15: Allergy, Hypersensitivity, and Chronic Inflammation Flashcards
What are hypersensitivities?
Inappropriately vigorous innate and/or adaptive response to antigens that pose little or no threat.
Immediate reactions:
- Caused by Ab-Ag interactions
Delayed-type hypersensitivity (DTH): 1-3 days
- Caused by T cell reactions
What is the differences between type I-IV hypersensitivity reactions?
Type I:
- Mediated by IgE Ab that bind to mast cells/basophils => mediator release
- Most common rx. to respiratory allergens (pollen, dust mites) and to food allergens.
Type II:
- Binding of IgG/IgM to surface of host cells => destruction by complement- or cell-mediated mechanisms.
- Ex. ABO blood system.
Type III:
- Ag-Ab (such as those generated by the injection of foreign serum proteins) deposited on host cells/ tissues activate complement or the release of mediators from granulocytes => inflammatory responses.
Type IV:
- Excessive/inappropriate T cell activation.
Allergens
Highly soluble proteins/ glycoproteins, usually with multiple epitopes.
Many are proteases and/or contain PAMPs => stimulation of the immune system.
Some activate T(H)2 cells => heavy-chain class switching to IgE.
Type I hypersensitivity:
IgE-mediated
IgE Ab bind to Ag via their variable regions and to one of two types of Fc receptor via their constant regions.
High-affinity FcεRI expressed by mast cells, basophils (and eosinophils) => mediators of allergy symptoms.
Cross-linking of FcεRI receptors by Ag-IgE complexes => signal cascades, resembling those of Ag receptors.
Cross-linking => degranulation of mast cells, basophils and eosinophils. Also secrete inflammatory cytokines and lipid inflammatory molecules.
Low-affinity FcεRI IgE receptor (CD23) on IgE-expressing B (and other) cells.
Helps regulate IgE responses, transports IgE across epithelium, and induces inflammatory cytokine production by macrophages.
Regulation of IgE-mediated hypersensitivity
Downregulation of mast cell and basophil activation by FcεRI signaling.
Inhibitory signals
- FcγRIIB signaling
- Phosphatases that remove key phosphate residues from signaling intermediates
- Ubiquitinylation
- Degradation of signaling molecules
What characterizes the early and late responses of type I hypersensitivity?
Early:
- Within minutes
- Release of histamine, leukotrienes and prostaglandins.
Late:
- Mediated by inflammatory cytokines and chemokines.
- Eosinophils recruit neutrophils. Combined => degranulation -> inflammation and tissue damage.
Phase 3:
- 3-4 days
- Identified i.e., at the skin
- Basophils and fibroblasts recruit other cells => inflammation
Categories of type I hypersensitivity reactions
Symptoms vary depending on where IgE response occurs, and whether it is local or systemic.
Local:
- Asthma, atopic dermatitis, allergic conjunctivitis, urticaria.
Systemic anaphylaxis:
- Serious IgE response
- Systemic (i.e. via the blood) introduction of the same allergen that induces local responses.
- Can have fatal effects on multiple organs.
Food allergies can cause both local responses and anaphylaxis.
Which factors effect our susceptibility to type I hypersensitivity?
Environmental:
- Substances, i.e., air pollution
- Things we take into our body, i.e., food.
- Microbes
- Exposure to some farm animals and their bacteria => more diversity
of intestinal microflora => protection against some allergies.
Genetic:
Loci encoding proteins involved in
- maintaining the integrity of the epithelial barrier.
- the generation and regulation of immune responses (innate receptors, cytokines+chemokines and their receptors, MHC, TFs).
- the activity of molecules involved in triggering allergic responses (FcεRI, GFs, proteolytic enz.)
How is an allergic response inducted?
Skin epithelial cells produce the innate cytokines TSLP (thymic stromal lymphopoietin), IL-33, and IL-25
=> activation of DCs
=> differentiation of allergen-specific T(H)2 cells. Secrete IL-4 and IL-13
=> class-switching to IgE -> via blood to intestinal tissue
In epithelial cells of intestine (may be at other locations):
- ILC2 cells, T(H)2, and T(H)9 secrete cytokines
=> recruit, support and activate (by IgE) mast cells and basophils
=> degranulation => symptoms
Type II hypersensitivity:
Antibody-mediated (IgG, IgM)
Which 3 mechanisms?
3 mechanisms:
- Ig subclasses can activate complement system => pores in the membrane of a foreign cell
- Antibody-dependent cell-mediated cytotoxicity (ADCC): cytotoxic cells bearing Fc receptors bind to the Fc region of Ab’s on target cells => cell death
- Opsonization:
Ab bound to a foreign cell can serve as an opsonin => enabling phagocytes with Fc receptors or (after complement has been activated by bound Ab’s) receptors for complement fragments such as C3b to bind and phagocytose the Ab-coated cell.
Give examples on type II hypersensitives
Transfusion reactions:
- Ab’s bind to A, B, or H carbohydrate Ag’s on the surface of red blood cells.
- Generate Ab against the Ag they do not express (everybody has H)
=> stimulate IgG-production => delayed and less severe reactions
Hemolytic disease of newborns:
- Caused by maternal Ab reaction to Rh Ag (mother Rh-, father Rh+).
- Fetal red blood cells enter maternal circulation can cause hemolytic disease in subsequent pregnancies.
- Can be prevented by eliminating fetal red blood cells or maternal Ab’s.
- Similar immunization of mother against A or B blood-group Ag of fetus.
Type III hypersensitivity:
Immune complex-mediated (Ag-Ab)
Factors associated with the initiation
- The presence of Ag’s capable of generating particularly extensive Ag-ab lattices.
- High intrinsic affinity of Ag’s for particular tissues.
- Presence of highly charged Ag’s (can effect immune complex engulfment).
- Compromised phagocytic system.
Prevent destruction of Ag-Ab complexes by phagocytic cells
=> degranulation of mast cells
=> inflammation
What decides the magnitude of type III hypersensitivity (immune complex-mediated)
- The levels and size of the immune complexes (Ag-Ab)
- The distribution of complexes in the body
- The ability of the phagocytic system to clear the complexes, thus minimizing tissue damage.
What is auto-antigens? How can they contribute to type III hypersensitivity (immune complex-mediated)
Self-antigen
In immune complexes (Ag-Ab):
Cannot be eliminated
=> chronic type III hypersensitivity
Type IV hypersensitivity:
Delayed-type (DTH)
Purely cell-mediated => initiated by T cells
1-2 days delayed response
Recruitment of macrophages as the primary cellular component at the site of infection.
