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
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Auto IgG and IgM bind to Fc and CR
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Rapidly cleared by mononuclear-macrophage phagocytic system in spleen
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or lysed by membrane attack complex of complement
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Autoantibodies against surface proteins (eg. autoimmune thrombocytopenic purpura)
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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.
For whatever reason, female occurence higher
GWAS identifies causal variants
- autoantigen availability or clearance
- apoptosis (regulate immune response) (FAS)
- signaling thresholds for T cell activation (PD-1 / CTLA-4).
- cytokines
- costims
- T_regs (Foxp3 mutation)
T_reg:
- Foxp3
- CD25
Monogenic Fas mutations
HLA-DRX alleles linked to type 1 diabetes
Genetic linkage of DR3/DR4 to DQ\beta (the actual gene with offending polymorphism)
Actually great case study for the loose binding hypothesis for T cell development
TODO: revisit dual nature of autoreactive display
Two hypothesis for HLA mutation and diabetes
1/ Inability to induce self tolerance during negative selection (from DC presentation) 2/ Or inability to create slightly autoreactive T cells that pass positive selection (these slightly autoreactive T cells are then assumed to have a regulatory function?)
Think about layers of innate immunitity between commensal bacteria and inner layers of epithelia:
- mucus from goblets
- epithelial junction
- antimicrobial peptides from Paneth cells
- phagocytic macrophages
- T_regs
With CD, you see dysfunction in one or more layers. Indirectly, this stimulates chronic T_H inflammation.
1/ NOD2 is an intracellular receptor that triggers inflammation (and release of antimicrobial granules in Paneth) 2/ CXCL8 dysfunction + lack of neutrophil accumulation 3/ Autophagy genes, ATG16L1 / IRGM, prevent clearance of swallowed microbes
Can also get upregulation of T_H response directly (eg. mutation in IL-23 for T_H17)
- Vitamin D levels (higher incidence of autoimmunity in Northern Hemisphere). Suppress T_H17 levels.
- 'hygiene hypothesis' - exposure to microbes
General activation of lymphocytes from different (pathogenic) antigens Tissue damage released stored self antigens
- Mice can develop diabetes after viral infection
Why are the self-reactive lymphocytes there?
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Some escape deletion as described previously
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Antigen present in much greater quantity activates these normally ignorant cells
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Autoimmune hemolytic anemia follows Mycoplasma blood infection
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Rheumatic fever. Similar epitopes of Streptococcus pyogenes to self leads to antibody + T cell mediated tissue damage, including heart valves + kidney
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Lyme disease. Borrelia burgdorferi. Infection followed by Lyme arthritis.
- Procainamide, for heart arrhythmias, induces autoantibodies
- Several lead to autoimmune hemolytic anemia
- Heavy metals, gold + mercury (mostly through haptenization)
Precise timing of infection with chance lymphocyte clones might be all needed. The pathogen / antigen might be different but lead to same disease.
- MHC mismatches almost always trigger a response
- immunosuppression + transplantation medication helps
- blood is less problematic because express small amounts of MHC I (and no II)
- To avoid, antibody destruction, patients must be matched for ABO and Rh group antigens
Basic terminology:
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autograft - from same organism
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syngeneic graft - from genetically identical organism
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allograft - from different organism
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acute rejection occurs 10-13 days after transplantation. (in contrast to hyperacute or chronic).
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T cell role clear in lack of response in nude mice. Acute rejection can be stimulated in nude mice by adoptive transfer.
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accelerated rejection occurs 6-8 days second time from clonal expansion of primed memory T cells
Actually origin of molecule name. Significant portion of T cell repertoire are reactive against nonself MHC
Immunosuppression makes MHC matching irrelevant for non bone marrow allografts (?).
Even HLA matched relatives experience rejection from non-MHC proteins.
Success in clinical transplants result of immunosuppression.
The set of proteins that cause graft reactions that are not MHC are called minor histocompatibility antigens.
H-Y responses come from proteins on Y chromosome (eg. Smcy). Male anti-female response (but not vice versa)
Most are autosomal and have yet to be characterized.
