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Hypersensitivity - Dissertation Sample

06 Mar 2017Dissertation Samples

Hypersensitivity, or allergic, reactions occur when the natural immunological and inflammatory reactions are inappropriately triggered by substances which are normally innocuous [1]. Thus, exaggerated or inappropriate responses of the, normally protective, immune system lead to actual harm of the organism. These hypersensitivity reactions have been classified in 1968 by Gell and Coombs according to their underlying effector mechanisms [2].

This classification distinguishes four types of hypersensitivity reaction and is still widely used today. The first three types of reaction are mediated by antibodies and the fourth is cell-mediated. Since this classification has been made, however, significant progress in the understanding of the molecular and cellular mechanisms of hypersensitivity has occurred and researchers have attempted to revise or reinterpret the logical framework proposed by Gell and Coombs. This paper shall attempt to discuss these classifications, the reactions involved and the conditions that belong to these classes. Towards the end of the paper, the possible relevance to Chinese medicine shall also be discussed.

Hypersensitivity

Type I

The first classification refers to immediate, or anaphylactic, hypersensitivy and occurs when antigenic material, which is not inherently noxious, evokes the immune system to produce IgE antibodies which affix themselves to mast cells. Subsequent contact with this stimuli (whether it was grass pollen, house dust mite particles or some foodstuffs) causes the release of histamine, platelet-activating factor, eicosanoids and cytokines from the mast cells. This release and the subsequent bodily reaction may be localized, for example in the nose during hayfever or the skin, as in urticaria. In other cases the reaction may not be restricted and may be more generalized resulting in anaphylactic shock. One clear cut example of Type I hypersensitivity is the condition known as asthma, where the above reactions occur in the bronchial tree.

Asthma is a syndrome in which a reversible obstruction of the sufferer’s airways occurs in response to stimuli that do not affect non-asthmatic subjects. The characteristic features of asthma are the inflammatory modifications to the airways associated with bronchial hyper-responsiveness [3]. Stimuli which affect asthmatics include emotional disturbances, physical exercise, respiratory tract infection, ingestion of drugs such as aspirin, inhalation of aerosols including fog, or chemicals such as ozone and sulfur dioxide which are common atmospheric pollutants, and allergens in sensitized subjects including parts of house dust, pollen and animal dander [4].

In allergic, or atopic, asthma, primary exposure to the allergens causes sensitization. Ingested allergen is presented to the immune system where it is recognized as being foreign, and in susceptible individuals, causes IgE to be produced. This kind of antibody is the primary kind involved in the initiation of immediate allergic responses. The immune system is thus primed, so that upon subsequent exposure of the immune cells to the particular allergen, several IgE molecules on the cells’ surface will bind the allergen causing inflammatory mediators to be released, which thus leads to the characteristic features of the disease [1]. In 1990, the cost of treating asthma sufferers in the United States was $3.64 billion [5]. It can thus be seen that asthma is major socio-economic problem that leads to a distressing shortness of breath that reduces the quality of life for a significant proportion of the world’s population.

Type II

The second type refers to cytotoxic hypersensitivity, which is dependent on antigen-antibody interactions resulting in the local production of anaphylotoxin (C5a), the recruitment of polymorphonuclear leukocytes (PMNs) and subsequent tissue injury due to the release of hydrolytic neutrophil enzymes after their autolysis. This type of hypersensitivity occurs when the natural mechanism to defend against attack from extracellular pathogens are directed against cells within the host, which are, or appear to be foreign. This reaction can occur after incompatible blood transfusions or if drugs have altered the surface of the host’s cells. Class II reactions are implicated in some types of autoimmune thyroiditis (e.g. the progressive form, Hashimoto’s disease where the immune system reacts against thyroglobulin, or another component of thyroid tissue; patients have goiter and gradually develop hypothyroidism) [6;7].

