Hypersensitivity – Definition, Types, Mechanisms

What is Hypersensitivity?

• Hypersensitive (also known as hypersensitivity reaction or intolerance) refers to unwanted immune system responses, such as allergies and autoimmunity.
• “Hypersensitivity illnesses” is frequently used interchangeably with “allergy”, meaning that all hypersensitivity reactions are immunologically-mediated (IgE and non-IgE).
• Reactions to hypersensitivity can range from moderate to life-threatening. Mild responses include itching and sneezing, although life-threatening anaphylactic reactions may occur.
• The cost of medication, doctors, and hospitalisation to address these diseases has direct economic effects. Indirect costs include lower productivity and the necessity to switch occupations in order to eliminate or reduce exposure to a harmful chemical.
• These reactions are typically referred to as an immune system overreaction, and they can be destructive and painful.
• The human immune system is a crucial aspect of the body’s protection against infection; yet, the immune system’s general defensive reaction can occasionally be damaging to the host. These responses are known as hypersensitivity responses, and their study is known as immunopathology.
• This phrase arose from the notion that individuals who have previously been exposed to an antigen and subsequently exhibited observable reactions to that antigen are considered to be sensitised.
• Endogenous self-antigens or exogenous antigens are capable of inducing hypersensitivity responses. Immune responses to endogenous or self-antigens contribute to the development of autoimmune disorders.
• Immune response against exogenous antigens, such as microbial and non-microbial (drugs, foods, pollens, chemicals, and dust) components, can take a variety of forms.
• Some of the most common reactions to exogenous antigens result in allergy, a group of diseases characterised by a wide range of symptoms including itching, rash, fever, asthma, and anaphylaxis.
• Generally, hypersensitivity occurs when there is an imbalance between the effector mechanisms and the regulator mechanisms that normally operate to limit such reactions.
• Specific genes are associated with the development of type I hypersensitivity responses. HLA genes and numerous non-HLA genes have been linked in a number of infection-specific instances.
• Hypersensitivity responses may also result from immunological reactions involving particular T-cells or IgG antibodies. While these effectors often contribute to the immune response’s defence against infection, they also induce acute or chronic hypersensitivity reactions in response to noninfectious antigens.
• Due to the complexity of the subject matter, it is difficult to provide a comprehensive explanation of all areas of immunology in this article.
• Symptoms and signs of hypersensitivity reactions vary considerably. Rhinitis and ocular conjunctivitis, cramps and diarrhoea, asthma-like respiratory obstruction, and skin rashes are included. In extreme, life-threatening reactions, bronchial blockage and/or vascular collapse may occur.

Causes Of Hypersensitivity Diseases

Hypersensitivity diseases can be caused by immune reactions against antigens derived from several sources.

1. Autoimmunity

• Failure of the normal mechanisms of self-tolerance results in autoimmunity, or reactions against one’s own cells and tissues.
• The disorders resulting from autoimmunity are known as autoimmune diseases. It is believed that 2% to 5% of the population in affluent nations suffers from autoimmune diseases, and the prevalence of these conditions is on the rise.
• Many of these disorders are prevalent among adults aged 20 to 40. They are also more prevalent in women than in men for unknown reasons.
• Chronic and persistent, autoimmune illnesses impose a tremendous medical and economic burden.
• In the early 21st century, numerous new treatments for various ailments based on scientific principles have been discovered; these are among the most astounding achievements in medicine.

2. Reactions against microbes

• If immune responses against microbial antigens are high or the microorganisms are unusually persistent, illness may result.
• This is the cause of tissue damage in tuberculosis and several other chronic infections, where T cell responses against persistent bacteria can lead to severe inflammation and granuloma formation.
• If antibodies are created against microbial antigens, they may attach to the antigens to generate immune complexes that deposit in tissues and cause inflammation.
• Antibodies or T cells against a microorganism may rarely cross-react with the tissue of the host.
• In some disorders involving the intestinal tract, called inflammatory bowel disease, the immune response is focused towards commensal bacteria that usually exist in the gut and cause no harm.
• Sometimes the immune response to a disease-causing agent is completely normal, but host tissues are harmed during the process of eradicating the infection.
• In viral hepatitis, the virus that infects liver cells is not cytopathic, but the immune system recognises it as foreign.
• This normal immune response damages liver cells as cytotoxic T lymphocytes (CTLs) seek to destroy infected cells. This reaction is not considered hypersensitivity.

3. Reactions against environmental antigens

• Nearly 20% of the population reacts abnormally to one or more of these environmental toxins, despite the fact that the vast majority of healthy persons do not react to these compounds.
• These people develop immunoglobulin E (IgE) antibodies, which are responsible for allergy disorders.
• Some individuals get sensitised to environmental antigens and chemicals that come into touch with the skin, leading to T cell reactions that culminate in cytokine-mediated inflammation and contact sensitivity.

In all of these circumstances, the processes that cause tissue damage are identical to those that ordinarily kill pathogenic germs. Among these mechanisms are innate immunological responses, T lymphocytes, assorted other effector cells, and inflammatory mediators. The difficulty with hypersensitivity illnesses is that the response is inappropriately induced and maintained. Because the stimuli for these abnormal immune responses (such as self antigens, commensal microbes, and environmental antigens) are difficult or impossible to eliminate and the immune system has many built-in positive feedback loops (amplification mechanisms), it is difficult to control or terminate a pathologic immune response once it has begun. Consequently, these hypersensitivity illnesses have a propensity to be chronic and progressive, posing significant therapeutic hurdles in clinical medicine.

Mechanisms Of Hypersensitivity Reactions

Commonly, hypersensitivity illnesses are categorised based on the type of immune response and the effector mechanism responsible for cell and tissue damage. This classification was created by two British immunologists, Philip Gell and Robin Coombs, at the outset.

Type I Hypersensitivity

• The most widespread type of hypersensitivity disorder is immediate hypersensitivity (type I hypersensitivity), which is produced by IgE antibodies specific for environmental antigens and mast cells.
• Immediate hypersensitivity diseases, also known as allergic or atopic disorders, are the prototypical diseases resulting from the activation of the TH2 subset of helper T cells, in which the T cells induce the synthesis of IgE antibodies and inflammation.

