L10: Hypersensitivity Reactions Flashcards Preview

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Flashcards in L10: Hypersensitivity Reactions Deck (23):

4 types of immune system hypersensitivities. What is the pathologic immune mechanism and mechanism underlying disease and tissue injury

1.) type I = allergy and and anaphylaxis
– IgE and TH2 cells
– Mast cells, eosinophils and their mediators

2.) type II = antibody-mediated cytotoxicity
- IgM, IgG againsts cell surface or ECM antigens
- Leads to opsonization, phagocytosis, complement and Fc-mediatoed recruitment and activation of leukocytes, also abnormalities in cellular functions

3.) type III = immune complex disease
- IgM and IgG immune complexes
- Complement and Fc-mediated recruitment and activation of leukocytes

4.) type IV = delayed-type
- TH1 and TH 17 cells (CD4+) and CD8+
- Cytokine mediated inflammation and direct target cell killing


What immune system hypersensitivities are antibody mediated, what are cell-mediated?

- types I-III are antibody mediated
- type IV is cell-mediated


Types of reactions seen in type I hypersensitivity

1.) Systemic anaphylaxis: to food, drugs or venoms
2.) Acute urticaria: in allergy testing, instect bites and animal hair
3.) Seasonal rhinoconjunctivitis: pollen, dust-mite feces
4.) Asthma: dander, pollen, dust-mite feces
5.) Food allergy: to fish, shellfish, peanuts, tree nuts, milk, soy, eggs, wheat


What is atopy?

- Increased tendency to develop allergies usually via IgE antibodies. Why? Some people are good IL-4 producers


True/False. Anaphylaxis reactions don’t require prior exposures

- False, it is a memory response


Describe how anaphylaxis develops

- First exposure is allergen leads to activation of naïve T cell via DC
- Naïve T cell differentiates into an IL-4 producing TFH cell that stimulates IgE switching in B cells and differentiation into a plasma cell
- IgE binds to FC-gamma receptor on mast cells
- Repeated exposure to allergen cross-links IgE on mast cells leading to activation and degranulation, such as histamine
- Leads to immediate reaction: within 2-30 minutes: histamine leads to increased bronchial smooth muscle contraction and increased vascular permeability (edema)
- Late phase response: with 6-8 hours after immediate reaction: mediated by prostaglandins, leukotrienes etc by mast cells leading to second phase of SM contraction, sustained edema, recruitment of eosinophils and TH2 cells and remodeling of tissue (SM hypertrophy and hyperplasia)


Contents of mast cell granules and their effects

1.) histamine: bronchial SM contraction, increased vascular permeability
2.) proteases: activate MMPs to cleave tissue matrix proteins to cause damage
3.) TNF-alpha: promotion of inflammation
4.) Eosinophil chemotactic factor of anaphylaxis: accumulation of eosinophils locally or in bloodstream as an attempt to counteract effects of histamine


Leukotrienes are also formed during anaphylactic events. Function? Compare to histamine

- most potent mediator of SM contraction and increased vascular permeability
- released more slowly (as synthesized), but has longer effect than histamine, which is preformed in granules


Sam experiences an immediate anaphylactic reaction to peanuts while in the woods on a camping vacation. Luckily, he brought his last Epi pen with and injects himself upon the onset of the first symptoms. Sam starts become asymptomatic shortly thereafter. Should Sam be taken to the ER?

- Yes, he should be concerned about the late phase anaphylactic response take place 6-8 hours after the immediate reaction


Anaphylaxis treatments

1.) Epi – binds beta-adrenergic receptors leading to increased cAMP, relaxing bronchial SM, tightening EC junctions
2.) Antihistamines – bind to histamine receptors to block binding of histamine
3.) Cromolyn sodium – blocks degranulation of mast cells
4.) Theophylline – blocks degranulation of mast cells


True / False. Antihistamines is the only treatment that reverses anaphylaxis

- False. Epi is the only treatment that reverses anaphylaxis. Antihistamines prevents histamine binding


Primary cytokine implicated in type I hypersensitivity reactions

- IL-4


Examples of type II hypersensitivity diseases?

