Conclusion

Immune responses can be a double-edged sword. Their roles in protecting us from infections are essential to life, as evidenced by the fatal consequences of immunodeficiency diseases left untreated (to be discussed in Chapter 18). To provide effective protection, a wide variety of innate and adaptive immune mechanisms has evolved that usually enable us to generate a response that will be effective against the type of pathogen that has entered our body. But immune responses are by their very nature destructive, and if those responses are excessive, persistent, or reactive with the wrong targets, they can do damage to the body. Several of these conditions—the four classes of hypersensitivity reactions and chronic inflammation—have been the focus of this chapter.

Type I hypersensitivity reactions, what we recognize as common allergies, are caused by IgE antibodies that are bound by FcεRI receptors on mast cells, basophils, and eosinophils and then are cross-linked by antigens they recognize. This induces degranulation, and the mediators that are released cause the common symptoms of allergies, which include local responses in the respiratory tract for airborne allergens and in the GI tract for food allergens, but can also be systemic if the allergen gets into the bloodstream (as can occur with insect stings, drugs such as penicillin, and foods). While IgE and the granulocyte degranulation responses it triggers probably evolved to combat parasitic worms and animal and insect venoms, and while many allergic symptoms, such as hay fever, are usually just inconveniences, anaphylaxis and asthma are clear examples of maladaptive responses.

Type II and type III hypersensitivity responses are caused by normal IgM and IgG antibody-antigen interactions that can be harmful if misdirected or excessive. Type II reactions result from extensive cell death; examples are transfusion reactions in which antibodies and complement attack transfused blood cells or fetal cells differing in blood-group antigens; this can cause excessive red blood cell death from complement-mediated lysis and toxic levels of bilirubin from the released hemoglobin. Fortunately, blood-group testing can prevent mismatched blood transfusions, and treatments are available to prevent hemolytic disease of newborns. Binding of penicillin and other drugs to red blood cells can cause similar problems if antibodies to the drugs are present. Type III hypersensitivity results from excessive levels of immune complexes; deposition in tissues and complement activation can trigger local inflammatory responses such as vasculitis, glomerulonephritis, and arthritis.

Type IV hypersensitivity reactions are mediated by T cells, generally T_H1, T_H17, and CD8⁺ cells, which activate inflammatory responses. These responses can be triggered by intracellular bacteria and cause tissue damage if not resolved, as in tuberculosis. Another example is contact dermatitis induced in the skin by the lipid toxins of poison oak and poison ivy, which induce sensitized T cells to produce chemokines and proinflammatory cytokines and may also involve CD8⁺ T-cell killing of cells modified by the toxin.

Chronic inflammatory responses constitute another class of beneficial immune responses gone bad. A wide array of persistent infectious and noninfectious causes can lead to ongoing innate and adaptive responses that result in chronic local inflammation, such as that which causes the lung damage in tuberculosis or the joint damage in arthritis, or chronic systemic inflammation, such as the inflammatory link between obesity and type 2 diabetes.

Considerable progress has been made in recent years in understanding the causes of hypersensitivity reactions and chronic inflammation. That information is leading to approaches for preventing, diagnosing, and treating these undesirable immune system responses.

REFERENCES

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• Cavani, A., and A. De Luca. 2010. Allergic contact dermatitis: novel mechanisms and therapeutic perspectives. Current Drug Metabolism 11:228.
• Donath, M. Y., and S. E. Shoelson. 2011. Type 2 diabetes as an inflammatory disease. Nature Reviews Immunology 11:98.
• Forsberg, A., et al. 2016. Pre- and probiotics for allergy prevention: time to revisit recommendations? Clinical and Experimental Allergy 46:1506.
• Gladman, A. C. 2006. Toxicodendron dermatitis: poison ivy, oak, and sumac. Wilderness and Environmental Medicine 17:120.
• Graham, M. T., S. Andorf, J. M. Spergel, T. A. Chatila, and K. C. Nadeau. 2016. Temporal regulation by innate type 2 cytokines in food allergies. Current Allergy and Asthma Reports 16:75.
• Gregor, M. F., and G. S. Hotamisligil. 2011. Inflammatory mechanisms in obesity. Annual Review of Immunology 29:415.
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• Hidaka, T., et al. 2017. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin. Nature Immunology 18:64.
• Julia, V., L. Macia, and D. Dombrowicz. 2015. The impact of diet on asthma and allergic diseases. Nature Reviews Immunology 15:308.
• Kim, H. H., et al. 2016. CD1a on Langerhans cells controls inflammatory skin disease. Nature Immunology 17:1159.
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• Minai-Fleminger, Y., and F. Levi-Schaffer. 2009. Mast cells and eosinophils: the two key effector cells in allergic inflammation. Inflammation Research 58:631.
• Mortuaire, G., et al. 2017. Specific immunotherapy in allergic rhinitis. European Annals of Otorhinolaryngology, Head and Neck Diseases 134:253.
• Mukai, K., M. Tsai, P. Starkl, T. Marichal, and S. J. Galli. 2016. IgE and mast cells in host defense against parasites and venoms. Seminars in Immunopathology 38:581.
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Useful Websites