Type II Hypersensitivity

• By activating the complement system, recruiting inflammatory cells, and interfering with normal cellular activities, IgG and IgM antibodies can cause tissue damage.
• Some of these antibodies are specific for antigens of particular cells or the extracellular matrix and are discovered either attached to these cells or tissues or as unbound antibodies circulating in the blood; the diseases generated by such antibodies are termed type II hypersensitivity disorders.

Type III Hypersensitivity

• Other antibodies may form immunological complexes in the circulation, which are then deposited in tissues, especially blood vessels, and cause damage. Immune complex diseases are sometimes known as hypersensitivity disorders of type III.

Type IV

• T lymphocytes that produce inflammation or directly kill target cells can cause tissue damage; these illnesses are known as type IV hypersensitivity disorders.
• We now understand that many hypersensitivity disorders are caused by the activation of TH1 or TH17 subsets of helper T cells, which produce cytokines that induce inflammation, and that the recruited leukocytes, primarily neutrophils and macrophages, are responsible for tissue harm.
• Additionally, helper T cells drive the creation of antibodies that are damaging to tissues and inflamatory. In some disorders, CTLs may potentially contribute to tissue harm.

Therapeutic Approaches For Immunologic Diseases

The creation of innovative medicines based on an understanding of fundamental science and its application to human disease has been one of the most remarkable achievements of immunology. Therapies can be categorised into numerous main categories.

1. Anti-inflammatory Agents

• Anti-inflammatory medications, namely corticosteroids, have been the cornerstone of hypersensitivity illness treatment for many years.
• These medications aim to reduce tissue damage, specifically the inflammatory component of pathological immune responses.

2. Depletion of Cells and Antibodies

• Antibodies that decrease all lymphoid cells, only B cells, or exclusively T cells are administered.
• Anti-CD20 antibody (rituximab), which depletes exclusively B cells, has been used successfully to treat disorders that were previously believed to be caused primarily by T cell–mediated inflammation.
• Some patients with rheumatoid arthritis and multiple sclerosis have exhibited positive responses to this medication. Plasmapheresis has been utilised to remove autoantibodies and immune complexes from circulation.

3. Anti-Cytokine Therapies

• A significant range of inflammatory cytokines are being addressed by specialised antagonists for the treatment of T cell-mediated chronic inflammatory disorders.
• The first achievement with this class of biologic treatments was a soluble version of the TNF receptor and TNF-neutralizing anti-TNF antibodies.
• Numerous patients with rheumatoid arthritis, Crohn’s disease, and psoriasis benefit greatly from these medications. Antibodies against various proinflammatory cytokines, such as IL-1, the p40 chain found in both IL-12 and IL-23, IL-6, IL-17A, and numerous more, are in use or in clinical development for the treatment of inflammatory illnesses.

4. Agents That Inhibit Cell-Cell Interactions in Immune Responses

• B7 costimulator-blocking agents are licenced for the treatment of rheumatoid arthritis and psoriasis, and are currently being evaluated for SLE and other illnesses.
• Antibodies against CD40 ligand inhibit T cell–mediated activation of B cells and macrophages and have been found to be beneficial in patients with inflammatory bowel disease; however, a small number of treated patients have developed thrombotic episodes, presumably because this molecule is expressed on human platelets (where its function is unknown).
• Multiple sclerosis has been treated using anti-integrin antibodies to prevent leukocyte migration into tissues, particularly the central nervous system (CNS).

5. Intravenous IgG

• In certain hypersensitivity illnesses, large doses of intravenous IgG (IVIG) are useful. It is unclear how this drug inhibits immunological inflammation; nevertheless, it is possible that the IgG binds to the inhibitory Fc receptor (FcRIIB) on macrophages and B cells, thereby dampening inflammatory reactions.
• IVIG may also compete with pathogenic antibodies for binding to the neonatal Fc receptor (FcRn), which in adults serves to protect antibodies from catabolism, hence reducing the half-lives of the pathogenic antibodies.
• Ongoing efforts include developing tolerance in disease-producing T cells and creating regulatory T cells that are selective for self antigens.
• Multiple sclerosis and type 1 diabetes are two immunological illnesses for which the target antigens have been identified; in both cases, antigens to inhibit specific immune responses are being tested in clinical studies.
• Numerous medications that inhibit specific immune system components pose the risk of interfering with the immune system’s natural function in combating germs, hence making persons susceptible to infection.
• Antigen Specific Tolerance circumvents this issue by targeting just the disease-causing lymphocytes. These general ideas are comparable to those upon which transplant rejection management is based.

Types/Classification of Hypersensitivity

Five types of hypersensitivity reactions can be distinguished.

• Type I: Immediate response mediated by IgE
• Type II: Reaction mediated by antibodies (IgG or IgM antibodies)
• Type III:Immune complex-mediated type III response
• Type IV: delayed cytotoxic, cell-mediated hypersensitivity
• Type V (Stimulatory Type) Hypersensitivity

1. Type I hypersensitivity

• Type I hypersensitivity is produced by IgE antibody and resulting in anaphylactic reactions to insect venoms, drugs, and foods.
• These allergic reactions are systemic or local because allergens induce IgE antibody production.
• Type I hypersensitivity is caused by an antigen cross-link to a basophil or mast cell’s membrane-bound IgE antibody.
• During an anaphylactic reaction, histamine is released and causes potential tissue damage within the body.

Characteristics

• It is also known as acute hypersensitivity or anaphylaxis and is mediated by IgE.
• The reaction happens with second allergen exposure. First exposure (sensitising dose) sensitises the host to allergen, and subsequent exposure (s) (shocking dose) causes an allergic reaction.
• Sensitized animals have anaphylactic shock within seconds to minutes (15 to 30 after exposure to the allergen) after exposure to the antigen, now known as an allergen. Sometimes the reaction’s onset may be delayed (10-12 hours).
• In type I hypersensitivity reactions, the allergens are proteins between 10 and 40 kDa in molecular weight.
• Diagnostic tests for acute hypersensitivity include skin (prick and intradermal) tests that produce a wheal and flare reaction, measurement of total IgE and specific IgE antibodies against the suspected allergens by ELISA, and the Radioallergosorbent test (RAST).