1.) HDN (hemolytic disease of newborn)
2.) Grave’s disease: antibodies to TSH receptors produced causing overproduction of thyroid hormones leading to hyperthyroidism
3.) Myasthenia gravis: antibodies to ACh receptor blocks nerve impulse transmission to muscles


Diseases that induce type III hypersensitivity

1.) SLE or RA
2.) Serum sickness
3.) Drug reactions (penicillins or sulphonamides)
4.) Infectious diseases: subacute bacterial endocarditis, chronic viral hepatitis, poststreptococcal glomerulonephritis
5.) Inhaled allergens: farmer’s lung (mold spores or hay dust)


Describe pathogenesis of type III hypersensitivity

- Requires antigen to be persistent for long periods of time and also optimal ab:ag proportions
- Immune complexes deposit in tissue leading to complement and fc receptor recruitment and activation of inflammatory cells. C5a leads to neutrophil accumulation. Lysosomal enzymes damage tissue leading to fever, urticaria, arthritis, LN enlargement and proteinuria


What is serum sickness?

- repeat injection of foreign serum (used in treatments) leads to immune system mistaking proteins as harmful antigens
- leads to type III hypersensitivity


Immune complexes normally form as a result of the immune system doing its job. How? Why is this problematic in type 3 hypersensitivities?

- RBCs bear CR1 protein that bind C3b and C4b on immune complexes shuttling them to liver and spleen where they are removed by macrophages
- In T3 hypersensitivity, the system is overwhelmed due to increased production of these complexes


Diseases that induce type IV hypersensitivity

1.) Contact dermatitis
2.) Delayed graft rejection
3.) Intracellular bacteria when antigen not eradicated leads to granuloma formation – utilizes this mechanism. CD4+ T cells found in granulomas to maintain macrophage activation and structural integrity of granuloma


Describe mechanism underlying type IV hypersensitivity reactions

- Manifests 24-72 hours after antigen exposure
- Cell-mediated response, TH1 and some forms of DTH mediated by TH17 cells. Requires prior sensitization to antigen
- CD4+ and CD8+ cells secrete inflammatory cytokines including IFN-gamma


What is contact dermatitis?

- Type IV hypersensitivity reaction resulting from skin exposure to nickel, chromium cosmetics, hair dye, poison oak, poison ivy – these are haptens, which complex with skin proteins and are presented to T-helper cells (poison ivy expressed on class I for recognition by CTLs)


Describe how type IV hypersensitivity can be used diagnostically

- In tuberculin skin reaction
1.) Occurs if memory T helper cells against M. tuberculosis are circulating in blood stream. When PPD protein is injected intradermally, macrophages or endothelial cells present antigen to these memory T helper cells that migrate into skin
2.) Memory T cells activate and secrete IFN-gamma, increases MHC II expression on macrophages to amplify reaction
3.) Tissue damage occurs as a result of inflammatory cytokine release. Redness and induration = positive PPD skin test


Implication of granulomas in AIDs pts?

- AIDs patients have a loss of CD4+ cells. CD4+ cells required to maintain previous granulomas with intracellular bacteria and pathogens that were unable to be eradicated. As a result, bacteria escape and this leads to systemic infections. AIDs pts that are infected with Mycobacterium TB don’t develop granulomas


A 9-year old female brought to the ER with airway obstruction due to laryngeal edema and swelling of the lips, tongue, face and trunk. Urticaria (i.e. hives) were absent during these episodes. A 14-year old brother had a similar history of attacks. Physical exam was unremarkable. The patient was treated with epinephrine. Based on the clinical manifestations, what disease do you suspect?
1.Anaphylactic shock
2.Familial complement deficiency
3.Hereditary angioedema
4.Immunodeficiency involving IgE production
The following laboratory results are reported:
- Serum IgE levels: Normal
- C2 and C4 levels: Significantly decreased
Based on the laboratory results and the patient history, which disease would you now suspect? Epi had no effect on the pt’s condition.
1.Anaphylactic shock
2.Hereditary angioedema
3.Familial complement deficiency
4.Immunodeficiency involving IgE production
What is underlying cause of this disorder? Why does epi not cause reversal of condition?

- Initially suspected to be anaphylactic shock. Following arrival of lab results with ineffectiveness of Epi, pt diagnosed with HAE (hereditary angioedema). Underlying cause is a C1-inhibitor deficiency. Epi doesn’t reverse symptoms as the cause isn’t histamine.