Autoimmunity Flashcards
autoimmune diseases are …
… chronic, progressive and self-perpetuating
sterile inflammation
TISSUE INJURY: inflammation -> repair -> fibrosis, metaplasia and or tumor
TISSUE STRESS/MALFUNCTION: inflammation -> adaptation to stress -> homeostasis -> shift leads to new homeostasis, disease or autoinflammation
autoinflammatory disorders
definition, example
inherited
involve “unprovoked” innate-mediated inflammation
rhythmic, recurrend
e.g. familial fever syndromes -> FMF -> mutated FMF gene encoding for PYR -> excessive inflammasome activation if homozygous
therapy of autoinflammatory disorders
recombinant IL6R Ab
neutralizing IL1b Ab
IL1R atagonist
decoy IL1R
anti-TNF blockers
causes for autoimmunity (general)
genetics + infection + environment lead to breakdown of tolerance
abnormal display of self-Ag, inflammation, initial innnate response, genetically linked to MHC (HLA complex) abnormalities
infections triggring autoimmunity
mechanisms
BYSTANDER ACTIVATION: activated T cells are not specific!
MOLECUAR MIMICRY: Ag similar to endogenous protein (e.g. EBV and myelin in MS), cross-reactivity
systemic vs organ-specific manifestation of autoimmunity
SYSTEMIC: by self-nucleolar Ab or specific Ab (circulating!)
ORGAN-SPECIFIC: Ab or response against tissue-restricted features
environmental trigger tissue injury
autoimmunity
tissue injury can lead to exposure of previously concealed Ag
autoimmunity induced by immune complexes, circulating auto-AB or autoreactive T cells
causes for tolerance failure
- defects in negative selection of T and B cells
- defects in receptor editin (B cells)
- defects in inhibitory pathways and receptors
- reduced number or function of Tregs
TGFb
driver of Treg and TH17 (in combination with IL6) differentiation
inhibits TH1 and TH2
produced by DC, Treg, MDSC, TAM2 and tumor cells
activates RORgt (TH17)
immunosuppressive towards CD4, CD8, NK cells
beneficial for Treg and TAM (and TH17)
IL6
proinflammatory cytokine
produced by many cells and initiated by many cytokines
with TGFb -> activation of STAT3 -> TH17
loss of IL6 -> Treg increases
promotes T cell survival, proliferation, recruitment and subset committment
IL23
promotes TH17 poarization
IL23R initially not expressed on naive T cells -> not involved in initiation
important for full, sustained and stable differentiation
induces IL17 and IL6, IL1 and TNF -> inflammation (GIT)
Treg in autoimmunity
balance the immune response
establish peripheral tolerance
prevent autoimmunity
autoimmunity developes when numbers or function is reduced, or T cells become resistant
DC in autoimmunity
establishing central tolerance -> mTEC (TRA) and AIRE-mediated
maintaining peripheral tolerance by self-Ag presentation and induction of irrreversible unresponsiveness
B cells in autoimmunity
formation of immune complexes (Ab) -> can engage B cells, FcR bearing cells, and complement system -> inflammation
can display Ag and co-stimulators -> T cell activation
cytokine release
organized lymphoid structure organisation (via lymphotoxin)
single-gene abnormalities causing autoimmunity
influence tolerance
- central tolerance (AIRE)
- generating T reg (FoxP3, IL2, IL2R)
- anergy and function of Treg (CTLA4)
- peripheral T and B differentiation
factors involved in autoimmunity
genetic
infections
tissue alterations
hormones
microbiota
Ab as autoimmunity-causing factor
- TISSUE DISRUPTION: via opsonization and phagocytosis -> Ab bind cells -> immmune recruitment and tissue injury
- IMMUNE COMPLEXES: deposition in vessel walls -> vascular inflammation, ischemic damage, e.g. serum sickness
- RECEPTOR INTERACTIONS: blocking receptor-ligand interaction or activating receptor
GBS
target, effect, pot. cause
Guillain-Barré-Syndrome
TARGET: PNS via Ab (depending on Ab different symptoms)
EFFECT: rapid progressive weakness, maybe respiatory muscles affected
POST-INFECTION: can develop 1-3 weeks after infections, esp. GBS I since not predominant in women, no HLA association and monophasic disease course
SLE
target, cause, pathogenesis
systemic Lupus erthematodes
chronic, remitting and relapsing
TARGET: many different autoAb, most frequent are anti-nuclear Ab
CAUSE: auto-Ab form immune complexes -> inflammatory disease
- GENETIC: insufficient clearance of apoptotic fragements (C1q deficiency)
- ENVIRONMENTAL: extensive cell death or injury -> increased DNA exposure
PATHOGENESIS: clearance hypothesis
- inadequate clearance leads to increased nuclear Ag burden
- immune complex formation
- FcgRIII on pDC binds immune complexes
- TLR7/9 signalling -> DC maturation
- stimulation of self reactive B cells -> Ab increases
TLR7 escape during X inactivation -> extensive TLR 7 signalling in 35% of women
SLE
clinic, therapy
M:F = 1:10
can cause glomerulonephritis, anemia, thrombocytopenia, CNS manifestations
small arteries freuently affected