Type III

Type III hypersensitivity occurs when the antibody–antigen reaction occurs in the blood, forming complexes which are then deposited in the glomerular and/or pulmonary basement membranes. These complexes can activate component or attach to mast cells, thus stimulating the release of mediators. These complexes on the tissues result in tissue injury and compromised function, which is aggravated by the PMNs attracted by the complement. Mast cells, stimulated by C3a, also release mediators. This process has been implicated in conditions known as ‘farmer’s lung’ in the reaction to mouldy hay and in certain types of autoimmune kidney and arterial disease. Systemic lupus erythematosus is a chronic, autoimmune inflammatory disease of connective tissue. Its presentation hasa wide variety of abnormalities including arthritis, nephritis, central nervous manifestations, hemolytic anemia and leukopenia or thromboctopenia [7].

Patients with this disease have antibody–antigen complexes deposited in the renal glomerulus, which causes renal failure [8]. Multi-organ system involvement characteristically occurs during periods of disease activity [9]. The autoantibodies in this case are directed against ubiquitous intracellular antigens such as chromatin and could be due to genetic mutations resulting in the chromatin being recognised as foreign. Although the etiology is unclear, the hormonal status of the patient is important as research has shown that high levels of female sex hormones and progesterone are implicated in the initiation and progression of autoimmune diseases [8].

Type IV

Type IV reactions differ from the first three by being cell-mediated, i.e. mediated by lymphocytes, not antibodies. The autoimmune disease insulitis is an example of this and occurs in the early phases of insulin-dependent diabetes mellitus. Activated T-lymphocytes infiltrate the islet cells in the pancreas and, along with macrophages and natural killer cells, destroy the beta cells via localized release of cytokines, nitric oxide and oxygen free radicals [10]. The free radicals induce DNA damage, which needs NAD+ to be repaired; once the intracellular NAD+ pools are depleted, the islet cells are destroyed. Because the inflammatory response occurs on the surface of the insulin-producing beta cells, these are no longer recognized as self and antibodies are produced against them, which result, over the course of several years, in their destruction and the clinical appearance of diabetes, which is characterized by wide, unpredictable fluctuations of blood glucose values and is difficult to control [11].

Type V

Although widely accepted for many years, the Gell and Coombs classification of hypersensitivity reactions has recently come under fire. Rajan suggests that the confusion caused when trying to fit disorders of the immune system into these four types of reaction could be due to the undue focus on ‘antigens’ [12]. He suggests that, although the immune system does recognize antigens, its primary function and evolutionary drive is to recognize invading organisms. The immunological response to these antigens is thus a by-product of non-self recognition. The classification of Gell and Coombs has thus been avoided by some recent editions of principle textbooks (e.g. Harrison’s Principles of Internal Medicine) in favor of describing immunopathological diseases and conditions in terms of the way the condition is thought to cause injury [13].

Rajan suggests that there is a fifth type of hypersensitivity reaction, which is phylogenetically ancient [12]. Species of insects have been observed to ensheath invading organisms with pseudo-coelomic hemocytes, often followed by a series of reactions resulting in the deposition of melanin and the death of the parasite [14;15]. Melaninization does not appear to be used by mammalian cells but the ensheathment of indigestible foreign material is used and is called granuloma formation. This is orchestrated by the T-cells and is used against inanimate foreign bodies and mycobacteria, fungi and metazoan extracellular parasites.

A potential Type V disease is sarcoidosis. The etiology of this disease is presently unknown but it affects many organs and tissues, notably the lungs. Granulomas are formed on the organs in response to an exaggerated immune reaction mediated by T-cells and IgM antibodies are also implicated. The T-helper cells, together with other inflammatory cells (e.g. macrophages, B cells), compose the granuloma. In some cases, as in tuberculosis, the granuloma forms around the invading mycobacterium so that the foreign substance can be isolated or eliminated [16]. The macrophages release IL-1, IL-6, tumor necrosis factor (TNF), 1,25-dihydroxyvitamin D, and angiotensin-converting enzyme. If the inflammatory reaction is prolonged, fibroblast proliferation mediated by IL-1, IL-6, and TNF occurs with consequent fibrosis of healthy tissue. The affected organ’s function is altered, not by the inflammatory mediators but by the volume the granuloma occupies and the symptoms vary according to the location of the granuloma.

