immuno: tolerance and autoimmune disease Flashcards
tolerance
process by which body ensures immune responses are directed against foreign Ags or altered self (tumors) NOT against normal self tissues/cells
- specific unresponsiveness of individual to an Ag
- need Ag-sp rec. to be tolerant
T and B lympho: Ag binding rec
TCR (T)
Ig (B)
generated at random, potential for self rxn
tolerance that occurs early in lymphocyte development
central tolerance
peripheral tolerance catches “escapees” (from both is rare)
central B cell tolerance: once B cells express IgM on surface in BM–>tolerance induced via
clonal anergy: (soluble Ags) become “tolerant” OR
clonal deletion: (particulate, cell-assoc. Ags) dev. arrested–>apoptosis
peripheral B cell tolerance
constant low level stim. of BCR but no secondary sigs (T cell, inflamm) maintains B cell in anergic/unresp. state
central T cell tolerance
in thymus
cell clones that strongly recog. self-peptides pres. in MHC molecules–>apoptosis
(almost always self peps in thymus)
peripheral T cell tolerance
primary stim of T cells (MHC/peptide-TCR) w.out secondary stim (B7-CD28)–>no IL-2 prod–>clonal anergy
B7-CD28 interaction needed to stabilize IL-2 mRNA
cannot become activated
if repeatedly stim–>apoptosis
more rapid and prolonged than B cell tolerance
reg. T cells can inhibit activation of T cells by self peptide/MHC
regulatory T cells (Tregs/T suppressor cells)
+??
cytokines??
lysis of ??
typ. CD4+, FoxP3+
produce inhib. cytokines:
IL-10 (Th2) inhibits Th1 response
TGF-B suppresses T lymphocyte prolif (w.out: uncontrolled inflamm. response)
lysis/apotosis of B/T cells expr. peptides w. HLA (via CD8+)
specific suppression
regulatory B cells (Bregs)
produce IL-10: inhib Th1 CD4+ and CD8+ cells, can dampen auto reactive responses
(dec. in MS, SLE)
individuals that may be anergic to TB skin test
MMR vaccine, have measles
immune response depends on inherited HLA types, i.e.
HLA-B27 in ank spond and reactive arthritis
immunogen factors
dosage over time may induce tolerance
self-Ags may be hidden–>exposed by trauma–>IR (lens prot. of eye, synovial chondrocytes, sperm. Ags)-sympathetic opthlamia
weak immunogens induce tolerance
etiology of AIs
genetics (HLA)
molecular mimicry of IDs–>cross-reacting IR
environ. triggers (celiac)
impaired immunoreg mechs (T cell defects, imm. deficiency)
hormonal/gender (F>M, estrogen)
exs of molecular mimicry
S. pharyngitis: RF and heart valve destruction
H. pylori: gastric ca
Campylobacter jejuni: Guillain-Barre (IR agains LPS, cross reacts with motor nerves–>sev. paralysis, polyneuritis)
Klebsiella: ank spond (chr. inflamm, fibrosis, ossification of spine articulations, 90% HLA-B27+, HLA classI)
pathogens that can polyclonally activate lymphos
celiac disease (CD)
malnutrition, diarrhea, abd pain from intestinal inflamm. from gluten
-bowel mucosa changes: villus atrophy, T cell infiltration (CMI)
>95% have autoAgs agains tissue transglutaminase (anti-TG)
>90% have HLA-DQ2, the rest 10% HLA-DQ8
-assoc. with IgA deficiency
Myasthenia gravis
organ-specific: anti-ACh receptor Abs at NM junctions, organ specific
blocks nerve impulses–>sev. musc wkness
eyelid drooping, diff chew/swall/breathe–>resp fail
assoc. w/ HLA-DR3
autoimmune hemolytic anemia (AIHA)
org-sp: Abs agains Rh antigen or “I” Ags, target RBCs for destruction via compl. med lysis or phago by macros (spleen)
primary or sec. to another illness
AIHA dx
anemia, hemolysis, reticulocytosis, low haptoglobin, inc. LD, elev. ind. bilirubin, + direct antiglobulin test (Coombs test)
AIHA caused by…
hemagluttinins:
warm (IgG, find RBC at 37d, sp. for Rh Ag) or
cold (IgM, attach RBC when seen up to 30% of pts w. Mycoplasma pneumonia)
SLE
systemic, multi organ: Abs against ds-DNA (ANAs)–>form soluble ICs–>trapped in BM of kidneys, arteriolar walls, synovium–>activate complement, attract PMNs and other granulos–>local, acute inflammation–>fever, jt pain, malar face rash (butterfly) CNS, heart, kidney damage
80% of individuals with ??? will have SLE
complement deficiency: C1, C4, C2
due to lack of C3b production (opsonizer for phagos)
SLE: spontaneous ??
loss of control of ???
