Risk Factors and Pathogenesis of an Allergy: Analytical Essay

Chapter one. Introduction

1.1 Brief history of inheritance

The origins of genetics i.e study of inheritance lie in the development of theories of evolution. It was in 1858 that the origin of species and how species variability was developed after the research of Charles Darwin and Wallace. They described how new species arose through evolution and how natural selection occurred to evolve new forms. Around the same time Gregor Mendel an Austrian Monk also described the unit of hereditary as a particle that does not change and is passed on to offspring through his experiment on inheritance and genetics of sweet peas plants. His work is the basis of understanding the principles of genetics, therefore, he is regarded as the father of genetics, Also Haeckel and Miescher predicted the location of the hereditary material in the living cell i.e the nucleus and the material is nucleic acid respectively. A chromosome was also discovered during this period.

In the early and mid-20th century some scientists also worked and established the Mendelian Principles and the Chromosomal Theory of Inheritance. They also discovered that DNA is the genetic material and Watson and Crick also determined the structure of DNA, and others suggested that the DNA contains a genetic code. ( Ananya Mandal, MD).

1.2 What is inheritance?

Inheritance is the process by which an offspring cell or organism acquires or becomes predisposed to characteristics of its parent cell or organism. Through inheritance, variation exhibited by individuals can accumulate and cause a species to evolve. the study of biological Inheritance is called Genetics ( Devdutt Saha).

Inheritance can also be defined as the transmission of traits or information from one generation of individuals or cells to the next (encyclopedia of Reproduction,2018).

Inheritance refers to the mechanism that genes, and more specifically the permanent condition, or allele that can be distinguished from other alleles of the same gene, is transmitted from parent to offspring. Also can be referred to as the mechanism for either the transmission of specific traits or the transmission of all biological information required for life without specifying genotypes (J.Merriam, 2001).

1.3 Mechanism of inheritance

There are several ways a gene is inherited, and each has an underlying mechanism, the following are some major mechanisms of inheritance:

1.3.1 Autosomal dominant inheritance

This mode of inheritance refers to the conditions where a mutation in one allele can cause the relevant phenotype. It is not required that both alleles have a mutation for the mutant phenotype to be expressed. This occurs when the amount of protein produced by both the alleles is just sufficient for normal function, when one allele is mutated, the protein produced by the allele becomes insufficient for normal function, leading to the phenotype, which could be a diseased state.

Such inheritance can also occur when a mutated allele produces a new protein that has a deleterious effect on the normal function of a cell.

1.3.2 Autosomal recessive inheritance

This mode of inheritance occurs when both alleles of a gene carry mutations that results in a phenotype, Mutations in one of the alleles does not express the mutant phenotype because enough protein is produced by the allele to continue normal function. Individuals which carry such mutations are called carriers.

1.3.3 X-linked inheritance

This kind of inheritance refers to conditions that are caused by mutations on the X-chromosome, any mutation in this chromosome expresses its phenotype in the males, while females usually remain carriers, because they have two copies of X-chromosomes, and one normal copy of the gene is usually sufficient to mask the deleterious effect of the other copy.

1.3.4 Mitochondrial inheritance

Mitochondrial are cellular organelles which possess their own genetic material. During fertilization, the male sperm does not contribute any mitochondrial DNA to the embryo. (all of the cytoplasms comes from the female). Any defect due to mutations in the mitochondrial DNA follows a maternal pattern of inheritance. Defects in mitochondria generally affect the process that uses energy a lot.

1.4 Brief history of allergy

The term “Allergy” was born on July 24, 1906, in the Münchener Medizinische Wochenschrift as “specifically altered reactivity of the organism”. Today, we define allergy as immunological hypersensitivity that can lead to a variety of different diseases via different pathomechanisms, and thus different approaches in diagnosis, therapy, and prevention can be taken. Several misconceptions can be delineated.

