13. Lung Immunology: Allergic Airway Diseases Flashcards
Outline hypersensitivity
Hypersensitivity is an exaggerated response that may be immunological or non-immunological:
- Immunological - i.e. allergy; may be IgE-mediated (e.g. atopic diseases including hayfever, eczema, asthma) or non-IgE-mediated (e.g. farmers’ lung)
- Non immunological - intolerance (e.g. food), enzyme deficiency (e.g. lactate dehydrogenase / LDH), pharmacological (e.g. aspirin hypersensitivity)
Outline allergy
Allergy is an exaggerated immunological response to a foreign substance (allergen) which is either inhaled, swallowed, injected, or comes in contact with the skin or eye
An allergy is a mechanism, not a disease, but the mechanisms often play a temporary or permanent role in disease
It can be subdivided into different categories:
o Asthma o Drug reactions o Food reactions o Rhinitis o Eczema, urticaria (hives), angioedema (swelling similar to hives, but not on surface of skin)
Outline atopy
Atopy means ‘out of place’; the hereditary predisposition to produce IgE antibodies against common environmental allergens
The atopic diseases are allergic rhinitis, asthma and atopic eczema
Allergic tissue reactions in atopic subjects are characterised by infiltration of Th2 cells and eosinophils
The term ‘allergic match’ is used to describe the common progression from atopic dermatitis to allergic asthma
Contrast Th1 and Th2 cells
Proliferating helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as Th1 and Th2 cells (also known as Type 1 and Type 2 helper T cells, respectively)
Th1 cells’ main partner cells are Macrophages and CD8+ T cell
Th2 cells’ main partner cells are B-cells, Eosinophils and Mast cells
Outline IgE-mediated allergic reactions in the upper and lower airways
May present with either acute or chronic symptoms of allergy
Acute symptoms result from the binding of allergen to IgE-coated mast cell, which causes mast cell degranulation and histamine release
Chronic symptoms present from the interaction of the allergen with antigen-presenting-cells, involving the release of Th2 cytokines and chemokines
Outline Th2 responses with regards to IgE-mediated allergic reactions in the upper and lower airways
Involves the collaboration between innate and adaptive immune responses
PAMPs present on allergen interact with barrier cells e.g. epithelial cells lining airway - stimulates secretion
of IL-33 and IL-25
Interleukins attract natural helper cells, nuocytes and MPPtype2 cells (which differentiate to form mast cells, basophils and macrophages)
These cells then secrete IL-4, IL-5 + IL-13, which induces Th2 cell differentiation, B1 cell proliferation and anti-allergen effector functions; this is where the adaptive immune response is involved
Th2 cells are CD4+, therefore release:
o IL-4 –> IgE synthesis
o IL-5 –> Eosinophil development
o IL-9 –> Mast cell development
o IL-13 –> IgE synthesis and airway hyper-responsiveness
Outline nuocytes
The nuocyte is a cell of the innate immune system that plays an important role in type 2 immune responses that are induced in response to helminth worm infection or in conditions such as asthma and atopic disease
What are MPPtype2 cells?
Multipotent progenitor type 2 cells
Contrast totipotency, multipotency, pluripotency, oligopotency and unipotency
Totipotency is the ability of a single cell to divide and produce all of the differentiated cells in an organism; spores and zygotes are examples of totipotent cells; in the spectrum of cell potency, totipotency represents the cell with the greatest differentiation potential
In cell biology, pluripotency refers to a stem cell that has the potential to differentiate into any of the three germ layers: endoderm (interior stomach lining, GI tract, the lungs), mesoderm (muscle, bone, blood, urogenital), or ectoderm (epidermal tissues and nervous system)
Multipotency describes progenitor cells which have the gene activation potential to differentiate into discrete cell types; for example, a multipotent blood stem cell is a hematopoietic stem cell (HSC), and this cell type can differentiate itself into several types of blood cell types like lymphocytes, monocytes, neutrophils, etc., but it is still ambiguous whether HSC possess the ability to differente into brain cells, bone cells or other non-blood cell types
In biology, oligopotency is the ability of progenitor cells to differentiate into a few cell types; it is a degree of potency; examples of oligopotent stem cells are the lymphoid or myeloid stem cells; a lymphoid cell specifically, can give rise to various blood cells such as B-cells and T-cells, however, not to a different blood cell type like a red blood cell; examples of progenitor cells are vascular stem cells that have the capacity to become both endothelial or smooth muscle cells
In cell biology, a unipotent cell is the concept that one stem cell has the capacity to differentiate into only one cell type; it is currently unclear if true unipotent stem cells exist; hepatoblasts, which differentiate into hepatocytes (which constitute most of the liver) or cholangiocytes (epithelial cells of the bile duct), are bipotent; a close synonym for unipotent cell is precursor cell.
