Peripheral tolerance & auto-immunity

mandatory because central is not complete (escapes)

low avidity T-cells

can be activated in unknown circumstances & mediate auto-immune reaction ( self-reaction escaped cells somehow activated)

psoriasis

rheumatoid arthritis

graves’ disease

systemic lupus erythematosus

multiple sclerosis

in the CNS normally myelinated neurons but the formation of plaque (delineated area)

demyelinated neurons can’t fulfill their function —> handicap

MS due to self-reactive CD8+ T-cells killing oligodendrocytes that produce myelin

Central tolerance

Peripheral energy

Regulatory T-cells

Activation-induced cell death

signal 1 but low signal 2

no priming of T-cells to effector T-cells

cellular inactivation by weak signaling without co-stimulus

in secondary lymphoid tissue

suppression by cytokines, intercellular signals

in secondary lymphoid tissue and sites of inflammation

multiple tissues in steady state

Apoptosis

in secondary lymphoid tissue and sites of inflammation

thought that a physical barrier exists to prevent self-antigen access to the lymphoid system

but also migration of DC with antigen in steady-state (presentation of self-antigens to B-&T-cells)

can be the reason for an autoimmune reaction

OT-I CD8 T cells transgenic for a TCR specific for an OVA peptide presented by H-2kb

OVA expressed in melanocytes & injection of class I restricted TCR specific for OVA

Gut draining lymph node control: see transferred labeled CD8 T-cells

in skin DLN: proliferation due to dilution of the dye

—>without any infection migration of DC to present self-antigens

—>no activation of DC, no upregulation of costimulatory signals & B7

—> strong signal 1 without signal 2 (peripheral tolerance)

—>start to be activated by proliferation but never stage of effector T-cell

stain cells with fluorescent dye CFSE (covalent binding of cytoplasmic proteins, stable, upon cell division intensity of dye divided between both cells)

in

brain

eye

testis

uterus

more immuno-suppressive microenvironment

tissue grafts often last indefinitely & antigens placed there don’t elicit destructive immune responses

stimulation of naive T-cell —> proliferating T-cell —> differentiation —> active effector T-cells

kill virus-infected target cells

without signal 2: stop at the PROLIFERATION stage

never effector phase

T-cell specific for self-antigen recognized in thymus becomes a natural regulatory T-cell (nTreg)

induced in the thymus with high avidity for self (Hassal corpuscle)

in periphery constantly activated by self-antigen

bith express CTLA-4, TCR, CD4, CD25 at the cell surface

TF Foxp3 specific for nTreg

at distance secreted factors: cytokines IL-10 & TGFß inhibit other self-reactive T-cells

cell/cell contact manner: CTLA4/B7 reverse signaling —> indoleamine2,3deoxygenase (ILDO expression) tryptophane catabolism (reduced proliferation as essential AA)

not antigen-specific!

inhibit any kind of immune reaction —>naturally dampens immune reactions

B1 (unconventional) & Breg express TLR, BCR/IgM, CD40, CD5 at surface

the only difference is that Breg produces IL-10 (but not easy to detect secreted factor —> no marker)

B2 (conventional) expresses TLR, BCR/IgM & CD40 (no CD5)

the end of central tolerance in the periphery SLO (bone marrow central for B-cells)

transitional B-cells that enter the follicle receive maturation & survival signals —> differentiate into follicular B-cells or marginal zone B-cells

transitional B-cells: IgM high, IgD negative

BCR signaling (mutation in BCR) = ligand-dependent + BAFF signaling

BAFF: important factor (TNF SF) produced by FDC stimulating the development of final maturation of B-cells (signal 1 to transitional B-cells BCR dependent)

too strong signal = exclusion from the follicle & death or MZ B-cell but not conventional B2

BAFF deficient mice have no mature B-cells —> strong phenotype by mutation of 1 gene

somatic hypermutation generates novel B-cell specificities within germinal centers

some of these B-cells may now be able to bind self-antigens

encounter of autoreactive B-cell with self-antigen within germinal center causes apoptosis —> lack T-cell help

auto-reactive T-cells eliminated in the thymus

antibodies: antagonist, agonist or pro-inflammatory

auto-reactive T-cells

Graves’ disease with an agonist Ab against Thyroid-stimulating hormone receptor —> pathway overactivated

Myasthenia gravis: antagonist Ab against Ach receptor

muscle weakness

antagonist Ab against a signaling receptor

neuromuscular function: muscle needs nerves for stimulation of contraction —> release of Ach & stimulation of AChR on the surface of muscle —> Na+ influx & contraction

when auto-Abs against AchR their binding induces internalization & degradation —> muscle unresponsive to ACh —> no Na+ influx & no muscle contraction

blood test: take the serum of the patient & inject it in animal —> disease symptoms also triggered —> immunoprecipitation of Abs for AChR —> binds mouse & human AChR

for production of Ab also auto-reactive CD4 T-cells present

antagonist Abs against adhesion molecules

first mucose than skin —> blistering of the skin

different B-cell epitopes on desmogleins are targeted by auto-Abs (early epitope in the mucosal stage of disease vs. late epitope in skin stage of disease)