Allergology is the science regarding allergic diseases and their differential diagnoses and mechanisms. It requires clinical experience in allergic diseases, a basic understanding of the immune system in physiology and pathology, and finally extensive knowledge of environmental factors in eliciting or modulating allergic reactions. Allergy is not a disease itself, but a mechanism leading to disease.

In clinical practice, allergy manifests in form of various different conditions such as anaphylaxis, urticaria, angioedema, allergic rhinoconjunctivitis, allergic asthma, serum sickness, allergic vasculitis, Hypersensitivity pneumonitis, atopic dermatitis (eczema), contact dermatitis

1.5 What is an allergy?

An allergy is an abnormal immune response that occurs as a result of exposure to certain substances. An allergic reaction occurs when an allergen-specific antibody called Immunoglobulin E (IgE) which is produced by the immune system and binds to cells in the body, comes into contact with a specific allergen for which it is produced(Micheal Miller, M.D, 2005).

Allergies are associated with serious respiratory illnesses such as allergic rhinitis, asthma, and anaphylaxis.

1.5.1 Allergens

Allergens can be defined as any environmental agent that induced IgE-mediated hypersensitivity reactions following inhalation, ingestion, or injection (M.D.Chapman, Anna Pomes, 2003). From immunological point of view we have two types of allergy; complete allergens(true sensitizing allergens) and incomplete allergens(non-sensitizing) allergens Non-sensitizing allergens are able to interact with IgE antibodies but are unable to induce the production of IgE antibodies.

Examples of allergens include; pollen, pet dander, drugs such as penicillin, chloroquine, and sulfonamide food such as egg, milk, fish, peanut, soy, shellfish, etc.

1.5.2 Risk factors of an allergy

The following are the factors that predisposed to an allergic reaction;

• Genetic factors
• Geographical distribution
• Environmental facsocio-economic status, air pollution, climate
• Hygiene hypothesis
• Exposure to certain foods
• Exposure to antibiotics during infancy

1.5. 3 Pathogenesis of an allergy

Chapter two. Types of allergy; causes, signs and symptoms, pathophysiology.

2.1 There are four major common types of allergy;

• Allergic rhinitis
• Allergic Asthma
• Food allergy
• Atopic dermatitis

2.2.1 Allergic rhinitis

Allergic rhinitis also known as Hay fever is a type of inflammation in the nose which occurs as a result when the immune system overreacts to allergens in the air.

Allergic rhinitis is also an allergic disorder characterized by an exaggerated immune response to pollen grains and other substances.

Allergic rhinitis are of two types: Seasonal which occurs only during the time of the year in which certain plants pollinate. The second type of allergic rhinitis is perennial which occurs all year round.

Allergic rhinitis is the type of allergy that affects the greatest number of people. In western countries, between 10-30% of people are affected in a year. It is very common between the ages of twenty and forty.

2.2.2 Causes

Allergic rhinitis is caused mainly by the pollens of specific seasonal plants. The pollen that causes allergic rhinitis varies between individuals and from region to region; in general, the tiny, hardly visible pollens of wind-pollinated plants are the predominant cause. Examples of plants commonly responsible for allergic rhinitis include:

1. Trees: such as pine(pinus), birch(Betula), alder(Alnus), cedar(Cedrus), hazel(Corylus), hornbeam(Carpinus), horse chestnut(Aesculus) etc.
2. Grasses(Family Poaceae): ryegrass(Lolium sp.) and timothy (Phleum pretense).
3. Weeds: ragweed (Ambrosia), plantain(Plantago) mugwort(Artemisia Vulgaris), etc.

2.2.3 Signs and symptoms

The characteristics and symptoms of allergic rhinitis are rhinorrhea (excess nasal secretion), itching, sneezing fits, and nasal congestion and obstruction.

Physical signs include conjunctival swelling and erythema, eyelid swelling, lower eyelid swelling, lower eyelid venous stasis (rings under the eyes), Swollen nasal turbinate, and middle ear effusion.