However, the above hypothesis by Rajan has yet to gain favor with other authorities. Type V hypersensitivity has instead been added as a distinction from Type II. This additional class of reaction refers to stimulatory hypersensitivity where, instead of binding to cell surface components and destroying the cells (as happens in Type II), IgG antibodies recognize and bind to the cell surface receptors. IgG bound to the cell surface receptors thus either prevents ligand binding, or mimics the effect of the endogenous ligand, thus impairing cell signaling [17]. This is a useful distinction to Type II reactions where the cytotoxic binding of antibody causes cell death. Stimulatory hypersensitivity occurs when the autoantibodies cause inappropriate stimulation of the cell. A pathological example of this is Graves’ disease (exophthalmic goiter).

During normal functioning, thyroid stimulating hormone (TSH), from the pituitary, binds to the thyroid cell receptors, which thus activates adenylcyclase and the production of cAMP, which aids the stimulation of the thyroid cell. In Graves’ disease, most patients have circulating thyroid stimulating antibodies that are directed towards the site of TSH reception and cause an excessive secretion of iodinated thyroid hormones [7]. This leads to hyperthyroidism and, usually, the development of a goiter, ophthalmic symptoms, tachycardia and excessive perspiration. Type V hypersensitivity has also been implicated in the pathogenesis of neonatal hyperthyroidism, where maternal simulating anti-thyroid IgG antibodies are able to cross the placenta.

Relevance to Chinese medicine

It is unclear what the relevance of the Gell and Coombs classification to Chinese medicine is, as practitioners of this tradition do not follow the ‘Western’ model of medicine, but prefer to treat the whole body (holistic medicine). Traditional Chinese Medicine (TCM) comprises acupuncture, Chinese herbology, massage, exercise and nutritional therapy [18]. The acupuncturist looks for constitutional signs in patients presenting with allergic symptoms. According to TCM, patients with chronic allergies often display signs of spleen or kidney deficiency and lung signs.

A TCM diagnosis typically includes an interview, pulse check, looking at the tongue and inspecting the body to discern the ‘patterns of disharmony’. The acupuncturist develops a treatment plan aimed at addressing the acute symptoms and also the underlying ‘immune system imbalance’ and uses dietary modification, acupuncture and specifically chosen herbal formulae. A typical treatment for allergies would include taking ‘Minor Blue Dragon’ formula, which has decongestant properties and other herbs to ‘tonify’ the lungs and spleen and to avoid dairy products and sweet or spicy foods. Strengthening the immune system consists of replacing coffee with green tea, which is rich in catechins and by taking quercetin, a bioflavonoid, which has been shown to stabilize mast cells, thus slowing the release of chemical mediators.

TCM often views allergic rhinitis, a Type I disorder, as related to Wind, due to the rapid onset of symptoms and the patient’s desire to avoid windy situations. This Wind often co-exists with a deficiency of the protective, or wei, qi (pronounced “chee”). A Western concept of qi would be the ‘resistance to colds’ or roughly speaking, the immune system. According to TCM, allergy symptoms are caused by an imbalance in the distribution of qi. The blockages, excesses and imbalances occurring at the different ‘meridians’ (in which the qi flows) and organs need to be identified and corrected. Allergies are referred to as Bi Yuan (literally ‘nose-pool’) [18]. The goal of TCM is to promote the healthy flow of qi.

