When the immune system goes wrong Flashcards

1
Q

What does the immune system protect us from?

A

-Bacteria
-Viruses
-Parasites
-Cancer

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2
Q

What is hypersensitivity?

A

-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

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3
Q

What is an immediate hypersensitivity reaction?

A

Allergy
-Mediated by IgE, mast cells and Th2 responses
-Harmless molecule is called allergen

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4
Q

What is atopy?

A

-An inherited tendency to make immediate hypersensitivity
responses
-30-50% of the population suffer

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5
Q

What causes immediate hypersensitivity response?

A

-Mast cell degranulation and histamine release
-When it happens in the skin there is a wheal and flare

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6
Q

What causes allergy and allergic response?

A

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

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7
Q

What are the symptoms of allergy or atopy?

A

-Sneezing
-Wheal and flare

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8
Q

Common and rare immediate hypersensitivity diseases

A

Common:
-Asthma
-Perennial rhinitis (hay fever)
-Allergic eczema

Rare:
-Anaphylaxis (bee/wasp stings)

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9
Q

Common and rare immediate hypersensitivity therapies

A

Common:
-Anti-histamines
-B2-adrenoceptor agonist
-Corticosteroids

Rare:
-Desensitisation
-Monoclonal antibody
against IgE (Omalizumab)

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10
Q

What is immunological self tolerance?

A

-Controlled failure to respond to self
-Despite having the capability to do so

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11
Q

Autoimmune disease definition

A

-Loss of immunological tolerance to self components
-Associated with pathology
-Disease accompanied by one or more manifestations of
autoimmunity (T or B cell)

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12
Q

Spectrum of autoimmune diseases

A

Organ specific:
-Type 1 diabetes
-Grave’s disease

Non-organ specific:
-Systemic lupus erythematosus
-Rheumatoid arthriris

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13
Q

Features of serum antibodies which break self tolerance

A

-Usually IgG class
-Important diagnostic tools
-Useful for monitoring disease activity
-Useful for predicting future disease
-May be pathogenic (cause disease)

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14
Q

AutoAntibodies linked with pathology

A

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

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15
Q

How do you prove autoimmunity?

A

-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

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16
Q

What was the first disorder to be associated with autoimmunity?

A

-Grave’s disease?
-Anti-thyroid autoantibodies discovered in 1950s

17
Q

Homeostasis vs Grave’s disease

A

-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

18
Q

Homeostasis vs Myasthenia Gravis

A

-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

19
Q

Autoimmunity from mother to child example

A

-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

20
Q

Example of T cell mediated autoimmune disease pathology

A

Rheumatoid arthritis

21
Q

How do we know that Type 1 Diabetes is T cell mediated?

A

-Success of humanised monoclonal antibody against T cells as therapy for Type 1 Diabetes

22
Q

How is Type 1 Diabetes T cell mediated?

A

-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

23
Q

Primary vs Secondary Immunodeficiencies

A

Primary
-inherited defect
-rare

Secondary
-acquired defect
-common

24
Q

Cells of the immune system

25
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
26
What is SCID?
Severe Combined Immune Deficiency -No B cells or T cells
27
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
28
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
29
Example of secondary immunodeficiency deficiencies
HIV
30
How does HIV work?
-Virus infects T cell through CD4+ T cell -CD4+ T cell count decreases
31
What is the treatment for HIV?
Highly Active Anti Retroviral Therapy
32
What is iatrogenic immune deficiency?
-Increasing numbers of patients being treated with immune based therapies -These may cause highly focused secondary immune abnormalities
33
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
34
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
35
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