There can also be behavioral signs; in order to relieve the irritation or flow of mucus, people may wipe or rubs their nose with the palm of their hand in an upward motion: an action known as nasal salute or the allergic salute.

2.2.4 Pathophysiology of allergic rhinitis

When the antigen enters the body system, the Antigen-presenting cells(APCs) such as the dendritic cells, process the antigen and present some peptides from the allergens on the major histocompatibility complex (MHC) class II molecules ().

This MHC class II and antigen complex serve as the ligand of T-cell receptors on CD4+ cells to allegen-specific Th2 cells. Activated Th2 cells release several cytokines, which trigger isotype switching of B cells to produce specific IgE and proliferation of eosinophils, mast cells, and neutrophils. The produced antigen-specific IgE joins the high-affinity IgE receptors on mast cells or basophils. The stimulated mast cells induce nasal symptoms by secreting chemical mediators such as histamines, prostaglandins, and leukotrienes (). The chemical mediators produced cause eosinophil chemotaxis where several inflammatory cells and T cells migrate to nasal mucosa, break up and remodel normal nasal tissue, and these processes result in nasal obstruction which is the main symptom of Allergic rhinitis patients.

2.3 Allergic Asthma

Allergic asthma is defined as a chronic inflammatory disease of the airways. Chronic inflammation is associated with airway narrowing response to allergens.

Asthma is one of the serious public health problems throughout the world, affecting people of all ages. It is estimated by the World Health Organization that 300 million individuals have asthma worldwide and that with current rising trends this will reach 400 million by 2025. Approximately 250,000 people die prematurely each year from asthma.

2.3.1 Causes

Allergic asthma is mostly caused by aeroallergens such as dust, pollen, pet dander, etc. Also, Other causes of asthma include exposure to environmental tobacco smoke, air pollution, early life respiratory viral infections, certain drugs, and stress.

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2.3.2 Signs and symptoms

The characteristics and symptoms of allergic asthma include:

1. Wheezing
2. Coughing, especially early in the morning or at night
3. Chest tightness
4. Shortness of breath

2.3.3 Pathophysiology

Allergic asthma is related to T helper cell type-2(Th2) immune responses various allergens such as dust mites, pollen, etc. triggers produce a cascade of immune-mediated events leading to chronic airway inflammation. High levels of Th2 cells in the airway release specific cytokines including interleukin (IL)-4, IL-5, IL-9, and IL-13 that aids eosinophilic inflammation and IgE production by mast cells, this, in turn, triggers the release of inflammatory mediators such as histamine that causes contraction of the smooth muscle in the airways, swelling and increased mucous secretion which leads to the characteristic symptoms of asthma.

2.4 Food allergy

Food allergy can be define as the adverse immunologic response to a food protein. Many food allergies particularly allergies to milk, egg, soy, and wheat are usually outgrown within the first ten years of life(). While other food allergies such as peanut and shellfish are often lifelong, although 20% of individuals may outgrow peanut allergies.

Food allergy is also a leading cause of anaphylaxis( a severe, potentially fatal allergic reaction).

2.4.1 Causes

Food allergies can arise to any food, but the allergens responsible for more than 85% of food allergies are:

• Milk
• Egg
• Peanut
• Tree nuts
• Shellfish
• Fish
• Wheat
• Soy etc.

2.4.2 Signs and symptoms

Food allergy is associated with a variety of signs and symptoms which can involve many body systems which include the skin, gastrointestinal, respiratory tract, and cardiovascular systems.

