
What is immunological self tolerance?
-Controlled failure to respond to self
-Despite having the capability to do so
Autoimmune disease definition
-Loss of immunological tolerance to self components
-Associated with pathology
-Disease accompanied by one or more manifestations of
autoimmunity (T or B cell)
Spectrum of autoimmune diseases
Organ specific:
-Type 1 diabetes
-Grave’s disease
Non-organ specific:
-Systemic lupus erythematosus
-Rheumatoid arthriris
Features of serum antibodies which break self tolerance
-Usually IgG class
-Important diagnostic tools
-Useful for monitoring disease activity
-Useful for predicting future disease
-May be pathogenic (cause disease)
AutoAntibodies linked with pathology
Rheumatoid arthritis
-Rheumatoid factors (anti-IgG)
-Anti-citrullinated peptide
SLE
-Anti-DNA and nucleoprotein
Autoimmune vascultitis
-Anti-myeloperoxidase or proteinase 3
Type I diabetes:
-Anti-islet cell antibodies
-Antibodies to Insulin, GAD65, IA-2, ZnT8
Multiple sclerosis:
-Anti-myelin basic protein
Grave’s disease:
-Anti-thyroid stimulating hormone receptor
Myasthenia gravis:
-Anti-acetylcholine receptor
How do you prove autoimmunity?
-Passive transfer of disease by immune effectors (e.g. T cells,
antibodies)
=>E.g. IgG mediated pathology in Grave’s disease and myasthenia gravis: transfer of disease to foetus via
placental IgG
-Clinical responsiveness to immune suppression or to reestablishment of tolerance
=>E.g. rheumatoid arthritis and Type I diabetes
What was the first disorder to be associated with autoimmunity?
-Grave’s disease?
-Anti-thyroid autoantibodies discovered in 1950s
Homeostasis vs Grave’s disease
-Production of thyroxine by thyroid gland is regulated by TSH, produced by pituitary gland
-Binding of TSH to the TSH receptor stimulates the production of thyroxine
-Negative feedback by thyroxine prevents excess TSH production by the pituitary gland
Grave’s
-Constant stimulation of the thyroid and pituitary with no feedback loop
Homeostasis vs Myasthenia Gravis
-Neuronal stimulus releases acetylcholine at junction, which acts on receptor and causes muscle contraction
Myasthenia Gravis
-Antibody to acetylcholine receptor means signal is not received and there is no/poor muscle contraction
Autoimmunity from mother to child example
-Maternal IgG is transported across placenta to protect the baby during the first weeks of life
-Until the baby’s own antibody response develops
-Mother with Grave’s disease has IgG antibodies to TSH receptor
-Cross placental transfer of disease manifestations from mother to foetus by IgG proves that antibody causes pathology in Grave’s disease and Myasthenia Gravis
Example of T cell mediated autoimmune disease pathology
Rheumatoid arthritis
How do we know that Type 1 Diabetes is T cell mediated?
-Success of humanised monoclonal antibody against T cells as therapy for Type 1 Diabetes
How is Type 1 Diabetes T cell mediated?
-Beta cell autoantigens are taken up by APCs and presented to CD4+ T cells
-CD4+ differentiate into Th1, Th2, Th17
-Th2 cells promote production of autoantibodies
-Inflammatory CD4+ cells drive CD8+ response
-Beta cells present autoantigens to CD8+ T cells, causing killing of Beta cell
-Meanwhile, Regulator T cells are not suppressing inflammation
Primary vs Secondary Immunodeficiencies
Primary
-inherited defect
-rare
Secondary
-acquired defect
-common
Cells of the immune system
What is Di George’s syndrome?
-Thymus doesn’t form
-No T cells in blood or lymphatics
-Pharyngeal arches don’t develop properly
-Causes immunodeficiency and abnormalities of heart/facial features
What is SCID?
Severe Combined Immune Deficiency
-No B cells or T cells
What is chronic granulomatous disease?
-Neutrophils protect against bacterial infections
-In CGD, Neutrophils can surround bacteria, but they can’t kill it
-Thus, granulomas form
What is Hypergammaglobulinemia (hyper IgM syndrome)?
-Gene defect impairs CD40 ligand
-In absence of CD40 ligand, B lymphocyte responses are not made, plasma cells do not develop, and only IgM can be made
Example of secondary immunodeficiency deficiencies
HIV
How does HIV work?
-Virus infects T cell through CD4+ T cell
-CD4+ T cell count decreases
What is the treatment for HIV?
Highly
Active
Anti
Retroviral
Therapy
What is iatrogenic immune deficiency?
-Increasing numbers of patients being treated with immune based
therapies
-These may cause highly focused secondary immune abnormalities
Examples of iatrogenic immune deficiency?
-Monoclonal anti-TNF-α therapy for rheumatoid arthritis results
in unusual opportunistic infections including mycobacterial infections
-Monoclonal anti-IL-17 therapy for psoriasis can give rise to severe systemic fungal infections; telling
us that IL-17 is a key component of protection from fungi
What causes Cancer?
-Failure of immune surveillance (CD4+ Treg)
-Programmed death-1 are present on effector cells
-Programmed death- ligand 1 are present on cancer cells
-Monoclonal antibody that blocks PD1/PDL1 interaction takes away stop signal for immune surveillance
-Immune surveillance can work properly and remove cancer cell
What is post transplant lymphoproliferative disease (PTLD)?
-In healthy individuals B cells may be infected with Epstein Barr virus (EBV) -This is normally controlled by cytotoxic T cells
-T cells may be suppressed (e.g. by drugs to prevent
rejection of a transplant)
-In this case the cytotoxic T cell response cannot control infected B cells
-They undergo malignant transformation and form a B cell lymphoma
