Hypersensitivity and Immunological Disorders

Hypersensitivity is the pathological consequence that leads to the fatal host responses mediated by the immune system. It occurs when a pre-sensitized immune system of the host overreacts in response to an antigen.

Hyperactive immune system thus produces effector molecules that induce inflammatory responses, which is undesirable to the hosts.

P. G. H. Gell and R. R. A. Coombs classified hypersensitivity reactions into four types based on the reactions involved and mediators. They are type I or IgE-mediated hypersensitivity, type II or antibody-mediated hypersensitivity, type III or immune complex-mediated hypersensitivity, and type IV or delayed-type hypersensitivity. Among these four types, first three are categorized under humoral immune responses and the last one is under cell-mediated immune response. Types I, II, and III are also called immediate hypersensitivity due to their earlier onset.

5.4.1 Type I or IgE-Mediated Hypersensitivity

Type I hypersensitivity reactions occur in response to some antigens called allergens that bind with IgE molecules. The allergen-IgE complexes thus produced attach with the mast cells or basophils to cause degranulation and release some inflammatory mediators. It can take 15-30 min from the time of exposure to the antigen. The allergens are of different types. They may be pollens of birch tree, rag seed, or rapeseed oil; drugs such as penicillin or salicylate; foods like nuts, eggs, or seafood; and insect products like bee venom and animal hair. Type I hypersensitivity reaction is mediated by IgE, which binds with the primary cellular components of type I hypersensitivity reactions of mast cell or basophil. The other cellular components such as platelets, neutrophils, and eosinophils help to amplify the reaction.

5.4.1.1 Mechanism of Type I Hypersensitivity Reaction

Production of IgE antibody: The initial response of type I hypersensitivity is similar humoral response, except the nature of antibody produced.

In exposure to normal antigens, IgG or IgM is produced, but in response to allergens, IgE is produced.

Sensitization: The IgE antibody thus produced binds with FcRI receptors present in mast cells or basophils and sensitizes them. It is also called pre-sensitization of immune system against the particular allergen.

Shocking dose of antigen: The second exposure of the allergens is called shocking dose. During the second exposure, the allergens bind with Fab region of IgE molecules attached on the surface of mast cells or basophils during the pre-sensitization stage.

Activation and degranulation of mast cell: Binding of allergens to IgE antibody causes the activation of mast cells or basophils through intracellular signaling cascade by phosphorylation, adenylation, and methylation. The activated mast cells undergo degranulation and release certain pharmacologically active substances of various functions detailed in Table 5.12.

5.4.1.2 AnaphylacticReactions

Pharmacologically active substances released from mast cells cause vasodilation, smooth muscle contraction, mucus production, and sneezing that leads to allergic response either localized or systemic.

5.4.1.3 Examples of Type I Hypersensitivity Reactions

The manifestation of type I hypersensitivity reactions could be either localized or systemic. The generalized type I hypersensitivity leads to systemic anaphylaxis (anaphylactic shock) with a short period of time after the exposure of the allergens. Lung is the primary target organ for most of the domestic animals, but in dogs, the liver is mostly affected. The clinical signs include excitement, pruritus, salivation, vomiting, dyspnea, convulsions, or even death. The localized type I hypersensitivity includes allergic rhinitis, asthma, allergic enteritis, and atopic dermatitis.

5.4.2 Type II or Antibody-Mediated Hypersensitivity

In this reaction, the antibodies (IgG or IgM) induced against cellular antigens and this antibody-mediated immune reaction lead to cellular damage by either of the three mechanisms.

1. The antibodies bind with the target cell that expresses the antigen. The Fc portion of the antibody binds with Fc receptor of the phagocytic cells and leads to the opsonization. The opsonin then activates phagocytic cell, and the target cell is phagocytosed. In some cases, the Ag-Ab complex activates complement system and terminal complement complex (C5b6789) and lysis of target cells. This is called antibody-dependent cellular cytotoxicity (ADCC). The classical examples are autoimmune hemolytic anemia and erythroblastosis fetalis.