Skin-related signs and symptoms include acute urticaria(hives), angioedema (swelling), and erythema(redness of the skin). Respiratory tract symptoms include laryngeal edema, rhinorrhea, and bronchospasm. Gastrointestinal symptoms include nausea, vomiting, abdominal pain, and diarrhea

2.4.3 Pathophysiology

The protein component of these foods i.e milk, egg, peanut, etc. leads to sensitization and allergy. The allergenic components of these proteins rend to be very small in size, water-soluble glycoproteins, and are resistance to denaturation that occur as a result of heat, or acid and therefore remain intact even after cooking or digestion. During initial sensitization to the food, the consumption of the allergenic food protein induces the production of IgE antibodies that is specific to that food which then bind to the tissue basophils and mast cells. When the food is subsequently eaten, they bind to their specific IgE antibodies and trigger the secretion of mediators such as histamine and leukotriene causing clinical reactivity and allergic symptoms.

2.5 Atopic dermatitis

Atopic dermatitis which is also known as atopic eczema is a type of inflammation of the skin It results in itchy, red, swollen, and cracked skin, clear fluid may also be coming out of the affected area which often got thickened over time. Many people with atopic dermatitis develop hay fever or asthma, although the condition may occur at any age, it usually starts in childhood and in severity over the years.

2.5.1 Causes

The cause of atopic dermatitis is unknown, although there is some evidence of genetic, environmental, and immunologic factors. In a small percentage of cases, atopic dermatitis is caused by sensitization to foods, Also exposure to allergens from the environment such as dust mites

2.5.2 Signs and symptoms

People that are affected by atopic dermatitis often have dry and scaly skin that covers the entire body, intensely itchy red, splotchy, raised lesions to form in the bends of the arms, legs, face, and neck.

Flexural distribution with ill-defined edges with or without hyperlinearily on the wrist, finger, knuckles, ankle, feet, and hand are also commonly seen.

2.5.3 Pathophysiology

The pathophysiology may involve a mixture of type 1 and type IV-like hypersensitivity reactions.

Chapter three. Diagnosis, prevention, and management of allergic diseases

3.1 diagnosis

Accurate diagnosis of allergic diseases is essential for the effective management of allergic diseases(). Allergy testing helps to confirm or rule out allergies. There are two different methods that can be used in assessing the presence of allergen-specific IgE antibodies: A skin prick test and an allergy blood test. Early and more accurate diagnoses save cost due to reduced consultations referrals to secondary care, misdiagnosis, etc.

Allergy undergoes frequent changes over time, regular allergy testing of relevant allergens helps to provide information on if and how patient management can be changed, in order to improve health and quality of life.

3.1.1 Skin testing

A skin allergy testing is carried out by using a small plastic or metal device to puncture the skin and a small amount of suspected allergens and or their extract is introduced to the sites on the skin marked with a pen or dye. Sometimes, the allergens are injected intradermally into the patient’s skin, with a needle and syringe. This test is usually carried out inside the forearm and the back.

If the patient is allergic to the substance, a visible inflammatory reaction occurs within 30 minutes. This response ranges from slight reddening of the skin to a full-blown hive. The results is usually interpreted by an allergist. A skin test has been shown to be much better than patient observation to detect allergies.

3.1.2 Patch testing

Patch testing is a method used to determine if a specific substance causes allergic inflammation of the skin. It tests for delayed reactions. It is used to confirm the cause of skin contact allergy.

It is usually carried out by using an adhesive patches that has been treated with a number of common allergic chemicals or skin sensitizer which are applied to the back. The skin is then checked for possible local reactions at least usually after 48hours of the application of the patch and two or three days later.

3.1.3 Blood testing

An allergy blood testing can be carried out by collecting the patient’s blood sample, which is then send to the laboratory for further analysis and the results are sent back a few days later. Multiple allergens can be detected with a single blood sample. The test measures the concentration of specific IgE antibodies in the blood.

Unlike skin-prick testing, a blood test can be performed irrespective of age, skin condition, medication, symptom, disease activity, and pregnancy. The laboratory methods used to measure specific IgE antibodies for allergy testing include enzyme-linked immunosorbent assay(ELISA), radioallergosorbent test(RAST), and fluorescent enzyme immunoassay(FEIA)().

