Type I Immunopathology Flashcards
What T cells fight parasites and what Ig?
What are helminths and ectoparasites?
What do worms stimulate production of?
Fighting parasites is the real reason we have Th2 cells and IgE. Worms are the most successful metazoan group; 4 out of 5 land animals are microscopic nematodes ! Our major parasites are single - celled protozoa, helminths (the medical name for worms), and ectoparasites, which include things like *ticks and mosquitoes.
- The closer your mouth is to the ground, the more likely you are to have parasites, and for wild - living rats IgE is the most important of the isotypes.
- The closer you live to the equator, the higher your chances are of having intestinal helminths, most of which are harmless.
- Worms in particular stimulate IgE responses. [In fact, an old lab trick to get good IgE production in animals is to mix your antigen with adjuvant and ground-up roundworms.] It has been shown that a particular protein of worms, incubated with dendritic cells, polarizes them such that they induce a strong Th2 response
What pattern - recognition receptor recognizes the worm protein (or more likely the protein - associated glycans) remains to be determined (it may not be a TLR , as you know there are several other PRR systems ).
Do IgG can kill worms?
Explain how do IgE kills worms?
What are the major players of the late-phase response?
What do Eosinophils release once thye phagocyte worms?
A person with a worm infestation will make both IgE and IgG against them. The IgG binds the worm or its ova, activates complement (to the lytic effects of which worms are impervious) and C3a and C5a attract neutrophils. They arrive, seize the opsonized wo rm with their IgG and C3 receptors , and…nothing. Neutrophils lack a helminthocidal mechanism.
►That’s where IgE comes in. As the worm sheds antigens they diffuse to nearby mast cells, whose FcεR have become loaded with anti-helminth IgE. Antigen cross- links the IgE and the mast cells degranulate. **Histamine causes gut smooth muscle contraction, and violent peristalsis can help expel worms.
–>But the real action is in the late-phase response (below), where prostaglandins and leukotrienes are elaborated by the mast cell ; as “ECF-A” they attract eosinophils in large numbers. Like other phagocytes, eosinophils have Fc receptors for IgG, which as we’ve noted is coating the worm. When an eosinophil engages an opsonized worm it release the contents of its granules, which include **Major Basic Protein (the reason eosinophils bind the acidic dye eosin). ► MBP is highly toxic to helminths.
What is the role of Th2?
What cells does it attract when it encounter helminth antigens?
What lymphokines does it make?
What is th effect of these lymphokines in macrophages?
Eosinophilia in blood or sputum is almost always a sign of either _____ or ______ immunopathology.
The second partner in the response to parasites is the Th2. Its close relative, the Th2 - like Tfh, is busy in the lymph node helping B cells switch to IgE production.
The Th2 itself goes out into the body like a Th1 cell does, finds helminth antigens presented by APC, and attracts both eosinophils and macrophages ; ► but the suite of lymphokines a Th2 makes, IL - 4, IL - 5 and IL - 13, turn the macrophages into alternatively activated M2 macrophages, the cells that heal damage and wall off M1 - resistant invaders. This is fine and desirable in a parasite infection. If it becomes chronic and extensive , as in asthma, all that fibrosis is far from fi ne.
**Eosinophilia in blood or sputum is almost always a sign of either parasitic disease or severe Type I immunopathology.
Type I immunopathology
Type I immunopathology involves IgE and mast cells, and is roughly equivalent to allergy. In allergy studies antigens are usually called allergens. Note that the term allergy is widely misused to include even such obvious Th1 cell-mediated phenomena as poison ivy and organ transplant rejection.
The basic mechanism is straightforward : IgE binds strongly to Fcε R1 receptors on the surface of mast cells. When 2 adjacent IgE molecules so bound are cross-linked by allergen, the mast cell is signaled to release the contents of its characteristic granules, including histamine, which causes local or systemic vasodilation and increased permeability, and gut and bronchial smooth muscle contraction. Biochemical processes are launched as well, which lead to the late-phase reaction.
SYNDROMES AND SHOCK ORGANS
What symptoms a person gets on exposure to allergen depends on the route of entry and other less-defined factors. Although antigens (e.g., poison ivy) that T cells see may penetrate intact skin, that is ►uncommon in Type I allergy.
- State the approximate incidence of atopic diseases in the general population, and in individuals with allergic parents
Most common seasonal allergy?
What percent of US population has had at least one asthma attack?
Allergic disease are among the most common conditions suffered by humans, a clear indication that this is a normal mechanism going slightly wrong.
Estimates as high as 20% of all people have been published; ► 15% seem more likely to experience allergic symptoms at some time in their lives.
There is a strong multifactorial genetic component; risk of developing allergy climbs to 35% if a newborn has one allergic parent, and to ► 65% with two such parents.
Allergic *seasonal rhinitis is the most common , followed by food allergy and eczema in children, and by asthma. In 1995 the CDC estimated that 10% of the US population had had at least one asthma attack.
► The incidence of asthma nearly doubled in the US from 1980 to 1995, and it’s still going on. A lot of that increase is real, not just better diagnosis. Happily, deaths from asthma are decreasing every year.
The atopic state
Atopy, atopic disease, and allergy are all terms of somewhat vague definition 6 . It now means “prone to develop any of the range of allergic syndromes.” An atopic individual may begin life as an infant with eczema (also called atopic dermatitis), go on to have allergies to milk, fish, or eggs, and develop asthma in middle school or hay fever in college. Allergy (Greek “other response”) is roughly the same as atopy. It is an atypical immune response to environmental antigens, eventually becoming characterized by increased reactivity of the end - organs to inflammatory mediators and irritants.