Mechanism of Type-I hypersensitivity

• The reaction mechanism involves preferential IgE synthesis in response to specific antigens (allergens).
• Individuals prone to type-I hypersensitivity produce IL-4 and IL-13, which favour IgE class switch, more frequently.
• The Fc component of IgE binds to the FcIII and CD23 receptors found on the surface of mast cells and basophils.
• A subsequent exposure to the same allergen cross-links the cell-bound IgE and induces the release of numerous pharmacologically active chemicals through a process known as ‘degranulation’; mast cell degranulation is preceded by an important increase in Ca++ influx.
• These substances trigger the initial phase of allergic responses, which manifests minutes after antigen exposure.
• Cross-linking of the IgE Fc-receptor is essential for mast cell activation.
• Degranulation of cells leads to the creation and secretion of inflammatory mediators, including platelet-activating factor, leukotreins, bradykinins, prostaglandins, and cytokines, which contribute to inflammation.
• PAF (platelet activation factor), which stimulates platelet aggregation and release of histamine, heparin, and vasoactive amines, amplifies the reaction. Eosinophil chemotactic factor of anaphylaxis (ECF-A) and neutrophil chemotactic factors, respectively, attract eosinophils and neutrophils, which then release different hydrolytic enzymes that cause necrosis.
• These substances trigger the initial phase of allergic responses, which manifests minutes after antigen exposure.
• Late phase allergy responses may develop several hours following antigen exposure.
• Cell-bound IgE on the surface of basophils of sensitive individuals binds a chemical known as histamine releasing factor (perhaps generated by macrophages and B-lymphocytes), resulting in the release of more histamine.

Effects of Type-I Hypersensitivity

The following results from the release or production of inflammatory agents:

• Dilation of blood vessels, resulting in local redness (erythema) at the allergen injection site. This can contribute to lower vascular resistance, a reduction in blood pressure, and shock if dilatation is widespread.
• Increased capillary permeability, which induces localised tissue enlargement (edema). If widespread, it can decrease blood volume and cause shock.
• Bronchial airway constriction, resulting in wheezing and trouble breathing.
• Stimulation of mucous secretion, which causes airway congestion.
• Stimulation of nerve endings, which causes skin irritation and discomfort.

Pathology of Type-I hypersensitivity

• Type I is primarily composed of mast cells and basophils. Platelets, neutrophils, and eosinophils modify and/or amplify the reaction.
• The reaction may affect the skin (urticaria and eczema), the eyes (conjunctivitis), the nasopharynx (rhinorrhea, rhinitis), the bronchopulmonary tissues (asthma), and the gastrointestinal tract (gastroenteritis). The reaction may result in anything from a small annoyance to death.
• In the majority of domesticated species, the lungs are the primary target organs and the portal-mesenteric vasculature is a secondary target; however, in dogs, the roles are inverted.
• The liver is the primary organ affected by anaphylactic shock in dogs, and indications are related with constriction of hepatic veins, which results in portal hypertension and visceral blood pooling. Dogs are more likely to have gastrointestinal than respiratory symptoms.
• Human IgE-mediated illnesses include systemic anaphylactic shock, asthma, allergic rhinitis (hay fever), tropical pulmonary eosionophila, allergic conjunctivitis, skin reactions (urticaria, eczema), and food allergies.
• Systemic anaphylactic shock, urticarial reactions (hives), atopic dermatitis, food allergies, allergic enteritis, atypical interstitial pneumonia in cattle, chronic allergic bronchitis and pulmonary infiltration with eosinophilia in dogs, and allergic bronchiolitis and asthma in cats are IgE-mediated diseases in animals.

Type-I Hypersensitivity Summary Table

Alternative Name	Allergic hypersensitivity
Principle	Antibody-mediated degranulation of granulocytes leads to the destruction of cells.
Primary Mediator	IgE
Other components as mediators	Mast cells, Basophils, histamine & other pharmacological agents
Reaction time	Immediate or within a few hours
Antigen	Free in circulation (Soluble)
Antigen origin	Exogenous
Antibody	Fixed on mast cells and basophils
Mechanism	IgE antibodies specific for allergens bind to mast cells via their Fc receptor. When a specific allergen binds to IgE, cross-linking of IgE triggers mast cell degranulation.
Complement activation	No
Appearance	Weal & flare
Transfer with serum	Passive transfer possible with serum
Desensitization	Easy but short-lived
Examples	Asthma, Rhinitis, Atopic eczema, Bee sting reaction

2. Type II Hypersensitivity (Antibody-mediated cytotoxic hypersensitivity)

• Type II hypersensitivity reactions are triggered by the toxic characteristics of antibodies bound to cell-surface antigens.
• Antibodies can trigger complement-dependent lysis, which damages tissue. In a cytotoxic reaction, the antibody responds directly to the antigen bound to the cell membrane in order to induce complement-mediated cell lysis.
• These antigens may be “self,” as in autoimmunity, or “non-self.”
• IgM and IgG are mediators of cytotoxic responses. One of the best instances of cytotoxic reactions is a newborn’s Rh-incompatibility. Blood transfusion responses, Good pasture’s syndrome, and autoimmune disorders are more instances.

Characteristics

• Type II hypersensitivity refers to antibody-mediated cytotoxic reactions that occur when an antibody binds to cell-surface antigens (usually RBCs). The response time ranges from minutes to hours.
• It is predominantly mediated by IgM or IgG antibodies.
• The antibody may induce cell lysis by activating the conventional complement system, enhancing phagocytosis (opsonization), or via ADCC.
• This cell death may be triggered by a variety of antigens, but an infection in a genetically susceptible animal appears to be the most important trigger.
• Antigens are often endogenous, although exogenous substances (haptens, such as poison ivy or medications) that may adhere to cell membranes and trigger type II reactions are also capable of doing so.
• Examples include autoimmune hemolytic anaemia, transfusion responses, erythroblastosis fetalis, drug-induced hemolytic anaemia, granulocytopenia, and thrombocytopenia.

Mechanism of Type II Hypersensitivity

• IgM or IgG antibodies are produced against self antigens either due to a loss of immunological tolerance or the development of cross-reactive antibodies during infection, which can bind to normal tissue antigens and induce antibody-mediated cytotoxicity.
• The consequence of the subsequent binding of these antibodies to the surface of host cells is:
  • Opsonization is the process by which phagocytes adhere to host cells via IgG, C3b, or C4b and then release their lysosomes.
  • Classical complement pathway activation resulting in MAC-induced lysis.
  • ADCC mediates the death of host cells by the attachment of NK cells to the Fc region of the antibodies.