3.2 Prevention

There are different preventive measures for allergies they include:

• Early exposure to potential allergens()
• Fish oil supplementation during pregnancy and exclusive breastfeeding
• Probiotic supplements are taken during pregnancy or infancy

3.3 Management

Management of allergies involves avoiding what triggers the allergy and medications to improve the symptoms(). Allergen immunotherapy may be useful for some types of allergies.

3.3.1 Medications

Several medications can be used to block the action of allergic mediators or to prevent activation of cells and degranulation processes. These include antihistamines, glucocorticoids, epinephrine, mast cell stabilizers, and anti-leukotriene agents which are commonly used for the treatment of allergic diseases. The severity of anaphylaxis often requires epinephrine injection(). Anti-cholinergic, decongestants, and other compounds can be used to impair eosinophil chemotaxis

3.3.2 Allergen immunotherapy

Allergen immunotherapy also known as desensitization or hypo-sensitization involves exposing people to a larger amounts of allergens in order to change immune system’s response.() Allergen immunotherapy is very useful in environmental allergy, allergies to insect bites, and asthma.

Studies has shown that injections of allergens under the skin is effective in treatment of allergic rhinitis in children. The benefits of allergen immunotherapy may last for years after treatment is stopped.

There are two different types of allergen immunotherapy:

• Subcutaneous
• Sublingual

In allergen immunotherapy, the aim is to induce or restore tolerance to the allergens by lessening its tendency to induce IgE production through the administration of large amount doses of allergen that gradually reduce the IgE-dominated response. The objective of immunotherapy is to direct immune response away from humoral immunity and toward cellular immunity.

Chapter four. Inheritance and allergy

Most of the allergies are inherited. When one parent has an allergy, the child has a 50% risk of also having one, when both parents are allergic the risk of the child having an allergy increases to 75%. However, although parents may transfer the tendency to be allergic to their children, the children may not inherit an allergy to the exact allergen.

In a study that took place in Arizona in which 344 families were tested to determine if there is a link between genetics and allergic asthma. The result of the study confirmed that allergic asthma can be passed from generation to generation. From families where neither parent had a history of asthma, only 5% of the children suffered from asthma, 20% of children suffered from the condition where either the father or mother suffered from asthma, while in families where both parents had a history of asthma nearly 70% of the children as well.

Studies of the inheritance of human allergic diseases are not likely to give data that are in perfect agreement with Mendelian ratios. For some reasons;

1. It is difficult to tell whether the manifestation was brought about by definite germinal transmission or as a result of sensitization while in utero.
2. It is impossible to control the material; mating occurs as one finds them, not as one wishes.
3. Generations are long and families are not large enough to be sure that all possible combinations of genes are present.
4. Individuals possessing the predisposition may not manifest it at all or may have manifested it in a form not recognized or remembered, while in children the hereditary factor may exist, but not show as a clinical state until later in life.
5. The extreme multiplicity of types and causes and the same type arising from different. causes are a difficulty. All these factors add to the confusion in studies of inherited allergy.

4.1 Study of inheritance and allergy

The inheritance of allergy can be study under the following condition; physiologically, degree of inheritance, mode of inheritance, and sex incidence.

1. Physiology: According to Cooke and Verde it is generally agreed that it is not the specific sensitization that is inherited but rather the predisposition to develop allergic reactions, as they were the first set of people to agree to this principle. For instance, when the shock tissues, in this case, the respiratory tissues, come in contact with the allergen (the critical substance to which the shock tissues are sensitized), a specific antibody is formed in the body cells. The presence of the antibody makes the tissues of the individual permanently hypersensitive to the allergen when introduced. The weather seems to have an effect as an environmental factor.
2. Degree of inheritance: The high incidence of allergy in a family suggests strongly that an hereditary fact, or is involved in the etiology of the disease. For instance in a situation whereby there is bilateral family history i.e both parents had a history of allergy 70% of their offspring suffer from allergy while in the whereby there is unilateral family history i.e one of the parents had a history of allergy 50% of their offspring suffer from allergy.