IgE production
Dependent on what?
IgE production is Tfh/IL-4 dependent, so these Tfh are related to Th2 cells.
Development of symptomatic levels of IgE is slow; allergic people, when they move to a new continent, take about 7 years to show symptoms to the common all ergens of the new environment. Multiple exposures to the allergen usually boost the immune response, resulting in symptoms that are increasingly severe. Patients may report that they can tolerate a snack of shrimp, for example, but break out in hives when they make a meal of it.
The immediate reaction:
Describe the mechanism of IgE-mediated hypersensitivity in terms of: IgE attachment to basophils or mast cells; reaction to allergens; mediator release; effects of mediators on target tissues and cells.
Why are plasma levels of IgE very low?
What triggers mast cell degranulation?
What do mast and basophils have in common?
Of the granule components which one is the clinically most important one?
IgE binds to the main mast cell and basophil IgE receptor, FcεRI, with an association constant of 10 - 10 , which is so avid that the off rate is expressed in months.
-Thus plasma IgE levels are very low (about 150 ng/mL); any secreted IgE is almost immediately bound by receptors. Highly allergic people can have IgE con centrations over 1 mg/mL, but that is unusual and ► total IgE levels are of limited use in diagnosis or prognosis.
IgE-loaded mast cells are triggered to release the contents of their granules when two adjacent IgE molecules are ►cross-linked by allergen, which must therefore be at least divalent.
This explains why a normal individual may have IgE on her mast cells, but since the IgE represents the products of many weakly-activated clones, the chances of 2 adjacent IgEs being specific for 2 epitopes on the same allergenic protein are small; whereas in an allergic person, a few clones are responding strongly to the immunodominant allergens, and statistics will often put 2 IgEs from those clones side by side.
Mast cells in tissues and basophils in the blood are similar, though for the specialist, not identical; they come from the same bone marrow progenitors , but express different transcription factors . They have in common large basophilic granules.
Degranulation releases histamine, heparin, enzymes, and TNF. These are preformed in the granules so their action is very rapid; within 15 minutes of the intradermal injection of an allergen, a positive wheal-and-flare response (a “hive”) is very obvious.
Of the granule components the clinically most important is ► histamine, which will cause itch, blood vessel dilation, and leakiness. Its half-life in tissues is only a minute, so fortunately the reaction is transient.
The late phase reaction
What effect do leukotrienes and prostagladins have on late phase reaction?
The effects are together called? What cells do they attract?
How do you limit the inital response?
Do antihistamines work in the late response?
IL-4 to attract eosinophils are released by?
The activated mast cell also initiates a series of enzymatic steps: phospholipase PLA2 cleaves arachidonic acid from membrane phospholipids, and arachidonic acid can be converted by the cyclooxygenase pathway to prostaglandins, and by lipoxygenase to leukotrienes.
► These active compounds initiate inflammation, constrict bronchioles, and are together called “eosinophil chemotactic factor of anaphylaxis” or ECF - A, because they are particularly good at attracting eosinophils. Cytokines are also released by the mast cell.
► Thus Type I reactions are often observed to have two phases. The immediate reaction is due to histamine, and can be blocked effectively by antihistamines, which are receptor antagonists.
The late phase, beginning perhaps 4 to 10 hours later, is ► not affected by antihistamines, as it depends on prostaglandins, leukotrienes, and cytokines . Since it is the important feature in the bronchoconstriction of asthma, it is not surprising that antihistamines have only a minor role to play in that condition. Similarly, atopic dermatitis (eczema) , which seems to be chronic late - phase Type I immunopathology , needs anti-inflammatory rather than histamine - blocking therapy, though antihistamines can help if itching is prominent.
Chronic Type I reactions often show, on biopsy, infiltration with Th2 cells and eosinophils. The eosinophils are attracted by ECF - A from mast cells, and by IL-4 released by Th2. They are there, of course, because the body believes the allergen is actually a protozoan or worm pathogen.
Non-speficic triggers
Dagnosis
- Discuss intradermal skin tests with reference to procedure, safety and specificity.
- Discuss the reasons for using glucocorticoids in asthma treatment.
Asthma is defined as a ► reversible bronchoconstrictive disease with progressive inflammation leading to fibrosis. It is easily tested for by spirometry, the measurement of air flow. The patient blows into a mouthpiece connected to an apparatus that measures air flow rates and volumes. Various measures can be made; ► the most often used is the FEV1, which is the volume of air that can be forcibly exhaled from full lungs in 1 second. It is measured as a baseline and then the patient inhales a bronchodilator and repeats the test; a significant improvement in FEV1 indicates a bronchoconstrictive condition.
For a long time it was observed that this value would inevitably decline in asthmatics, even with good bronchodilator treatment. Now we know that the other *late-phase reactants and Th2 cells present in the lung are pro-inflammatory, and untreated chronic inflammation inevitably leads to fibrosis, which is mostly irreversible.
► So inhaled glucocorticoids are added early to the asthma treatment regimen; they are scarcely absorbed and can be used, with monitoring, in growing children without the serious side effects associated with system ic steroid treatment.
Treatment
- Discuss specific immunotherapy of allergic disease, considering duration of effect, risk of anaphylaxis, and percent of patients obtaining significant relief.
