Allergy and Allergic Diseases Flashcards
Allergic Reactions
Sensitization: Acute adaptive immune response made by susceptible individuals on first exposure to an allergen (innocuous antigen).
In some of these individuals, subsequent exposure to the allergen will provoke an allergic reaction (hypersensitivity reaction).
Allergy the state in which a symptomatic immune reaction is made to normally innocuous environmental antigen.
- 40% of the population is sensitised
to environmental allergens - Allergic rhinitis affects 10-30% of the population
- 20% of deaths due to anaphylaxis (a systemic allergic reaction) may be caused by drugs
Atopy: predisposition to become IgE-sensitized to environmental allergens
Both atopic parents = 40-60% chance of developing an IgE-mediated allergy
No atopic parents = 10% chance
Classification of hypersensitivity reactions due to immunological responses
There are 4 types of hypersensitivity reactions:
- Type I:
includes IgE reactant, which involves a soluble antigen and mast cells activation. The mast cells will have the accumulation of histamines and will result in serious allergic reactions, like allergic rhinitis, asthma, anaphylaxis, atopic eczema, etc.
- Type II:
involves a a cell or matrix ssociated antigen, IgG and activation of the complement system, resulting in some drug allergies and for cell-surface receptor antigens we have antibody altering the signaling, resulting in chronic urticaria. - Type III:
involves soluble antigens, IgGs and activation of the complement system resulting in serum sickness and arthus reactions - Type IV:
includes soluble antigensa, cell-associated antigens and T cells, and activation of macrophages resulting in allergic contact dermitis, tuberculin reaction, IgE production, eosinophil activation and mastocytosis resulting in chronic asthma and allergic rhinitis, and cytotoxicity, resulting in graft rejection, allergic contact dermatitis to poison ivy.
Type I
Antigen binding to IgE on mast cells leads to amplification of IgE production.
The plasma cells will release IgE and the Fc receptor on the mast cells will bind them. When we have an allergen present, it will crosslink the receptors and the cells will release granules containing histamines and other factors that produce the allergic reactions. But also the mast cells can release cytokines that will bind to the plasma cells, to release even more antibody, so the next time the allergic reaction can be stronger, so the activated mast cell will secrete signals to B cells to stimulate IgE production.
Features of the allergens that may promote the T helper cells to drive IgE responses
- Proteins, often with carbohydrate side chains;
- Low dose, which favours the activation of IL-4 producing CD4 T cells. Ragweed is an example of a common allergen, only 1 ug per year is enough.
- Low molecular weight, so they can diffuse out of particles into the mucosa
- Highly soluble, so they can be readily eluted from particles
- Stable, so they can survive in desiccated particles
- Contains peptides that bind host MHC class II, which is required for T cell priming.
IgE mediated reactions
- systemic anaphylaxis, which is caused by drugs, venoms, food or serum, enters intravenously, and results in edema, increased vascular permeability, circulatory collapse and death.
- acute urticaria (wheal-and-flare) caused by animal hair, insect bites or allergy testing, enters through the skin or systemically, and results in local increase of the blood flow, and vascular permeability or edema.
- seasonal rhino-conjunctivitis (hay fever) caused by pollens or dust-mite feces (they contain an enzyme that is able to cleave occludents in the tight junctions and enter the mucosa, so it can be taken by the dendritic cells which will present them as antigens to the plasma cells which will release IgE, bind to mast cells and degranulate), enter in contact with the eyes and nasal mucosa and results in edema of conjunctivitis and nasal mucosa, sneezing.
- asthma is caused by danders (cats), pollens or dust-mite feces, enters through inhalation leading to contact with mucosal lining or lower airways, and results in bronchial constriction, increased mucus production and airway inflammation.
- food allergies are cause by peanuts, fish, milk, soy, wheat, etc, enters orally and result in vomiting, diarrhea, pruritis, urticaria, or anaphylaxis.
Genetic susceptibility
The type I hypersensitivity can be caused by a genetic component - the susceptibility loci identified by genome screens. Which means a site in a chromosome that usually passes the information for a gene. There are different genes that can produce susceptibility. Some of them match for autoimmune diseases.
The asthma susceptible genes will contain different familiar factors, such as the transcription factors, cytokines, antigen presentation molecules, chemokines, antimicrobial peptides, etc. They will have all of these because if there is a differential strain in the epithelial cell barrier then it is more likely that you can get across the allergens. They can have different innate immune receptors because there can be different antigen presentation that is very strong for allergens.
The genetic susceptibility will be combined with the environment. So if we are not exposed to a diverse environment while growing up, then there is a high chance to become atopic, meaning that you will have the tendency to develop an allergic disease.
If you have the genetic component, but are growing up being exposed to the outside environment, then it is mostly possible that you will become non-atopic. But this is not not same for all allergens.
For food allergens it will be different, because we cannot be exposed to all kinds of foods from the early childhood.
Effector mechanisms in IgE-mediated allergic reactions
IgEs can result in allergic reactions because the mast cells contain granules can result in increased permeability, blood flow in the blood vessels, decreased diameter, and increased mucus secretion in the eyes or nasal airways, and increased fluid secretion and peristalsis in the GIT.
This happens because of the components in the granules of the mast cells, such as enzymes, toxic mediators (histamines), cytokines, chemokines, and lipid mediators.
Some of them are important because it is not only about inflammation, but being toxic to parasites. So the IgE is all about getting rid of the multicellular pathogens quickly.
