Topic 16 Hypersensitive Reactions

Introduction

Under some circumstances, immunity, rather than providing protection, produces damaging and sometimes fatal results. Such deleterious reactions are known collectively as hypersensitivity reactions, but remember that they differ from protective immune reactions only in that they are exaggerated or inappropriate and damaging to the host. The cellular and molecular mechanisms of the two types of reaction are virtually identical. Reactions within the humoral branch are initiated by antibody or antigen-antibody complexes and are termed immediate hypersensitivity because the symptoms manifest within minutes or hours following an encounter with antigen by a sensitized recipient. Reactions within the cell-mediated branch are imitated by T_DTH cells are referred to as delayed-type hypersensitivity (DTH) in reference to the delay of symptoms for days following antigen exposure.

Hypersensitivity reactions are divided into four classes, designed types I-IV, by Gell and Coombs. In this lesson we will examine the mechanisms and consequences of the four primary types of hypersensitive reactions.

Objectives

On completion of this section and the required readings, you should be able to:

n list the Gell & Coombs classification for hypersensitivity reactions; give examples of each type;

n describe stimulatory hypersensitivity and give a specific example;

n discuss the difference between primary and secondary exposure to antigen in immunity and in hypersensitivity;

n describe the structural and functional characteristics of IgE;

n discuss the cytotropic nature of IgE;

n describe the role of mast cells in immediate hypersensitivity reactions;

n distinguish between release of preformed and newly formed mediators from mast cells and give examples of each type of mediator;

n discuss the hallmarks of delayed type hypersensitivity;

n explain the mechanisms of Delayed Type Hypersensitivity induction and development;

n distinguish between different types of Delayed type hypersensitivity;

n describe tuberculosis in terms of hypersensitivity reactions.

Required Reading

Please refer to the textbook key for specific readings for this section.

P Key Words

• allergen • allergy • anaphylactic shock • anaphylaxis • anergy • atopy • basophils • contact sensitivity • degranulation • delayed type hypersensitivity • desensitization • granulomas • homocytotropic antibodies • hypersensitivity • hyposensitivity

• immediate hypersensitivity • late phase reaction • mast cells sensitization • sensitizing dose • shocking dose • systemic anaphylaxis • triple response: edema, erythema, wheal and flare • tubercules • tuberculine reaction • tuberculosis • Type I hypersensitivity • Type II hypersensitivity • Type II hypersensitivity • Type IV hypersensitivity

P Key Concepts

n Hypersensitivity reactions are inflammatory reactions within the humoral or cell-mediated branches of the immune system that lead to extensive tissue damage or even death. These reactions are classified into four main types based on the mechanism that induces them.

n Allergy, or type I hypersensitivity, results from the release of pharmacologically active molecules from mast cells. This release is caused by the combination of antigen with IgE bound to receptors on the mast-cell surface. The most important manifestation of anaphylaxis is hay fever, and asthma. The tendency to develop this type of hypersensitivity is inherited.

n Type II hypersensitivity results from the destruction of cells by antibodies or complement. An example of this is the destruction of foreign red blood cells as a result of incompatible blood transfusion.

n Type III hypersensitivity occurs as a result of the deposition of immune complexes in tissues. These immune complexes activate complement and attract neutrophils. The neutrophil enzymes cause damage. Immune complexes deposited in the skin, lungs, joints, or walls of blood vessels therefore causing local inflammatory responses.

n Type IV hypersensitivity reactions result from a cell-mediated response to antigen. They usually take more than 24 hours to develop and are therefore called delayed hypersensitivity reactions. They are mediated by factors released by T cells and macrophages.

DID YOU KNOW?

Case Study 1

At the end of a trip abroad, Yvonne, aged 35, developed acute diarrhea and vomiting. On her return home, she visited her doctor who gave her an antibiotic co-trimoxazole (sulphamethoxazole and trimethoprim), which she was to take for eight days. She finished the course of the antibiotics and three days later developed a headache and red itchy lumps on her skin. This was associated with aching and swollen joints, mainly wrists and knees although her hands were also affected. The headache was not sever, but she decided to visit her doctor.