Pathology of Type II Hypersensitivity

• Abs directed against antigens located on cell surfaces or the extracellular matrix (type IIA) or Abs with agonistic/antagonistic characteristics mediate this interaction (type IIB).
• Blood cells are the most common type of involved cells. The result could be:
  • hemolytic anemia if RBCs are involved,
  • leukopenia involving WBCs, or
  • thrombocytopenia involving platelets.
• Under some circumstances, a cytotoxic attack on vascular epithelial cells will cause a vasculitis with local vascular leakage.
• The lesion contains antibody, complement and neutrophils.

Examples of Type II Hypersensitivity

Blood group AB and Rh responses (blood transfusion reactions, erythroblastosis foetalis)

Autoimmune diseases:

• In rheumatic fever, antibodies cause damage to joints and heart valves.
• Idiopathic thrombocytopenia purpura in which antibodies cause platelet breakdown.
• In myasthenia gravis, antibodies attach to acetylcholine receptors on muscle cells, resulting in abnormal muscular enervation.
• In Goodpasture’s syndrome, antibodies cause the death of kidney cells.
• Graves’ disease is characterised by the production of antibodies against thyroidstimulating hormone receptors on thyroid cells, resulting in impaired thyroid function.
• Multiple sclerosis characterised by the production of antibodies against the oligodendroglial cells that produce myelin, the protein that forms the myelin sheath that insulates the nerve fibres of neurons in the brain and spinal cord.

Alternative Name	Cytotoxic hypersensitivity
Principle	Antibody-mediated destruction of healthy cells.
Primary Mediator	IgG/IgM
Other components as mediators	Complement, Neutrophils
Reaction time	5-8 hours
Antigen	Fixed on cells
Antigen origin	Exogenous or endogenous
Antibody	Free in circulation
Mechanism	IgG or IgM antibody binds to cellular antigen, resulting in activation of the complement system and cell lysis. IgG is also capable of facilitating ADCC with cytotoxic T cells, natural killer cells, macrophages, and neutrophils.
Complement activation	Yes
Appearance	Lysis & necrosis
Transfer with serum	Passive transfer
Desensitization	Easy but short-lived
Examples	Rhesus incompatibility (Rh hemolytic disease), Transfusion Reactions, Cell Destruction due to autoantigens, Drug-Induced Hemolytic Anemia

3. Type – III Hypersensitivity (Immune complex mediated hypersensitivity)

• The development of antigen-antibody complexes promotes type III hypersensitivity. IgG and IgM bind antigen, deposit antigen antibody (immune) complexes.
• This complex promotes the complement system, which influences PMN chemotaxis and initiation. PMNs then release enzymes that damage tissue into the cell.
• Serum sickness is one of the most common forms of type III hypersensitivity response in the human body.

Characteristics

• In type III hypersensitivity, soluble immune complexes are generated in the blood, deposited in various tissues (usually skin, kidney, and joints), activate the classical complement system, and result in inflammatory damage.
• It is mediated by immunological complexes that are soluble. They are predominantly IgG, however IgM may also be present.
• The reaction takes between three and ten hours to develop.
• Exogenous (chronic bacterial, viral, or parasite infections) or endogenous (self-produced) antigens may be present (non-organ specific autoimmunity: e.g., Systemic Lupus Erythematosus-SLE).
• The antigen is water-soluble and is not linked to the affected organ.
• A sustained presence of soluble antigen and antibody is required for the development of an immune-complex illness.

Mechanism of Type III Hypersensitivity

• Complexes of soluble antigen-antibody (IgG or IgM) are typically eliminated by macrophages in the spleen and liver.
• On production of excessive quantities or big immune complexes, these become lodged in capillaries, pass between endothelial cells of blood vessels – particularly those of the skin, joints, and kidneys – and become trapped on the basement membrane surrounding these cells.
• The Ag-Ab complexes subsequently activate the traditional complement pathway, with platelets and neutrophils causing the damage:
  • Massive inflammation, attributed to complement protein C5a.
  • Due to complement protein C5a, an influx of neutrophils causes neutrophils to release their lysosomes, resulting in tissue damage and additional inflammation.
  • The MAC caused the death of adjacent tissue cells.
  • platelet aggregation, leading in increased inflammation and the production of capillary-blocking microthrombi.

Pathology of Type III Hypersensitivity

• The affinity of antibodies and the size of immune complexes are crucial for the development of disease and identification of the implicated tissue.
• The lesion is predominantly composed of neutrophils, immune complex deposits, and complement.
• Later-stage infiltrating macrophages may have a role in the healing process.
• The route by which antigen enters the body has a significant impact on the placement of immune complexes:
  • Antigens inhaled through the lungs cause pneumonitis.
  • Antigens that penetrate the skin result in localised skin lesions.
  • Antigens that enter the bloodstream generate immune complexes that are deposited in the glomeruli of the kidneys or the joints.
• Variable clinical manifestations may include fever, dermatological manifestations, polyarthritis, ataxia, behavioural changes, or nonspecific manifestations such as vomiting, diarrhoea, or abdominal pain.

Alternative Name	Immune complex hypersensitivity
Principle	Antigen-antibody complex-mediated destruction of cells.
Primary Mediator	IgG/IgM
Other components as mediators	Complement, phagocytes and K cells
Reaction time	2-8 hours
Antigen	Free in circulation ( Soluble)
Antigen origin	Exogenous or endogenous
Antibody	Free in circulation
Mechanism	In tissues, antigen-antibody complexes are deposited. Activation of the complement produces inflammatory mediators and attracts neutrophils. Neutrophil-released enzymes are destructive to tissue.
Complement activation	Yes
Appearance	Erythema & edema
Transfer with serum	Passive transfer
Desensitization	Easy but short-lived
Examples	Glomerulonephritis, Systemic Lupus Erythematosus, Farmer’s lung arthritis, Vasculitis

4. Type – IV Hypersensitivity (Cell Mediated Hypersensitivity) (Delayed Type Hypersensitivity)

• Initial descriptions of delayed or type IV hypersensitivity focused on the duration of the responses, which took 12 to 24 hours to develop and persisted for two to three days.
• T-lymphocytes initiate cell-mediated responses, which are then mediated by effector T-cells and macrophages.
• This reaction contains the antigens bound to the lymphocyte surface. Lymphocytes that have been pre-sensitized can generate cytokines, which can cause cell damage.
• Many chronic illnesses, such as tuberculosis, have delayed type hypersensitivity.