2. The activation of complement complex leads to the formation of C3a and C5a that are extremely chemotactic and attracts neutrophils and eosinophils towards target cells. The reactive oxygen species generated in neutrophils then destruct the cell (e.g., Goodpasture syndrome).

3. Autoantibodies cause cellular dysfunctions without inflammation or cell lysis. In Graves’ disease, the autoantibodies bind with thyrotropin receptors, which leads to overproduction of thyroid hormones.

Table 5.12 Pharmacologically active substances of type I hypersensitivity reactions

Mediators	Functions
Histamine	Bronchoconstriction, mucus secretion, vasodilatation, and increased vascular permeability
Tryptase	Proteolysis
Kininogens	Vasodilatation, vascular permeability, edema
Eosinophil chemotactic factor of anaphylaxis (ECF-A)	Attracts eosinophil and neutrophils
Leukotriene B4	Attracts basophils
Leukotriene C4, D4	Similar to histamine but 100 times more potent
Prostaglandins D2	Edema and pain
Platelet-activating factor (PAF)	Platelet aggregation and heparin release

5.4.3 Type III or Immune Complex-Mediated Hypersensitivity

In this condition, larger amount of Ag-Ab complexes causes tissue-damaging reactions.

The reaction usually takes 3-10 h after exposure to the antigen in a pre-sensitized individual. The tissue damage is caused by neutrophils, macrophages, or other phagocytes. At first, the Fc region of the antibody binds with Fc receptors present in the phagocytes, and activation of the receptors leads to the production of inflammatory mediators such as prostaglandins, leukotrienes, nitric oxide, cytokines, and chemokines and promotes inflammation and migration of neutrophils at the site. When the neutrophils try to destroy the immune complexes, they deposit their granular contents in the surrounding structures like basement membrane and collagen fiber and disrupt them. In some cases, the migration of neutrophils occurs in response to chemotactic complement products (C3a and C5a). The severity of the reaction depends upon the amount of Ag-Ab complex and their site of deposition. It may cause localized tissue reactions at the site of deposition. The typical reactions are systemic lupus erythematosus and Arthus reaction in the skin. Sometimes, the immune complexes are deposited in various tissues via blood, and the reactions develop at their site of tissue deposition. The examples are lupus nephritis in kidneys, aspergillosis in lungs, polyarteritis in blood vessels, and rheumatoid arthritis in joints.

5.4.3.1 The Arthus Reaction

It is a localized type III hypersensitivity reaction due to the formation of Ag-Ab complexes after the intradermal injection of an antigen. The immune complexes form local vasculitis. It is seen very frequently after the vaccination against diphtheria and tetanus.

Know More.......

Some dogs develop “blue eye,” corneal edema, and opacity after infected or vaccinated with live canine adenovirus type 1. It usually takes 1-3 weeks after the exposure and resolves by its own after the elimination of the virus.

5.4.4 Type IV or Delayed-Type Hypersensitivity

It is mediated by antigen-specific T cells. The type I reaction differs from other types of hypersensitivity in terms of the time taken to respond.

It usually takes 1-3 days after the antigenic exposure and hence is called delayed type. Another important unique feature of type IV hypersensitivity from other types is the involvement of T cells in contrast to antibody as in other three types. Here, in this reaction, the antigens after processing and presentation by ABP stimulate type 1 helper T (TH1) cells to secrete cytokines and chemokines like IFN-γ, TNF-α and -β, and interleukin 2 (IL-2). TNF-α and -β increase the vascular permeability, and IFN-γ causes macrophage activation to secrete their lethal contents and subsequent tissue damage. Type IV hypersensitivity reaction is important for intracellular pathogens where antibodies are unable to reach. The lethal damage to the tissue causes the destruction of pathogens together with the cells. Type IV hypersensitivity reaction is of three types.

The contact hypersensitivity dermatitis occurs when an exogenous antigen invades the skin and induces inflammatory reaction in dermis and epidermis. The antigen-presenting dendritic cells and Langerhans cells process the antigen and present to type 1 helper T (TH1) to induce inflammatory reaction.

Tuberculin-type hypersensitivity occurred in response to intradermal injection of purified protein derivative (PPD) named tuberculin (product of tuberculosis bacillus). It is used to detect tuberculosis in animals.

