Hypersensitivity Reactions

Hypersensitivity Reactions

• Immune responses can cause tissue injury and disease.
• Aberrantly directed or excessive immune reactions are called hypersensitivity reactions.
• Hypersensitivity can occur against foreign antigens (from microbes/environment) or self-antigens due to failure of self-tolerance.
• Reactions against self-antigens are autoimmunity, and result in autoimmune diseases.

Types of Hypersensitivity Reactions

• Classified based on the primary immunological mechanism responsible for tissue injury/disease.
• Type I: Immediate hypersensitivity, mediated by mast cells releasing mediators, often dependent on IgE antibody against environmental antigens.
• Type II: Antibody-mediated, where antibodies (typically IgG) directed against cell or tissue antigens cause harm or impair function.
• Type III: Immune complex diseases, result from Antibodies (usually IgG) forming complexes with soluble antigens that deposit in blood vessels.
• Type IV: T cell-mediated diseases caused by T lymphocyte reactions to self-antigens or microbes in tissues.
• Human diseases exhibit both antibody and T cell-mediated reactions, making classification complex.

Immediate Hypersensitivity

• IgE antibody- and mast cell-mediated reaction to antigens causing rapid vascular leakage, excessive mucosal secretions, and smooth muscle contraction, followed by inflammation.
• Allergy/atopy refers to IgE-mediated immediate hypersensitivity, atopic individuals are prone to these reactions.
• Allergic disorders include hay fever, food allergies, asthma, atopic dermatitis, and anaphylaxis.
• In allergic reactions, Th2 cells and IL-4/IL-13-secreting Tfh cells activate, stimulating IgE antibody production in response to an antigen.
• Upon subsequent exposure, the antigen cross-links bound IgE on mast cells, activating them and releasing mediators.
• Reactions involve a rapid increase in vascular permeability and smooth muscle contraction (immediate) and cytokine-mediated recruitment of neutrophils/eosinophils (late-phase).

Th2 Cell Activation and IgE Antibody Production

• Individuals prone to allergies experience Th2 cell activation, IL-4, and IL-13-secreting Tfh cell activation, and IgE antibody production upon exposure to some antigens.
• Many people do not have strong Th2 responses to environmental antigens.
• A strong response happens when people encounter proteins in pollen, insect venom, certain foods, dander, or certain drugs.
• IL-5 and IL-13 may be produced early by Group 2 innate lymphoid cells (ILC2s).

Mast Cell Activation and Mediators

• IgE antibody made in response to an allergen binds to high-affinity Fc receptors on mast cells.
• Process of coating mast cells with IgE = sensitization.
• Non-allergic persons also carry diverse IgE specificities, with individual antigen IgE not concentrated enough to trigger reaction.
• Mast cells under epithelia, close to vessels, are activated based on allergen route, i.e. inhaled activating bronchial submucosa, ingested activating intestine.
• FceRI (high-affinity IgE receptor) on mast cells is cross-linked by the allergen binding to IgE which activates the mast cells to secrete inflammatory mediators.
• Mediators of importance include vasoactive amines/proteases (histamines), arachidonic acid metabolites, and cytokines.
• Histamine increases vascular permeability, vasodilation, and stimulates muscle contraction.
• Prostaglandins cause vascular dilation, leukotrienes stimulate prolonged bronchial smooth muscle contraction, and cytokines induce inflammation.
• Mast cell cytokines recruit leukocytes (eosinophils, neutrophils, Th2 cells) relating to late-phase response.
• TNF and IL-4 mediate inflammation.
• Chemokines aid leukocyte entry.
• Th2's also cause cytokine creation, and eosinophils trigger tissue harm which are paramount in allergic reactions and cause damage.

Allergic Diseases and Therapy

• Immediate hypersensitivity reactions have diverse clinical and pathological features depending on mediators and tissues.
• Rhinitis/sinusitis (hay fever) result from nasal mucosa mast cells creating histamine/Th2 cells generating IL-13 leading to mucus.
• Ingested allergens resulting in mast cell degranulation leads to histamine release causing intestinal peristalsis increasing, and diarrhea/vomiting.

Clinical Syndromes

• Allergic rhinitis/sinusitis involves mucus secretion and upper airway/sinus inflammation.
• Food allergies lead to intestinal muscle contraction, increasing peristalsis.
• Bronchial asthma involves bronchial smooth muscle hyperactivity causing airway obstruction/inflammation.
• Anaphylaxis shock is resulted from vascular dilation/airway obstructions, and bronchial constriction.
• Atopic dermatitis involves itchy red/scaly skin regions.