systemic, psychological manifestations, afferences (figers, toes, nose) affected
THERAPY: no cure or prevention, clinical trials for
- anti-IFNg Ab
- TLR inhibition
- anti-CD20 or anti-BAFF mediated B cell depletion
clearance hypothesis
pathogenesis of SLE
PATHOGENESIS: clearance hypothesis
- inadequate clearance leads to increased nuclear Ag burden
- immune complex formation
- FcgRIII on pDC binds immune complexes
- TLR7/9 signalling -> DC maturation
- stimulation of self reactive B cells -> Ab increases
TLR7 escape during X inactivation -> extensive TLR 7 signalling in 35% of women
Cause of SLE
CAUSE: auto-Ab form immune complexes -> inflammatory disease
- GENETIC: insufficient clearance of apoptotic fragements (C1q deficiency)
- ENVIRONMENTAL: extensive cell death or injury -> increased DNA exposure
Pathogenesis SLE
PATHOGENESIS: clearance hypothesis
- inadequate clearance leads to increased nuclear Ag burden
- immune complex formation
- FcgRIII on pDC binds immune complexes
- TLR7/9 signalling -> DC maturation
- stimulation of self reactive B cells -> Ab increases
TLR7 escape during X inactivation -> extensive TLR 7 signalling in 35% of women
Therapy SLE
THERAPY: no cure or prevention, clinical trials for
- anti-IFNg Ab
- TLR inhibition
- anti-CD20 or anti-BAFF mediated B cell depletion
RA
target, cells & cytokines, therapy
rheumatoid arthritis
TARGET: synovium -> inflammation , destruction of cartilage and bone
CELLS and CYTOKINES: many involved
-> TH17, TH1, cells, macrophages, tertiary lymphoid structures
-> IL1, IL6, TNF & IL8, IL17, IFNg
THERAPY: TNF antagonists, anti-IL6 Ab, IL1 antagonists, JAK inhibition, anti-CD20, B7:CD28 interaction blockage
RA
therapy
THERAPY:
- TNF antagonists
- anti-IL6 Ab
- IL1 antagonists
- JAK inhibition
- anti-CD20, B7:CD28 interaction blockage
MS
target, onset therapy
multiple sclerosis
TARGET: myelin (CNS)
ONSET: genetically predisposed exposed to unknown trigger (ev. EBV infection -> molecular mimicry)
THERAPY:
- HALT MS: prevention of relapsng remitting MS -> chemo and autologous HSC Tx -> CD4 reduced, Tregs increased, but re-emergence of myelin-specific cells
- FINGOLIMOD: reduces SIP1 receptors (mediate T-CM circulation), retention in LN and no CNS invasion
- mRNA VACCINE: non-immunogenic vaccine Ag delivered to DC, expansion of Ag-specific effector Treg
MS
target, onset therapy
multiple sclerosis
TARGET: myelin (CNS)
ONSET: genetically predisposed exposed to unknown trigger (ev. EBV infection -> molecular mimicry)
THERAPY:
- HALT MS: prevention of relapsng remitting MS -> chemo and autologous HSC Tx -> CD4 reduced, Tregs increased, but re-emergence of myelin-specific cells
- FINGOLIMOD: reduces SIP1 receptors (mediate T-CM circulation), retention in LN and no CNS invasion
- mRNA VACCINE: non-immunogenic vaccine Ag delivered to DC, expansion of Ag-specific effector Treg
MS therapy
- HALT MS: prevention of relapsng remitting MS -> chemo and autologous HSC Tx -> CD4 reduced, Tregs increased, but re-emergence of myelin-specific cells
- FINGOLIMOD: reduces SIP1 receptors (mediate T-CM circulation), retention in LN and no CNS invasion
- mRNA VACCINE: non-immunogenic vaccine Ag delivered to DC, expansion of Ag-specific effector Treg
DM1
target, disease complictions and pathogenesis
Diabetes mellitus Type I
TARGET: pancreal beta-clells producing Insulin
Complications: CV diseasem renal failure, severe sight impairment
PATHOGENESIS: inflammation in islet cells leads to necrosis and lymphocyte infiltration
- TH1 reactive towards islet Ag
- CTL mediated lysis
- autoAb
- damaging local TNF and IL1
DM1
genetics
strong HLA association
HLA-DQ 2&8, HLA-DR3&4 have increased susceptibility
HLA-DQ6, HLA-DR2 is potective
polymorphisms in IL2 & CD25, IDD12 (CTLA4) or IDD2 (insulin)
reduced Vitamin D exposure
DM1
therapy
try to induce tolerance with diabetogenic peptides from islet Ag
generating/giving Tregs
TEPELIZUMAB: anti-CD3 mAb, improves/stabalizes beta cell function in Ab+ high risk patinets
tepelizumab
treatment of DM1
anti-CD3 mAb, improves/stabalizes beta cell function in Ab+ high risk patinets
Inflammatory bowel disease
definition, cause, clinic, therapy
heterogenous group of chronic remitting inflammations
-> e.g. Chron’s, ulcerative colitis
CAUSE: most likely poorly regulated response to commensal bacteria
CLINIC: abdominal pain, vomitiing, diarrhea, weight loss
THERAPY: anti-inflammatory drugs
APS-I
cause, symptoms
autoimmune polyendocrine syndrome type 1
AIRE-deficiency
AIRE: mediates TRA presentation by mTECs -> no negative selection
SYMPTOMS: chronic candidiasis, hypoparathyreoidism, adrenocortical failure
Therapeutic approaches for autoimmune diseases
- anti-inflammatory agents
- depletion of cells or Ab
- anti-cytokine drugs/Ab
- interrupting cell interaction/migration (B7 block, intergin Ab)
- Tolerisation (Ag-specific, blunt autoimmunity and no impairment of IS)
-Treg transfer