Characteristics of Type IV Hypersensitivity

• As the reaction takes more than 12 hours to develop, type IV hypersensitivity is also known as delayed type hypersensitivity. The maximal reaction time is typically between 48 and 72 hours.
• It is mediated by cells that induce an inflammatory response to external or endogenous antigens.
• The predominant cells are T lymphocytes and monocytes/macrophages.
• T cells and antigen-presenting cells (APC) release cytokines that trigger a local inflammatory response in a sensitised individual in response to foreign antigens.
• DHR cannot be transmitted via antibodies or serum from one animal to another. However, it is transmissible by T cells, specifically CD4 Th1 cells.

Mechanism of Type IV Hypersensitivity

• CD8 cytotoxic T cells and CD4 helper T cells detect antigens bound to type I or type II MHC antigens.
• In this instance, macrophages serve as antigen-presenting cells; they secrete interleukin 1, which further encourages the growth of CD4 cells.
• Other lymphokines involved in delayed hypersensitive reaction include monocyte chemotactic factor, TNF, etc.
• Keratinocytes, APC, and T cells create cytokines that recruit antigen-nonspecific T cells and macrophages to engage in a local inflammatory response.
• Activated CD8 cells destroy target cells upon contact, whereas activated macrophages create hydrolytic enzymes and develop into large cells with many nuclei.

Pathology of Type IV Hypersensitivity

• Many autoimmune and infectious disorders (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis, etc.) and granulomas caused by infections and foreign antigens are associated with Type IV hypersensitivity.
• There are three types of delayed hypersensitivity, and their maximum reaction time is indicated between brackets:
  • Contact (48 to 72 hours)
  • Tuberculin (48 to 72 hours)
  • Granulomatous (21 to 28 days)
• Lesions of delayed hypersensitivity consist predominantly monocytes and a few T lymphocytes.
  • Contact: Infiltrates of mononuclear cells are present in both the dermis and epidermis.
  • Tuberculin: leukocyte infiltration of the skin
  • Granulomatous: epithelioid-cell granuloma and large cells at the lesion’s centre, surrounded by lymphocytes.

Alternative Name	Cell-mediated hypersensitivity/ Delayed type of hypersensitivity
Principle	T lymphocytes mediated the destruction of cells.
Primary Mediator	Specific subsets of CD4+ helper T cells or CD8+ cytotoxic T cells.
Other components as mediators	Dendritic cells, macrophages, and cytokines
Reaction time	After 24 hours only, mostly 48-72 hours after contact
Antigen	Soluble or cell-bound
Antigen origin	Exogenous or endogenous
Antibody	Not applicable
Mechanism	Th2 cells secrete cytokines, which activate macrophages and cytotoxic T cells.
Complement activation	No
Appearance	Erythema & induration
Transfer with serum	Cannot be transferred with serum; but possible with T cells transfer
Desensitization	Difficult but long-lived.
Examples	The tuberculin reaction, Granuloma formation, Allergic contact dermatitis, Type-1 diabetes

5. Type V (Stimulatory Type) Hypersensitivity

• In this form of hypersensitive reaction, antibodies bind with antigens on the cell surface, inducing cell proliferation and differentiation and boosting the activity of effector cells.
• The type V hypersensitivity reaction plays a crucial part in the pathophysiology of Graves’ disease, in which excessive thyroid hormones are produced.
• Long-acting thyroid-stimulating antibody, which is an autoantibody to thyroid membrane antigen, is hypothesised to combine with thyroid-stimulating hormone (TSH) receptors on the surface of a thyroid cell.
• Graves’ illness is caused by the interaction between the TSH receptor and TSH, which exerts a similar effect to that of TSH and results in the overproduction and secretion of thyroid hormone.

Diagnosis of Hypersensitivities

• The diagnosis of type I hypersensitivities is a difficult procedure requiring multiple diagnostic tests and a meticulously recorded medical history. Serum IgE levels can be tested, although a higher IgE level does not necessarily indicate allergy.
• In order to determine the antigens responsible for a type I response allergy, a prick-prick skin test (PPST) or an intradermal test can be conducted.
• On the patient’s back or arms, allergens are introduced by a series of superficial skin pricks during PPST.
• According to the US Joint Council of Allergy and the European Academy of Allergy and Immunology, PPSTs are the most practical and cost-effective method for diagnosing allergies.
• The second method of testing, intradermal testing, involves injecting a tiny needle into the dermis. This needle, also known as a tuberculin needle, is connected to a syringe that contains a small quantity of allergen.
• Both the PPST and intradermal tests require 15–20 minutes of observation for a wheal-flare reaction to allergens.
• The stronger the wheal-flare reaction, the higher the patient’s sensitivity to the allergen.
• Because of their general inflammatory character, Type III hypersensitivities are often misdiagnosed. The symptoms are readily apparent, but they may also be connected with a variety of other conditions.
• A robust and exhaustive patient history is indispensable for thorough and accurate diagnosis. Bronchoalveolar lavage (BAL), pulmonary function tests, and high-resolution computed tomography are tests used to establish the diagnosis of hypersensitivity pneumonitis (coming from type III hypersensitivity) (HRCT).

