Introduction to Allergy and Immunology
Preface
The focus of this course is allergy and immunology two highly interrelated phenomena in the human body. The immune system involves those functions of the body designed to protect it from various kinds of pathogens. When it functions normally, individuals can survive various kinds of external and internal insults. When it functions abnormally, it can lead to things like autoimmunity and immunosuppression. Allergic responses are also a part of an abnormal immune system at work. In allergies, individuals are highly sensitive immunologically to things in the environment that don’t affect the non-allergic individual.
The discussion in chapter one of the course involves innate immunity or the “innate immune system”. This is the evolutionarily older of the two major immune systems in humans and other vertebrates. The main aspects of this system are that it acts more quickly than the adaptive immune system and that it is relatively nonspecific. It starts with effective barrier systems and involves cells that can quickly identify a pathogen, killing it before it becomes a solid infection.
The subject of chapter two is adaptive immunity or acquired immunity. This is an important aspect of the immune system that isn’t present at the time of birth. It gradually develops as the immune system comes in contact with pathogens and identifies them as being abnormal. Antibodies are made to various antigens and this facilitates the death of pathogens. It also develops memory cells, in which cells retain the “knowledge” of a particular antigen and can react much more quickly should the individual develop a repeat infection with the same pathogen. This part of the immune system takes longer to develop but is long-lasting.
Antigens and antibodies are the subject of chapter three in the course. These represent a “lock and key” mechanism in the immune system as unique molecules/substances that are a part of the adaptive humoral immune system. The antigens are processed and presented on antigen producing cells to B cells that make the antibodies. Antibodies come in several types and have unique functions that aid in the immune process. Immunologically speaking, the lock is the antigen and the key is the antibody that binds to it. Each of these components is discussed as part of this chapter.
Chapter four of the course examines the phenomenon of autoimmunity. Autoimmunity is the process by which the immune cells of the body see a self-antigen as being foreign and create an autoimmune response to it. There are hundreds of different autoimmune diseases, some of which are tissue-specific, while others are system-wide autoimmune problems. The theories and practices behind autoimmunity will be discussed along with several common autoimmune diseases.
The focus of chapter five is immunosuppression and immunodeficiency states. Immunosuppression involves a decrease in the effectiveness of the immune system. It can be genetic or acquired. Drugs can cause immunodeficiency states. There are a number of inherited immunodeficiency diseases affecting several parts of the immune system to varying degrees. Each of these will be covered as part of this chapter.
Chapter six in the course examines immediate hypersensitivity, including the different types of hypersensitivity reactions. These are protective mechanisms that sometimes become out of control, leading to immunopathological conditions. There are several types of hypersensitivity reactions that
have different effects on the immune system. The phenomenon of hypersensitivity reactions and their treatment are covered in this chapter.
This subject of chapter seven in the course is transplant immunology, including stem cell transplants and solid organ transplants. Transplants of any kind from a donor will necessitate an HLA-matched donor, usually from a matched sibling. Many different organs can be transplanted successfully with today’s medical techniques, providing a great option for patients who have no other hope for a cure of their illness besides an organ or stem cell transplantation. The immunology behind transplantation is discussed in this chapter.
Chapter eight is about the allergic response and allergy testing. The allergic response is one of the hypersensitivity reactions that involve an allergen and the IgE antibody. The allergic response can involve the airways, the skin, or the GI tract. Itching and inflammation are common. Allergy testing is one way of identifying the allergy the individual has. Once this is known, the option for allergy desensitization shots or allergy immunotherapy can be undertaken.
Chapter nine in the course examines the allergic phenomenon of allergic rhinitis. rhinitis or “hay fever” involves nasal inflammation that is secondary to an overactivity of the immune system, usually to allergens the nose is exposed to through inhalation. Typical signs and symptoms include a stuffy or runny nose, red and watery eyes, sneezing, and itching of both the eyes and the nose. There may be swelling around the eyes as well. The reasons behind allergic rhinitis, its diagnosis, and treatment are covered in this chapter.
The topic of chapter ten in the course is allergic asthma. Allergic asthma involves narrowing of the bronchial airways and airway inflammation that stands from inflammatory mediators that are commonly caused by allergens. Genetically susceptible people become allergic to certain substances and this affects their airways, leading to short of breath and wheezing. The pathophysiology of this disorder will be discussed in this chapter.