Outline allergic diseases
Allergic diseases include:
Atopic allergy (IgE mediated):
- Allergic asthma - including occupational asthma
- Allergic rhinitis - including hay fever
- Anaphylaxis - e.g. food, insect stings, drugs, latex
- Skin allergies - e.g. urticaria, angioedema, atopic eczema
Non-atopic allergy (IgG mediated/T-cell mediated):
- Contact dermatitis
- Extrinsic allergic alveolitis
- Coeliac disease
Outline non-allergic hypersensitivity/intolerance responses
Usually apply to food intolerance
Non-immunological mechanisms
E.g. include enzyme deficiency (Lactase DH), migraine (triggered by coffee, wine), IBS (exacerbated by
various foods), bloating due to wheat intolerance
Also idiopathic environmental intolerance (also known as multiple chemical hypersensitivity; cause unknown)
Outline allergic rhinitis
Can be either seasonal or perennial (triggered indoors); prevalence is up to 17% of the population
It is characterised by a blocked or runny nose, sneezing, itching and streaming eyes
Seasonal allergic rhinoconjunctivitis (more commonly referred to as hayfever), is caused by allergenic substances contained within pollen
o Commonly the causative factor is grass pollen but allergy to tree and weed pollen is also on the
increase
Worst symptoms usually at the height of summer when vast clouds of grass pollens become airborne; due
to mild winters and warmer springs, pollination of grasses in the UK is now starting earlier,
therefore the worst symptoms can be well established by the first week in June and tend to peak around mid-June to early July
When the pollen counts are very high, some wheeziness can also co-exist with rhinitis, in a condition known as seasonal allergic asthma
Perennial allergic rhinitis involves troublesome chronic symptoms such as a blocked, runny nose and sneezing
Can have non-allergic causes of perennial rhinitis such as infection and structural abnormalities, and a small
minority of patients have underlying immunodeficiency problems too
Allergy to the house dust mite (Dermatophagoides species) and allergens derived from animals such as cats,
dogs, horses and pet rodents are the most important causes
Define asthma
A chronic disorder characterised by episodes of wheezy breathlessness, but which may also present as an isolated cough, particularly in children
It affects 8-12% of the population
Outline the aetiology of asthma
The aetiology os still uncertain, but the pathology involves inflammation of the large and small airways (bronchi and bronchioles)
The consequence is an irritable or twitchy airway in which airflow obstruction results from exposure to a variety of non-specific irritants (bronchial hyper-responsiveness)
Define aetiology
The cause, set of causes, or manner of causation of a disease or condition
Outline the clinical presentation of asthma
Clinical presentation: A wide clinical spectrum of asthma symptoms result, ranging from mild occasional wheezing, which is usually controlled by the occasional use of inhaled bronchodilators, through to severe intractable disease which requires treatment using systemic corticosteroids)
Outline the relationship between asthma and allergy
Allergy can trigger an attack in around 75% of asthmatics, and this is most commonly due to sensitivity to house dust mites or pollen
However, even in patients who suffer from allergic asthma, there are usually other triggers such as viral infections, exercise, exposure to fumes and other irritants such as tobacco smoke, and certain drugs (especially aspirin and related compounds)
Food allergens and additives are rarely responsible but can also occasionally be implicated in triggering asthmatic symptoms
In a few cases, the role of allergy in asthma is obvious, such as in patients who wheeze when the pollen count is high but not at other times of the year
But in many cases it is difficult to determine the exact role of allergy in asthma
A significant proportion of asthmatics (about 25%) are not sensitised to common airborne allergens, and so are ‘non-atopic asthmatics’
Their disorder often starts in later life and can be more severe than those who have asthma which begins in childhood
In intermittent, mild asthma, allergy frequently is very important
In persistent but manageable asthma, allergy is sometimes important
In chronic, severe asthma, allergy is less important, but infection is important
Outline the symptoms of general anaphylaxis
- Dizziness, seizures, loss of consciousness
- Anxiety, sense of gloom
- Arrhythmia
- Vomiting, diarrhoea, pain
- Urticaria/hives
- Tingling in hands and feet
- Bronchoconstriction
- Laryngeal oedema
- Lip, tongue swelling
Outline the causes and treatment of general anaphylaxis
Causes:
- Drugs, e.g. penicillin
- Foods, e.g. peanuts, tree nuts, milk, eggs, fish, shellfish, sesame seeds, soybeans, celery, celeriac
- Insect stings e.g. bees, wasps, hornets
• Latex
Treatment: use of an EpiPen
Define Extrinsic allergic alveolitis (EAA)
Extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis (HP) is a non-IgE T cell mediated inflammatory disease effecting the alveoli and interstitium, affecting 0.1% of the population
Define interstitium
The interstitium is a contiguous fluid-filled space existing between the skin and the body organs, including muscles and the circulatory system
The fluid in this space, called interstitial fluid composed of extracellular fluid and its solutes; it drains into the lymph system
Outline the causes of Extrinsic Allergic Alveolitis (EAA)
Cause: It occurs in susceptible people following the repeated inhalation of certain antigens
These antigens typically include bacterial or fungal microorganisms in the workplace or bird antigens.