Treatments of Hypersensitivities

• There are numerous treatments for allergic responses. Desensitization (hyposensitization) therapy, which reduces the hypersensitivity reaction through repeated allergen injections, can be used to prevent allergic reactions.
• Extremely diluted amounts of known allergens (measured by allergy testing) are injected at predefined intervals into the patient (e.g., weekly).
• The amount of allergen administered by the injections is gradually increased over a building time until an effective dose is identified, and this level is then maintained for the length of the treatment, which can last for years.
• In the event that the allergens administered create a significant systemic reaction, patients are typically advised to remain in the doctor’s office for 30 minutes following an injection.
• The offices of physicians who conduct desensitisation therapy must be equipped to provide resuscitation and pharmacological treatment in the event of an allergic reaction.
• Insect sting and environmental allergies are treated with desensitisation therapy. Instead of IgE, allergy injections induce the development of various interleukins and IgG antibody responses.
• When allergen-specific IgG antibodies are produced in excess and attach to the allergen, they can function as blocking antibodies to prevent the allergen from binding to IgE on mast cells. There are promising early investigations of oral treatment for desensitisation of food allergies.
• These trials involve gradually administering allergens (e.g., peanut flour) or similar proteins to children with allergies. As a result of the treatment, the severity of the reaction to the food allergen has decreased in a number of patients.
• Additionally, there are treatments for severe allergic reactions. Initial treatment for systemic anaphylaxis is an injection of epinephrine, which can offset the decline in blood pressure.
• Individuals with known severe allergies frequently carry an auto-injector for use in the event of contact to the allergen (e.g., an insect sting or accidental ingestion of a food that causes a severe reaction).
• By self-administering one or two epinephrine injections, the patient can halt the reaction long enough to seek medical assistance. Antihistamines and slow-acting corticosteroids are typically administered to the patient for several days following the reaction to prevent potential late-phase reactions.
• However, the effects of antihistamine and corticosteroid treatment have not been adequately explored, and they are employed on the basis of theoretical concerns.
• In most cases, antihistamines and other anti-inflammatory medicines are used to treat milder allergic reactions.
• Antihistamine medications are available in both prescription and over-the-counter formulations. There are also antileukotriene and antiprostaglandin medicines that can be used in conjunction with antihistamines for a more successful combined therapy.
• Treatments for hypersensitivities of type III include limiting future antigen exposure and the use of anti-inflammatory medications. Some conditions can be treated by preventing antigen exposure.
• Inhalers containing anti-inflammatory corticosteroids can also be used to reduce inflammation and allow lung lesions to heal. Treatment with oral or intravenous corticosteroids is frequent for type III hypersensitivities involving bodily systems.
• The treatment for hypersensitivity pneumonitis includes avoiding the allergen and, if necessary, anti-inflammatory prescription medicines such as prednisone.
• Type IV hypersensitivities are treated with antihistamines, anti-inflammatory medications, analgesics, and, if possible, the elimination of additional antigen exposure.

Selected Immunologic Diseases: Pathogenesis And Therapeutic Strategies

In the part that follows, we detail the pathogenesis of certain diseases caused by antibodies and T cells, as well as the application of novel therapeutics to these diseases, to demonstrate the previously described ideas.

Systemic Lupus Erythematosus: The Prototypic Immune Complex–Mediated Disease

• SLE is a chronic, remitting and relapsing, multisystem autoimmune illness that primarily affects women, with a female-to-male ratio of 10:1 and an incidence of 1 in 700 among women between the ages of 20 and 60 (approximately 1 in 250 for black women).
• Principal clinical signs include rashes, arthritis, and glomerulonephritis; however, hemolytic anaemia, thrombocytopenia, and involvement of the central nervous system are also prevalent. Multiple autoantibodies are detected in SLE patients.
• Antinuclear antibodies, especially antiDNA antibodies, are the most common; others include antibodies against ribonucleoproteins, histones, and nucleolar antigens.
• Immune complexes produced from these autoantibodies and their unique antigens are the cause of glomerulonephritis, arthritis, and vasculitis affecting the body’s tiny arteries.
• Hemolytic anaemia and thrombocytopenia are caused by erythrocyte- and platelet-specific autoantibodies, respectively.
• The presence of antinuclear antibodies is the primary diagnostic test for the condition; antibodies against double-stranded native DNA are specific for SLE.

Pathogenesis of Systemic Lupus Erythematosus

• SLE is a complex disease in which environmental and genetic variables contribute to the loss of tolerance in self-reactive B and T cells.
• Among the genetic factors is the transmission of certain HLA alleles. The odds ratio (relative risk) for persons with HLA-DR2 or HLA-DR3 is 2 to 3, and the odds ratio is approximately 5 if both haplotypes are present.
• In around 10% of SLE patients, genetic deficits of classical route complement proteins, specifically C1q, C2, or C4, are observed.
• The deficits in complement may lead to poor clearance of immunological complexes and apoptotic cells, as well as the absence of B cell tolerance.
• Some patients have been shown to have a polymorphism in the inhibitory Fc receptor FcRIIB; this may contribute to insufficient inhibition of B cell activation immunological cells.
• Genome-wide association studies have identified a large number of additional genes, but their roles and contributions to the development of the disease remain unknown. Environmental considerations include exposure to ultraviolet (UV) light.

• It is hypothesised that this results in apoptotic cell death and the release of nuclear antigens.
• Recent observations have led to the development of new hypotheses on the pathophysiology of SLE. First, patient investigations have demonstrated that blood cells exhibit a remarkable molecular signature (pattern of gene expression) that suggests exposure to IFN-, a type I interferon that is mostly produced by plasmacytoid dendritic cells.
• According to a number of studies, plasmacytoid dendritic cells from SLE patients also produce unusually high levels of IFN. Toll-like receptors (TLRs) that identify DNA and RNA, particularly the DNA-recognizing TLR9, play a crucial role in the activation of B lymphocytes specific for self nuclear antigens, according to animal model research.
• A model for the pathogenesis of SLE has been developed on the basis of these investigations.
• UV irradiation and other environmental stressors result in cell death, according to this concept.
• Due in part to abnormalities in clearance systems such as complement proteins and receptors, inadequate clearance of the nucleus of these cells leads in a high load of nuclear antigens.
• Polymorphisms in several lupus susceptibility genes result in impaired ability to maintain self tolerance in B and T cells, resulting in the survival of self-reactive lymphocytes.
• Failure of B cell tolerance may be caused by receptor editing, faulty elimination of immature B cells in the bone marrow, or faulty peripheral tolerance.
• Self-nuclear antigens excite self-reactive B cells that have not been rendered tolerant, resulting in the production of antibodies against the antigens.
• Antigen-antibody complexes can be internalised via binding to Fc receptors on dendritic cells and the antigen receptor on B cells.
• The nucleic acid components activate TLRs and encourage B cells to make autoantibodies, as well as activating dendritic cells, especially plasmacytoid dendritic cells, to create IFN-, which further enhances the immune response and induces additional apoptosis.
• The end result is a cycle of antigen release and immune activation that results in the development of high affinity autoantibodies or a failure to suppress innate inflammatory responses.

New Therapies for Systemic Lupus Erythematosus

• Recent breakthroughs in our understanding of SLE have led to the development of novel therapy strategies.
• The efficacy of anti–IFN- antibodies is being evaluated in clinical studies, and efforts to suppress TLR signals are being examined.
• Using an antibody against the B cell surface protein CD20 to deplete B cells has generated significant interest. For the treatment of SLE, an antibody that inhibits the B cell growth factor BAFF has now been licenced.

