Chapter 18

Type I hypersensitivity reactions

-Immediate hypersensitivity -*IgE antibody mediated* and are *due to a Th2 response* after prior exposure to antigen that produces IgE antibodies. -*Cross-linking IgE antibodies on mast cells*, after a second exposure to allergens, *leads to mast cell degranulation and release of histamine*, leukotrienes and other mediators of inflammation. -Examples are classic allergic responses that could progress to anaphylactic shock

The arthrus reaction

-is an experimental model of immune complex formation and tissue damage in animals -Hypersensitivity Type III

Myasthenia gravis

-is due to an antibody that binds, downregulates and blocks the ACh receptor -Hypersensitivity Type II

Allergic rhinitis (hay fever)

-most common allergic disease and is due to environmental allergen exposure -Constant exposure may lead to nasal polyps. Antihistamines are the most common treatment.

Mast cell chemical mediators

1) Histamine 2) Lipid Mediator 3) Cytokines 4) Enzymes

What induces a Th2 response?

1. The type of allergen 2. Genetic factors 3. Environmental factors/how the allergen is presented -Of these factors, only the environmental factors can easily be altered

Polyarteritis nodosa

-due to antibodies to hepatitis B virus that form immune complexes and deposit in blood vessels. -Hypersensitivity Type III

Allergic Diseases

-*Atopic individuals* may have one or more of the following diseases: allergic rhinitis (hay fever), bronchial asthma (allergic asthma), atopic dermatitis (eczema) and food allergies. The point of contact with the allergen determines where and what the symptoms are - but *all of these diseases involve IgE mediated responses*. -Mast cells are most abundant in the skin, the mucosa of the respiratory tract and GI tract and this is where the symptoms of these diseases occur

What are critical cytokines for the promotion of a Th2 response?

-*IL-4 and IL-13* -Some allergens may promote the differentiation of Th2 cells that then secrete these cytokines -*IL-5 (secreted by Th2 cells) also promotes eosinophils activation* and this contributes to eosinophils promoting Th2 cells. -Repeated exposure of allergens, then, *can increase IgE* and make allergies worse over time. -The clinical goal is to reduce allergen exposure

IgE

-*Normally, circulating IgE levels in the blood are extremely low (1ug/ml)* -*most IgE is bound to high affinity FcεR1 receptors on mast cells and basophils*. -Atopic individuals have extremely high circulating IgE levels (1000 ug/ml). -Mast cells, basophils and eosinophils all have cytoplasmic granules but *only mast cells and basophils can degranulate in response to cross-linking by IgE* bound to *FcεR1 receptors* -*In an allergic individual*, a high proportion of bound IgE molecules may be due to a particular allergen -*non-allergic individuals* many different IgE molecules may be bound on the surface in low amounts - and they cannot be easily cross-linked

What can cause allergies?

-*Only proteins or molecules attached to proteins can cause an allergy*, since there must be a Th2 response to produce IgE antibodies. -*Some haptens* (such as penicillin/penicilloic acid) can bind to proteins and produce a strong Th2 response

Genetic associations with Atopy and asthma

-*The genes for the cytokines IL-4, IL-5 and IL-13 have been associated with asthma*. -Also the genes for certain Class II MHC molecules that may regulate allergen biding and Th2 tilt have been associated with an increased risk for asthma. -Strong innate responses tend to tilt towards Th1 responses and some *gene defects in the Th1 response may predispose to asthma*

Enzymes

-*Tryptase (in the granules)* can cause tissue damage

Type II hypersensitivity

-*caused by direct cell killing, mediated by IgM or IgG antibodies*. -Cell death is initiated by antibody opsonization or complement activation -Examples of type II hypersensitivity responses include autoimmune hemolytic anemia, rheumatic fever (heart disease), myasthenia gravis, Grave's disease and pernicious anemia

Type IV hypersensitivity

-*cell mediated and cause delayed-type hypersensitivity* (DTH)- (typically takes 24-48 hours to develop) -The *only hypersensitivity rxn that does not involve antibody* -*activate Th1 or Th17 cells that secrete IFN-γ*. -In the Th1 response, CD4 and CD8 T cells are both activated and killing and *cell damage occurs due to CD8 T cell and macrophage activation*. In the Th17 response neutrophils are also activated. -Examples include multiple sclerosis, rheumatoid arthritis, type I diabetes, inflammatory bowel diseases (including Celiac disease, Crohn's disease and Ulcerative colitis), autoimmune myocarditis, tuberculosis skin tests and poison ivy/oak skin responses

