Hypersensitivity and Autoimmunity Flashcards
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
Atopy
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
- Granule Exocytosis: proteases that can cause cell damage by degrading cellular components; vascular dilation and smooth muscle contraction
- Enzymatic modification: of arachidonic acid to create prostaglandins that contribute to inflammation; vascular dilation and smooth muscle contraction
- Transcriptional activation: of cytokine genes to cause cytokine production; inflammation and leukocyte recruitment
IgE Mediated Allergic Reactions
Anaphlyaxis 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
Antihistamines
Type II Hypersensitivity
IgG or IgM specific for cellular or tissue Ag to cause damage to:
- RBCs
- Damage to tissues
- 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
Prevention:
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
Treatment:
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 RA Type I DM Pemphigus vulgaris Goodpasture’s syndrome: lung, kidney MS: SNC Hasimoto’s Grave’s Disease SLE Scleroderma Primary Sjogren’s Syndrome Polymyositis Polyarteritis Nodosa Psoriasis
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
SLE Polyarteritis nodosa Post streptococcal glomerulonephritis Serum sickness Arthus reaction
