Regulation of Immune Response Flashcards
What autoimmune disease is associated with dry eyes and dry mouth?
Sjogren disease
Which of the following antibodies are of most use for diagnosis of pernicious anemia?
Anti-parietal cells
What is the reaction to self-antigens called?
Tolerance
Loss of self tolerance
autoimmune disease
Shift in immune responses
Hypersensitivity
Decrease in immune response
Immunodeficiency
Th0 cell is stimulated by Il-12, what occurs?
Differentiates to Th1 cells
Th0 is stimulated by IL-23 and IL-6, what occurs?
Th17 cells develop
Th0 cell is stimulated by IL-4, what occurs?
Th2 cells develop
what cytokines are produced by Th1 cells?
IL-2
IFN-y - activates Macrophages
what cytokines are produced by Th2 cells?
IL-4
IL-5
IL-10 and IL-13 - these are regulatory
IL-10 inhibits Th1 cells to favor a shift to humoral immunity
TGF-b and IL-10 induce Tregs to produce
more TGF-b and IL-10
How do Th2 cells negatively regulate Th1 cells?
through IL-4, IL-10 and TGF-b
How do Th1 cells negatively regulate Th2 cells?
IL-2 and IFN-y
Tolerance
specific state of unresponsiveness induced by prior exposure to an antigen
When is self tolerance induced?
in the embryonic developmental states
Main mechanisms of Tolerance:
Clonal deletion
Clonal anergy
Ignorance
where does natural tolerance take place?
Primary lymphoid organs
How can tolerance by induced?
injection of stem cells in neonatal animals
grafting of allogenic bone marrow or thymus in early life results in tolerance to donor type cells and tissues
factors that influence induction of tolerance
physical form route of entry/location Dosage Antigen Processing Age
Factors that stimulate the immune response
large, complex molecule subQ, IM Optimal dosage High level of costimulators adult
Factors that stimulate unresponsiveness
soluble or small molecules Oral, IV very large or small amount (dosage) Low level of costimulators early age
Immune privilege organs
eye
testis
uterus
what axis does the CNS-immune relationship take place on?
H-P-A axis
hypothalamus-pituitary-adrenal gland
clonal anergy promoted through
- no costimulation - lack of B7/CD28 interaction
or - interaction of CTLA-4 and B7 which prevents T cell activation
Ignorance
antigen in low amounts
antigen in organs where there is no access - immune privileged
organs with enhanced immune regulation and induce tolerance through TGF-b
Autoimmune response in eye
against antigens from melanin containing structures in retina
damage to one eye causes inflam response in other eye
Granulomatous uveitis can leave person blind
how is peripheral tolerance achieved?
Anergy - through CTLA-4 and B7
Activation induced cell death - through Fas and FasL
Cytokine regulation - IL10 and TGF-b from Tregs
T regulatory cells
T suppressor cells - suppress immune response
CD4+, CD25+ outside the thymus
express Fox3p
produce IL10 and TGF-b to dampen immune responses
inactivate effector cells - functionally unresponsive
Autoimmunity
more common in women
genetic disposition - African american - SLE, Native Americans - scleroderma, RA
Left handed ppl slightly over right handed ppl
Type II hypersens. - Complement mediated
Transfusion reaction
Eythroblastosis fetalis
certain drug reactions
Type II hypersensitivity
Graft rejection
Type II hypersensitivity - Antibody mediated cellular dysfunction
Myasthenia gravis
Graves disease
Autoimmunity triggers
Genetic factors - asso. with HLA haplotypes, autoimmune regulator (defective thymic deletion (central)), complement deficiency, Foxp3 defect -> IPEX (x linked defect in Treg activation)
Environmental factors - drugs, hormones (estrogen), Toxins, geographic clustering
Infection: molecular mimcry* -
Ankylosing Spodylitis HLA allotype
B27
Rheumatic fever - pathogen, mimicking?
Strept. Pyogenes
M protein similar to molecules on Heart, skin, nerve and connective tissue
Ankylosing spondylitis - pathogen mimicry?
Klebsiella Pneumoniae
Dx of autoimmune disorders
symptoms
immunofluorescence
complement levels maybe decreased
biochemical assays for specific antibodies
Treatment of autoimmune disorders?