Type III hypersensitivity

-*mediated by immune complex formation*. Circulating complexes of *antigen and IgM or IgG antibody can deposit in blood vessels* (vasculitis), in synovial joints (arthritis) or the glomerulus (glomerulonephritis) leading to cell death and inflammation. -*must involve a circulating immune complex that binds to tissues.* -Examples include *systemic lupus erythematosusa* (SLE or lupus), polyarteritis nodosa, post-streptococcal glomerulonephritis and serum sickness

Histamine effects

-*secreted from mast cells when granules exocytose*. -Histamine effects are *short term and immediate.* -*causes vasodilation* (stimulates NO and PGI2 production in endothelial cells that causes smooth muscle cells to relax (vasodilate)). -*triggers a reflex parasympathetic bronchoconstriction and peristalsis* -causes *increase in blood vessel permeability*, leading to local edema (swelling). This leads to the wheal and flare effect seen when allergens are injected into the skin. -*The wheal is* the raised area (due to vasodilation and increased permeability at the site of allergen injection) -*the flare is* due to blood vessel dilation at the margins of the area.

Lipid mediators

-Activation of mast cells also activates *phospholipase A2 (PLA2)*, an enzyme that causes increased arachadonic acid (AA) synthesis from membrane lipids. -Arachadonic acid, in turn, can be broken down into prostaglandins and leukotrienes. PGD2 and LTC4 are two of the major products of AA metabolism in mast cells. -*PGD2 also causes bronchoconstriction and vasodilator*. -*LTC4 also causes bronchoconstriction* (it used to be called one of the slow reactive substances of anaphylaxis). -*Mast cells also release platelet activating factor (PAF)* that can contribute to asthma if it is not rapidly broken down

Factors the alter allergies

-Breast feeding has been shown to decrease IgE levels and may correlate with less asthma and fewer food allergies -The 'hygiene" hypothesis postulates that lack of early exposure to microbes may enhance the Th2 response -it has been shown that some intestinal parasites may down regulate the Th2 response (that can kill them) -*B cells require T cell help to class switch to IgE* and *IL-4 is the key cytokine that enhances Th2 production*. However, *IFN-γ and prostaglandins inhibit Th2 responses* -*frequent use of NSAIDs* (PG synthesis inhibitors) may *enhance the Th2 response and promote allergies*.

Serum sickness

-In the acute form of serum sickness, foreign antigens in the blood induce immune complexes that lead to vasculitis in small arteries, glomerulonephritis and arthritis. -Hypersensitivity Type III

Tuberculosis and granuloma formation

-Intracellular infections with Tb bacteria can lead to a strong T cell (Th1) and macrophage response (activated by IFN-γ secretion). -The PPD (purified protein derivative) Tb test causes a tuberculin reaction (DTH, type IV hypersensitivity reaction) in the skin 24-48 hours after injection (called a tuberculin reaction). -If the tuberculosis bacteria replicate within macrophages and are not killed (because the macrophages are not activated by IFN-γ), then *a chronic DTH (type IV) reaction can occur and a granuloma may develop*. -The macrophages in a granuloma are continuously activated and may become "epitheloid" cells or fuse to become *"giant" cell*s. Granulomatous inflammation can wall off and prevent the spread of mycobacteria - but it can also damage tissue and cause fibrosis.

Cytokines

-Preformed TNF-α may increase local inflammation. -*IL-4, IL-5 and IL-13 may enhance Th2 cells* and recruit eosinophils

FcεR1 receptor

-The high affinity FcεR1 receptor *on mast cells and basophils can bind free IgE* and essentially hold it on the cell

Poison ivy/oak/sumac allergic contact sensitivity

-This Type IV hypersensitivity reaction is due to chemical haptens from the plant (urushiols - pentadecylcatechols) that bind to skin proteins creating foreign antigens. -After 24-48 hours the rash may develop and *blisters with fluid filled pus may develop* on the skin - this is *due to inflammation and the fluid does not contain urushiol*. -Direct skin contact with the plant is required to deposit the urushiols - but clothing, pets and contaminated articles that contact the plant may then cause sensitivity by secondary contact with the skin.

Food allergies

-True food allergies are type I hypersensitivity reactions that can lead to increased peristalsis, vomiting, diarrhea and stomach aches. -*Peanuts and shellfish are two of the most common* food allergies and food allergies *require a specific IgE response to a food protein*. -It is thought that the antigen may leak into the bloodstream across epithelial barriers to set up the allergy and to cause the clinical effects. *GI infections or increased permeability of the GI tract may allow food antigens contact with blood and this can lead to a Th2 response* instead of generating T regulatory cells

Urticaria (hives) and eczema

-a *wheal and flare reaction on the skin* in response to direct allergen contact or after the allergen enters the bloodstream -Antihistamines are most effective for urticaria -*Chronic eczema (atopic dermatitis)* is thought to be due to a late-phase reaction to an allergen in the skin but recent data suggest that skin permeability may be the primary defect and that a Th2 response can be secondary to a defect in the epidermal barrier. There may also be a link between food allergies and atopic dermatitis - especially in children

Basophils

-also bone marrow derived, circulate in the blood but may be recruited to sites of inflammation.