Granulomatous-type hypersensitivity occurs in more serious condition when the recruited macrophages are unable to destroy the antigens. As a result, more number of macrophages are recruited and these macrophages filled with intracellular antigen lead to granuloma.

5.4.5 Immunological Disorders in Animals

5.4.5.1 Thyroiditis

In this condition, the antibodies are generated against thyroglobulin or thyroid peroxidase. The lymphocytes invade the thyroid gland and cause epithelial cell destruction through antibody-dependent cell-mediated cytotoxicity. The clinical manifestations include dry and dull hair coat, loss of hair, scaling, hyperpigmentation, and pyoderma.

Thyroiditis is common in dogs that are more susceptible, and susceptible dog breeds are Beagles, Great Danes, and Doberman.

5.4.5.2 Polyneuritis

It is an autoimmune disease against myelin proteins of nerve tissues. It occasionally occurs in horses and dogs. The characteristic symptoms are hyperesthesia and paralysis of tail, rectum, and urinary bladder. Sometimes, facial and trigeminal paralysis also occurs. In dogs, the disease is also called “coonhound paralysis” as it occurs as a result of bite or scratches from raccoons.

5.4.5.3 Uveitis/Blue Eye

It is an autoimmune disorder in response to autoantigen interphotoreceptor retinoid-binding protein and is characterized by the inflammation of uveal tract (iris and ciliary body) of the eye. It can be seen in horses and dogs. In horses, the inflammatory site is infiltrated with Th1 cells and neutrophils along with fibrin and C3 depositions, which may lead to blindness. In puppies, uveitis may develop after vaccination with canine adenovirus (CAV)-2-modified live viral vaccine and the prognosis is good. The characteristic symptoms include conjunctivitis, ulcers in cornea, vascularization, and corneal scarring.

5.4.5.4 Immune-Mediated Hemolytic Anemia

The immune-mediated hemolytic anemia occurs due to the production of autoantibodies against RBC membrane proteins like glycophorins, spectrin, and anion-exchange protein CD233. It occurs in cattle, horses, dogs, cats, and mice. The major clinical manifestations are anemia and others secondary symptoms like fever, jaundice, tachycardia, and splenomegaly.

5.4.5.5 Myasthenia Gravis

It is a skeletal muscle disease that occurs due to the formation of autoantibodies against acetyl choline receptor, which leads to blockage of the receptors and complement-mediated destruction of the receptors, which ultimately causes nerve impulse transmission. The clinical signs are abnormal fatigue, muscle weakness, and exercise intolerance. The species involved are dogs, cats, ferrets, and humans.

5.4.5.6 Systemic Lupus Erythematosus (SLE)

It is an autoimmune disorder due to the development of autoantibodies against nucleic acids, nucleoproteins, and chromatin. These autoantibodies are called antinuclear antibodies. It is a classic example of type III hypersensitivity reaction. The immune complexes are deposited in various tissues like glomeruli to form glomerulonephritis, synovial joints to form arthritis, arteriolar walls leads to fibrosis and skin leads to ulcerative lesions. It is mostly seen in dogs with symptoms like localized ulceration in the skin and mucous membrane, glomerulonephritis, lymph node enlargement, splenomegaly, nervous symptoms like lameness, and lethargy. In equines, SLE is characterized by skin diseases like dermal ulceration, alopecia, and crusting together with anemia.

5.4.5.7 Rheumatoid Arthritis

It is an immune complex-mediated hypersensitivity reaction that occurs in response to the deposition of immune complexes in the joints. It is very common in humans but is occasionally seen in dogs (mostly in toy breeds) characterized by lameness immediately after awaking in the morning in addition to anorexia, depression, and pyrexia.

5.4.5.8 Canine Leukocyte Adhesion Deficiency

It is an autosomal recessive genetic disorder due to mutation in integrins, the cell adhesion molecule. The neutrophils are unable to adhere with vascular endothelium and thus unable to migrate to the site of injury (see Sect. 5.2.9—Leukocyte migration). The affected dogs are prone to recurrent infections. Leukocyte adhesion deficiency is also seen in cows.

