Hypersensitivity: An Overview

Friday, 24 November 2023 08:04

The term "hypersensitivity" denotes a condition in which a previously sensitized immune system reacts to a subsequent exposure to an antigen, resulting in tissue damage. This heightened immune response surpasses the normal bounds of protective immunity, leading to detrimental and occasionally severe effects. It's essential to distinguish diseases stemming from hypersensitivity reactions from specific autoimmune disorders, as they exhibit fundamental differences, particularly in terms of the antigen source.

A significant contrast lies in the origin of the antigen. Hypersensitivity reactions are predominantly triggered by exogenous antigens, which originate from external sources. In contrast, autoimmune diseases arise from endogenous antigens, those that are intrinsic to the body's own tissues. The specific antigens involved in hypersensitivity reactions are referred to as "allergens."

While "hypersensitivity" is a commonly used term, it shares equal prominence with its synonym, "allergy," in the realms of immunology and immunopathology. Historically, in 1906, Von Pirquet initially defined hypersensitivity as a state of altered reactivity within the host, encompassing both protective and harmful responses upon encountering an agent for the second or subsequent time. However, contemporary usage has narrowed the term's definition, restricting it to denote harmful immune responses and rendering it synonymous with Type-I hypersensitivity.

Classical Types of Hypersensitivity

Hypersensitivity was initially categorized into two distinct groups based on the nature of the antigens triggering the immune response and the timing of their appearance following exposure to the provoking agent: immediate (humoral) and delayed (cell-mediated).

Immediate Hypersensitivity

Immediate hypersensitivity can be defined as an immunopathological reaction that swiftly manifests in sensitized individuals shortly after exposure to an antigenic stimulus. This reaction is characterized by tissue responses that occur within mere seconds to a few minutes after the antigen induces cross-linking of cell-bound Immunoglobulin E (IgE). Notably, this reaction transpires with such rapidity that it often leaves no discernible trace of tissue injury in its wake.

Within the preceding paragraph, we introduced two novel terms: "sensitized individual" and "shocking dose." To elucidate these terms before delving further into the subject matter, consider the following definitions:

1. Sensitized Individual: When an individual encounters a specific allergen for the first time, their immune system initiates a response, culminating in the production of IgE antibodies by a specific subset of B cells. At this point, the individual is considered sensitized.
2. Sensitizing Dose: The initial exposure to an allergen is termed the sensitizing dose, and this process is referred to as sensitization. During sensitization, IgE molecules bind to specific Fc receptors on the surface membrane of mast cells.

Upon subsequent encounters with the same allergen, this sensitized state is pivotal. The allergen engages IgE molecules, leading to their cross-linking, which, in turn, triggers immediate mast cell degranulation. This degranulation event results in the release of numerous bioactive mediators from the activated mast cells, leading to the characteristic pathological symptoms associated with immediate hypersensitivity. These symptoms often target specific tissues, particularly smooth muscle, and include manifestations such as edema, erythema, swelling, and localized pain at the site of the reaction. The subsequent dose of the allergen responsible for this acute response is referred to as the "shocking dose."

Delayed Hypersensitivity

Delayed hypersensitivity, also referred to as cell-mediated hypersensitivity, is characterized by tissue reactions that typically manifest more than 24 hours after exposure to the relevant antigen, following interaction with sensitized T cells. Unlike immediate hypersensitivity, which often targets specific organs, delayed hypersensitivity is not associated with specialized target organs; rather, it affects various tissues throughout the body.

Crucially, delayed hypersensitivity does not rely on the production of IgE antibodies. Instead, its mechanism hinges on the presence of sensitized T cells and the mediators they produce, known as lymphokines. Passive transfer of this response is only feasible through sensitized T cells. The key players in this reaction are the lymphokines, which serve as chemical mediators. They activate macrophages and initiate a delayed acute inflammatory response in reaction to particular skin-contact or bacterial antigens.

Classification of Hypersensitivity on Immunopathological Basis

In 1963, P.G.H. Gell and R.R.A. Coombs introduced a comprehensive classification of hypersensitivity reactions, encompassing four distinct types based on their immunopathological underpinnings: Type I, or anaphylactic reactions; Type II, or cytotoxic reactions; Type III, or immune complex reactions; and Type IV, or cell-mediated reactions. This classification system is particularly valuable as it considers the precise immunopathological mechanisms that underlie the effects of hypersensitivity reactions.

The first three types, Types I, II, and III, primarily involve antibody-mediated processes. Type I reactions are mediated by Immunoglobulin E (IgE), produced by plasma cells in response to typically harmless environmental antigens, such as pollen, house-dust, mites, or animal dander. Type II reactions predominantly rely on antibodies that bind to either autoantigens or foreign antigens on cell surfaces, subsequently activating the complement cascade. Type III hypersensitivity arises when immune complexes accumulate in substantial quantities within both the circulation and tissues, triggering the complement cascade.

In contrast, Type IV hypersensitivity is distinguished by its mediation through sensitized T cells. Upon activation, these T cells release lymphokines, which, in turn, stimulate macrophages. This macrophage activation leads to the infliction of tissue damage, resulting in localized destructive effects.

Type I - Immediate Anaphylactic Reactions

Type I hypersensitivity, commonly known as an allergic reaction, is characterized by its rapid onset in sensitized individuals upon exposure to a specific allergen. This hypersensitivity response hinges on the precise interaction between the allergen and IgE-sensitized mast cells. IgE antibodies are generated in response to foreign proteins commonly encountered in the environment, such as pollen, animal dander, or house dust mites.

The key players in this response are mast cells, which, when triggered, release a spectrum of pharmacological mediators. These mediators play a pivotal role in initiating the inflammatory response that is emblematic of Type I hypersensitivity reactions.

Allergens

Type I hypersensitivity reactions are not incited by all antigenic molecules. Notably, T-independent polysaccharide antigens do not stimulate the production of Immunoglobulin E (IgE), the pivotal antibody in Type I reactions. The subset of antigens capable of eliciting immediate hypersensitivity reactions is categorized as "allergens."

The term "allergen" was initially introduced by von Pirquet to encompass all foreign substances capable of eliciting an immune response. However, its usage was subsequently refined to selectively refer to those proteins that induce a state of heightened sensitivity or "supersensitivity." These allergenic proteins typically possess a molecular weight ranging from 10,000 to 40,000 daltons. They are readily soluble in aqueous solutions and exhibit diverse biological functions, including roles as digestive enzymes, carrier proteins, and pollen recognition proteins. Owing to their high sulfhydryl group content, these allergens have a pronounced propensity for cross-linking. There are three primary categories of allergens.

1. Complete protein allergen. These allergens primarily possess the capacity to elicit a humoral response, ultimately resulting in the high-level production of Immunoglobulin E (IgE). Among the notable examples of such allergens are pollen, animal dander, mold spores, as well as exogenously administered proteins like horse serum and animal hormone extracts. It's important to note that a significant proportion of these allergens are encountered exclusively on mucosal surfaces, such as the nasal and lung linings, as well as the conjunctiva of the eyes.
2. Low molecular-weight substances. These substances typically engage with tissue or serum proteins within the living organism, subsequently prompting the generation of Immunoglobulin E (IgE). This category encompasses numerous drugs and haptens, which share this characteristic of inducing IgE production.
3. Modified allergens. These particular allergens exist in chemically modified states that do not initiate IgE production, nor do they bind to preexisting IgE molecules. Consequently, they do not incite allergic reactions. They are occasionally referred to as "allergoids." Experimental investigations involving ragweed pollen that has been denatured using urea or conjugated with polyethylene glycol have demonstrated a noteworthy suppression of IgE responses. As a result, they are regarded as the preferred option for allergy treatment.