Eosinophils are major contributors of tissue damage. Eosinophils also have granules, that will be important for the multicellular pathogens because they have toxic components towards the multicellular pathogens, mediators for contraction of smooth muscles, promotion influx of leukocytes. Which is very good for pathogens, but not when we get it from allergic reactions, which is just going to increase the response.
The enzymes are able to remodel the connective tissue matrix and matrix protein degradation, which will result in the damage in our airway tissues.
IgE-mediated allergic reactions have a rapid onset but also chronic responses.
The chronic responses are because of the granules in the mast cells, which will contain multiple components. Some cytokines inside the granules can activate the eosinophils and helper cells, and that is when we get the chronic response.
Autoimmunity and transplants
- Autoimmunity is caused by the activation of the ignorant T cells.
This is not going to be a continuous immune response because when the tissue recovers, the leak is not going to be continuous. There is just going to be an immune response and it will stop. - But there can be other diseases that can have continuous immune response, like rheumatoid arthritis. It will continue with the damage in our own body. It will produce an initial focus on inflammation in the synovial joint. The synovial membrane contains the synovium, and there will be leakage of dendritic cells and leukocytes, and activation of a reactive CD4 T cell and macrophage, which will release the cytokines. The cytokines will activate the fibroblasts in the joints. The fibroblasts will respond and release MMP, witch will degrade the matrix and attack the tissues. This that we will have the activation of the osteoclasts that will destroy and remodel our bones.
So because now the autoimmunity will have access to the synovium, we will have constant damage of our joints. - Multiple sclerosis is another examples in which the barriers are broken.
This disease refers to a motor neuron , located in the spinal cord in the CNS. So it is protected by the BBB. The motor neurons have longer projections, because the have to transmit information through the axons. Because of that they are myelinated, that is why they will have a faster response.
An unknown trigger sets up an initial focus of inflammation, resulting in increased permeability, so leakage of the components of the immune system. So it will activate the T cell, then it will activate the B cell, releasing antibodies, and then we have the targeted destruction of the myelin. Without the myelin there will not be rapid responses from the neurons, and we will not be able to control our muscles.
The barrier can be broken by another disease or trauma.
Autoimmune responses can be controlled by regulatory T cells
Organ-specific autoimmune diseases or systemic immune diseases
The organ-specific autoimmune diseases can be Type 1 diabetes, multiple sclerosis, Crohn’s disease (malabsorption in the GIT), psoriasis, Graves disease and Hashimoto’s thyroiditis, which are disease of the thyroid gland, anemia and Addison’s disease, Vitiligo, against the melanocytes in the skin, or Myasthenia gravis.
Systemic autoimmune diseases like Rheumatorid arthritis, Scleroderma, or lupus. They are systemic because they cause changes in the skin, kidneys, etc.
There are antibodies against them, but they also involve the T cells.
Epitope spreading
Specific for systemic lupus erythematosus.
In here we will have a B cell that recognises the Histone1 from a nucleosome. Histone 1 comes from any cell in your body. If there is necrosis of a tissue, we are going to have continuous activation of the B cells. The B cells will incorporate everything, process the peptides and load into the MHC molecules different peptides. Then the activated T cell will be able to recognise multiple B cells that bind different epitopes. So we will have different antibodies against different epitopes, so you are spreading.
Antibodies that recognise your own cells are called autoantibodies.
Autoantibodies against receptors cause disease by stimulating or blocking receptor function.
T cells specific for self antigens can cause direct tissue injury.
For example the CD8 T cells can recognise the insulin on the Beta pancreatic cells, so they will get destroyed. But we have more cells in there, but because they are interspersed, and we lose Beta cells, we will completely lose the tissue.
Females have a higher probability of getting the autoimmune diseases.
Transplantation
Alloantigens: antigens from different members of the same species.
Graft rejection is an immunological response mediated primarily by T cells, it is called an alloreactive response.
If we do a T cell transfer from a synthesised animal that already had a transplant, there will be an accelerated rejection, because the T cells will be activated already.
Initiation of graft rejection involves migration of donor antigen-presenting cells from the graft to local lymph nodes
Alloantigens in grafted organs are recognized in two different ways:
The alloantigen presentation happens from the transplant, which has it’s own dendritic cells.
The dendritic cells from the donor wil travel into the body of the recipient and will activate the T cells, this is the direct recognition. The indirect recognition is when the T cells are activated from the recipient.
Preexisting antibody against donor graft antigens can cause hyperacute graft rejection, which happens because of the alloantibodies. They will promote the inflammatory response and occlusion of the blood vessels, and the graft will become purple because it will not have enough circulation.
The conventional immunosuppression drugs will be in the clinical use, because if we have inflammation, then we use the corticosteroids. We have Ciclusporin A tacrolimus that inniatiates the activatory pathway of the naive T cells, so they don’t mature into effector cells.
We have Rapamycin, which inhibits the proliferation of the effector T cells by blocking mTor activation.
The corticosteroid therapy works because it will have an effect on adhesion molecules, which are important during immune response, or decreases the nitrogen species.
Antibodies against cell surfaces molecules can be used to eliminate lymphocytes subsets.
Omabs are fully mouse antibodies. The problem with them is that the Fc region will be different from our antibodies, so the immune response will work only for a while.
Ximab is chimeric - the Fc region from human and the variable region from the mouse, but still the antibody doesn’t work after a while because of the mouse parts;
Zumab is humanized, mostly from humans with parts from mouse ;
Umab is fully human, so we don’t mount responses against them.