Chapter eleven of the course examines the phenomenon atopic dermatitis. This is a chronic, itchy, inflammatory skin disease that has no known origin but that seems to be strongly related to allergic asthma and allergic rhinitis. It is commonly seen in infancy can be seen in adults as well. The fact that there are high levels of IGE antibodies in these patients points to an allergic reaction involving the skin. The pathophysiology and treatment of this disease will be discussed in this chapter.
Food allergies are the topic of discussion in chapter twelve of the course. In some ways food allergies are no different from any other type of allergy; however, there is a greater degree of severe systemic reactions including anaphylaxis can occur with these types of allergies. There are numerous foods that a child or person can be allergic to, mostly involving proteins in eggs, milk, soy, peanuts, shellfish, wheat, and tree nuts. Each of these will be discussed as part of this chapter.
The focus of chapter thirteen is contact dermatitis. This is usually a well circumscribed rash that occurs because of a localized contact with an allergen. The allergy can be to many things including chemicals and metals. It is relatively easy to diagnose, particularly if the allergen is known, because the rash will only be in the place that the individual came in contact with the allergen. The different allergies and manifestations of this rash will be discussed in this chapter.
Chapter fourteen in the course covers the severe allergic reaction called anaphylaxis. Anaphylaxis can occur secondary to an insect sting, medication, food, or immunotherapy treatment. It involves extreme shortness of breath, narrowing of the airways, and hypotension. Without epinephrine, this disorder can be rapidly fatal. The phenomenon of anaphylaxis and its treatment will be discussed in this chapter.
Chapter One: Innate Immunity
This first chapter involves innate immunity or the “innate immune system”. This is the evolutionarily older of the two major immune systems in humans and other vertebrates. The main aspects of this system are that it acts more quickly than the adaptive immune system and that it is relatively nonspecific. It starts with effective barrier systems and involves cells that can quickly identify a pathogen, killing it before it becomes a solid infection.
Background on Innate Immune System
The innate immune system is also referred to as the inborn immunity system or the nonspecific immune system. It is evolutionarily older than the adaptive immune system and is designed to get rid of pathogens quickly but without specificity. The immunity is not long-lasting but must re-engineer a new response even when in contact with the same pathogen it had encountered before. This is not the dominant immunity seen in vertebrates like humans but it is dominant in fungal organisms, plants, and insects.
The innate immune system has several functions. It uses cytokines to recruit other immune cells to the sites of infection. It activates the complement cascade so that there can be bacterial or other pathogen identification, cellular activation, and clearance of dead or damaged cells. It involves specialized white blood cells that get rid of foreign substances seen in infected body areas. It links itself to the adaptive immune system by participating in the antigen presentation process. It also is involved in the barrier function against pathogens.
Barrier Function of the Innate Immune System
Anatomical barriers in the innate immune system do more than just act as a physical barrier. Each barrier does something to keep pathogens from entering the body. Some of these include the following:
Skin it provides a barrier by means of desquamation, sweating, and by having organic acids on the surface that repel organisms
Gastrointestinal uses gut flora, mucus, bile acids, gastric acid, digestive enzymes, defensins, and peristalsis to repel organisms
Nasopharynx uses mucus, lysozyme, and saliva to repel organisms
Respiratory airways use cilia, defensins, mucus, and surfactant to repel organisms
Eyes uses tears to repel microorganisms and to wash them away
The thing in common with all of these barriers is that they have epithelial surfaces that form a physical barrier. Desquamation or shedding of the epithelium removes pathogens along with the epithelium. In the skin, the presence of the sebaceous glands and lack of circulation to the area make for an inhospitable environment for pathogens. The GI tract uses peristalsis and the respiratory tract uses cilia to remove pathogens. Both the GI tract and the respiratory tract use mucus to trap pathogens. The gut flora is important in keeping pathogens away.
The Inflammatory Response
One of the main functions of the innate immune system is the inflammatory response. Inflammation is the body’s first response to irritation and infection. It is triggered by chemical factors that are derived from injured cells. Inflammation harbors the infection in a single area and helps to enhance tissue healing by getting rid of pathogens.
Steps in the inflammatory response include the following:
Increased circulation, which leads to skin redness
Increased local temperature, leading to warmth of the affected area
Swelling of the affected area from an influx of water to the affected area
Increased mucus production in GI and respiratory tissues
Increased pain that may be local or generalized
Organ dysfunction if an organ is involved
Complement System
The complement system is actually a series of molecules that act as a biochemical cascade, starting with one molecule and leading through a series of triggered molecules that enhance the ability to mark pathogens for destruction or help clear out pathogens by helping the antibody system. Most of the complement system consists of plasma proteins that are synthesized in the hepatocytes in the liver.