Classical allergens are typically encountered in minuscule amounts, ranging from 5 to 20 nanograms per day. This exposure occurs either continuously indoors or over the course of weeks or months outdoors. Inhaling substantial quantities of these allergens may lead to localized inflammation in the lungs but is not expected to trigger acute bronchospasm.

In addition to inhalation, allergens can gain entry into the body through various other routes, including ingestion, as seen with food allergens, or the intake of drugs. Furthermore, antigens from fungi that colonize the body and venoms from certain sources can also serve as pathways for allergen entry. It's important to recognize that these routes significantly influence how antigens are presented to the immune system and the specific sites where genetic factors play a pivotal role.

For example, inhalant allergens are known to induce conditions like hay fever, chronic rhinitis, and asthma, particularly in school-aged children and young adults. Common sources of airborne allergens include pollen grains, mite fecal particles, particles from fungal hyphae or spores, and skin flakes (dander) shed by animals, particularly when they are transported on particles.

Conversely, food-borne allergens encompass a broader spectrum, including milk, eggs, wheat, soy, tree nuts, peanuts, fish, and shellfish. These protein allergens are often consumed in substantial quantities, in contrast to inhalant allergens, with estimated daily intake ranging from 10 to 100 grams.

Regain

In line with the information provided earlier, allergens are the driving force behind the production of Immunoglobulin E (IgE), a pivotal player in Type I hypersensitivity reactions. This unique antibody, also known as reagin or reaginic antibody, was first linked to allergic responses by Ishizaka in 1967. Importantly, every normal individual possesses the capacity to synthesize reaginic antibodies tailored to a variety of allergens when these allergens are introduced parenterally in the appropriate manner.

The structure of IgE consists of two heavy chains and two light chains, with heavy chains possessing an additional constant domain and a distinctive hinge region. Notably, IgE harbors binding sites for both high- and low-affinity IgE receptors, FCERI and FCERII, respectively. The primary cells equipped with FcεRI receptors are mast cells and basophils, the only cells in the human body that store significant quantities of histamine. Low-affinity IgE receptors, FCεRII or CD23, are also found on B lymphocytes and might contribute to antigen presentation. Because IgE can bind to the Fc receptor on the surface of mast cells and basophils, it is also referred to as a cytotrophic antibody.

IgE demonstrates heat-labile properties, which result from alterations in the Fc portion of the molecule, rendering it unable to sensitize skin mast cells. Importantly, the antigen-binding capacity residing in the Fab portion remains unaffected. While serum IgE has a notably shorter half-life compared to other isotypes (approximately 2 days as opposed to 21-23 days for IgG), IgE bound to mast cells in the skin maintains a half-life of roughly 10 days.

Crucially, IgE molecules cannot be transferred passively from mother to fetus, either due to their degradation in endosomes or the absence of essential Fc receptors on placental tissues. In endosomes, IgE molecules do not bind to FcyRn receptors and are subsequently broken down by cathepsin under high acidic pH conditions. In contrast, IgG molecules bind to Fc receptors and are thereby protected.

The production of IgE is intricately reliant on the cooperation of macrophages, T cells, and B cells. Plasma cells activated to generate IgE are primarily situated in the lamina propria of the respiratory and gastrointestinal tracts, along with their associated lymphoid tissues. Under normal circumstances, the serum IgE level is significantly lower than that of IgG. It is well-established that the production of IgE hinges on TH2 cells, known for their efficient production of primary cytokines including IL-4, IL-5, IL-10, and IL-13. Any priming initiated by cytokines IL-12 and IFNy, produced by activated TH1 cells, leads to the inhibition of IgE production. Experimental evidence confirms that the expression of the IgE gene is dependent on IL-4, demonstrated by the active synthesis of IgE antibodies when immature human B cells are cultured in the presence of anti-CD-40 and IL-4.

In humans, IgE antibodies are produced in response to a specific group of allergens, selectively regulated by cytokines produced by TH2 cells, as mentioned earlier.

Atopy

In 1923, Coca and Cooke introduced the term "atopy" (derived from the Greek "atopos," meaning out of place or uncommon) to delineate the clinical manifestations associated with Type I hypersensitivity reactions. These presentations encompass a spectrum of conditions, such as asthma, eczema, urticaria, and food allergies. One distinctive feature noted by the researchers was a family history characterized by a predisposition to these ailments or similar complaints, alongside positive skin reactions (wheal and flare responses) to common inhaled allergens. Crucially, Coca and Cooke discerned atopic diseases as distinct from anaphylaxis, another form of Type I hypersensitivity, which lacked any hereditary associations.

Anaphylaxis

Anaphylaxis represents an acute manifestation of Type I hypersensitivity, typically triggered by the administration of an allergen to a sensitized individual. This hypersensitivity reaction is characterized by the rapid onset of tissue responses, occurring within seconds to minutes of the interaction between a specific allergen and its corresponding mast cell-bound IgE antibodies. The ensuing antigen-antibody interaction at the mast cell surface prompts the release of histamine and other vasoactive mediators. These mediators induce a cascade of vascular changes, platelet activation, eosinophil involvement, and initiation of the coagulation cascade.

The discovery of anaphylaxis can be attributed to Portier and Richet, who were investigating the effects of a toxin from a Mediterranean Sea anemone in dogs. Their study involved an initial injection of the toxin, followed by a subsequent dose several weeks later to assess the development of immunity in the dogs. Their findings yielded intriguing results: while some dogs displayed resistance to the anemone toxin, others exhibited unusual clinical symptoms. These symptoms encompassed increased salivation, defecation, respiratory difficulties, hind limb paralysis, and, in the most severe cases, death within minutes of toxin administration.

Portier and Richet drew a pivotal conclusion from their observations, postulating that under certain conditions, the immune response might paradoxically lead to harmful effects on the host instead of bolstered resistance. This phenomenon, they termed "anaphylaxis" (derived from the Greek "ana," signifying away from, and "phylaxis," signifying protection), in stark contrast to "prophylaxis," which implies protection against. Subsequent research unveiled the immunological underpinnings of anaphylaxis, establishing it as a hypersensitivity reaction. Portier's significant contributions in discovering anaphylaxis earned him the prestigious Nobel Prize.

Antigens involved in anaphylaxis

Anaphylaxis, a severe and potentially life-threatening allergic reaction, can be triggered by a diverse array of allergens. These allergens primarily encompass proteins or chemical compounds that are conjugated with proteins.

Mediators of anaphylaxis

The activation of mast cells and basophils leads to the degranulation of these cells, resulting in the subsequent release of multiple bioactive pharmacological mediators. These mediators can be categorized into two main groups: preformed and newly synthesized.

