2.5.3 Hypersensitivity

Introduction to Hypersensitivity 🌡️

Hypersensitivity refers to exaggerated or inappropriate immune responses that cause tissue damage. The key feature is that the immune system reacts to an antigen that is usually harmless or reacts in a way that harms the body more than it helps. Hypersensitivity always requires prior exposure to the antigen. The first exposure sensitizes the immune system, and subsequent exposures trigger the damaging response.

Hypersensitivity reactions are classically divided into four main types, labeled I through IV. Each type involves different immune mechanisms, different timing, and different clinical examples. Step 1 questions often test your ability to identify the type based on the immune components involved and the time course of symptoms, not just the disease name.

Classification of Hypersensitivity Reactions 📚

The four main types of hypersensitivity can be summarized by immune mechanism and timing.

Each type has unique features that you must differentiate in clinical scenarios. The same antigen can sometimes trigger different types in different people or in different contexts, but the mechanism defines the type, not the antigen itself.

Type I Hypersensitivity: Immediate, IgE Mediated ⚡

Type I hypersensitivity is classically called an immediate hypersensitivity reaction. It happens rapidly on re-exposure because preformed mediators are released from mast cells and basophils that were sensitized earlier.

In the sensitization phase, first exposure to an allergen leads to production of IgE antibodies. These IgE molecules bind to high affinity Fc receptors on mast cells and basophils and remain attached. The person is now sensitized but may have no symptoms yet.

Upon re-exposure, the allergen cross links IgE bound on the surface of these cells. This cross linking triggers degranulation of mast cells and basophils. Preformed mediators such as histamine, along with newly synthesized mediators such as leukotrienes, are released. These cause increased vascular permeability, vasodilation, and smooth muscle contraction in organs such as the lungs and gastrointestinal tract.

Clinically, Type I reactions can be localized or systemic. Local reactions include allergic rhinitis with sneezing and nasal congestion, urticaria with hives, or mild bronchospasm in atopic asthma. Systemic reactions can lead to anaphylaxis with hypotension, laryngeal edema, bronchospasm, and shock. Timing is typically within minutes of exposure to allergens such as peanuts, bee stings, or certain drugs given intravenously.

Type I reactions often have an early phase due to histamine and a late phase several hours later due to cytokines and leukotrienes that recruit additional inflammatory cells. This biphasic pattern can appear in conditions like asthma with initial wheeze followed by recurrent symptoms.

Type II Hypersensitivity: Antibodies against Cells and Tissues 🧬

Type II hypersensitivity involves IgG or IgM antibodies directed against antigens that are present on the surface of cells or in the extracellular matrix. These antigens can be intrinsic to the host tissue or can be extrinsic such as a drug that binds to a cell and forms a new antigenic target.

Once antibodies bind to these targets, they can damage cells in several ways. They can activate complement, which leads to formation of membrane attack complexes or deposition of complement fragments that recruit inflammatory cells. They can tag cells for phagocytosis through opsonization. Antibody binding can also recruit natural killer cells and cause antibody dependent cellular cytotoxicity.

In addition to direct cell destruction, antibodies in Type II reactions can alter cell function without killing the cell. For example, antibodies can mimic a ligand and stimulate a receptor, or they can block a receptor and prevent normal signaling. These functional changes are still considered Type II because they involve antibodies directed against cell surface molecules.

Clinically, Type II hypersensitivity includes conditions where specific cell types are targeted. Red blood cells may be destroyed in autoimmune hemolytic anemia. Platelets may be attacked in immune thrombocytopenia. Basement membranes may be targeted in diseases like Goodpasture syndrome that cause bleeding in lungs and kidneys. Some endocrine disorders are also Type II due to stimulatory or blocking antibodies against hormone receptors.

Timing is often within minutes to hours after exposure in cases such as transfusion reactions when a patient receives incompatible blood. Chronic autoantibody mediated diseases can develop slowly but still follow Type II mechanisms at the cellular level.