Rheumatoid Arthritis

• The inflammatory disease rheumatoid arthritis (RA) affects the small and big joints of the extremities, including the fingers, shoulders, elbows, knees, and ankles.
• The condition is characterised by inflammation of the synovium, loss of cartilage and bone in the joint, and a morphology that suggests a local immune response.
• It is possible that both cell-mediated and humoral immune responses contribute to the development of synovitis. Inflamed synovium contains CD4+ TH1 and TH17 cells, activated B lymphocytes, plasma cells, and macrophages, as well as other inflammatory cells; in severe cases, lymphoid follicles with germinal centres may be present.
• In the synovial (joint) fluid, several cytokines, including IL-1, IL-8, TNF, IL-6, IL-17, and IFN-, have been discovered.
• It is hypothesised that cytokines recruit leukocytes whose products cause tissue damage and stimulate resident synovial cells to create proteolytic enzymes, such as collagenase, that mediate breakdown of cartilage, ligaments, and tendons of the joints.
• The release of the TNF family cytokine RANK (receptor activator of nuclear factor B) ligand by activated T cells may be responsible for the increased osteoclast activity in the joints that contributes to bone loss in RA.
• RANK ligand stimulates the differentiation and activation of osteoclast precursors by binding to RANK, a member of the TNF receptor family expressed on osteoclast precursors.
• Lung damage and vasculitis, probably produced by immune complexes, are systemic consequences of rheumatoid arthritis.
• Although T cells have been the primary focus of research on RA, antibodies may potentially contribute to joint damage.
• Frequently, the synovia of afflicted joints contains activated B cells and plasma cells. Patients commonly have IgM or IgG antibodies that react with the Fc (and infrequently the Fab) regions of their own IgG molecules.
• These autoantibodies are referred to as rheumatoid factors, and their existence is utilised to diagnose RA. Rheumatoid factors may be involved in the production of harmful immune complexes, although their pathogenic role has not been determined.
• Antibodies specific for cyclic citrullinated peptides (CCP), which are produced from particular proteins changed in an inflammatory milieu by the enzymatic conversion of arginine residues to citrulline, have been found in at least 70% of patients.
• These so-called antiCCP antibodies serve as a disease marker and may be involved in tissue damage.

Pathogenesis of Rheumatoid Arthritis

• Similar to other autoimmune illnesses, RA is a complicated disorder in which genetic and environmental variables contribute to the loss of self-antigen tolerance.
• Because the specificity of pathogenic T and B cells is unclear, our understanding of pathophysiology is insufficient.
• The HLA-DR4 haplotype correlates with RA susceptibility. Recent linkage and genome-wide association studies have identified a large number of genes whose polymorphisms are related with rheumatoid arthritis (RA).
• There is a relationship with the PTPN22 gene, which encodes a tyrosine phosphatase, however the function of this enzyme in lymphocyte control remains unclear.
• Anti-CCP immune responses have led to new theories on the pathophysiology of RA.
• According to one theory, environmental insults, such as smoking and some diseases, cause the citrullination of self-proteins, which results in the formation of new antigenic epitopes. Failure of tolerance to these epitopes in genetically vulnerable people results in T cell and antibody responses against the proteins.
• If these altered self-proteins are also present in the joints, T cells and antibodies will target the joints. TH17 and maybe TH1 cells generate cytokines that recruit leukocytes to the joint and stimulate synovial cells to manufacture collagenases and other enzymes.
• The end effect is increasing cartilage and bone degeneration. The immunological response in the joint may be powerful enough to induce the formation of tertiary lymphoid tissues in the synovium, which may maintain and perpetuate the local inflammatory response.

New Therapies for Rheumatoid Arthritis

• Understanding the essential function of T cells and cytokines in the disease has resulted in a tremendous advancement in treatment based on the targeting of specific molecules.
• Principal among these novel medicines are TNF antagonists, which have altered the disease history in many patients from relentless and inexorable joint destruction to smouldering but controlled chronic inflammation.
• An IL-1 antagonist, an antibody against the IL-6 receptor, and a fusion protein consisting of the extracellular domain of CTLA-4 and the Fc part of IgG, which binds to B7 molecules and inhibits B7:CD28 interactions, are all authorised therapy.
• Antibodies that inhibit IL-17 are undergoing clinical testing. In some cases, the B cell-depleting anti-CD20 antibody is beneficial.
• The positive effect of B cell elimination does not appear to be fully attributable to decreased autoantibody formation, suggesting that B cells may play additional functions in the disease, such as presenting antigens to harmful T cells.

Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

• Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) in which CD4+ T cells of the TH1 and TH17 subsets react against self myelin antigens, causing inflammation in the CNS with activation of macrophages around nerves in the brain and spinal cord, destruction of the myelin, abnormalities in nerve conduction, and neurologic deficits. It is the most prevalent neurologic condition among young adults.
• On pathologic inspection, the white matter of the CNS is inflamed and demyelinated secondarily. Multiple sclerosis is characterised clinically by weakness, paralysis, and ocular symptoms with exacerbations and remissions; CNS imaging reveals that there is frequent new lesion formation in patients with ongoing illness.
• Experimental autoimmune encephalomyelitis (EAE) in mice, rats, guinea pigs, and nonhuman primates serves as a model for the disease since it is one of the best-characterized experimental models of an organ-specific autoimmune disease mediated mostly by T cells.
• Animals are immunised with antigens normally found in CNS myelin, such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein, together with an adjuvant containing heat-killed mycobacterium, which is required to elicit a robust T cell response.
• Animals develop encephalomyelitis 1 to 2 weeks after vaccination, which is characterised by perivascular infiltrates of lymphocytes and macrophages in the white matter of the CNS, followed by demyelination.
• Lesions of the nervous system can be modest and self-limiting or chronic and recurring. These lesions cause gradual or intermittent and recurrent paralysis.
• Using T cells from infected animals, the illness can also be transmitted to healthy animals. Although antibodies against myelin antigens have been found in both people and animal models, the pathogenic significance of these antibodies has not yet been determined.