Preformed mediators, like histamine, are stored in granules within mast cells and basophils. Upon activation, these cells promptly release histamine. Histamine plays a pivotal role in the early phases of an allergic response, causing vasodilation and increased vascular permeability, which contribute to the characteristic symptoms of allergy, such as redness, swelling, and itching.

Newly synthesized mediators are generated de novo in response to cell activation. This group includes prostaglandins, leukotrienes, platelet-activating factor (PAF), and cytokines. Prostaglandins and leukotrienes are lipid-derived compounds that contribute to the inflammatory response by inducing vasodilation and smooth muscle contraction. Platelet-activating factor (PAF) plays a role in platelet aggregation and inflammation, further intensifying the immune reaction. Cytokines, on the other hand, are signaling molecules that orchestrate various aspects of the immune response, regulating cell communication and immune cell activity.

The activation of mast cells and basophils triggers the release of pharmacological mediators, both preformed (e.g., histamine) and newly synthesized (e.g., prostaglandins, leukotrienes, PAF, and cytokines). These mediators collectively contribute to the complex and orchestrated immune response seen in allergies and other hypersensitivity reactions, making them a subject of significant interest for researchers and healthcare professionals in the field of immunology.

Mechanism of anaphylaxis

The mechanism of anaphylaxis can be effectively dissected into three distinct phases: (1) the sensitization phase, (2) the activation phase, and (3) the effector phase. This categorization allows for a comprehensive understanding of the intricate processes involved in this severe allergic reaction.

Sensitization phase

The sensitization phase marks the initial stage in the development of an allergic response. It commences when an individual comes into contact with a specific allergen, which can occur through repeated mucosal exposure, ingestion, or parenteral injection. During this phase, antigen-presenting cells (APCs) play a crucial role. They capture the allergen and subsequently present it to T-helper (TH) cells. It's worth noting that certain APCs may provide co-stimulatory signals that promote the activation of TH2 cells, which are particularly proficient at inducing the synthesis of immunoglobulin E (IgE), a key player in allergic reactions.

The activated TH2 cells release cytokines, including interleukin-4 (IL-4) and interleukin-13 (IL-13). These cytokines, in turn, facilitate the differentiation of B cells into plasma cells and memory cells. The plasma cells assume the task of synthesizing and secreting IgE. This pivotal phase, marked by the production of IgE, classifies the individual as "sensitized" to the specific allergen.

IgE exhibits a distinctive affinity for binding to high-affinity Fc receptors found on the surfaces of mast cells in local connective tissues and mucosal linings. Notably, "spillover" IgE enters the circulation, where it attaches to receptors on circulating basophils and tissue mast cells throughout the body. These IgE molecules can persist at the cell surface for weeks, maintaining the sensitization of mast cells and basophils.

Crucially, the initial binding of IgE to mast cells and basophils does not provoke an immediate cellular response. Instead, the trouble begins when the specific allergen reenters the body in a particular manner. The allergen cross-links the IgE molecules on the cell surface, setting off the activation of these cells and initiating the cascade of allergic reactions.

Sensitization can also be achieved through the passive transfer of serum containing IgE molecules specific to a given allergen. This phenomenon was first observed by Küstner in 1921, who, being allergic to fish, injected his own serum into Prausnitz, an individual allergic to grass pollen but not fish. The observations made during this experiment laid the foundation for the concept of passive sensitization, demonstrating that intact allergenic components from fish could be absorbed into the circulatory system. These findings formed the basis for what is now known as the Prausnitz-Küstner (P-K) test, used to ascertain the involvement of a particular IgE in anaphylactic reactions.

The P-K test involves intradermal injection of a serum sample from an allergic individual into a non-allergic recipient. The antibody within the serum diffuses and binds to neighboring mast cells at the injection site, sensitizing it within 24-48 hours. Subsequent injection of a suspension of the suspected antigen elicits an urticarial reaction at the injection site. A positive P-K test confirms the individual's allergic response to the test antigen, thus offering valuable insights into the mechanisms of anaphylaxis.

Activation phase

The anaphylactic reaction is notably triggered by a second or subsequent injection of the specific allergen intradermally into a sensitized individual. This additional dose of the allergen is commonly referred to as the "shocking dose," and the process itself is termed "shock." Upon injection, the allergen serves as the catalyst for the sensitized mast cell to initiate the release of its granules, along with their pharmacologically active mediators.

The mechanism behind shock hinges on the interaction of at least two distinct IgE molecules that are bound to Fc receptors on the surface of the mast cell. These IgE molecules are cross-linked by the multivalent antigen, an essential step in the cascade of events leading to the anaphylactic reaction. It's worth noting that alternative methods of cross-linkage have been documented, such as the addition of anti-IgE antibodies and antibodies specific to the IgE receptors on the mast cell's surface.

Furthermore, mast cells may not only be activated by IgE but also by anaphylatoxins C3a and C5a, which are products of complement activation, various drugs like codeine and morphine, and certain physical agents such as heat, cold, and pressure.

The activation of mast cells, brought about by the bridging of their receptors, results in three distinct types of biological responses:

1. The activated mast cell and basophil undergo degranulation, leading to the release of the preformed contents stored within their granules through a process known as exocytosis.
2. The mast cell and basophil exhibit enhanced metabolic activity, leading to the synthesis of lipid mediators.
3. The mast cell (but not the basophil) synthesizes and secretes cytokines, playing a role in orchestrating various aspects of the immune response.

The release of granules involves the movement of these granules by microfilaments to the cell surface, where their membranes fuse with the cell membrane. The granular membrane becomes integrated into the cell membrane, facilitating the rapid release of granular contents to the external environment. Importantly, this process does not result in cell lysis or cell death, as the release of granules is a physiological function of the cell.

It's pertinent to mention that the degranulation process is initiated through the cross-linking of two specific IgE molecules by their corresponding allergen. This cross-linkage essentially involves the binding of two IgE receptors (FCER1) and sets in motion signal transduction via the γ chains of the receptor, leading to an influx of calcium. This intricate signaling cascade serves as the trigger for both degranulation and the synthesis of newly formed mediators, further highlighting the complexity of the anaphylactic response.

Effector phase

The clinical manifestation of an anaphylactic reaction is primarily a result of the actions of pharmacologically active mediators that are released by activated mast cells. As previously outlined, these mediators can be categorized into two distinct groups: preformed mediators and newly synthesized mediators.

Preformed mediators, as the term implies, are stored within the granules of mast cells and are released in response to the antigen-triggered influx of ions, notably calcium and sodium. This release of preformed mediators is a pivotal aspect of the rapid response seen in anaphylaxis.

Conversely, newly synthesized mediators are generated during the course of the anaphylactic response. They originate from the lipids within the cell membrane and are subsequently released to exert their effects. These newly formed mediators play a significant role in the overall response and contribute to the wide range of clinical symptoms observed during anaphylactic reactions.

Clinical features

Typical anaphylactic reactions typically manifest within minutes of allergen exposure and tend to subside within a period ranging from half an hour to one hour. However, these immediate reactions may be succeeded by inflammatory sequelae referred to as late-phase reactions. The clinical signs and symptoms associated with anaphylaxis are primarily a result of the pharmacological actions of mediators released by mast cells upon activation. Anaphylaxis can be artificially classified into two primary categories: localized anaphylaxis and generalized anaphylaxis.