There are several functions of the complement system. They are responsible for recruiting other inflammatory cells to the infection area. They also “tag” pathogens by opsonizing the pathogen’s surface. Opsonization is the molecular mechanism whereby molecules, microbes, or apoptotic cells are chemically coated by opsonins to have stronger interactions with cell surface receptors on phagocytes and NK cells. These opsonins are usually complement proteins. They form holes in the plasma membrane of the pathogen (usually a bacterium or injured cells), that result in the cell death of the pathogen. Finally, the complement system acts to neutralize antibody-antigen complexes.
Complement Pathways
There are three different complement pathways. The most common is the classical complement pathway. The start of this pathway is the binding of an IgG or IgM antibody to an antigen on the pathogen’s surface. Activation occurs and a series of proteins are generated that causes C3 convertase to cleave the C3 protein. The next thing that happens is that the C3b molecule (coming off the cleaved C3) binds to the C3 convertase molecule to make the C5 convertase (enzyme) that cleaves the C5 protein. These cleaved molecules tag target cells for elimination and attract phagocytes (which do the pathogen killing). The last part of the complement system is to make the MAC (membrane attack complex) that makes pores on the surface of the infected cell, creating cell lysis and death.
While the main thing that triggers the classical pathway is the antibody-antigen binding, it can also be activated by acute phase proteins, necrotic cells, and apoptotic cells. When it is started by the antigenantibody complex, the C1q protein binds to the Fc region of antibody isotopes IgM or IgG only. This C1q protein can be initiated by any of the other activating factors. C1q is part of the C1 complex, which is made from several subunits (including C1q, C1r, and C1s).
There is a series of events that lead to the formation of the C3 convertase molecule. Its job is to cleave C3 into C3a and C3b. The function of C3a is to recruit leukocytes to the site of the infection, while the function of the C3b molecule is to continue the complement activation process. C3b actually binds to the C3 convertase molecule, forming the C5 convertase enzyme. This cleaves C5 into C5a and C5b. C5a acts just like C3a and attracts leukocytes to the site of infection. C5b goes on to bind to other complement proteins (C6 through C9) to make the MAC (membrane attack complex), which acts to directly kill pathogenic cells.
The complement cascade and its disorders can be important clinically. Complement causes inflammation of fatty tissues leading to obesity. Fat cells make a great deal of C1, which leads to insulin resistance in obesity. In addition, patients with HIV can be treated by immunotherapies directed at enhancing complement-associated killing of HIV-infected cells. Activation of the classical pathway works against methicillin-resistant Staphylococcus aureus infections.
There are disorders of the classical complement pathway. These include deficiency in the C1-inhibitor, leading to angioedema. This molecule helps control vascular permeability. A deficiency causes increased vascular permeability seen in angioedema. On the other hand, the deficiency of C1q leads to systemic lupus erythematosus. C1q is responsible for clearing immune complexes and dead cells by activating the classical pathway. A lack of C1q leads to autoantibodies and a buildup of apoptotic cells. Antibodies to C1q have been implicated as possible markers for systemic lupus erythematosus.
There is also the alternative complement pathway. This does not begin with an antigen-antibody complex but starts immediately by the binding of C3b to the microbe, by foreign materials in the body, or by tissues that have become traumatized. C3 is spontaneously hydrolyzed and involves two plasma factors (Factor B and Factor D). Factor B is cleaved into Ba and Bb. Bb combines with other peptides to form a type of C3 convertase that cleaves C3 into C3a and C3b. This binds to properdin (a protein in the serum), which aids in the development of C5-convertase. This cleaves C5 into C5b and C5a. C5b acts the same as in the classical pathway to make the MAC. There are several regulatory mechanisms that keep this pathway in check.
When this pathway is dysregulated, it can cause disease. For example, age related macular degeneration is believed to be due, in part, to the action of MAC on eye tissues. It may also be dysregulated in patients with lupus.
The lectin complement cascade is similar to the classical complement pathway. It is activated differently but eventually looks like the classical pathway. It doesn’t, however, bind to antibodies but starts when mannose-binding lectin (MBL) binds to sugars (like mannose and glucose), which are found on certain bacteria (Listeria, Salmonella, and Neisseria) and viruses like RSV and HIV. It should be noted that MBL, like other complement proteins, is made by the liver. MBL combines with sugars on the pathogens to form a complex similar to C1r and C1s. The pathway may start differently but eventually acts like the classical pathway.