1/ Donor origin APCs migrate to lymph tissue. Direct allorecognition Interestingly, migrating cells move through blood not lymphatics because solid organ allografts disrupt functioning lymph system.
2/ Uptake into recipient's own APCs. Indirect allorecognition. Key here is self MHC molecules do the presenting.
Complement dependent reaction occurs in minutes
- ABO-matching
- cross matching - looking for reactivity against donor white blood cells
Antibodies occlude vessels connecting organ graft to rest of body, leading to purple color and enlarged state.
Some transplanted organs less susceptible to ABO incompat + cross-matching
- \alpha-Gal, surface carbohydrate
- hyperacute rejection occurs quickly with xenografts
- exacerbated because complement regulatory proteins (DAF, CD59, etc.) work less efficiently across species boundaries
chronic allograft vasculopathy:
- concentric arteriosclerosis
- hypoperfusion (cut off nutrients, blood)
Caused by recurring rejection events by antibodies + T cells
Some specific examples of tissue destruction:
- 'vanishing bile duct syndrome' in liver
- 'bronciolitis obliterans', accumulation of scar tissue in bronchioles
Other examples of failure causes:
- ischemia-reperfusion injury. Sudden blood flow can lead to tissue damage
- viral infections from immmunosuppression
- same disease in allograft as original organ
Kidney first transplanted organ in 1950s (between twins).
- Kidney (17.8K)
- Liver (6.7K)
- Heart (2.7K)
Cornea (45K HSC (20K)
Corneal transplants are particularly successful because of lack of vasculature: harder for lymphocytes to move around and react to antigens.
Organ availability Progression of same disease Immunosuppression can lead to infection or cancer
1/ More targeted immunosuppression that does not lead to cancer 2/ Graft tolerance 3/ Xenografts
Cell surface antibodies
- Rabbit anti-thymocyte globulin (rATG). Polyclonal molcules made in rabbits against human T cells.
- anti-CD52 (alemtuzumab). Mature lymphocytes (eg. T / B / NK) marker for depletion.
- anti-CD3 (muromonab). Binds to TCR-CD3 complex for depletion.
- anti-CD25 (basiliximab). IL-2 mediated proliferation (proliferation/survival pathway).
- CTLA-4-Ig Fusion (belatacept). CTLA-4 binds B7, competing with CD28 on T cells. Ig region is for stability of long half-life in blood.
Calcineurin inhibitors
- Cyclosporine (CsA)
- tacrolimus
Inhibit phosphatase required for nuclear translocation of NFAT. Recall calcium dependent serine phosphotase. TCR increases calcium concentrations in the cytoplasm.
mTOR inhibitors
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Sirolimus (Rapamycin)
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Downstream of IL-2/CD25 signaling
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CD25 -> mTOR -> cyclin/CDK
Antiproliferative drugs
- azathioprine. Inhibits purine synthesis, blocking replication
- mycophenolate. Inosine monophosphate dehyrogenase
Corticosteroids
- Prednisone
Think of major function as downregulating eg. IL-2, for proliferation
- Remove host T cells with chemo / radiation
- Introduce marrow graft
- Mature lymphocytes in donor marrow attack
Can be demonstrated with MLR
In leukemia patients, GVH is actually good for clearing cancerous lymphocytes graft-versus-leukemia effect
One strategy is donor T cell depletion. But can cause immunodefficiency + opportunistic infection if overboard. Also might be bad for GVHD.
Rather than depleting T cells, deplete the APCs. Still functional immunity. Graft-vs-leukemia more unclear.
Supplementing CD25+ T_reg reduces symptoms or even prevents death from GVHD
(Though conventional T cells will express CD25 when activated, persistent high CD25 expression is a hallmark of T_reg.)
(Anergic T cells lack CD28 expression)
- physical separation of T cells from mother by trophoblast (placenta outer layer)
- No MHC II + Limited MHC I on trophoblast
- Nutrient depletion (IDO)
- Regulatory cytokines - TGF-\beta + IL-10. (iT_res might have evolved from maternal tolerance) in environment
- Stromal cells of decidua