Systemic lupus erythematosus (SLE)

-autoantibodies bind nuclear proteins or DNA, leading to immune complexes that bind to blood vessels, the glomerulus or in joints -affects women between 20-60 years old (1:700 incidence) and has a higher incidence in African American women (1:250 incidence). -*"butterfly rash"* -*high load of nuclear antigens* that are not cleared. Additionally, a *failure of self-tolerance in B cells*. -*Excessive IFN-α secretion by plasmacytoid dendritic* cells may promote excessive autoantibody secretion of anti-nuclear IgG from B cells. -Hypersensitivity Type III

Type I hypersensitivity responses

-begin within minutes of antigen challenge and can peak within an hour -usually a late-phase response that starts 2-4 hours later and often peaks 4-6 hours after the initial exposure -Both genetics and environmental factors can predispose a person towards Th2 responses -*most extreme form of Type I hypersensitivity reaction is anaphylactic shock *

Mast cells

-bone-marrow derived and are found in epithelial tissue and surrounding blood vessels - but mature mast cells are not typically seen in the blood -Mast cells are *activated by cross-linking FcεR1 receptors* -It is the *high proportion of bound IgE to a particular allergen that can allow cross-linking* and trigger mast cell degranulation

Clinical Response

-can include: Skin rashes (urticaria, hives), sinus congestion, bronchial constriction, abdominal pain, diarrhea, tearing of the eyes and watery nose and systemic shock.

Rheumatoid arthritis

-cell-mediated and humoral, although the cell-mediated response (Th17 and Th1) more critical for pathogenesis of the disease. -presence autoantibodies against the Fc portion of IgG. -cyclic citrullinated proteins and antibodies are markers for the disease -smoking and other environmental insults may lead to the creation of new antigenic epitopes on self-proteins. -active Th1 and/or Th17 response occurs in the synovial joints and this promotes inflammation and cellular damage that leads to increased lymphocyte migration -Newer therapies include anti-TNF antibodies (*Etanercept, Infliximab* and others), an IL-1 antagonist (*Anakinra*) and a CTLA-4 fusion protein (*Abatacept, Belatacept*).

Anaphylaxis

-characterized by a *rapid drop in systemic blood pressure and locally severe edema* -In the lung, there can be *rapid constriction of the bronchioles* that can lead to asphyxiation -examples include allergic responses to bee stings and some food allergens

Cromolyn

-decreases mast cell degranulation and is used prophylactically

Eosinophils

-develop in the bone marrow but circulate more in blood than mast cells. -migrate to tissue sites under normal conditions but can be recruited by inflammation via *IL-5 (produced by Th2 CD4 T cells) is a potent activator* -*recruited to late-phase allergic reaction sites and to sites of helminth infections*. -release granules that are *toxic to helminthes* and also can damage normal tissues

Grave's disease

-due to an antibody that binds and activates the TSH receptor -Hypersensitivity Type II

Pernicious anemia

-due to an antibody that neutralizes intrinsic factor causing decreased B12 absorption. -Hypersensitivity Type II

Goodpasture's syndrome

-due to antibodies that bind to basement membrane in the glomerulus and lung -Hypersensitivity Type II

Type I Diabetes

-loss of the pancreatic β cells that secrete insulin -peak age of onset for type I diabetes is 10-11 years -Once the pancreatic β cells are lost, the disease is *irreversible* and the patients need to be on insulin replacement for the rest of their lives -*Th1 CD4 T cells that stimulate CD8 T cells invade the pancreas early in the disease and are thought to be responsible for destroying the pancreatic β cells*. -*Loss of Treg cell activity* is thought to be involved in the disease. -90-95% of Caucasians with type I diabetes have the *MHC class II DQ0302 allele*. -viral infection with *Coxsackie virus B4 may promote cross-reactive T cells* by initiating cell injury, inflammation and co-stimulation but repeated infections appear to be protective.

The three responses to IgE cross-linking

1. Degranulation 2. Synthesis and secretion of lipid mediators 3. Synthesis and secretion of cytokines

Allergic reactions sequence of events

1. Exposure to allergen (or to a protein epitope similar to the allergen). 2. Activation of Th2 cells 3. Class switching and production of IgE 4. Binding of IgE to the mast cell Fcε receptor 5. Second exposure of allergen and cross-linking of IgE on the mast cell 6. Mast cell degranulation 7. Physiological effects of mast cell degranulation