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Flashcards in Hypersensitivity and Autoimmunity Deck (28):

Type I Hypersensitivity

driven by IgE by non-infectious Ag through muscosal tissues where the response is like it was an infectious agent

Immediate Response: develops after 1st exposure to allergen where mast cells become sensitized via IgE Ab covering the cells so next contact = immediate degranulation

Late Response: occurs once immediate response subsides and thus reaction lasts longer and has presence of eosinophils; driven by synthesis (de novo) of cytokines by mast cells



inherited propensity for continual IgE production to common natural allergens due to reduced Treg response


Type I: TH2 Responses Regulate IgE Production

TH0 = have not decided what kind of TH cells yet they will develop into
APC presents Ag to Th0 cell and it develops into TH2 cell

Primary contact with allergen induces IgE antibodies
TH2 derived IL-4,IL-13, plus CD40L cause B cell class switching to IgE and IgG


Type I: Sensitization and Secondary Contact

IgE antibodies bind to high affinity FcRe on mast cells and eosinophils (sensitization)

Upon a secondary contact, the allergen binds IgE on mucosal or connective tissue mast cells causing crosslinking of FcRe resulting in “immediate phase” inflammation due to extracellular release (degranulation) of pre-formed inflammatory mediators such as histamine in mast cell granules

Finally, mast cells synthesize and release secondary mediators (cytokines, lipid mediators, chemokines) to cause a “late phase” cellular infiltrate


Type I: Kinetics of Immediate and Late Phases

A. The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in a previously sensitized individual). The late-phase reaction develops 2 to 24 hours later.

B. Morphology of the immediate reaction is characterized by vasodilation, congestion, and edema.

C. Late-phase reaction is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells.


Type I: Mast Cell Signaling Pathways

1. Granule Exocytosis: proteases that can cause cell damage by degrading cellular components; vascular dilation and smooth muscle contraction

2. Enzymatic modification: of arachidonic acid to create prostaglandins that contribute to inflammation; vascular dilation and smooth muscle contraction

3. Transcriptional activation: of cytokine genes to cause cytokine production; inflammation and leukocyte recruitment


IgE Mediated Allergic Reactions

Acute urticarial (wheal and flare)
Allergic rhinitis/sinusitis (hay fever)
Bronchial asthma
Food allergies
Allergic transfusion reactions


IgE Allergic Reaction Tx

Epinephrine causes:
(1) In peripheral circulation, smooth muscles around blood vessels (arterioles) contract, diverting blood from peripheral circulation to essential internal organs
(2) In lungs, smooth muscles around tubes carrying air (bronchioles) relax, so lungs can expand more and you can breathe more deeply.

Corticosteroids: reduces inflammation
Leukotriene antagonists: relax bronchial smooth muscle and reduce inflammation
Phosphodiesterase inhibitors: relax bronchial smooth muscle
Desensitization: Treg induction or modification of TH1/2 balance
Anti-IgE Ab


Type II Hypersensitivity

IgG or IgM specific for cellular or tissue Ag to cause damage to:
1. RBCs
2. Damage to tissues
3. Functional Effects


Type II: RBCs

RBCs: Rh factor in fetus and mother where IgG crosses the placenta and attacks
IgG does not destroy RBCs, Fc receptors on spleen macrophages bind the coated IgG RBCs and then destroyed
Ab against RBCs with IgM it can induce lysis of cell
Acute hemolytic transfusion reaction for example; donor cells interact with patient cells and cause agglutination and destruction


Type II: Damage to Tissues

Damage to tissues: Ag is associated with ECM and the Ag-Ab complex activate complement system and get neutrophil accumulation that produce toxic factors to cause damage the tissues


Type II: Functional Effects

Functional Effects: Grave's disease; Autoantibodies recognize and activate the thyroid-stimulating hormone (TSH) receptor mimicking the effects of the hormone


Type II Prevention

Transfusion reactions can be prevented by evaluating the possibility of cross-matching between donor’s and recipient’s bloods

The hemolytic disease of the newborn is preventable by ensuring that rhesus-negative women receive anti-D antibodies after miscarriage or labor. This will rapidly eliminate the RBCs w/o inducing an immune response


Type II Tx

Treatment aims to reduce effector antibody levels or prevent effector cells from causing damage (particularly for autoimmune diseases).