Localized anaphylaxis

When an individual who has been sensitized to a specific allergen receives an intradermal injection of that allergen, the allergen has the ability to cross-link IgE antibodies that are attached to the surface of mast cells in the localized region. This cross-linking event triggers the release of mediators by each mast cell in the immediate vicinity. Notably, histamine is the primary mediator to be released, and its local secretion results in a rapid and distinctive "wheal and flare" reaction. This reaction is characterized by the dilation of blood vessels (manifesting as a flare) and an increase in vascular permeability (producing a wheal). The clinical symptoms associated with localized anaphylaxis encompass redness, a burning sensation, itching, and localized warmth.

Generalized anaphylaxis

When a significant amount of allergen is widely dispersed within a sensitized individual, it results in what is referred to as generalized or systemic anaphylaxis. This widespread distribution of allergen initiates the systemic release of histamine and other mediators, primarily affecting various systems, including the respiratory tract, gastrointestinal tract, skin, and cardiovascular system.

As a consequence, a profoundly severe clinical condition ensues, characterized by bronchospasm, bronchoedema, dyspnea (shortness of breath), uterine cramps, and involuntary urination and defecation. Additionally, the extensive increase in vascular permeability may lead to a significant loss of fluid into tissue spaces, evident as hives and edema, along with a dramatic decrease in blood pressure. Generalized urticaria (hives), nausea, diarrhea, and vomiting are common manifestations. Involvement of the central nervous system may cause generalized anxiety, while cardiovascular complications can result in hypotension, shock, and even coma.

The progression of this reaction can be remarkably swift, peaking within minutes. In such cases, individuals may face three potential life-threatening conditions: (1) asphyxiation due to laryngeal edema (swelling of the voice box), (2) suffocation resulting from severe bronchospasm, or (3) severe blood pressure drop caused by extensive angioedema (swelling of deeper layers of skin).

Asthma

Asthma is a chronic medical condition characterized by the persistent challenge of breathing, typically accompanied by wheezing and the over-inflation of the lungs. These clinical manifestations can be attributed to the action of mast cell mediators within the pulmonary blood vessels and bronchial smooth muscles. These mediators induce bronchial spasms and stimulate the excessive production of thick mucus by the bronchial glands. The overproduction of mucus can obstruct the bronchial passages, exacerbating respiratory difficulties. Asthma is classically categorized into two main forms: extrinsic, which is mediated by IgE and commonly associated with symptoms like rhinitis, urticaria, and other atopic reactions, and intrinsic, which stems from non-immunological causes, such as infectious respiratory illnesses.

It is important to note that asthma has a complex genetic basis, with various genes playing a role in its development across different populations. Genetic analyses of type I hypersensitivity have identified both allergen-specific and non-specific genetic factors influencing its occurrence. Furthermore, specific human leukocyte antigen (HLA) associations have been identified in relation to atopy (genetic predisposition to allergic reactions) in general, as well as sensitization to particular allergens. Genomic studies have unveiled specific regions of the genome linked to asthma, which can be explored further to identify the precise genes involved in the condition.

Hay Fever

Hay fever, a condition that affects atopic individuals, presents as acute catarrh (inflammation of the mucous membranes) and conjunctivitis. It is triggered by the inhalation of antigenic substances, such as pollen, which are typically harmless to individuals without atopic predisposition. When inhaled, these allergens are deposited on the mucosal surface of the anterior nasal cavity, releasing allergenic components into the mucus layer.

These allergenic components initiate a response within the body, interacting with cells that have been sensitized with immunoglobulin E (IgE). Notably, IgE is produced locally in lymphoid tissues and mucosa. Upon contact, these cells release a cascade of mediators, primarily from basophils and mast cells. These mediators induce vasodilation, edema (fluid accumulation in tissues), and nerve irritation, ultimately resulting in a range of distressing symptoms.

These symptoms commonly include nasal congestion, frequent sneezing, pruritus (intense chronic itching, typically associated with the anal region), rhinorrhea (runny nose), and excessive lacrimation (tear production).

Diagnosis of Type I Hypersensitivity

The primary method employed for diagnosing type I hypersensitivity is skin testing, which stands as a cornerstone in the evaluation of allergic reactions. This diagnostic approach involves the intradermal injection of allergens. Two common techniques used in skin testing are:

1. Prick Test: In this method, a minute amount of allergen extract, typically measuring 0.1 μl, is introduced into the dermal layer of the skin. This is achieved using a fine 25-gauge needle or a lancet.
2. Intradermal Injection: Here, a slightly larger quantity of the allergen extract, typically ranging from 0.02 to 0.03 ml, is injected into the skin.

Following the introduction of allergens, the skin's response becomes apparent within a relatively short timeframe, generally taking between 5 to 15 minutes, and can last for approximately 30 minutes. The hallmark reaction observed is the formation of a distinctive "wheal and flare."

The evaluation process involves measuring the diameter of the wheal and comparing it to both a positive control (typically histamine) and a negative control (typically saline). A positive skin test is typically denoted by the presence of a wheal that measures at least 3 x 3 mm in children and 4 x 4 mm in adults. This positive test result signifies the presence of IgE antibodies on mast cells within the skin. Importantly, it suggests an increased risk of developing clinical hypersensitivity upon sufficient exposure to the respective allergen.

Factors Influencing Type I Reactions

Genetic factors

Epidemiological data provides compelling evidence indicating a higher likelihood of allergic parents having offspring with allergies. These findings underscore the hereditary nature of allergic conditions, with a particular focus on diseases such as asthma, hay fever, and atopic dermatitis. Immunological investigations have further illuminated this genetic predisposition, highlighting four distinct inherited characteristics:

1. General Predisposition to Allergy: Individuals may inherit a general susceptibility to allergic reactions, which can manifest across various conditions.
2. Predisposition to a Specific Disease (e.g., Asthma): Some individuals may carry a genetic predisposition that specifically increases their susceptibility to certain allergic diseases, such as asthma.
3. Predisposition to Overproduce IgE: A genetic predisposition can result in an individual's heightened capacity to synthesize excessive levels of IgE, an antibody class central to allergic responses.
4. Predisposition to React to Specific Allergens: Genetic factors can also lead to a heightened susceptibility to respond to particular allergens, potentially triggering allergic reactions.

Environmental factors

Allergic reactions are undoubtedly subject to a myriad of environmental influences, encompassing factors such as the extent of allergen exposure, the individual's nutritional status, and the concurrent presence of underlying infections or acute viral illnesses. Furthermore, environmental pollutants, including sulfur dioxide, nitrogen oxide, diesel emissions, and fly ash, have the potential to elevate mucosal permeability, consequently amplifying the ingress of antigens and the responsiveness of IgE.

It's noteworthy that seasonal fluctuations in the concentration of environmental allergens not only impact the incidence of allergic conditions but also contribute to a heightened susceptibility to allergic diseases. These multifaceted environmental elements intricately interact with the immune system, culminating in the complex manifestations of allergic responses.