www.aaaai.org This is the website of the American Academy of Allergy, Asthma, and Immunology. It has descriptions of various types of allergic response, current treatment recommendations, and a variety of resources.

www.webmd.com/allergies Contains information for the lay public on types of allergic reactions and their management, including treatments.

https://chriskresser.com/how-inflammation-makes-you-fat-and-diabetic-and-vice-versa This is an interesting and credible series of commentaries by Chris Kresser, who did not go to medical school, but graduated from an alternative medicine program and is open about his interest in examining the assumptions that underlie medical practices. His online articles on obesity and inflammation are informed and clearly written.

Four excellent animations about the four types of hyper-sensitivity:

https://www.youtube.com/watch?v=2tmw9x2Ot_Q—Type I

https://www.youtube.com/watch?v=kLaUz58CBMc—Type II

https://www.youtube.com/watch?v=SyxzU2Sl_Yw—Type III

https://www.youtube.com/watch?v=C3E5COZ1XC8—Type IV

STUDY QUESTIONS

1. You have in your possession five mouse strains. The mice of each strain lack a specific gene (i.e., they are gene knockout animals). How might the type I hypersensitivity response of each knockout strain (a–e) differ from that wild-type mice? How might the type II hypersensitivity response differ? Explain your answers.
   • Strain a: Mice are unable to generate an ε heavy chain.
   • Strain b: Mice are unable to generate a high-affinity FcεRI receptor.
   • Strain c: Mice are unable to generate a low-affinity FcεRII receptor.
   • Strain d: Mice are deficient in the ability to generate the complement attack complex.
   • Strain e: Mice are unable to express CD21.
2. What is the difference between primary and secondary pharmacological mediators in the type I hypersensitivity response? Name two of each.
3. How does histamine suppress its own release?
4. Describe two mechanisms by which desensitization through allergy shots or oral immunotherapy are thought to reduce IgE responses to allergens.
5. A mother has an Rh⁺ blood type and the father has an Rh⁻ blood type. Under these circumstances, the family pediatrician is not worried about the possibility of a type II hypersensitivity reaction. However, if the converse is true, and the mother is Rh⁻ and the father Rh⁺, the pediatrician does worry and asks the obstetrician to inject the mother with antibodies toward the end of her first pregnancy. Explain her reasoning in both cases.
6. A mother has an Rh⁻ blood type and the father has an Rh⁺ blood type. The first baby born to the parents was Rh⁺. However, the parents elect for the mother not to receive RhoGAM. Are all future babies of this couple at risk for type II hypersensitivity reactions? Why or why not?
7. Describe type III hypersensitivity, describing both the initiating cells and molecules and the cells and molecules that bring about the pathological effects, and indicate two triggers for this type of response.
8. Indicate which type(s) of hypersensitivity reaction (I–IV) apply to the following characteristics. Each characteristic can apply to one, or more than one, type.
   1. Is an important defense against intracellular pathogens.
   2. Can be induced by penicillin.
   3. Involves histamine as an important mediator.
   4. Can be induced by poison oak in sensitive individuals.
   5. Can lead to asthma.
   6. Occurs as a result of mismatched blood transfusion.
   7. Systemic form of reaction is treated with epinephrine.
   8. Can be induced by pollens and certain foods in sensitive individuals.
   9. May involve cell destruction by antibody-dependent cell-mediated cytotoxicity.
   10. One form of clinical manifestation is prevented by RhoGAM.
   11. Localized form characterized by wheal-and-flare reaction.
9. Describe how infections can lead to chronic inflammation. Give two examples. (Hint: One was extensively discussed in an earlier section of this chapter!)
10. As described in the text, a small number of obese individuals (6% or so) do not suffer from the chronic inflammatory state characteristic of most forms of obesity.
    1. These individuals do not develop type 2 diabetes. Why not? Provide a specific, molecular-based answer.
    2. Some have suggested that these individuals express genetic polymorphisms that make them less susceptible to obesity-generated inflammation. Describe one possible genetic polymorphism that could uncouple obesity from inflammation.