Patients who have a mannose-binding lectin deficiency can have an increase in infections, including those of the respiratory tract. Infections tend to be more severe and recurrent. People who have this deficiency and who become immunosuppressed for other reasons have a particular risk for infections. Cells of the Innate Immune System
There are several cells associated with the innate immune system. These include different types of leukocytes, which are also called WBCs or white blood cells. They help protect the body against infections and foreign invaders. They are made in the bone marrow from hematopoietic stem cells and live in the bloodstream and lymph system until they are necessary for infection control. These are nucleated WBCs that have phagocytic properties. There are actually five different types of leukocytes, including neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Both monocytes and neutrophils are phagocytic cells.
The lymphocytes are divided into T cells, B cells, and NK cells (which are part of the adaptive immune system). The normal WBC count is 4000-11,000 cells per microliter. Leukocytes have pattern recognition abilities through pattern recognition receptors (PRRs) that recognize molecules associated with pathogens called PAMPs (pathogen-associated molecular patterns). A PRR recognizes a PAMP, causing the release of inflammatory mediators that cause the typical signs of inflammation. The mediators include bradykinin, histamine, leukotrienes, serotonin, and prostaglandins (which cause inflammation). Pain receptors are sensitized and blood vessels are dilated to allow for the passage of neutrophils and other phagocytes to the infection sites. The cytokines are released, including TNF, HMGB1, and IL-2.
Types of leukocytes include the following: Mast cells these are a kind of innate immune cell that live in the connective tissues of the body or stay around the mucous membranes. They act in pathogen defense and in wound healing. They are highly linked to anaphylaxis and allergy. When they become activated, they release both heparin and histamine (as well as chemokines, which are chemotactic cytokines). The histamine causes blood vessel dilatation, while the heparin prevents blood clotting. These cells look like basophils and are highly linked to wound healing, angiogenesis, immune tolerance, defense against pathogens, and blood–brain barrier function. Phagocytes these are cells responsible for ingulfing, “eating”, or phagocytosing damaged cells, particles, and pathogens. It does this by extending out parts of the cytoplasm until it wraps around the particle or pathogen. The particle becomes part of the cell in what’s called a phagosome. This merges with a lysosome (which creates an environment that is toxic to cells). The pathogen or particle is broken down. These cells scavenge the body for pathogens but also are drawn to a site by having responsiveness to phagocyte-attracting cytokines. The only cells that phagocytize pathogens include dendritic cells, neutrophils, and macrophages. When apoptosis occurs, the phagocytes are responsive to the dead cells and get rid of the debris. Macrophages these are large leukocytes that are primarily responsible for phagocytosis. They can circulate in the system and slip through blood vessel walls in order to reach the site of the infection. Those macrophages that are tissue-resident are called monocytes. Macrophages are the most efficient of the phagocytes because they don’t die after phagocytizing a particle and can phagocytize many things in a row. They can generate a respiratory burst, which causes oxygen free radicals to be released (which kills pathogens). Chemokines are also released by these cells, attracting other infection-fighting cells to the infection site.
Neutrophils—these are also called granulocytes or polymorphonuclear cells (PMNs). The granules consist of toxic substances that can kill or block the growth of fungal organisms or bacteria. They also have a respiratory burst containing various oxidizing agents (such as hypochlorite or hydrogen peroxide). About half of all leukocytes in the bloodstream are
neutrophils. They arrive at the site of infection first as there are more than 100 billion of these produced per day by the healthy bone marrow.
Dendritic cells these are “tissue resident” cells that stay in contact with the external environment (such as the intestinal and respiratory lining, and the skin). They look like neuronal dendrites but have no connection to them. These are the cells that connect the innate to the adaptive immune syndrome by acting as the main antigen presenting cells to the cells of the adaptive immune system.
Eosinophils and basophils these belong to the same cell line as neutrophils but have adaptations to do different things. The basophil plays a strong role in releasing histamine during an anaphylactic or allergic reaction. Eosinophils play a strong role in fighting off parasites and helminths. They can get rid of pathogens too large for phagocytosis. The activation of eosinophils is tightly regulated because they have a wide range of oxygen free radicals and toxins that can damage local tissue if left unchecked.