Type II - Cytotoxic Reactions

Type II cytotoxic reactions encompass a spectrum of immunological conditions in which a specific antibody directly interacts with an antigen located on the cell's surface or the tissue membrane. This interaction may also occur with an antigen or hapten that has become affixed to the cell surface. These reactions culminate in cellular damage through various mechanisms. These mechanisms primarily entail the activation of the complement system, which may lead to cell lysis, or opsonization mediated by receptors for Fc or C3b. The cytotoxic antibodies involved in these reactions are typically either of the IgG or IgM class.

The most common antigens that provoke this type of hypersensitivity reaction are human Major Histocompatibility Complex (MHC) molecules found on the cells of transplants and blood group antigens present on transfused erythrocytes. It is worth noting that certain Type II reactions are primarily mediated by autoantibodies bound to self-antigens located on the host's own cells, contributing to autoimmune responses.

Mechanims of Type II Cytotoxic Reactions

Type II hypersensitivity reactions involve the mediation of IgG or IgM antibodies, each possessing dual functions. These antibodies serve the crucial role of connecting target cells to effector cells, which include macrophages, neutrophils, eosinophils, and K cells, through the utilization of Fc receptors (FCR) present on these effector cells. Upon attachment to the cell or tissue surface, these antibodies can initiate complement activity by activating C1, specifically through the classical pathway, ultimately resulting in cytolysis. This mechanism enables cytotoxic cells to eliminate infected host cells, as well as combat pathogens and parasites.

During this process, certain complement fragments, such as C3a and C5a, are generated and serve to attract macrophages and polymorphs to the site of action. Additionally, they stimulate mast cells and basophils to produce chemokines that, in turn, attract and activate other effector cells. These chemokines also bind to host tissues and pathogens, facilitating the phagocytic uptake of opsonized particles. In the course of phagocytosis, phagocytes not only neutralize pathogens but may also inadvertently cause immunopathological damage. The binding of antibodies to Fc receptors on phagocytes triggers the release of mediators involved in the development of inflammation. Chemoattractants, such as C5a, fibrin, leukotrienes, and chemotactic peptides originating from mast cells and lymphocytes, play a significant role in recruiting these phagocytes. Another mechanism of Type II hypersensitivity is also mediated by antibodies. In this scenario, the antibodies bind to K cells through high-affinity Fc receptors. These antibody-coated K cells then adhere to antigen-coated target cells via the Fab portion of the bound antibody, resulting in cytotoxicity. When the target is host tissue, cytotoxicity becomes a primary cause of damage.

Types of Cytotoxic Reactions

Type II hypersensitivity reactions manifest in several distinct examples, each characterized by specific immune responses targeting the body's own cells or foreign antigens. The most prevalent instances of Type II reactions include:

1. Transfusion Reactions: Transfusion reactions occur when an individual's immune system reacts against the transfused blood components, such as red blood cells, platelets, or plasma. This response can lead to the destruction of the transfused cells by antibodies produced by the recipient's immune system.
2. Hemolytic Disease of the Newborn (HDN): HDN is a condition in which a pregnant woman's immune system produces antibodies against red blood cell antigens present in her fetus. These antibodies can cross the placenta and result in the destruction of fetal red blood cells, leading to anemia and jaundice in the newborn.
3. Autoimmune Reactions: Autoimmune reactions involve the immune system mistakenly recognizing the body's own cells or tissues as foreign and producing antibodies against them. This can lead to damage to various organs or systems, depending on the specific autoimmune disease.
4. Drug-Induced Reactions: Some medications can trigger Type II hypersensitivity reactions by binding to specific cells or proteins and inducing an immune response. This can result in various symptoms or clinical conditions, depending on the drug involved.
5. Anti-Receptor Antibody Disease: In this context, antibodies are generated against specific receptors on the surface of cells. The binding of these antibodies can disrupt normal cellular signaling and function, leading to various pathological consequences.

Transfusion reactions

One of the prominent Type II hypersensitivity reactions occurs in response to erythrocytes, particularly in cases of incompatible blood transfusion. Transfusion reactions ensue when a recipient possesses antibodies against the erythrocytes of the donor. For instance, when a blood type A individual receives a transfusion of blood from a group O donor, a scenario unfolds. While the individual with blood type O lacks blood group antigen A or B on their erythrocytes, they do harbor IgM anti-A and anti-B antibodies in their circulation. In the event of an A blood transfusion to this individual, the IgM anti-A antibodies swiftly bind with the antigen A present on the donor's erythrocyte surface. Subsequently, this interaction triggers the activation of the complement cascade, ultimately leading to intravascular lysis of the erythrocytes. Moreover, the individual may also experience kidney damage due to the blockage caused by a substantial amount of membrane debris from the ruptured erythrocytes and the toxic effects of the released heme complex during hemolysis.

Transfusion reactions have also been documented in cases of minor blood group incompatibilities, including MN, Ss, Kell, and Duffy blood groups. These reactions in the recipient of the transfused blood manifest as diverse symptoms, such as fever, hypotension, nausea, vomiting, and discomfort in the back and chest. The severity of the reaction hinges on the antibody class and titer involved. In the context of ABO incompatibility, the pivotal antibody driving the reaction is IgM, which induces agglutination, complement activation, and intravascular hemolysis. In contrast, other blood group systems typically involve IgG antibodies, which induce less agglutination than IgM. Erythrocytes sensitized with IgG are predominantly phagocytosed by liver and spleen phagocytes, although severe reactions can lead to cytolysis in the presence of complement. Such reactions can result in circulatory shock, anemia, and the release of erythrocyte contents, ultimately leading to acute tubular necrosis of the kidneys. Understanding the intricacies of these reactions is crucial for both clinical management and the study of immunology.

Hemolytic Disease of Newborn

Hemolytic disease of the newborn (HDN) arises from an incompatible Rh factor (Rhesus factor) reaction in infants born to parents with Rh-incompatible blood groups. This condition is typically triggered when an Rh-positive baby is born to an Rh-negative mother. During childbirth, a portion of the baby's erythrocytes may enter the mother's circulation, inciting an immune response against the Rh antigen. Notably, it is IgG anti-Rh antibodies that are generated and pose a threat to subsequent Rh-positive babies. It's crucial to remember that IgG is the only antibody capable of traversing the placental barrier. Consequently, in second or subsequent pregnancies, these anti-Rh antibodies traverse the placenta, binding to the Rh antigen on the surface of fetal erythrocytes. This interaction culminates in the destruction of fetal or newborn erythrocytes, leading to pathological consequences, which encompass anemia, jaundice, and hydrops. Understanding the mechanisms of HDN is vital for effective clinical management and prevention in cases of Rh incompatibility.

Autoimmune reactions

In certain individuals, the immune system generates antibodies against antigenic molecules present on their own erythrocytes, platelets, or other cellular components, a phenomenon known as autoimmunity. This immune response directed against self-antigens can lead to the destruction of these cells, resulting in various pathological consequences. An illustrative instance of autoimmune reactions is the production of autoantibodies targeting platelets. These autoantibodies employ mechanisms such as the complement cascade or phagocytosis to initiate the destruction of platelets. The outcome of this immune-mediated process, termed thrombocytopenia, is characterized by a reduction in the number of platelets, which in turn can lead to bleeding tendencies, clinically manifested as purpura. Understanding the intricacies of autoimmunity and its impact on cellular components is crucial, particularly in the context of hematological disorders.