TCM claims to be able to treat and cure diabetes (a Type IV disease, at least in the early stages of type I diabetes mellitus) by putting needles into certain locations in the body (where qi can be manipulated) and claim that Chinese herbology, largely relying on formulae of 8–16 herbs [19], is effective in treating all stages of both type I and type II diabetes.

Graves’ disease (a Type V class disease) is treated in TCM by a combination of products, mainly iodine-containing materials from the sea, although iodine is not known to have an impact on chronic, autoimmune-based thyroid disease [20]. Hyperthyroidism, according to TCM, is thought to start with an excess ‘fire syndrome’, which later becomes yin-deficiency fire. Therefore, fire-purging herbs are used. The hyperthyroid symptoms are thought to be characteristic of a yin deficiency syndrome and is related to emotional factors, kidney yin deficiency, fatigue or congenital weakness [21]. While Western doctors seek a cause of autoimmune-induced thyroid disease in a combination of genetic determinants and possible viral initiators[17], Chinese doctors attribute the cause primarily to emotional disturbance such as the disturbance of qi by sorrow or by anger, which produces liver fire and dries yin and blood.

Hashimoto’s thyroiditis (Type II) is treated by administering qi and yang tonics. Diabetes (Type IV class), systemic lupus erythematosus (Type III class), and myasthenia gravis (Type II class) is treated with yin tonic herbs, which sometimes contains tortoise shell.

Thus we have seen that TCM treats conditions in all the original Gell and Coombs hypersensitivity classifications and also the additional class V. However, the treatment, diagnosis and even the etiology is radically different from Western concepts and ignores these hypersensitivity classifications. Instead, the disease is treated as resulting from qi, yin or yang deficiencies or derangements.

The scientific literature is, at present, inconclusive and contradictory on the efficacy of TCM methods. An analysis of the results is beyond the scope of this paper but, briefly, one double-blind, randomized, placebo-controlled trial of acupuncture for treatment of allergic rhinitis (Type II) showed that active acupuncture was more effective in reducing symptom scores than sham acupuncture [22]. But, after measuring the concentration of IgA, IgG and IgM and total and differential white blood cell counts, it was seen that a course of acupuncture and transcutaneous stimulation analgesia (performed for major abdominal surgery) did not affect the body’s immune system [23]

In another single-blind randomized, controlled clinical trial of 49 healthy subjects, patients were not able to distinguish between the effects of real or sham acupuncture [24]. But another study has shown that acupuncture influences leukocyte migration in chronic spastic bronchitis [25]. Another study has shown that Type IV hypersensitivity to trinitrochlorobenzene was suppressed upon the use of electroacupuncture and that opioid receptor-mediated mechanisms are involved in this immune response [26]. A later study implicated the pituitary gland and the neuroendocrine system to be involved in the suppression [27]. Conclusive proof or refutation of the efficacy of acupuncture and other treatment modalities must await further controlled, clinical trials and experimentation.

References

[1] Holgate ST, Church MK, Lichtenstein LM (2000) Allergy, 2nd edition, Mosby, London.

[2] Coombs RRA and Gell PGH (1968). Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Clinical aspects of immunology (Coombs RRA, Gell PGH, eds). Blackwell Scientific publications, Oxford

[3] Bochner BS, Undem BJ, Lichtenstein LM (1994) Immunologic aspects of asthma. Ann Rev Immunol 12: 295-335.

[4] Morley M (1993) Immunopharmacology of asthma. Trends in Pharm Sci 14: 275-85.

[5] Weiss KB, Gergen PJ, Hodgson TA (1992). An economic evaluation of asthma in the United States. N Engl J Med 326: 862-6.

[6] Rang HP, Dale MM, Ritter JM (1995) Pharmacology, 3rd edition. Churchill Livingstone.

[7] Dorland WAN (2003) Dorland’s Medical Dictionary, 30th ed. WB Saunders Co.

[8] Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (2001) Immunobiology: the immune system in health and disease, 5th edition. Garland Publishing, New York.