Yvonne’s doctor confirmed that her rash was urticaria and that her joints were swollen. Her temperature was also raised. Examination of her urine showed evidence of protein, and a full blood count was normal with only minimal elevation of eosinophil count. He gave Yvonne antihistamines and told her that the rash and joint swelling would clear in a few days. A diagnosis of drug allergy was made.

Answer the following questions:

• What type of hypersensitivity is given above?

• What is the likely mechanism of the reaction?

Case Study 2

Simon, a 10 year old school boy, was seen by his doctor with a three week history of polyuria, excessive thirst, and weight loss. Childhood illnesses had included mumps and measles, which resolved without incident. His brother aged seven was fit and well, but there was a family history of thyroiditis and pernicious anaemia.

On examination, Simon was underweight for his age. Respiratory, cardiovascular, and abdominal examinations were unremarkable. Two consecutive random blood glucose tests showed results above 10mmol/l. The indirect immunofluorescence test for circulating pancreatic islet cell antibodies was positive.

A diagnosis of insulin-dependent diabetes mellitus (IDDM) was made. Further tests were performed to eliminate the possibility of other organ-specific autoimmune diseases in the light of an extensive family history. Thyroid function tests were normal and he had no evidence of autoantibodies to thyroid antigens or intrinsic factor. He was given advice about modifying his diet and was started on subcutaneous injections of insulin to normalize his diet and glucose level. At routine follow-up he was coping well with the regimen and had a well-controlled blood glucose level.

Answer the following questions:

• What is the classification of diabetes mellitus?

• What is the immunopathology of IDDM?

• What is the chance of immunotherapy stopping the disease process?

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 17. The answers with explanations are available at the end of the textbook.

2. Multiple Choice Questions

1. Injection therapy (hyposensitization)

A) is safe if used initially with high concentrations of antigen

B) is more effective for symptoms of hay fever than for a wasp sting

C)directly affects stability of membranes

D) is a form of active immunity

E) induces large amounts of endogenous antihistamines

2. Mast granules contain:

A) immunoglobulin

B) complement

C) epinephrine

D) acetyl choline

E) histamine

3. During anaphylaxis, which mast-cell product stops blood clotting?

A) histamine

B) serotinin

C) bradykinin

D) platelet-activating factor

E) heparin

4. Hypersensitivity is due to

A) An altered immune response

B) The presence of an antigen

C) Immunity

D) Allergies

E) The presence of antibodies

5. Allergic contact dermatitis is diagnosed by

A) complement fixation assay

B) provocation test

C) patch test

D) intrapalpebral test

E) intradermal skin test

3. Definitions/Short Answer Questions

1. By derivation, what does allergy mean and what does hypersensitivity mean? Are they synonymous?

2. The main difference between immediate and delayed types of hypersensitivity is the time of appearance of the reactions. True or false? If false, name the main differences.

3. What is the type II reaction described by Gell & Coombs? Does this reaction require complement?

4. Is there a tendency to cause immediate hypersensitivity reactions? Explain.

5. Differentiate between antigen and allergen.

6. What immune and nonimmune cells are involved in immediate hypersensitivity?

7. What class of antibody in responsible for immediate hypersensitivity?

8. Describe some structural and biological characteristics of this antibody.

9. What do we mean by homocytotropic antibodies?

10. Briefly describe the result of the interaction of IgE, with mast cells in the presence of allergen and in the absence of allergen.

11. What are the chemical mediators of immediate hypersensitivity reactions?

12. Some effector molecules of immediate hypersensitivity reactions are preformed mediators; others are newly synthesized mediators. Distinguish between the two.

13. Briefly describe the two pathways for the production of newly synthesized mediators.

14. How can you determine whether a person is allergic to a foreign protein?

15. What is the triple response?

16. What is the mechanism for desensitization for immediate hyper sensitivities?

17. Is this desensitization lifelong? If not speculate on the reasons.

18. What are some other modes of treatment for immediate hypersensitivity?

19. Describe the differences between systemic anaphylaxis and atopy.

20. Are the mechanisms of cell-mediated immunity and DAH the same?

21. Name the effector cells in DAH.

22. What are some of the hallmarks of DAH reactions?

23. Describe contact sensitivity.

24. How does contact sensitivity differ from the tuberculin skin reaction?

25. What is the mechanism of the tuberculin skin test? If the test is positive, what causes the induration (hardening) of the test site?