ANALYZE THE DATA

A group in Finland has been investigating the association between exposure to various bacterial species and the development of allergies. They showed previously that children in homes surrounded with forests and agriculture are less likely to have allergies than those in other environments, such as along the sea. The researchers examined the children for bacterial species that might be correlated with reduced allergies and found that children from forest and farm areas had higher levels of skin bacteria of the genus Acinetobacter than did children from other regions. To attempt to establish a causal relationship between exposure to Acinetobacter and protection from allergies, they used a mouse model in which intranasal exposure to the allergen ovalbumin can cause respiratory allergic responses. (Fyhrquist, N., et al. 2014. Acinetobacter species in the skin microbiota protect against allergic sensitization and inflammation. Journal of Allergy and Clinical Immunology 134:1301.)

Mice were injected intradermally several times over 3 weeks with the diluent phosphate-buffered saline (PBS) alone, or with the allergen ovalbumin (OVA) without or with Acinetobacter lwoffii (Al) or, as controls, two other skin bacteria, Staphylococcus aureus (Sa) or Staphylococcus epidermidis (Se), which had been shown not to be associated with reduced allergies in children. A week after this initial sensitization to OVA the mice were given three daily intranasal exposures to ovalbumin, after which bronchoalveolar fluid, lung tissue samples, and sera were obtained. The results of various assays are shown in the figure: (a) numbers of eosinophils in lung fluid, and levels of IL-5 and IL-13 mRNAs in lung tissue; (b) levels of IgE and IgG2a antibodies specific for OVA in the serum; and (c) levels of IL-10 and IFN-γ in the skin.

Section a:

Eosinophils: A scatter graph plots relative quantity of P B S, O V A, O V A plus A I, and O V A plus S e. The relative quantity is depicted as follows: P B S-0; O V A- 40 to 65; O V A plus A I-10 to 40; and O V A plus S e-20 to 65.

IL-5: A bar graph plots relative quantity of P B S, O V A, O V A plus A I, and O V A plus S e. The relative quantity is depicted as follows: P B S-400; O V A- 1600; O V A plus A I-500; and O V A plus S e-900.

I L-13: A bar graph plots relative quantity of P B S, O V A, O V A plus A I, and O V A plus S e. The relative quantity is depicted as follows: P B S-50; O V A- 7000; O V A plus A I-1800; and O V A plus S e-2000.

Section b:

O V A-I g E: A bar graph plots optical absorbance of P B S, O V A, O V A plus A I, and O V A plus S e at 405 nanometers. The optical absorbance value reads as follows: P B S-0.1; O V A- 0.5; O V A plus A I-0.3; and O V A plus S e-0.5.

O V A-I g G 2 a: A bar graph plots optical absorbance of P B S, O V A, O V A plus A I, and O V A plus S e at 405 nanometers. The optical absorbance value reads as follows: P B S-0.1; O V A- 1; O V A plus A I-0.7; and O V A plus S e-0.6.

Section c:

I L-10: A bar graph plots relative quantity of P B S, O V A, O V A plus A I, and O V A plus S e. The relative quantity is depicted as follows: P B S-50; O V A- 60; O V A plus A I-250; and O V A plus S e-50.

I F N-gamma: A bar graph plots relative quantity of P B S, O V A, O V A plus A I, and O V A plus S e. The relative quantity is depicted as follows: P B S-25; O V A- 30; O V A plus A I-200; and O V A plus S e-25.

1. What do the three panels in part (a) indicate about the effect of co-injection of A. lwoffii on the response to OVA?
2. What do the two panels in part (b) indicate about the effect of co-injection of A. lwoffii on the nature of the antibody response to OVA?
3. What do the two panels in part (c) indicate about the effect of A. lwoffii co-injection on the skin cytokine environment?
4. Based on the data (and what you have learned about the regulation of immune and allergic responses), provide an overall mechanism by which co-injection with A. lwoffii may reduce the allergic response to OVA in this study.
5. Do these findings support the hygiene hypothesis; if so, how?