Plasmapheresis reduces autoantibody levels and is reserved for cases in which antibody needs to be rapidly removed

Immunosuppressive drugs can reduce B-cell autoantibody secretion, although the benefits only take place gradually, over several weeks


Type III Hypersensitivity

driven by insoluble Ag-Ab complexes, which recruit complement system and cause a local or systemic effect similar to Type II
The Ag is soluble, but then when combines with Ab, the complex becomes insoluble


Type III: Mechanism of Injury

IgM or IgG antibodies generated against a first contact with soluble antigen generate soluble immune complexes when the organism is confronted with large quantities or chronic exposure of that antigen
These immune complexes are inefficiently eliminated and can deposit on blood vessels walls
These lodged immune complexes induce a robust and localized immune response mediated by Fc interaction with phagocytes or more importantly, activating the classic complement cascade causing tissue injury (e.g., complement-mediated vasculitis)


Type III: Prevention and Tx

Antigen avoidance is possible in some cases of type III hypersensitivity-for example, farmer's lung (mold antigen) or some drugs and vaccines
In the case of autoantigens (e.g. DNA) avoidance is clearly not possible

In autoimmune causes of immune complex disease, corticosteroids block some of the damage caused by effector cells-for example, neutrophils.
Cyclophosphamide reduces B-cell proliferation and hence autoantibody levels and is often used in severe SLE


Type IV Hypersensitivity

delayed response because driven by cytokines (INF gamma, TNF alpha, and IL-6) produced by T cells (TH and TC)
CD4 cells = tissue injury is caused by activated macrophages and inflammatory cells
CD8 cells = T cell mediated cytolysis; delayed type


Type IV: TH1 Cell Mediated

Primary TH1 (and Tc) response to antigen and expansion of memory T cells sensitizes the individual

Secondary antigen contact triggers TH1 cytokine release (and Tc activation) resulting in delayed (6-48 h) or chronic tissue infiltration by activated macrophages and activated T cells

Cytokines involved are IFN-gamma, TNF-alpha and IL-6 among others


Type IV, TH1 Mediated Examples

Delayed Type Hypersensitivity: insect venom, mycobacterial proteins (TB)

Contact Hypersensitivity: poison ivy, metal ions

Gluten sensitive enteropathy (celiac disease): gliadin

Microbes cannot be eliminated to continuous signaling to attract more monocytes and T cells and then form granuloma by T cells to create a wall around the infection = calcification and inflammation cause damage to the tissue


Type IV, TH2 Mediated

Primary TH2 response to antigen and expansion of memory T cells sensitizes the individual

Secondary chronic exposure to antigen triggers TH2 cytokine release resulting in chronic tissue infiltration by activated eosinophils and activated T cells

Chronic or cyclic release of toxic mediators causes cycles of tissue injury, tissue repair, and tissue remodeling

Major cytokines involved are IL4, IL5 and IL-10

*expansion of T memory cells by the above cytokines, attraction of eosinophils via IgE and activated T cells and the chronic signaling causes the cycles


Type IV, TH2 Mediated: IL-5 and Eotaxins

In these reactions, IL-5 produced by TH2 cells increases bone marrow production of eosinophils
Eotaxins (chemokines) attract eosinophils to the site of reaction
Cytokine activated eosinophils release factors to amplify inflammation and cause tissue injury


Type IV Therapy

Reducing inflammation, using corticosteroids and antagonists against cytokines such as TNF alpha, and to inhibit T cell responses with immunosuppressive drugs such as cyclosporine

For example, antagonists of TNF alpha have proved to be beneficial in patients with rheumatoid arthritis and inflammatory bowel disease


Mechanism of Immune Tolerance

Central tolerance involves clonal deletion of autoreactive T cells in the thymus and modification (or deletion) of reactive B cells at the level of bone marrow. In addition, some autoreactive T cell can differentiate into Treg

If immature lymphocytes recognize self antigen they can either undergo apoptosis, change receptors, or develop into Treg cells (CD4 cells only)

Mature self-reactive lymphocytes may be inactivated or deleted by encounter with self antigens in peripheral tissues, or suppressed by regulatory T cells = Peripheral Tolerance


Microbial Induction of Autoimmunity

Microbe causes presentation of self Ag/something similar to self Ag thus activating APCs to present them to self reactive T cells (B7 from APC + CD28 from T cell come together) and T cells attack self tissues


Genetic Influence on Autoimmunity

There is a greater likelihood of developing certain autoimmune diseases in persons who inherit particular human leukocyte antigen (HLA) alleles than in persons who lack these alleles (odds ratio or relative risk)

Ankylosing spondylitis
Type I DM
Pemphigus vulgaris
Goodpasture’s syndrome: lung, kidney
Grave’s Disease
Primary Sjogren’s Syndrome
Polyarteritis Nodosa


Type II Hypersensitivity Diseases

Autoimmune hemolytic anemia
Autoimmune Thrombocytopenic Purpura
Goodpasture’s Syndrome
Grave’s Disease
Myasthenia Gravis
Pemphigus vulgaris
Pernicious anemia
Rheumatic Fever


Type III Hypersensitivity Diseases

Polyarteritis nodosa
Post streptococcal glomerulonephritis
Serum sickness
Arthus reaction