Natural killer cells these are also called NK cells. They don’t directly kill microbes but kill cells that are virally-infected or tumor cells. They identify cells that don’t have a great amount of qualifying MHC I (the “self” antigen) so that the cell is seen as foreign. This “missing self” phenomenon accounts for the activity of these cells. Normally, cells with a normal amount of MCH I aren’t triggering to the NK cell but, if it is injured, dying, or infected, it will attract the attention of the NK cell by not having normal amounts of MCH I, causing it to be phagocytized. Gamma-delta cells these are uncommon cells that have a different type of T cell receptor on them. Rather than an alpha-beta T cell receptor, these cells have a gamma-delta receptor on them. These cells have both innate and adaptive immune system function. Certain types of gamma-delta cells will respond within a few hours to the site of an infection; however, their exact function is not entirely clear.
Pathogen Specificity in the Innate Immune System
The actions of the innate immune system depend on the type of pathogen the person is infected with. There are certain actions that happen just because of the type of organism involved. For intracellular viruses, the NK cells become prominent and kill off the infected cells (including those infected by mumps, influenza, measles, and rhinovirus). NK cells also kill off most intracellular bacterial infections (like Listeria, Mycobacterium, and Legionella). Complement is necessary for extracellular bacteria, which are phagocytized in the infectious process (like Streptococcus, Neisseria, and Staphylococcus).
Intracellular and extracellular protozoa are treated differently. Intracellular protozoa (like Leishmania and Plasmodium) can’t be killed with NK cells or phagocytosis, while extracellular protozoal infections require complement in order to be phagocytized (like Giardia and Entamoeba infections). Extracellular protozoans are killed with complement and NK cells. These include organisms like Candida, Cryptococcus, and Histoplasma infections.
Key Takeaways
The innate immune system is the oldest immune response.
The innate immune system is fast, nonspecific, but not long lasting.
The innate immune system is linked to the adaptive immune system by the dendritic cells.
Quiz
There is a missing-self phenomenon going on that will activate the NK cell to kill infected or damaged cells.
1. The innate immune system does a number of things. Which is not one of these things?
a. Kills dead or damaged cells b. Activates the complement cascade c. Releases cytokines d. Makes antibodies against pathogens
Answer: d. The innate immune system does not make antibodies against pathogens. It does, however, perform the other functions.
2. Barriers to pathogens include the skin, GI tract, and respiratory tract. What do all these barriers have in common?
a. Epithelial surface b. Defensins c. Mucus d. Cilia
Answer: a. The main thing in common with all barrier surfaces is that they have an epithelial surface that repel microorganisms.
3. The GI tract and the respiratory tract have similarities in the way they get rid of pathogens as barriers. What is one thing that these two barriers don’t have in common? a. Mucus b. Movement c. Acidic environment d. Defensins
Answer: c. The things the GI tract and respiratory tract have in common include the presence of mucus, movement, and defensins. Only the GI tract makes use of an acidic environment to repel pathogens.
4. Which molecule in the complement system binds and reacts to the Fc region of bound antibodies?
a. C1s b. C1r c. C1q d. C3
Answer: c. The start of the process is the binding of C1q to the Fc region of the bound antibody.
5. Which antibody or antibodies have specificity to the C1q protein of the complement system?
a. IgG only b. Any antibody type c. IgM only d. IgM and IgG
Answer: d. The C1q complement protein attaches to the Fc region of the IgM or IgG antibody type.
6. C3a in the classical complement cascade mainly acts in similar ways to what other complement molecule?
a. C5a b. C3b c. C5b d. C6
Answer: a. Both the C5a molecule and the C3a molecule act specifically to attract leukocytes to the site of the infection.
7. When neutrophils bind to the PAMPs on the pathogens, various things happen to the neutrophils. These include all but what event?
a. Release of cytokines b. Making of antibodies c. Sensitizing pain receptors d. Dilatation of blood vessels
Answer: b. Each of these happen when the PRRs bind to PAMPs on pathogens, except for the making of antibodies, which is not a neutrophil function.
8. There are only certain cells that undergo phagocytosis. Which cell does not undergo this process?
a. Dendritic cells b. Neutrophils c. Macrophages d. Gamma-delta cells
Answer: d. Each of these cells are responsible for phagocytosis, except for gamma-delta cells, which don’t phagocytize other cells.
9. Which cells most connect the innate and the adaptive immune system by being antigen presenting cells? a. Mastocytes b. Macrophages c. Dendritic cells d. Neutrophils
Answer: c. Dendritic cells are antigen presenting cells that connect the innate and adaptive immune systems.
10. What type of infection or problem is not possibly fixed by an NK cell?
a. The presence of a tumor cell b. The presence of an intracellular virus c. The presence of an intracellular bacterium d. The presence of an extracellular bacterium
Answer: d. NK cells only respond to a “missing self” phenomenon, which means they cannot kill pathogens outside of a cell directly.