Some antigens that cause asthma such as the mold, alternaria, can also induce EAA
Examples of extrinsic allergic alveolitis:
- Farmer’s lung - mouldy hay
- Bird fancier’s lung - bird droppings
- Air conditioner lung - air conditioner moulds
- Mushroom workers lung - mushroom compost
- Malt works lung - mouldy malt or barley
- Coffee workers lung - unroasted coffee beans
- Millers lung - infested flour
- Hot tub lung - bacterial contamination
Outline the prevalence and diagnosis of EAA
The prevalence of EAA varies and is related to the particular antigen and the host immune response
Studies have shown that, a minority of individuals exposed develop disease
Cytokine gene polymorphisms in the TNF-alpha promoter region appear to be a host susceptibility factor
Establishing the diagnosis of EAA is challenging requiring a high index of suspicion, a thorough history, careful examination, complete pulmonary function tests and radiographic studies:
- The histology reveals a lymphocytic infiltrate with a predominance of CD8+ lymphocytes, ‘foamy’ alveolar macrophages, and granulomas consistent with nonspecific interstitial pneumonia
- Early identification of patients with EAA with subsequent avoidance of the causative antigen is the key to a successful outcome
Outline the treatment for EAA
Pharmacologic treatment for acute EAA is limited to oxygen and oral corticosteroids
Oral steroids may not affect the long-term outcome
The prognosis is generally favorable if intervention takes place before pulmonary fibrosis occurs
Outline atopic disease
The atopic diseases (eczema, asthma and rhinoconjunctivitis) are clinical syndromes each defined by a group of symptoms and signs
Not all children with atopy will have atopic disease or develop symptoms after exposure to an allergen
Both genetic and environmental factors determine the development of atopic disease
Outline the prevalence of atopic disease
5,700,000 are diagnosed with asthma at some point
1/15 of people have a recorded diagnosis of allergic rhinitis
117% increase in the number suffering from a peanut allergy from 2001-2005
Number of hospital admissions due to anaphylactic shock has increased 7x from 1990-2000
Outline the trends in atopic disease
Decrease in infectious diseases (E.g. hep A, TB, measles, rheumatic fever) mirrors an increase in allergy and autoimmune disease (e.g. MS, Crohn’s diease, T1 diabetes, asthma)
Increase in hospital admission rates for urticaria, food allergy and anaphylactic shock among children <15 yrs
Outline the burden of atopic disease
Allergic disorders can make social interactions difficult as even simple everyday activities can pose a major health risk
On a national scale, the treatment of allergy patients forms a significant part of the work of the health care providers and the number of allergy-related work absences represents a large cost to the economy
Allergies affect all aspects of a patient’s life; hay-fever symptoms disrupt children’s sleep and often impair their performance at school and asthma has been associated with school absenteeism
Allergy patients often find it difficult to live a normal life
This is especially apparent in children, where special care has to be taken whilst engaging in everyday activities which in turn induces anxiety and impairs the quality of life
The prevalence of allergic disease has markedly increased over recent years. In the UK, by 2004, the scale of the ‘allergy epidemic’ was such that 39% of children and 30% of adults had been diagnosed with one or more of asthma, eczema and hayfever, and 38% of children and 45% of adults had experienced symptoms of these disorders in the preceding 12 months
In fact by the end of 2005, approximately 1in9 people had a recorded diagnosis of ‘any allergic disease’, including any one of asthma, hayfever, eczema, anaphylaxis or peanut allergy
Asthma, eczema and allergic rhinitis often occur together and this co-morbidity, or multiple allergic disease, often requires multiple referrals to different organ specialists
Outline the possible reasons for the rising trends in allergic disease
Marked increase in prevalence indicates importance of environmental influences in addition to genes
Hygiene hypothesis: the developing immune system is deprived of the microbial antigens that stimulate Th2
cells, because the environment is relatively clean and because of childhood vaccinations and the widespread use of antibiotics for minor illnesses in early life; this is in addition to a genetic predisposition to asthma involving chromosomes 5,6,11,12 and 14”