M or W??
presenting age??
remissions and exacerbations
B cell system (lack of C3b)
10x more freq. in women
15-45 yrs
SLE genetically linked to HLA…
HLA-DR3 and -DR2 (MHC Class II)
SLE dx
presence of ANA by ind. fluorescent Ab staining on Hep-2
type/pattern helps w. dx, px, classification
scleroderma
systemic: fibrosis, arthritis, hair loss, arteritis, GIT, kidneys, lungs, Raynaud’s
more EC matrix molecules (collagen) produced
ANAs against topoisomerase-1 and RNA polymerase I (sometimes centromere Ags) (synthesis enzs. vs DNA, RNA)
diff. staining patter than SLE
W>M, pres. 30-50 yrs
Sjogren’s syndrome
systemic: inflamm./destruction of exocrine glands (sal, lacrimal)–>dry mouth, dry eyes
50% have coex. AI
Abs against SS-A (Ro) and SS-B (La) (cytoplasmic prot-RNA complex Ags)
Abs agains muscarinic ACh rec (M3R) responsible???
Sjogen’s dx
ELISA, western blot
NOT IFA
Graves’ disease
hyperthyroidism
TSI (TS Ig) mimics TSH and binds/activates TSH receptor
W>M 4:1
HLA-DR3
passive, natural acq. Ab in neonate–>transient hyperthy.
TBIIs
thyroid binding inhibitory IgGs: block TSH rec–>hypothyroidism (diff. epitope)
NOT Grave’s
Goodpasture’s syndrome
type ?? hypersn
type II hypersn-med
Abs agains a3chain of BM collagen (type IV), bind BM in renal glomeruli–>dec. Ur output, inc. BUN, Cr
sometimes pulm alveoli–>hemoptysis, diff breathing
Fc portion of Ab ligates Gcy rec on monos, neutros, tissue basos, mast cells–>activation, complement activation, tissue injury
MS
T cell mediated, demyelination of CNS tissue, loss in nerve transmission
gen. susc, environ. exposure
CD4+, CD8+ involved, MHC class II present–>DTH response
relapsing-remitting MS
myelin destroyed, inc. in density of Na+ channels to overcome loss of AP–>neurological function restored
chronic progressive MS
myelin AND AXONS destroyed–>preventing function return
MS links
EBV
Adenovirus 2
Hep B
HLA-DR2
DM type 1
T cell-mediated, CD8+ CTLs destroy insulin-prod. Beta cells of pancr. islets of Langerhans (Abs play minor role)
CD8+ T cells sp. for insulin pres. in HLA-A2–>Beta cell destruction
“reverse vaccine” in making, dec. CD8+ response against pro-insulin
RA
BOTH Ab and T cell mediated
initiated by IC deposits–>sustained by chronic inflamm. infilt of synovial mem: macros, T cells, plasma cells–>aff. cells rel. cytokines, enz, granular components–>create “pannus” (fibrovasc tissue)–>destroys cartilage, exposes chondrocytes to imm. damage
RA markers
ACPAs : anti-citrullinated peptide Abs (2/3 RA pts), 90-95% likelihood, early marker
RF (IgM agains IgG Fc) titer do not always correlate with occurrence/severity
both form ICs deposited in synovium–>complement–>rel. chemotactic factors
- 20-30% RA pts have no RF, other conditions have RF (SLE)
- RA may be ANA+
RA may happen in ?? pts, showing Ab response is not essential to pathogen of disease
agammaglobulinemic
Hashimoto’s thyroiditis
T cell mediated (mono infiltrate, DTH, Type 4 hypersn. rxn)
Abs against thyroid peroxidase and thyroglobulin
dry skins, puffy face, brittle hair/nails, cold feeling
HLA-DR5, -DR8, -B8
myasthenia gravis tx
cholinesterase inhibitors
SLE lupus nephritis tx
organ transplant/renal dialysis (IC formation)
IC mediated AI disease can be tx w.
plasmaphoresis
immunosuppressive tx
anti-mitotics and cyclosporine (bad SEs! like infection)
anti-inflammatory (steroids, NSAIDs-PUD)
these do not reverse cause, tx end-stage
new, radical tx for life-threatening SLE, scleroderma
BM ablation
cytokine tx for MS
INF-B 1a
Ab tx: RA, ank spond, psoriasis
TNF-a or TNF-a rec blockade
Infliximab, Etanercept, Adalimumab, Golimumab, Certolizumab pegol
Ab tx w. costim modulation of T cell activation for RA
abatacept (CTLA-4-IgG fusion protein)
targeting B- cell using anti-CD20 Ab tx
Rituximab
IL-6 rec blocking for RA
Rocilizumab
???: humanized Abs against ??? for MS
Natalizumab
a4 integrins
???: human MoAb against BAFF cytokine (dec. B cells) used for ???
Belimumab, Benlysta
SLE
give low dose Ag….
“oral tolerance”
another tx: activation of Ag-sp. Th3 following low oral doses of Ag, how it works
CD4+ T cells (in Peyer’s patches, LP of intestine) cause isotype switching of B cells to produce IgA
if low dose Ag, T cells
–>Th2–>IL-4 and IL-10 (suppr. Th1) OR new phenotype:
–>Th3–>only TGF-B (suppr. Th1 and Th2 activation, inhib. inflamm. cytokine production)
if large dose Ag admin..
CD4+ T cells clonally exhausted, anergic (unknown)
clin. trials for MS
oral bovine myelin–>appearance of myeline basic protein-sp. Th3 in blood
clin. trials for RA
oral type II collagen, improvements
clin. trials for preventing allograft rejections
oral feeding of HLA molecules