Drug-induced reactions

Certain drugs possess the unique property of acting as haptens, small molecules that have the capability to bind to cells or other circulating constituents within the bloodstream, thereby eliciting an immune response. Noteworthy examples of these drug-hapten interactions include chloramphenicol's binding to leukocytes, phenacetin (a common analgesic) binding to erythrocytes, and the sedative Sedormid binding to platelets. This intriguing phenomenon was initially documented by Ackroyd. Subsequent to the drug's association with the respective blood cell type, antibodies against these drugs are produced. These drug-specific antibodies can subsequently adhere to the surfaces of erythrocytes, which, in turn, may lead to the activation of the complement system. Consequently, these immune reactions can result in specific conditions, such as leucocytopenia (a decrease in the number of leukocytes), hemolytic anemia, and thrombocytopenic purpura (characterized by the destruction of platelets and the development of a purpuric rash). Hemolytic anemias have been reported following the administration of a broad spectrum of drugs, including penicillin, quinine, and sulfonamides. Understanding the mechanisms by which drugs interact with the immune system to induce these reactions is essential, particularly in the context of adverse drug effects.

Type III - Immune Complex Reactions

Type III immune complex hypersensitivity, characterized by tissue damage mediated by immune complexes, is notably induced by the presence of soluble complexes, often formed in the context of a slight antigen excess. In this process, antibodies, typically of the IgM or IgG class, engage with freely dispersed antigenic molecules, creating soluble complexes. These complexes subsequently undergo deposition and localization within various tissues and organs. The consequence of this localization is the initiation of an inflammatory response, accompanied by the activation of the classical complement cascade.

Mechanism of Immune Complex Reactions

Type III hypersensitivity reactions are initiated by the interaction of antibodies with soluble antigens, typically in excess. This interaction leads to the formation of immune complexes, which can be found intravascularly or near the endothelial cells of capillaries in organs like the kidneys, lungs, joints, and skin. These immune complexes activate the complement cascade via the classical pathway, resulting in the release of physiologically active components, C3a and C5a, which act as chemoattractants. Simultaneously, vasoactive amines and prostaglandins are released by activated or damaged platelets, increasing vascular permeability and allowing the deposition of immune complexes on the blood vessel walls.

The deposited immune complexes continue to generate C3a and C5a. Macrophage-released cytokines play a crucial role in localized Type III reactions. Neutrophils are attracted to the complex deposition site, where they phagocytose the complexes, leading to the subsequent release of lysosomal enzymes. These enzymes can initiate damage to nearby cells and tissues. In certain cases, platelets aggregate on the exposed collagen of vessel basement membranes to form microthrombi. These aggregated platelets are a significant source of vasoactive amines and contribute to the production of C3a and C5a.

C5a functions as a chemotactic substance for neutrophils, attracting them to the site of C5a production. However, they may not successfully ingest the immune complexes since these complexes are bound to the vessel wall. Neutrophils, therefore, employ an alternative strategy by releasing lysosomal enzymes onto the deposition site. When these enzymes enter the bloodstream or tissue fluids, they don't harm the tissues as they are rapidly neutralized by serum enzyme inhibitors. However, when they are released in close proximity to tissue-bound immune complexes, these enzymes can damage the underlying tissues.

Immune complexes can persist in the blood for extended periods without causing harm. Problems arise when these complexes are deposited in the tissues. This deposition is typically prompted by an increase in vascular permeability, often occurring at sites with high blood pressure, such as glomerular capillaries. Sites with high pressure and erratic shear forces, like artery turns or bifurcations, are particularly susceptible to damage. Complex size also plays a role in the site of deposition. Smaller immune complexes can pass through the glomerular basement membrane and end up on the epithelial side, while larger complexes are generally trapped between the endothelium and the basement membrane.

Type III hypersensitivity reactions can lead to several diseases, which can be categorized into three groups:

1. Diseases associated with persistent infections: Immune complexes may form during infections caused by bacteria (e.g., streptococcal and staphylococcal infections, leprosy), parasites (e.g., Plasmodium vivax), or viruses (e.g., dengue hemorrhagic fever, viral hepatitis). A weak antibody response can lead to chronic immune complex formation and deposition in infected tissues and the kidneys.
2. Autoimmune diseases: Autoantibodies against self-antigens are common causes of immune complex diseases. Prolonged immune complex formation occurs when there's continued production of autoantibodies against self-antigens. This results in an increased number of complexes in the blood, overloading the systems responsible for their removal (macrophages, erythrocytes, and complement). Common autoimmune diseases leading to immune complex formation include rheumatoid arthritis, systemic lupus erythematosus, and polymyositis.
3. Diseases from repeated antigen inhalation: In specific conditions, immune complexes are formed in the lungs as a result of repeated inhalation of antigens, often associated with molds, plants, or animals. Diseases like farmer's lung and pigeon fancier's lung occur after prolonged exposure to the relevant antigens, leading to the production of circulating antibodies against these antigens. These diseases fall under the category of extrinsic allergic alveolitis.

Types of Immune Complex Reactions

Two major classic immune complex responses associated with Type III hypersensitivity have been observed in animals.

Serum sickness

Serum sickness is a condition induced by the injection of large quantities of horse antisera, often used for passive immunization purposes. It is characterized by the deposition of circulating immune complexes within the capillary walls and tissues, resulting in heightened vascular permeability and a sequence of inflammatory events. Typically, 1-2 weeks after the administration of horse antisera, recipients may experience symptoms such as fever, pruritic and edematous rashes on various parts of the body, painful joint swelling, and enlarged lymph nodes. In some cases, urine may contain erythrocytes and albumin, indicative of inflammation within the kidney's glomerular apparatus, a condition known as glomerulonephritis.

The underlying mechanism of serum sickness can be elucidated through a model experiment. In this experiment, a rabbit is subjected to a single intravenous injection of a substantial dose of bovine serum albumin (BSA). Approximately seven days following the injection, antibodies against BSA begin to form, reacting with the antigen still present in the bloodstream, consequently forming immune complexes. As these complexes circulate in the bloodstream, distinct symptoms manifest in the kidneys, blood vessels, and skin. Around ten days post-injection, symptoms reach their peak, coinciding with the near absence of the antigen in the bloodstream, a phenomenon referred to as immune elimination. Subsequently, free antibodies appear in the serum.

Arthus reaction

In 1903, the French scientist Maurice Arthus conducted an experiment in which he subcutaneously injected normal horse serum into rabbits repeatedly, with several days between each injection. After several weeks, he observed a distinct skin reaction characterized by firm induration, swelling, abscess formation, and eventual tissue necrosis. This phenomenon, now known as the Arthus reaction, was not limited to rabbits; similar reactions were also observed in guinea pigs, rats, dogs, and humans.