Pathogenesis of Multiple Sclerosis

• There is ample evidence that activated CD4+ TH1 and TH17 cells specific for myelin protein antigens cause EAE in mice.
• MS is believed to be caused by myelin-specific TH1 and TH17 cells, as these cells have been discovered in patients and isolated from their blood and CNS.
• The activation of these cells in patients remains a mystery. Molecular mimicry suggests that an infection, most likely a viral infection, triggers self-myelin-reactive T cells.
• It is possible for self-tolerance to fail due to the inheritance of susceptibility genes. Identical twins have a concordance rate of 25% to 40% for the development of multiple sclerosis, but nonidentical twins have a concordance rate of 1%, suggesting genetic influences in the disease’s development.
• MS is connected with genetic variations at the HLA locus, with the HLA-DR2 relationship being the greatest.
• Genome-wide association studies have uncovered a link between a variation in the noncoding region of the CD25 gene encoding the chain of the IL-2 receptor and a disease.
• Expression of CD25 on effector and memory T cells may differ between patients and healthy individuals, although it is unclear how this contributes to disease.
• Some studies have revealed that MS patients have faulty regulatory T cells, however it is unknown how this relates to a lack of self-tolerance.
• Once myelin-specific T cells are activated, they travel into the central nervous system (CNS), where they encounter myelin proteins and produce cytokines that recruit and activate macrophages and more T cells, resulting in the destruction of myelin.
• Epitope spreading appears to be the mechanism through which EAE spreads, according to studies on the disease.
• The disintegration of tissue results in the release of new protein antigens and the development of new, previously sequestered epitopes, which activate additional autoreactive T lymphocytes.

New Therapies for Multiple Sclerosis

• Immunotherapy treatment multiple sclerosis has depended heavily on methods whose scientific basis is not yet fully understood.
• The administration of -interferon, which may affect cytokine responses, and treatment with a random polymer of four amino acids, which is hypothesised to bind to HLA molecules and inhibit antigen presentation, are examples of such interventions.
• Patients have benefited from the use of an antibody against the VLA-4 integrin to inhibit leukocyte migration into the CNS.
• In a tiny proportion of patients, however, this treatment reactivated a latent JC virus infection that produces a severe and sometimes deadly CNS illness.
• Another recently approved treatment for MS inhibits leukocyte migration. The fingolimod (FTY720) medication inhibits the sphingosine 1-phosphate–mediated mechanism of T cell egress from lymphoid organs.
• In a substantial subset of patients, B cell depletion has been proven to be beneficial. These data show a significant role for B cells in the activation of pathogenic T lymphocytes.
• Due to the fact that myelin basic protein is an important self antigen that is the target of the immune response in multiple sclerosis, attempts have been made to inject peptides derived from this antigen into patients in the hopes of inducing tolerance or producing regulatory T cells specific to the relevant antigen.

Type 1 Diabetes Mellitus

• Type 1 diabetes mellitus, formerly known as insulin-dependent diabetes mellitus, is a multisystem metabolic illness caused by decreased insulin production. It affects approximately 0.2% of the U.S. population, with a peak age of start between 11 and 12 years, and its incidence is rising.
• The condition is marked by hyperglycemia and ketoacidosis. Progressive atherosclerosis of arteries, which can lead to ischemia necrosis of limbs and internal organs, and microvascular blockage that damages the retina, renal glomeruli, and peripheral nerves are chronic consequences of type 1 diabetes.
• Insulin insufficiency due to immune-mediated death of the insulin-producing cells of the islets of Langerhans in the pancreas necessitates constant hormone replacement therapy for these individuals.

Pathogenesis of Type 1 Diabetes

• Inflammation driven by CD4+ TH1 cells reactive with islet antigens (including insulin), CTL-induced lysis of islet cells, local production of cytokines (TNF and IL-1) that damage islet cells, and autoantibodies against islet cells may all contribute to cell loss.
• The islets exhibit cellular necrosis and lymphocytic infiltration comprised of both CD4+ and CD8+ T lymphocytes in the rare instances where pancreatic lesions have been studied during the early active phases of the disease.
• This condition is known as insulitis. In addition, autoantibodies against islet cells and insulin are identified in these patients’ blood.
• In vulnerable youngsters (such as relatives of patients) who have not yet developed type 1 diabetes, the existence of antibodies against islet cells is predictive of the development of the disease, suggesting that these antibodies are harmful.
• A useful animal model of the condition is the non-obese diabetic (NOD) mouse, which develops diabetes spontaneously. In this model, there is evidence of poor regulatory T cell survival and function, as well as effector T cell suppression resistance.
• Type 1 diabetes is connected with many genes. Significant focus has been placed on the function of HLA genes.
• 90% to 95% of Caucasians with type 1 diabetes have HLA-DR3, DR4, or both, compared to 40% of normal persons; 40% to 50% of patients are DR3/DR4 heterozygotes, compared to 5% of normal subjects.
• Intriguingly, vulnerability to type 1 diabetes is linked to alleles of DQ2 and DQ8 that are frequently in linkage disequilibrium with DR3 and DR4.
• Several non-HLA genes also play a role in illness development. Insulin is the first to be identified; tandem repetitions in the promoter region are connected with disease vulnerability.
• This association’s mechanism is unknown, although it may be related to insulin expression in the thymus, which controls whether insulin-specific T cells are eliminated (negatively chosen) during maturation.
• Several additional polymorphisms, including those in the IL-2 and CD25 genes, have been discovered in patients and NOD mice. Unknown are the functional effects of these polymorphisms.
• Several studies indicate that viral infections (such as coxsackievirus B4) may precede the onset of type 1 diabetes, possibly by commencing cell injury, generating inflammation and the production of costimulators, and initiating an autoimmune response.
• Nevertheless, epidemiological data imply that repeated infections protect against type 1 diabetes, comparable to the NOD model.
• In fact, it has been hypothesised that the management of infectious diseases contributes to the increased prevalence of type 1 diabetes in affluent nations.

New Therapies for Type 1 Diabetes

• The most promising novel therapy approaches for type 1 diabetes involve establishing tolerance with diabetogenic peptides derived from islet antigens (such as insulin) or creating or giving patients regulatory T cells.
• These clinical trials have just begun.

Inflammatory Bowel Disease

• Inflammation driven by T cells produces intestinal harm in Crohn’s disease and ulcerative colitis, the two diseases comprising inflammatory bowel disease.
• Chronic inflammation and breakdown of the intestinal wall, with frequent fistula formation, characterise Crohn’s disease.
• Lesions in ulcerative colitis are restricted to the mucosa and consist of ulcers with underlying inflammatory foci.
• Antibodies against TNF, IL-17, and the p40 chain of IL-12 and IL-23 are newly developed treatments for these disorders.

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