o Atopy and allergic asthma were less frequent in people exposed to agents in soil, air and water such as H. pylori, T. gondii and the hepatitis A virus
o Also a traditional lifestyle with a high gut bacterial turnover rate and intestinal colonisation with lactobacilli and bifidobacteria protect against allergy; such a lifestyle is usually associated with ‘organic’ food including spontaneously fermented vegetables
• Other related factors which may encourage the Th2 phenotype include a date of birth around the pollen season, and alterations in infant diet
Furthermore, atopic allergic diseases are less common in younger siblings and larger sibships and in those who have had measles and hepatitis A indicating that repeated ‘immune stimulation’ (e.g. by viruses) may be protective
The development of specific allergic diseases may be related to alterations in the target organ; for example, the co-factors required for the development of an asthmatic attack may include respiratory virus infections and exposure to increased allergens, tobacco smoke, and air pollutants; these factors alone, or in combination, may alter immunoregulatory mechanisms at mucosal surfaces in ways that promote a Th2 cell - mediated allergic inflammatory response
Outline the principles of the treatment of allergic airway diseases, including allergen specific immunotherapy
Consists of: allergen avoidance, anti-allergic medication and immunotherapy (also called desensitisation/hyposensitisation
Anti-allergic medication: antihistamines used to relief rhinitis symptoms, and topical corticosteroids (anti-inflammatory):
o Histamine1-receptor antagonists are less sedative and more selective than old antihistamines
Outline allergen specific immunotherapy
Immunotherapy involves administering increasing concentrations of allergenic extracts over long periods of time
Advantages - effective and produces long lasting immunity
Disadvantages - risk of developing anaphylaxis (particularly during induction), time consuming, standardisation problems:
o Attempts to minimise the systemic reactions include pre-treatment of allergen extracts with agents like
formaldehyde (leading to allergoids)
However, this results in reduced immunogenicity as well as a decrease
in IgE binding
Indications for use: grass/tree pollen allergic rhino-conjuctivitis uncontrolled by medication, bee/wasp sting anaphylaxis at risk for repeats
Mode of action is complex, but central to its principle is down-regulation and up-regulation:
- Down-regulation - Th2:
o Decreases TH2-type cytokines (IL-4, IL-5, IgE), Eosinophils, Mast cells, Basophils, Late-phase reaction and Immediate hypersensitivity
- Up-regulation - Th1:
o Increases Th1-type cytokines (IFN-γ, IL-12, IgG)
- Up-regulation - Treg cells:
o Induces IL-10, TGF-β1 and allergen-specific hyper-responsiveness
Outline TGF-β1
Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines
It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis
In humans, TGF-β1 is encoded by the TGFB1 gene
Outline TNF-α
Tumor necrosis factor (TNF, tumor necrosis factor alpha, TNFα, cachexin, or cachectin) is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction
It is produced chiefly by activated macrophages, although it can be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons
The primary role of TNF is in the regulation of immune cells
TNF, being an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, inflammation and to inhibit tumorigenesis and viral replication and respond to sepsis via IL1 & IL6
Outline IFN-γ
Interferon gamma (IFN-γ) is a dimerised soluble cytokine that is the only member of the type II class of interferons
IFNγ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral, some bacterial and protozoal infections. IFNγ is an important activator of macrophages and inducer of Class II major histocompatibility complex (MHC) molecule expression
Aberrant IFNγ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFNγ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects
IFNγ is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops
Define cachexia
Weakness and wasting of the body due to severe chronic illness
Summarise the 5 different types of hypersensitivity reactions
Type I:
o Allergy (Immediate)
o E.g. anaphylaxis, atopy, asthma, etc.
Type II:
o Cytotoxic; antibody-dependent
o E.g. thrombocytopenia, Grave’s disease, etc.
Type III:
o Immune complex disease
o E.g. serum sickness, reactive arthritis, etc.
Type IV:
o Delayed-type hypersensitivity; antibody-independent
o E.g. MS, coeliac disease, Mantoux test, contact dermatitis, etc.
Type V:
o Autoimmune disease; receptor-mediated
o E.g. Grave’s disease, myasthenia gravis, etc.