The Arthus reaction can be defined as an inflammatory response marked by edema, hemorrhage, and necrosis. It occurs following the administration of an antigen to an individual who already possesses specific precipitating antibodies. The antibodies interact with the antigen in subcutaneous tissues and within the walls of blood capillaries, leading to the formation of insoluble immune complexes. These complexes adhere to the vascular endothelium, where they activate the complement cascade. During complement activation, chemotactic factors are released, attracting neutrophils and platelets to the site of the reaction. Neutrophils adhere to the tissue-bound complexes with the intent of initiating phagocytosis. However, they are unable to do so as the complexes are firmly attached to the basement membrane. Consequently, the phagocytic process remains incomplete, and the contents of phagolysosomes are released into the surrounding environment. The lysosomal enzymes then proceed to damage the basement membrane and adjacent tissues, causing severe harm. Additionally, some mediators released from neutrophils stimulate mast cells and basophils, leading to their degranulation and further amplifying the inflammatory response. Furthermore, certain complement fragments released during activation induce platelet aggregation and the release of clotting factors, contributing to the intensification of the inflammatory reaction. The Arthus reaction reaches its peak intensity within 4-10 hours and typically subsides within 48 hours.

Type IV - Delayed Hypersensitivity

Type IV hypersensitivity encompasses immune reactions with a delayed onset of more than 12 hours. Unlike antibody-mediated hypersensitivity, these reactions are primarily initiated by antigen-specific T cells. This type is often referred to as delayed-type hypersensitivity (DTH) or cell-mediated immunity (CMI). One of the defining features of Type IV reactions that sets them apart from other types of hypersensitivity is their initiation without the involvement of antibodies and complement components.

In Type IV hypersensitivity, the antigen interacts with sensitized T cells, resulting in tissue damage caused by the release of lymphokines, direct T cell cytotoxicity, or, more commonly, a combination of both mechanisms. Additionally, an important characteristic of this reaction is that it cannot be transferred from an immunized or sensitized individual to a nonimmune individual through serum but can only be transferred via T cells. This distinguishes Type IV hypersensitivity from other hypersensitivity types where the transfer can occur through serum containing antibodies.

Mechanims of Type IV Hypersensitivity

The mechanism of Type IV hypersensitivity can be comprehensively understood by categorizing it into three distinct phases: sensitization or induction phase, challenge phase, and effector phase.

Sensitization phase

Type IV hypersensitivity reactions can be initiated by a diverse array of natural or synthetic proteins. In natural settings, infectious agents like bacteria may contain specific proteins capable of triggering hypersensitivity responses. Additionally, certain sensitizing antigens and self-antigens have been identified as contributors to the activation of T cells. Typically, T cells become sensitized to foreign antigens either through exposure during a microbial infection or by absorbing contact-sensitizing agents through the skin.

The antigen is presented on the surface of Antigen-Presenting Cells (APCs), and when a T cell encounters this antigen, it becomes activated. The T cells involved in this reaction are of the TH1CD4* type. Once activated, TH1 cells secrete cytokines, including IL-2 and IFN-γ, which serve as chemoattractants for macrophages and induce their activation. Among these cytokines, IL-12 plays a critical role in expanding the T cell population, consequently enhancing the secretion of more cytokines that further activate macrophages.

Challenge phase

The development of a Type IV hypersensitivity reaction requires a second exposure to the same antigen encountered during the sensitization stage. This antigen can enter the body through intradermal injection or topical contact on the epidermis. This event leads to the accumulation of antigen-specific T cells at the site and the subsequent development of a local inflammatory response over a period of 24-72 hours.

The antigen, presented by Antigen-Presenting Cells (APCs), binds with the expanded TH1 cells, resulting in their reactivation. These reactivated TH1 cells release a set of cytokines, including IL-2, IFN-γ, MCF, and TNF-β. These cytokines play pivotal roles in various biological processes, such as attracting macrophages to the reaction site, activating macrophages, and increasing the release of cytokines. The time required for these activities typically varies from 18-24 hours, and in some cases, may extend up to 48 hours.

Effector phase

The Type IV hypersensitivity reaction is significantly influenced by the presence of cytokines and macrophages at the reaction site. Among these factors, interferon-gamma (IFN-γ) plays a crucial role. IFN-γ has a multifaceted impact; it acts on monocytes in the bloodstream, inducing a sticky state in these cells. The sticky monocytes subsequently adhere to the endothelial membrane of veins. IFN-γ may also directly affect the endothelial membrane, causing damage that further attracts additional monocytes.

These adhering monocytes migrate from the bloodstream through the endothelium into the surrounding tissue. Some of them undergo transformation into macrophages, while others maintain a morphological similarity to circulating monocytes. This accumulation of macrophages and monocytes at the reaction site is termed "mononuclear cell infiltration." Over time, this condition leads to the formation of clusters of epithelioid cells, which eventually fuse to create giant cells in granulomas.

In some instances, the displacement of granulomas can result in caseous necrosis. Furthermore, the lysosomal enzymes released by monocytes and macrophages are responsible for the degradation of the vessel wall and the adjacent subcutaneous tissue, causing their destruction. It is important to note that tissue destruction during the Type IV hypersensitivity reaction is often accompanied by the ingestion and degradation of bacteria, parasites, foreign tissue, or tumor cells. Therefore, while this process is advantageous for providing immunity, it also has the drawback of causing tissue damage.

Manifestation of Type IV Reactions

Type IV hypersensitivity reactions can be categorized into two distinct types: local and systemic reactions. Local reactions are most prominently observed in the tuberculin test. These reactions occur following the subcutaneous injection of an antigen into a sensitized individual. Within a few hours of injection, the affected area becomes characterized by redness, warmth, and swelling, reaching its peak at approximately 48 hours. The indurated area typically measures around 10 mm in diameter, although it may be considerably larger in some cases. Over time, the swollen area undergoes necrosis, and the skin eventually sloughs off, leaving behind a shallow ulcer that tends to heal relatively quickly. Notably, the swollen area harbors a substantial accumulation of mononuclear cells, with approximately 90% of these cells being monocytes, while the remaining minority consists of lymphocytes. Neutrophils are rarely present in the skin lesion.

In contrast, systemic reactions result from the introduction of a significant quantity of the antigen into the bloodstream of a sensitized individual. These reactions manifest with symptoms such as fever, malaise, backache, joint pain, and lymphopenia. In severe cases, systemic reactions may progress to shock and even prove fatal.

Variants of Type IV Hypersensitivity

In previously sensitized individuals, Type IV hypersensitivity reactions exhibit three broad variants: contact hypersensitivity, tuberculin-type hypersensitivity, and granulomatous hypersensitivity. These variants share a fundamental underlying mechanism, yet they possess distinct characteristics that set them apart from each other.

Contact hypersensitivity

Contact hypersensitivity, also known as contact dermatitis, represents a localized and robust inflammatory dermal response to low molecular weight substances, such as nickel, chromate, turpentine, varnish, cosmetics, rubber-related chemicals, leather-tanning agents, poison ivy, or hair dyes. These substances are not inherently antigenic, but when they interact with proteins, such as albumin, they acquire the potential to stimulate lymphocytes. They can also penetrate the skin. Clinically, contact hypersensitivity is marked by the development of an eczematous reaction at the point of contact with the sensitizing substance, which typically occurs within a 48 to 72-hour timeframe.

The immunologically active components within sensitizing agents are referred to as haptens. These are low molecular weight substances, typically less than 1 kdal, characterized by their lipophilic nature, enabling them to traverse the epidermis. Within the epidermis, haptens form neo-antigens by covalently binding with proteins. This resulting conjugate functions as a sensitizer. Langerhans cells, prominent antigen-presenting cells (APCs) in the epidermis, play a pivotal role in this process. These cells express CD1, MHC class II molecules, and langerin. They capture neo-antigens through micropinocytosis and, under the influence of cytokines like IL-1 and TNF produced by keratinocytes and other cell types, undergo maturation, leading to an increase in MHC and co-stimulatory molecule expression.