Immunosuppressive and anti-inflammatory drugs disease modifying drugs thymectomy plasmapheresis monoclonal antibodies but first, always treat the symptoms
examples of systemic autoimmune disorders
SLE scleroderma sjogren syndrome Rheumatoid arthritis Polymyositis
Organ specific autoimmune disease
goodpasture's syndrome hashimoto's thyrodiditis grave's disease myasthenia gravis Addison's disease Diabetes melitus Type I
Systemic Lupus Erythematosus
Type III hypersens.
chronic affecting multi organs
90% females
onset 15-50 yo
Risk factors: certain HLA types, Asian, Hormones - Estrogens
5 yr survival rate is about 95% in US and canada
Pathogenesis of SLE
immune complex deposition
antinuclear antibodies against dsDNA, histone and smith-antigen
antinuclear antibodies against DNP
antiphospholipids
In general, C1, C2, C4 deficiency leading to decreased opsonization of immune complexes so there is decreased clearing
Note that Ab are not specific to Lupus
Clinical signs of SLE
often called The great imitator
symptoms diverse and often non specific
Skin manifestations: butterfly malar rash*
Alopecia - loss of hair
Oral ulcers
Photosensitivity rash (raised, erythematous)
Renal - Membranoproliferative glomerulonephritis, thickening of glomerular capillary wall, end stage renal failure leads to death
SLE - clinical signs in MS, pulmonary, neurological, cardiac systems
joint pain, muscle pain, no destruction of joints
SLE pneumonitis, pleuritis
cognitive, headache, seizures, neuropathies
Verrucous endocarditis (libman-sacks) -depostis around valves
pericarditis
antiphopholipid antibody syndrome (thrombotic disorder) leads to PTT
DX of SLE
Elevated ESR
decreased C3 and C4 levels
fluorescent antinuclear antibody
LE cells (not specific though)
Treatment of SLE
anti inflammatory drugs to prevent swelling and inflammation
immunosuppressants - azthioprine, methotrexate, cyclophosphamide
Rheumatoid Arthritis
autoimmune disease of the joints
Autoantibodies to cartilage
Rf has receptor for Fc portion of IgG
Immune complex formation leads trigger of complement
Clinical signs of RA
Joint pain - small joints and symmetric
Inflammation
Stiffness - usually in morning
keratoconjuctivitis
Diagnosis of RA
ESR and C reactive protein but these are non specific
Rheumatoid factor usually IgM, IgG and IgA
clinical manifestations
Radiological findings
Sjogren’s syndrome
Type III hypersens rxn
Progressive autoimmune (immune complex) disorder
destruction of lacrimal and salivary glands
Antiribonucleoprotein antibodies SS-A and SS-B
Clinical signs of Sjogren’s
xerostomia - dry mouth
unilateral parotiditis
xerophthalmia
Diagnosis of sjogren’s
schirmer’s test - filter paper to collect and measure tear production
SSA/Ro or SSB/La detection
Treatment of Sjogren’s
Anti inflammatory medications
Artificial tears
NSAIDs and disease modifying drugs
Goodpasture’s syndrome
Type III hypersens.
Autoantibodies against a3 chain of collagen IV in pulmonary and glomerular basement membrane
Reiter’s syndrome
mostly in males
Arthritis, Non gonococcal urethritis or cervicitis
Conjuctivitis
Risk factors for Reiter’s syndrome
positive for HLA-B27
shigella, yersinia, salmonella and chlamydia
Ankylosing spondylitis
Chronic autoimmune disorder of vertebrae
affects the vertebrae and sacroiliac joints
mainly in males
Symptoms: inflammation and stiffness of lower back
Risk factor: HLA-B27 and Klebsiella infections
Multiple Sclerosis
autoimmune neurological demyelinating defect
autoreactive cells against Myelin Basic protein (MBP)
mediated by Th17 cells
Symptoms of MS
slurred and slow speech blurred vision - often in one eye difficulty swallowing loss of bladder control loss of sensation MRI of brain and spine shows areas of demylenation
risk factors of MS
more common in high altitudes
more common in females
syphillus - tertiary
Measles and Herpes virus
Myasthenia Gravis*
Type II hypersensitivity
autoantibodies binding Ach receptors
blocks Ach binding leads to inhibition Ach at neuromuscular junction
Symptoms of Myasthenia Gravis
progressive muscle weakness
easy fatigability
blurred vision
difficulty swallowing and breathing
Diagnosis and treatment of Myasthenia Gravis
Dx - Acythylcholiesterase inhibitor (edrophonium), enlarged thymus
Tx - cholinesterase inhibitors, thymectomy
Graves disease
type II
Autoantibodies against TSH receptors in the thyroid - tricking thyroid into releasing more hormone
leads to hyperthyroidism and goiter
Symptoms of Graves disease
Tachycardia Weight loss agitation and irritability Pretibial myxedema - kids exophthalmos (propotosis)
Hashimoto’s Thyroiditis
Type II and IV
Autoantibodies -thyroid peroxidase and thyroblobulin
Gradual destruction of Thyroid gland - hypothyrodism
Clinical signs of Hashimoto’s Thyroiditis
Painless symmetric goiter weight gain and cold tolerance depression and fatigue dry and coarse hair bradycardia
Insulin dependent diabetes Mellitus
HLA-DR3 and HLA-DR4
Early: autoantibodies against beta cells
later: mediated by T lymphocytes (mostly cytotoxic)
Early sudden onset