Learning Outcomes

• Antigens: Antigens are the molecules that bind specifically with the products of immune response (i.e., antibodies or cytotoxic T lymphocytes) induced by immunogens, and this property is called antigenicity. The antigenicity is determined by several factors such as foreignness, chemical structure and molecular size, doses, and route of administration. Antigens can be classified into exogenous and endogenous based on their source. Antigens can also be classified into complete antigen (immunogen), incomplete antigen (hapten), and superantigen based on immune responses.

• Innate immunity: Innate immunity is the evolutionary nonspecific defensive reflex against foreign materials owned by birth. It serves as the first line of defense against infection. Components of innate immunity include anatomical barriers (skin and mucosal membrane), physiological barriers (body temperature, pH, and several other soluble factors), immune effector cells (granulocytes, monocytes/ macrophages, natural killer cells, dendritic cells, endothelial cells, epithelial cells, lymphoid cells, and platelets), pattern recognition receptors [Tolllike receptors, C-type lectin receptors, nucleotide- binding oligomerization domain (NOD) receptors, and retinoic acid-inducible gen-I (RIG)-like receptor], inflammatory serum proteins/acute-phase proteins (haptoglobin, serum amyloid A, ceruloplasmin), antimicrobial peptides (AMPs), complement system, and cytokines.

• Adaptive immunity: Adaptive or acquired immune responses are capable of selective elimination pathogens. It has some cardinal features like specificity, diversity, and memory. It also has a unique ability to discriminate the self and nonself antigens and to react accordingly. Adaptive immune responses are brought about by different classes of lymphocytes, namely B and T lymphocytes. The immune responses mediated through B lymphocytes are called antibody-mediated or humoral immune response as B cells are capable

(continued) of producing antibodies (or immunoglobulins) upon antigenic exposure, which bind with antigens and make them vulnerable for destructions. The cell- mediated immune responses are mediated through T lymphocytes that produce signals to activate phagocytic cells to destroy them.

• Hypersensitivity: It is the pathological consequence that leads to the fatal host responses mediated by the immune system when a pre-sensitized immune system of the host overreacts in response to an antigen. It can be classified into type I or IgE-mediated hypersensitivity, type II or antibody-mediated hypersensitivity, type III or immune complex-mediated hypersensitivity, and type IV or delayed-type hypersensitivity. Among these four types, first three are categorized under humoral immune responses and the last one is under cell-mediated immune response. Type I, II, and III are also called immediate hypersensitivity due to their earlier onset.

Exercises

Objective Questions

Q1. Arrange the biomolecules in their ascending order of immunogenic response proteins, polysaccharides, lipopolysaccharides, and nucleic acid.

Q2. Acute-phase protein associated with copper transport is

Q3. Which biomolecule protects host cells from complement-associated lysis?

Q4. The primary lymphoid organ of birds is____________.

Q5. Which immunoglobulin is predominant in external secretions?

Q6. Viral proteins are associated with which class of MHC? Q7. Anaphylactic shock is an example of ____________________ hypersensitivity.

Q8. Name one autoimmune disease associated with skeletal muscle.

Subjective Questions

Q1. Mention some features of acquired immunity.

Q2. Briefly describe the mechanism of action of cytokines.

Q3. How MHC helps to discriminate self and nonself?

Q4. Explain the inflammatory signs under the light of its cellular events.

Q5. “Thymus is the organ of tolerance”.... Justify the statement.

Answer to Objective Questions

A1. Proteins > polysaccharides > lipopolysaccharides > nucleic acid

A2. Ceruloplasmin

A3. Glycophorin A

A4. Bursa of Fabricius

A5. IgA

A6. Class I MHC

A7. Type I

A8. Myasthenia gravis

Keywords for Subjective Questions

A1. Specificity, diversity, memory, discrimination of self and nonself

A2. Receptor binding, intracellular signaling, response

A3. Antigen processing and presentation, exogenous antigen, MHC II, endogenous antigens, MHC I

A4. Vasodilation, redness, tissue permeability, edema

A5. T lymphocyte selection, positive, negative

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