Allergies are hyper immune response to foreign antigen.
Here we focus on immune reactions to self, bacteria and transplants.
We try to screen out self-reactive lymphocytes during development but:
- some weak interacting ones also respond to foreign antigens, so we need them
- some just escape
Paul Ehrlich discovered / described autoimmunity in early 20th century. Named "horror autotoxicus".
Autoimmune conditions are actually on the rise + comprise ~5% of population.
How does immune system identify "self" in the first place?
Central tolerance:
- broadly inactivation due to strong binding signals in thymus
Peripheral tolerance
- Antigens presented from normal cell turnover
- Not associated with cytokines or costim expression
- Either the activated T cell does nothing or T_regs induced
- Anergy (peripheral inactivation by signaling without inflammation or costims)
- Central tolerance (deletion by negative selection)
- T_regs (iT_reg/nT_reg, suppression in antigen or nonspecific way)
- functional deviation direct differentiation into T_reg
We have some amount of autoreactive lymphocytes in the first place. Why?
- positive selection requires loose binding to understand if MHC works
- constant stimulation in periphery from loose interaction to keep cells alive
Thymus epithelial cells and CD8\alpha+ DCs express antigen genes from elsewhere in the body (like insulin).
AIRE (autoimmune regulator) TF seems to cause this.
APECED -> disease of pancreas autoimmunity from deffective (Autoimmune Polyendocrinopathy-candidiasis-ectodermal dystroophy)
- interaction with TLR - unmethylated CpG can be internalized by B cells and interact with internal TLRs
- autoantibodies against DNA, chromatin + ribo
- antigen amount - release of cardiac antigen following heart attack leads to immune response days later
- antigen structure - IgG can crosslink B cells when it forms immune complexes
Brain, eye, testis, uterus
How do these sites reduce immune activity?
- tissue barriers prevent lymphocytes from entering
- TGF-\beta induces T_reg differentiation
- Fas ligand
Sites source of autoimmune disease (MS): T cells activated elsewhere. Sympathetic Ophthalmia: trauma to one eye creates antigens that active T cells outside and allow them to come in (they are able to get through barrier somehow)
different diseases depend on different T cell types type 1 diabetes mellitus - T_H1 psoriasis - T_H17
immune modulation
nT_reg - express FoxP3. Respond to self antigens specifically. iT_reg - develop in periphery in response to TGF-\beta. Not antigen specific.
Oral tolerance to antigen primarily caused by iT_reg generation
- Normal levels of defective T_reg present in MS patients
- Foxp3 negative (but IL-10 positive)
Often involve multiple components of system.
Antigen + adjuvant injected into animal elicits disease. But models are not faithful because we generally don't know how autoimmunity starts
Organ specific:
Hashimoto's thyroiditis Grave's disease
Systemic:
SLE Sjogren's syndrome
Commensal:
IBD - Chron's + UC
- autoantibodies block receptors
- immune complexes deposit + cause tissue damage
- effector T cells cause inflammation + tissue damage
Antibody mediated disease can be transferred to newborns across placenta. Some can cause tissue damange before successful clearance of blood plasma with plasmapheresis.
Myasthenia gravis - acetylcholine receptor Graves' - TSH (thyroid stimulating hormone) receptor Thrombocytopenic purpura - platelets
Examples. T cell mediated disease, like SLE + MS involve B cells (present antigen to T cell) and antibodies (generally around).
Antibody mediated disease involve T/B cell through antibody development (secretion + cross linking).
Initial response to antigen straightforward enough.
Removal of the antigen in normal immunity usually causes effector cells to die off. In autoimmunity, either because of quantity or ubiquity, antigen always around.
How does the immune response amplify?:
- Big component is the breakdown of "sequestration" by intial tissue damage.
- More epitopes on same antigen are recognized (epitope spreading):
- Hidden components (present in low concentrations) are efficiently presented by B cells
- Additional molecules recruited with original epitope are internalized accidentally by B cells
Examples of epitope spreading:
- SLE - B cell internalizes large DNA complex. Activates T cells for differnt pieces - histone pieces, ribosomal protein
- Pemphigus vulgaris - binds to desmosomes and causes dissolution of skin tissue. Starts with harmless Dsg-3 antibodies but spreading eventually creates the kind causing deep skin blistering.
Like allergies, we first thought grouped by degree of active/inactive Becoming clear that similar to allergy re-classification - most of the immune components are involved in each response.
However we still classify based on antigen and main mechanism.
Classified based on antigen and main mechanism
- Type 2 responses play almost no role in autoimmunity, exclusively atopy/allergy
-
Auto IgG and IgM bind to Fc and CR
-
Rapidly cleared by mononuclear-macrophage phagocytic system in spleen
-
or lysed by membrane attack complex of complement
-
Autoantibodies against surface proteins (eg. autoimmune thrombocytopenic purpura)
-
Nucleated blood cell lysis is less common but still happens
Tx strategies:
- Removal of the spleen to prevent macrophage clearance is a common tx strategy
- Also introduction of lots of nonspecific IgG (IVIG) - intravenous immunoglobulin.
- Can directly lyse cells
- Sublytic doses also causes problems:
- cytokine release
- respiratory burst
- arachidonic acid cleavage
C5a itself is a chemokine
Why?
In general, unnucleated cells lack metabolic machinery (mitochondria + nucleus) to make new proteins.
1/ Complement regulating surface proteins CD55 - DAF (decay-accelerating factor), accelerates C3 convertase decay CD59 - protectin (), binds c8/c9 components of membrane attack complex (MAC)
2/ Can repair some membrane damange caused by MAC
Examples of either:
Agonist (Grave's disease). Thyroid-stimulating hormone (TSH) from pituitary is controlled by thyroid hormone. Autoantibodies directly stimulate thyroid receptor and prevent negative feedback.
Antagonist (myasthenia gravis). Muscle contraction inhibited by autoantibody inhibition of nicotinic acetylcholine.
- Goodpasture's syndrome - type IV (basement membrane) collagen in renal glomeruli and pulmonary alveoli
Immune complexes:
- serum sickness (overwhlemed by immune complex)
- bacterial endocarditis (lodged in cardiac valve, unable to kill source)
- mixed essential cryoglobulinemia
- SLE
SLE main steps:
1/ Autoantibodies against proteins in nucleated cells ( 3 types:
- nucleosome subunits of chromatin
- spliceosome
- ribonucleoprotein complex ) 2/ Complexes traffic to renal glomerular basement membrane 3/ Poor clearance (due to dysfunction of complement proteins and lack of opsonization)
Cryoglobulins, soluble antibodies because of hydrophobic regions or clumping, that precipitate in joints/tissue.
Hard to study because adoptive transfer in people require MHC matching
Culture requires the exact tissue from patient presenting problematic antigen
Multiple sclerosis is a response against nervous system myelin angitens:
- myelin basic protein MBP
- proteolipid protein PLP
- myelin oligodendrocyte glycoprotein MOG
These live on oligodendrocytes (support glial cell that maintain myelin sheath).
1/ Initial antigen stimulus 2/ BBB is "opened up". Epithelial cells lose tight junctures in response to inflammation and express adhesion molecules 3/ Rolling and entering (diapedesis) 4/ Re-encounter antigen
The plaques come from combination of demylenation and astrocyte proliferation / ECM production.