Shnyra- Hypersensitivity Flashcards
What mediates Type I hypersensitivity responses?
IgE. They result from the actions of mediators secreted by mast cells
What mediates Type II hypersensitivity responses?
IgG & IgM that bind tissues Ags & cause complement-dependent tissue injury/disease
What mediates Type III hypersensitivity responses?
Circulating Ag-Ab complexes which deposit in vessel walls & cause complement dependent injury in vessel walls
What mediates Type IV hypersensitivity responses?
T cells & results from inflammation caused by cytokines produced by CD4+ Th1 cells, Th17 cells, and macrophage or killing host cells by CD8+ CTLs
Define atopy
A genetic tendency to develop allergic diseases/allergic rxns
What do the effects of histamine, prostaglandins & leukotrienes combined induce?
Increases in BP & permeability
What causes edema?
Increased movement of fluid from the intravascular to the interstitial space
In the mechanism of edema, how are leukotrienes and histamine different?
Leuko-drain larger venules (vasoconstriction)
Histamine- post cap venules (vasodilation)
Before clinical presentation, what is occurring in the process of immediate hypersensitivity?
Activation of Th2 cells by first exposure to allergens & generation of plasma cells which produce IgE, IgE bind to FceR1 receptors on mast cells
What are late phase Type I hypersensitivity rxns characterized by?
Inflammatory infiltrate rich in eosinophils, neutrophils, & T cells
What are the 4 purposes of Allergen Specific Immunotherapy?
- induce peripheral T cell tolerance
- Increase thresholds for mast cell & basophil activation by allergens
- to decrease IgE-mediated histamine release by mast cells
- to generate allergen-specific inducible FOXP3+ CD4+ CD25+ Treg cells
In terms of allergen desensitization, define immune deviation
Repeated exposure to desensitizing allergen induces a shift from Th2 to Th1 CD4 cells that results in the generation of cytokines (IFN-y) which inhibit IgE production
Explain Type II Hypersensitivity
IgG can opsonize cells that leads to phagocytosis of the cells through FcyR or CR1 receptors. Neutros and macros that are activated in this manner release their inflammatory mediators (ROS & lysosomal enzymes damage the adjacent tissues & cause inflammation)
IgM and IgG can act. classical pathway which produces C5a and C3a which promote leukocyte recruitment & inflammation
What do Ab-dependent effector mechanisms of Type II Hypersensitivity require?
Immune cells expressing Fcy receptor type III (FcyRIII) on their surface & target cells coated with Ab recognizing ags on the cell surface
NK cells express high levels of FcyRIII & are regarded as the key players in this process
What is myasthenia graves?
Inhibiting of the binding of acetylcholine neurotransmitter to the ACh receptor that causes autoimmunity
Define immune-complex anemias
Abs form immune complexes with a drug. the ICs can bind to the erythrocyte surface via CR1. Complement is activated on RBC surface which causes hemolysis
Define autoimmune anemias
Drug induces anti-drug Abs that cross react with an Rh Ag on RBCs. Ab binding to Rh Ag activates phagocytosis & complement. Treatment may require immunosuppression or removal of ICs by plasmapheresis
What is serum sickness (Type III hypersensitivity)?
Can be induced by IV administration of a protein Ag to a previously immunized patient that leads to formation of IC and systemic vasculitis
What is arthus rxn (Type III hypersensitivity)?
Induced by subcutaneous administration of a protein Ag to a previously immunized animal. Ag causes local formation of ICs at the site of AG injection that leads to local vasculitis (compare to the systemic vasculitis in serum sickness)
What 3 things trigger a Type IV hypersensitivity reaction?
Autoimmunity
Persistent responses to environmental Ags
Microbial Ags
How long does it take a Type IV hypersensitivity rxn to occur & what is it mediated by?
24-48 hours & it is mediated by Ag-activated CD4+ T cells, CD8+ T cells, and macrophages which release mediators
What is central tolerance?
Induced by immature self-reactive lymphocytes in the primary lymphoid organs. Ensures that mature lymphocytes are not reactive to self Ags
What is peripheral tolerance?