Immediate Hypersensitivity Treatments

• Therapy inhibits mast cell degranulation, antagonizes mediator effects, and reduces inflammation.
• Common drugs include antihistamines for hay fever, B-adrenergic agonists/corticosteroids for asthma, and epinephrine in anaphylaxis.
• Desensitization therapy includes continued small dose administration.
• Drugs blocking IgE binding on mast cells, or blocking cytokine receptors like IL-4, IL-5, TSLP work for asthma, and atopic dermatitis.
• IgE antibody- and mast cell-mediated immune responses may protect against pathogens/toxins.
• Eosinophils fight helminthic infections, mast cells help promote initial immunity against some bacteria and toxins from venomous species of animal including snakes/arachnids.

Diseases Caused by Antibodies Specific for Cell and Tissue Antigens

• Antibodies (typically IgG) binding to target antigens cause type II hypersensitivity disorders.
• These diseases are usually specific to a particular tissue based on where the cell and matrix components assemble.
• Disease driving antibodies are typically autoantibodies produced as a result of self-tolerance failure.

Mechanisms of Antibody-Mediated Tissue Injury and Disease

• Antibodies deposit in tissues and induce inflammation by attracting and activating leukocytes (IgG1/IgG3 crosslinking triggers neutrophil/macrophage activation).
• IgM/IgG activate classical complement pathway, inducing inflammation.
• Leukocytes release reactive oxygen species and enzymes destroying cells.
• Antibodies binding cell-antigens promote opsonization and phagocytosis.
• Some antibodies cause disease without causing tissue injury like intrinsic factor autoantibodies reduce vitamin B12.
• Antibodies may directly activate receptors mimicking ligands like stimulating thyroid cells by thyroid-stimulating hormone antibodies in Graves = Anti-TSHR antibody disease.

Diseases caused by Cell/Tissue-Specific Antibodies

• Antitissue antibodies that react to the membrane lead to inflammation of glomeruli resulting in glomerulonephritis.
• Anticyte antibodies opsonize cells to trigger hemolysis like in autoimmune anemia and thromboxytopenia.
• Other antibodies relating to receptor blocking like in hyperthyroidism are noted to also.
• Streptoccocal infections stimulate issues in bacterial creation which harms heart inflammation and is shown to be a characteristic of rheumatic fever.
• Antibody-mediated disease therapy reduces immune effects using things like corticosteroids.
• Severe inflammation is reduced by plasmapheresis to eliminate circulating antibodies.
• Hemolytic issues are improved via spleen removal due to macrophages existing within and improving phagocytosis.
• IVIGs are also shown to work for reasons of reducing inflammation and blocking key receptors that help promote issues with the previously listed diseases.
• Drugs blocking the complement or antibodies are designed in order to prevent the production pathway to become too stimulated due to infection.

Diseases Caused by Antigen-Antibody Complexes

• Antibodies (typically IgG) may cause immune complex deposition in vessels.
• Acute/chronic disorders are caused/associated with immune complexes.
• Immune complexes are produced as a result excessive amounts/bad phagocytosis.
• Positively charged antigens can bind with the membrane in vessels.
• Complexes mostly happen under high-pressure plasma filtration within kidney and joint.
• Immune complex diseases are broad, can affect different sites/vasculature.

T Cell-Mediated Diseases

• T cells significantly contribute to chronic diseases where inflammation is prominent.
• New therapies for efficacious treatment attempt to reduce inflammation and activity to key immune T Cells.

Etiology of T Cell-Mediated Diseases

• Autoimmunity/exaggerated responses cause hypersensitivity reactions.
• Autoimmune responses are restricted; do not tend to be systemic.
• Examples include chemical contact sensitivity.
• Microbe-antigen T cell responses may occur (Mycobacterium affecting and causing tuberculosis).
• Bacteria + Viruses = Excessive T cell activity, over inflammatory cytokines.
• Toxins are super antigen, which leads to syndrome development of septic shock.
• Antigen on the presentation regions affects T Cell receptor to trigger super activity that affects T Cell activity to kill and promote excess amounts inflammation across many avenues.

Mechanisms of T Cell-Mediated Tissue Injury

• Tissue injury is caused by cytokines from the CD4+ T Cells.
• Injury replicates same mechanisms used to remove any microbes within other cells.
• CD4+ T Cells cause various diseases via activating specific TH Cells used to recognize different triggers.
• TH1 cause increased cellular and macrophagic activity that damages tissues.
• Hypersensitivity is delayed as it takes several days for T Cells to reach source of infection and damage relating to prior exposure from various reactions.
• DTH (delayed-type sensitivity) leads to infiltration of immune tissue from previously activated infections.
• Infections may vary, like tuberculoid lesions.

Examples of Immune Cell-Mediated Diseases

• Most autoimmune issue arises from issues related on where cells originate, with similar animal models having different cell patterns.
• Disorders come from issues relating to what triggers tissue damage, as the memory of the immune system causes issues that is long and progressive.
• Autoimmune treatments reduce long term inflammation and activity within immune systems via steroids as seen for many years.
• Specific receptors for cells are developed to fix the root pathway of why these issues are happening.
• Receptors relating to TNF + IL-17 are important for inflammation, IL-12 causes T cells to affect.