Hypersensativity Reactions Flashcards
Humoral immunity overview
Naive B cells are shown antigens in the the lymph nodes or in blood and activate to proliferate and differentiate into plasma cells
Have two pathways:
1) T cell-independent:
- occurs with polysaccharides and lipid antigens/ epitopes
- these antigens can cross-link several antibodies on each B-cell to initiate B-cell activation
2) T cell-dependent
- occurs with protein antigens and are required to be bound to CD4 cells in order for B-cells to activate to them
- these are bound to MHC class 2 molecules also
B cells sometimes undergo heavy chain class switching (isotope switching) to change from IgG -> IgM/IgE for every specific single antigen
Sensitivity phases
1) sensitization phase
- an adaptive response to initial encounter of an antigen and activates B-cells to plasma cells and T cells to helper T-cells
- attaches IgE/IgG/IgM specific antibodies to immune cells to “sensatize” them to an antigen (depends on type of hypersensitivity)
2) effector phase
- response to subsequent exposure to the sensitization phase
- this is where the pathology actually is produced
- better targeted and more robust due to immunological memory
Type 1 hypersensitivity
Type 1 (immediate)
- caused by TH2 cells, IgE antibodies and mast cells
- mast cells release mediators that act on blood vessels and induce cytokines for inflammation
- when initiates occurs rapidly
TH2 cells release IL4/5/13 - IL4 = stimulating heavy chain class switching to IgE
- IL5 = stimulates eosinophils to activate
- IL13 = stimulates mucus secretions
First phase = TH2 cell response to first exposure to antigen.
- this initiates all the IL’s and also binds IgE to mast cells (sensitization
Second phase = 2nd exposure to the antigen causes IgE cross-linking and activates mast cells via FcRI receptors on the mast cells
Type 2 hypersensitivity
Type 2 (antibodies mediated) - caused by IgG/IgM antibodies which bind to tissues or cell surfaces that have self-antigen they react to - promote phagocytosis with macrophages and also activate classical complement pathway for cell lysis IgG = opsonization IgM = compliment activation
Syndromes associated
- autoimmune hemolytic anemia = binds to RBCs and are induced with B-lactam haptens
- autoimmune TPP
- pemphigus vulgaris
- ANCA (+) vasculitis
- blood transfusions
- MG
- Goodpasture syndrome
- acute rheumatic fever
- Graves’ disease = TSH receptor autoantibodies
- pernicious anemia
Type 3 hypersensitivity
Type 3 (immune complex mediated)
- caused by IgG/ IgM (most common in IgM) binding to antigens in circulation and form complexes that deposit in vascular beds and induce inflammation
- also recruits neutrophils and monocytes to the area to produce ROS
Usually produced via protein antigen exposure
Inflammation and tissue injury occurs via complement activation at the site of deposition
- marker is lowered C3 levels
Syndromes
- SLE (antinuclear-IgG antibodies, anti-dsDNA antibodies, anti-smith and Ro antibodies )
- post strep Glomerulonephritis
- PAN
- Reactive arthritis
- Serum sickness
- Arthus reaction
Type 4 hypersensitivity
Type 4 (T-cell mediated)
- caused by TH1/TH17 immune responses to antigens
- also brings in CD8+ T-cells to promote damage
Syndromes:
- RA
- MS
- T1DM
- IBD
- psoriasis
- contact sensitivity
- TB immune effects
- hashimoto thyroiditis (self-reactive CD8 Tcells and thyroglobulin and TPO-antibodies)
What does atopy mean?
Genetic predisposition to allergies (type-1 hypersensitivity)
These individuals have more IL-4 and serum IgE levels making allergies more likely
Self-tolerance
Occurs to make sure self-reactive T and B cells die
Central tolerance:
- occurs inside bone marrow for B cells and thymus for T cell
- introduces self antigens via AIRE proteins and if they react = death. If they dont react = lives
- some CD-4 T cells will survive if they react and become Treg cells
Peripheral tolerance
- occurs out in peripheral tissues for both B cells and T cells
- anergy = prevents self-reaction by turning off active cells (rather than killing them)
What is the costimulation signal for naive lymphocytes to activate?
B7:CD28
Need this on top of CD4/8: MHC 2/1 to activate
The costimulatory signal is upregulated due to APCs being bound to microbe/pathogen antigens
- sometimes in autoimmunity,the antigen the APC picks up is a self antigen
- *also molecular mimicry can occur, where the APC picks up a microbe antigens that is very similar to cell surface markers and induces cross reactivity**
- this is more common in B-cells with epitope spreading
What are generalized mechanisms of autoimmunity
Females get autoimmune disease more
Genes matter and HLA alleles matter as well
Autoimmunity results in
- relative decreases in inhibitor pathways
- increases costimulatory pathways
Positive feedback loop due to autoimmune disorders
Inflammation caused by self reactive antibodies causes cellular damage which releases more self-antigens
- more antigens = more self-reactive reactions
Neonatal Graves’ disease
Mother with Graves’ disease makes anti TSHR antibodies that can cross the placenta and induce newborn Graves’ disease
- needs plasmapheresis in newborn to cure disease**
Common autoimmune therapies
Rituximab = anti-CD20 and Fcy receptor mab
Cyclosporine and tacrolimus = calcineurin inhibitors
Abatacept and belatacept = blocks Fc:CTLA-4 fusion protein formation. Also blocks CD-28
Sirolimus = blocks mTOR