Subsequently, Langerhans cells exit the epidermis and migrate via the efferent lymphatics to regional lymph nodes. There, they present processed conjugates to T cells, initiating T cell activation and the release of cytokines. Some of these cytokines stimulate T cell proliferation, resulting in the production of effector and memory TH cells, along with regulatory THCD4 cells. Endothelial cells in the dermis may also express adhesion molecules, facilitating the recruitment of lymphocytes to the site of inflammation.

Additionally, the involvement of MHC class I-restricted CD8+ cells as major effector cells in contact hypersensitivity is well-documented. The sensitization process spans a period of 10-14 days in individuals. Subsequent contact with the sensitizer triggers T cell expansion, provoking the inflammatory response.

Histologically, the earliest changes in contact sensitivity become apparent after 4-8 hours, intensifying at 48-72 hours. A mild reaction is characterized by skin erythema and edema. In severe cases, the formation of blisters (vesiculation) across the body, except the palms and soles, is a prominent feature. These blisters may rupture, leaving exposed, weeping areas. The lesions gradually resolve over several days.

Tuberculin-type hypersensitivity

Tuberculin-type hypersensitivity, characterized as a delayed skin reaction resulting from the administration of tuberculin purified protein derivative (PPD) to a sensitized individual, was initially documented by Koch in 1890. In his observations, patients with tuberculosis, when subcutaneously injected with a tuberculin culture filtrate (an antigenic constituent derived from Mycobacterium tuberculosis), developed localized edema, induration, and accompanying symptoms like fever. This reaction follows a course of 24 to 48 hours and is distinguished by a prominent mononuclear infiltration.

The tuberculin, derived from cultures of Mycobacterium tuberculosis, induces an inflammatory response when injected in minute quantities intradermally into individuals who have previously encountered the pathogen or received the BCG vaccine. Tuberculin interacts with sensitized memory T cells, leading to their reactivation. These reactivated cells subsequently secrete IFN-γ, which in turn activates macrophages to produce TNF-α and IL-1. These cytokines exert their effects on the endothelial cells within dermal blood vessels, sequentially inducing the expression of adhesion molecules, including E-selectin, ICAM-1, and VCAM-1. These molecules bind to receptors on leukocytes, recruiting them to the site of the reaction.

Several of the cytokines also possess chemotactic properties, drawing peripheral blood monocytes into the area of interaction between tuberculin and T cells. These invading monocytes release a range of enzymes that target and degrade the collagen bundles within vessel walls and neighboring tissues. Further damage may be inflicted by additional cytokines secreted by reactivated T cells. Both infiltrating lymphocytes and macrophages express MHC class II molecules, enhancing the efficiency of activated macrophages as antigen-presenting cells (APCs).

The hallmark of this entire reaction is the presence of induration, erythema, and necrosis. Monocytes comprise a significant portion of the cellular infiltrate at the reaction site, accounting for 80-90% of the total cell population. Although the lesion ultimately resolves through normal repair mechanisms, in some instances, the normal tissue architecture is permanently altered, resulting in scar tissue.

It's important to note that tuberculin-type hypersensitivity can also manifest when soluble antigens from various other microorganisms, including Mycobacterium leprae and Leishmania tropica, are injected into sensitized individuals.

Granulomatous hypersensitivity

In contrast to contact sensitivity and tuberculin hypersensitivity, granulomatous hypersensitivity represents a chronic inflammatory response characterized by the prolonged presence of monocytes and macrophages at the site of antigen accumulation, ultimately giving rise to granulomas—small, nodular structures formed by the aggregation of mononuclear inflammatory cells or macrophages, often encircled by a rim of lymphocytes. Central to the development of granulomas in this variant of Type IV hypersensitivity are the antigen-stimulated T cells, as they produce cytokines that attract increasing numbers of monocytes to the inflammatory site. Subsequently, these monocytes secrete mediators that contribute to tissue damage. A notable feature of granulomatous hypersensitivity is that it predominantly occurs in tissues where the causative agent accumulates, as opposed to the skin.

Granulomatous hypersensitivity is commonly observed in diseases such as tuberculosis, leprosy, leishmaniasis, schistosomiasis, and blastomycosis. The pathogens responsible for these diseases subject their hosts to persistent antigenic stimulation, leading to the mobilization of both lymphocytes and monocytes. The granulomas formed in response to these agents may occasionally exhibit central necrosis and are characterized by high turnover, where macrophages have a short lifespan and are continuously replaced by new arrivals. Few macrophages within these granulomas contain infectious agents.

Importantly, immune-mediated granulomas can also develop in the absence of infection, as seen in sensitivity reactions to substances like zirconium and beryllium, as well as in diseases such as sarcoidosis (a long-term disease marked by small, round tissue bumps around various organs) and Crohn's disease (a long-term inflammatory bowel disease). In these cases, the antigens triggering the granulomatous response remain unidentified. Granulomas resulting from exposure to foreign inorganic materials, including talcum, silicate, asbestos, and glass fibers, or inert organic materials such as urate crystals, exhibit a low-turnover pattern. In this scenario, only a minimal number of new macrophages migrate to the reaction site, while the initial macrophages persist for extended periods, often laden with foreign materials.

Granulomatous hypersensitivity is characterized by the presence of epithelioid cells and giant cells. Epithelioid cells are large, flattened cells with expanded endoplasmic reticulum. They originate from activated macrophages exposed to chronic cytokine stimulation and release TNF, contributing to sustained inflammation. Giant cells result from the fusion of epithelioid cells and appear as multinucleated, abnormally large cells, sometimes referred to as Langhans' giant cells. In contrast to epithelioid cells, giant cells exhibit reduced endoplasmic reticulum, with mitochondria and lysosomes undergoing degeneration, indicating that giant cells represent the terminal differentiation stage of the monocyte/macrophage lineage.

Summary

1. Hypersensitivity can be defined as a condition in which tissue damage arises from the immune response to a subsequent exposure to an antigen in an already immunized individual. This condition is traditionally categorized into two main types: immediate and delayed hypersensitivity.
2. Gell and Coombs have further elaborated on hypersensitivity by outlining four distinct types based on the immunopathological characteristics of the reactions. These four types are known as Type I, Type II, Type III, and Type IV hypersensitivity.
3. Type I hypersensitivity, often referred to as anaphylaxis, represents an acute response that occurs when an allergen is administered to an individual who has been sensitized to it. This type is characterized by specific etiological factors and clinical manifestations.
4. In Type II hypersensitivity, various immunological conditions manifest where specific antibodies directly interact with antigens present on cell surfaces or tissue membranes. This interaction can also involve antigens or haptens that have become attached to the cell surface.
5. Type III hypersensitivity is typified by immune complexes that mediate tissue damage, particularly in cases where soluble complexes are formed in a slight excess of antigens.
6. Type IV hypersensitivity encompasses all delayed hypersensitivity reactions, including contact sensitivity and tuberculin hypersensitivity.