Type III Hypersensitivity: Immune Complex Mediated 💧

Type III hypersensitivity is driven by immune complexes, which are aggregates of antigen bound to antibodies, usually IgG. These complexes circulate in the bloodstream and can deposit in vessel walls and tissues, especially in areas of high filtration or turbulence such as glomeruli, joints, and small blood vessels.

Immune complex formation depends on the relative amounts of antigen and antibody. In Type III reactions, there is usually slight antigen excess, which favors small soluble complexes that are not cleared efficiently. Once deposited, these complexes activate complement and attract neutrophils. The activated complement fragments cause increased vascular permeability and chemotaxis. Neutrophils attempt to ingest the complexes but release enzymes and reactive oxygen species that damage the surrounding tissue.

The result is inflammation of vessels and tissues, often described as vasculitis or glomerulonephritis when kidneys are involved. Serum sickness is a classic Type III example in which a person develops systemic symptoms after exposure to foreign proteins such as non human antiserum or certain drugs. Arthus reaction is a localized Type III reaction that occurs when antigen is injected into the skin of a person who already has circulating antibodies, leading to local immune complex formation and tissue necrosis.

Clinically, Type III reactions often present hours to days after exposure, with fever, urticaria, arthralgias, lymphadenopathy, and sometimes proteinuria. Many autoimmune diseases, especially those with widespread immune complex deposition, have prominent Type III components. On pathology, deposition of immune complexes and complement can often be demonstrated by immunofluorescence showing granular patterns along structures like the glomerular basement membrane.

Type IV Hypersensitivity: T Cell Mediated ⏳

Type IV hypersensitivity is unique among the four types because it is not antibody mediated. Instead, it depends on sensitized T lymphocytes. It is often referred to as delayed type hypersensitivity because it typically appears 24 to 72 hours after antigen exposure.

There are two main T cell mechanisms in Type IV reactions. One involves CD4+ T helper cells. After initial exposure, these T cells recognize antigen presented on antigen presenting cells and become sensitized. Upon re exposure, they release cytokines that recruit and activate macrophages and other inflammatory cells. This leads to tissue damage at the antigen site. This pattern is seen in contact dermatitis due to substances such as nickel or poison ivy, and in the tuberculin skin test where a localized indurated lesion appears after intradermal injection of purified protein derivative.

The other mechanism involves CD8+ cytotoxic T cells, which directly recognize antigen expressed on host cells and kill those cells. This can occur in certain viral infections and in some autoimmune diseases that target specific tissues. Granuloma formation in chronic infections also involves T cell mediated mechanisms, although granulomas are more directly covered in general pathology.

Type IV reactions can be localized to the skin or can involve deeper tissues depending on where the antigen is encountered and which cells present it. Because there are no antibodies involved, laboratory tests that measure serum antibodies may be normal. Instead, the presence of sensitized T cells and the delayed time course are key clues.

Distinguishing Features and Exam Clues 🔍

In exams, you will often need to decide which type of hypersensitivity is operating based on a short clinical vignette. The most helpful clues are the time course after exposure, the involvement of antibodies versus T cells, and the pattern of tissue injury.

Immediate onset within minutes with wheeze, hypotension, or urticaria strongly suggests Type I. Presence of IgE, atopy, or prior allergy history points in the same direction.

Evidence of antibodies directed at a specific cell type or membrane structure supports Type II. Information about hemolytic anemia, thrombocytopenia, or receptor antibodies is typical. A fixed target and relatively direct damage to those cells is central.

Systemic symptoms with immune complex deposition in multiple organs, especially kidneys and joints, point toward Type III. Descriptions of serum sickness like illness after certain drugs or foreign proteins are classic. Granular immune complex deposition on immunofluorescence is a typical pathology clue.

Delayed skin reactions after a patch or intradermal injection and mention of T cells or macrophages indicate Type IV. A time lag of 1 to 3 days, and resolution over several days, fits with delayed type responses.

Remember that a single disease can involve more than one type at the same time, but test questions usually focus on the dominant or most characteristic mechanism. When reading vignettes, pairing the mechanism with the type using quick phrases can help, such as IgE with Type I, anti cell IgG or IgM with Type II, immune complexes with Type III, and T cells with Type IV.