Induced in mature self-reactive lymphocytes in peripheral sites. Prevents activation of these potentially dangerous lymphocytes in the tissues
In terms of central tolerance, what is positive selection?
Thymocytes that bind self-Ags below a certain threshold are positively selected & are allowed to migrate into the periphery as mature T cells
In terms of central tolerance, what is negative selection?
Thymocytes which strongly bind self-Ags undergo negative selection & are deleted by apoptosis
In some cases, strong binding of self-Ags leads to activation of FoxP3 gene & production of natural Treg cells (nTreg cells)
What is a critical factor for survival & functional competence of nTreg cells?
IL-2
What is RORyt and how is it induced?
It is induced by IL-6 and IL-1 in combination with TGF-B. It is a major transcription factor driving differentiation of Th17 cells which are important in autoimmunity
What do IL-10 & TGF-B inhibit?
Proliferation & effector functions of T cells, activation of M1 macrophages, differentiation of Th1 cells
What does TGF-B regulate/stimulate?
Regulates differentiation of induced FoxP3+ Treg cells
stimulates production of IgA in inducing B cells to switch to this isotype. Stimulates collagen synthesis by fibroblasts
Explain the importance of anti-CTLA4 & anti-PD1 Abs.
Used for treatment of cancer pts. Enhance antitumor immune responses & tumor regression. Side effect: may lead to autoimmune diseases
What leads to anergic cells?
Ag recognition without adequate CD80:CD28 costimulation induces anergy. Anergic cells survive but are incapable of responding to Ags
What two major mechanisms eliminate autoreactive B cells in central tolerance?
Anergy & clonal deletion
What is the purpose of BCR editing in Central B cell tolerance?
Leads to the repeated rearrangement & replacement of the genes that encode Ig Light chain until BCRs which do not recognize self-Ags are produced or the cell dies
What is CD22’s role in peripheral B cell tolerance?
It is an inhibitory coreceptor. When act., it recruits SHP-1 tyrosine phosphatase that attenuates BCR signaling. It is involved in B cell tolerance to self-Ags
What happens to cellular debris in pts with complement C1, C2, and C4 deficiencies?
It is NOT removed from circulation but instead stimulates the production of autoantibodies
What is the role of CTLA-4 in peripheral tolerance?
Inhibitory receptor. Provides signals that terminate immune responses. Prevents activation of autoreactive T cells & maintains self-tolerance in healthy pts. It may lead to a break of self-tolerance & the development of autoimmunity
What happens in CTLA-4 KO mice?
Uncontrolled lymphocyte activation with massively enlarged LNs & Spleen associated with FATAL multi-organ lymphocytic infiltrates. Blocking of CTLA-4 w/anti-CTLA-4 worsens the ongoing autoimmune diseases in animal models
What is Fas/FasL signaling?
Recognition of self-Ags may lead to expression of death receptors (fas) & its ligand (FasL) on T lymphocytes. Fas engagement leads to apoptosis of the cells by the death receptor (Extrinsic) pathway. Defects in Fas-FasL signaling result in autoimmune lymphoproliferative syndrome (ALPS)
What causes epitope spreading?
An immune response to secondary epitopes which are distinct from the primary disease causing epitope
What is the principal SLE diagnostic test?
The presence of anti-nuclear Abs
What are the principal immune cells involved in Rheumatoid Arthritis?
Th1, Th17, activated B cells, M1 macrophages
What cells can trigger an inflammatory response in the white matter of the brain?
TNF-a, IL-6, IL-17, TGF-B, IFN-y
What occurs in multiple sclerosis?
Development of plaques in the white matter by stripping myelin from neurons. Popular treatment= cytokine IFN-B that attenuates the action of the proinflammatory cytokines
What happens in the immunopatheogenesis of T1D?
Local APCs present Ags in the context of Class II MHC molecules & secret IL-12 that plays an important role in the pathogenesis of T1D. APCs activate Ag-specific CD4+ Th1 cells which produce IFN-y. IFN-y inhibits Th2 cytokines production (IL-4, 5, 10) & enhances IL-1b, TNF-a, ROS production by macrophages which all are toxic to islet beta cells