Abs made against Dsg-1 & Dsg-3 unzip the adhesive interactions in desmosomes —> intra- & intermolecular epitope spreading

desmoglein is an adhesion molecule in cell junctions holding together keratinocytes

interfere with the physiological adhesive interactions of desmoglein (necessary for skin integrity)

agonistic auto-Ab against a signaling receptor

thyroid-stimulating hormone TSH which acts on the thyroid inducing the release of thyroid hormones

the pituitary gland secretes thyroid-stimulating hormone TSH which acts on the thyroid inducing the release of thyroid hormones

TH acts on the hypothalamus & pituitary to shut down the production of TSH, suppressing further TH synthesis

—> Feedback suppression

Autoimmune B-cell makes Abs against TSH-R that also stimulates thyroid hormone production

loose regulation of thyroid hormones —> constitutive release (hyperthyroidism)

TH shut down TSH production but had no effect on auto-Ab production —> excessive TH production

patient with Graves’ disease makes anti-TSHR Abs transferred across the placenta to the fetus —> newborn with Graves’ disease

Plasmapheresis removes maternal anti-TSHR Abs & cures the disease

spread via non-classical MHC molecule, FCRN transporting IgG

transferable AIDs: myasthenia gravis, Graves’ disease,, thrombocytopenia purpura, pemphigus vulgaris, neonatal lupus rash and/or congenital heart block—>IgG mediated auto-immune disease

little lasting symptoms disappear along with maternal Ab

Inflammatory antibodies

multiple-organs affected: skin, blood vessels, kidney

antibodies against DNT & T-independent responses: BCR + TCR signaling

B-cells with specificity for DNA bind soluble fragments of DNA sending a signal through the BCR

cross-linked BCR is internalized with bound DNA molecule

GC-rich fragments from internalized DNA bind to TLR-9 in an endosomal compartment (co-stimulatory signal)—>hypomethylated CpG sequences rich in prokaryotes & apoptotic cells

B-cells with a strong affinity for DNA are eliminated but with lower affinity escape & persist

—> Cell apoptosis is needed so that DNA is visible to the immune system

DNA associated with proteins —> both internalized by BCR —> proteins can activate TH —>T-dependent high affinity & antibody switch

DNA-specific presents peptides from DNA-associated proteins to T-cells

autoimmune CD8 T-cells attack the myelin sheath from nerves axons in humans —> paralysis

animal model: experimental autoimmune encephalitis

injection of myelin basic protein & complete Freund’s adjuvant develop EAE —> paralyzed (also a drug for permeabilization BBB)

peripheral vaccination with MHC II-restricted peptide from myelin-associated protein disease is mediated by Th17 & Th1 cells specific for myelin basic protein

transmittable via transfer of T-cells from affected animals (activated CD4+ myelin-specific T-cells)

—>similar disease but different effector cells —> animal models not always optimal (in human CD8+)

CD8 T-cells infiltrate in the pancreas, in the beginning don’t kill ß-cells (insulitis = presymptomatic stage)

islets of Langerhans: several cell types secreting hormones —> each cell expresses different tissue-specific proteins

T1D: effector T-cell recognizes peptides from a ß-cell specific protein —> destruction of insulin-producing ß-cells —> hyperglycemia

glucagon & somatostatin still produced by the α & δ cells but no insulin made

innate cells as effectors: macrophages & CD4+ T-cells

effects the joints

unknown trigger sets up initial focus of inflammation in synovial membrane attracting leukocytes

auto-reactive CD4 T-cells activates macrophages —> production of pro-inflammatory cytokines & sustained inflammation

cytokines induce production of matrix metalloproteases & RANK ligand by fibroblasts

MMPs tissues & activation of bone-destroying osteoclasts by RANK ligand —> joint destruction

in past treated with nonspecific immunosuppressive drugs, today more specific TNFα

autoantigens

PAD (peptidyl arginine deaminase) converts positively charged arginine residues to neutral citrulline residues

—> loss of surface chages makes the protein more susceptible to proteolytic degradation —> recognized at non-self —> peptides with citrulline residues are presented by HLA class II to CD4 T-cells

Abs against citrullinated proteins —> epitopes recognized after post-translational modification

also rheumatoid factor = antibody against the Fc part of Ig, Abs against other Abs

PAD expressed in tissues stressed by wounds or infection

genetuc factors (susceptible genes) in combination with infection & environmental exposure

lead to immune dysregulation which can result in auto-immunity

HLA

different MHC molecules: bad ones bind better self-peptides

can be class I or class II

DQ6 HLA allele less susceptible for T1D

position 57 of the DQß chain affects susceptiblity to type 1 diabetes mellitus

Asp57 & salt bridge with arginine —> impair self-peptide presentation

Alanine 57: non-polar AA, no salt bridge—> self-peptide presentation possible

AA differences in the MHC groove after self-peptide presentation

environmental factor

RIP-OVA (Rat insulin promotor) & OVA expressing virus infection

mice produce OVA in pnacreas—> develop T1D when infected with virus recombinant for OVA

pathogen triggers immune response & if pathogenic antigen similar to a self-antigen

pathogen specific T-cells & Abs produced that may be cross-reactive with self-antigen —> MS & EBV best known examples

molecular mimicry for T-cells & B-cells between EBNA1 & myelin