[9] Fye KH and Sack KE (1991) Rheumatic diseases. In: Basic and clinical immunology, 7th ed. (Stites DP and Terr AI eds). Appleton & Lange.

[10] Gale EA (1996) Molecular mechanisms of beta-cell destruction in IDDM: the role of nicotinamide. Horm Res 45:39-43.

[11] Foster DW (1988) Diabetes Mellitus. In: Harrison's Principles of Internal Medicine. 11th edition. (Braunwald E, Isselbacher KJ, Petersdorf RG, et al, eds.) McGraw-Hill, New York

[12] Rajan TV (2003) The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation. TRENDS in Immunology 24: 376-379.

[13] Haynes BF and Fauci AS (2001) Disorders of the immune system. In Principles of Internal Medicine, 15th ed. (Braunwad E, Fauci AS, Kasper DL et al. eds.) New York: Mc Graw-Hill Professional.

[14] Strand MR and Pec LL (1995) Immunological basis for compatibility in parasitoid-host relationships. Annu Rev Entomol 40: 31-56.

[15] Christensen BM and Forton KF (1986) Hemocyte-mediated melanization of microfilariae in Aedes aegypti. J Parasitol 72: 220-225.

[16] (2003) Facts about Sarcoidosis. National Institute of Health, Publication No: 02-5060. Web Address: http://www.nhlbi.nih.gov/health/public/lung/other/sarcoidosis/sarcoid.pdf.

[17] (1999) Principles and methods for assessing allergic hypersensitization associated with exposure to chemicals. Environmental health criteria 212. World Health Organization Publication. Web Address: http://www.inchem.org/documents/ehc/ehc/ehc212.htm.

[18] Flaws B and Sionneau P (2002) The Treatment of Modern Diseases with Chinese Medicine: A Textbook & Clinical Manual. Blue Poppy Press. [19] Chen ZL, Chen M-F (1999) A Comprehensive Guide to Chinese Herbal Medicine. Book Sales.

[20] Shang X (1998) Practical Traditional Chinese Medicine and Pharmacology. Clinical Experiences. New World Press, Beijing.

[21] Dengbu Z, Kivity O (eds) (1993) Acupuncture Cases from China: A Digest of Difficult and Complicated Case Histories. Churchill Livingstone, London.

[22] Ng DK, Chow PY, Ming SP, Hong SH, Lau S, Tse D, Kwong WK, Wong MF, Wong WH, Fu YM, Kwok KL, Li H, Ho JC (2004) A double-blind, randomized, placebo-controlled trial of acupuncture for the treatment of childhood persistent allergic rhinitis. American Journal of Acupuncture 4:357-361.

[23] Kho HG, Van Egmond J, Eijk RJR, Kapteyns WMMJ (1991) Lack of influence of acupuncture and transcutaneous stimulation on the immunoglobulin levels and leucocyte counts following upper-abdominal surgery. European Journal of Anaesthesiology 8:39-45.

[24] Goddard G, Shen Y, Steele B, Springer N (2005) A controlled trial of placebo versus real acupuncture. J Pain 6:237-242.

[25] Sliwinski J, Kulej M (1989) Acupuncture induced immunoregulatory influence on the clinical state of patients suffering from chronic spastic bronchitis and undergoing long-term treatment with corticosteroids. Acupuncture and Electro-therapeutics Research 14:227-234.

[26] Kasahara T, Wu Y, Sakurai Y, Oguchi K (1992) Suppressive effect of acupuncture on delayed type hypersensivity to trinitrochlorobenzene and involvement of opiate receptors. International Journal of Immunopharmacy 14:661-665.

[27] Kasahra T, Amemiya M, Wu Y, Oguchi K (1993) Involvement of central opioidergic and nonopioidergic neuroendocrine systems in the suppressive effect of acupuncture on delayed type hypersensitivity in mice. International Journal of Immunopharmacy 15:501-508

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