Tolerance & Immunity Flashcards
What is clonal deletion?
Self reactive cells are killed by apoptosis in bone marrow and thymus
Constitue central tolerance
What is anergy?
Self reactive cells are alive but cannot respond
Constitue peripheral tolerance
How is autoimmunity achieved?
Failure to delete self reactive B and T cells in the bone marrow and thymus
Reactivation of anergic self reactive B and T cells
What are the steps of T cells thymic education?
Pro T cells enter subcapsular as double negative ( no CD4 or CD8)
DN move to cortex and become double positive(DP) express CD4 and CD8
DP go through a positive selection
If selected DP go through a negative selection
DP become single positive
What is the mechanism of positive selection?
DP cells bind to MHC 1 and 2
DP with moderate affinity to self MHC survive the selection
DP with too high or too low affinity for self MHC die by apoptosis
What is the mechanism of negative selection?
Positively selected DP move to corticomedullary junction, increase expression of TCR and interact with interdigitating dendritic cells (IDC)
IDC express thymic self antigens
Cells that recognize self antigens die
Cells that do not recognize self antigens survive
What is the second part of the negative selection?
Surviving cells move to the medulla and interact with medullary epithelial cells
Medullary epithelial cells express non thymic self antigens under the control of AIRE
Cells that recognize non thymic self die
Cells that do not survive
What is autoimmune polyendocrine syndrome 1?
Defect in the AIRE gene causing autoreactive cells to not be deleted
What are the symptoms of APS-1?
Chronic mucocutaneous candidiasis Alopecia Vitiligo Hypoparathyroidism Adrenal insufficiency Thyroiditis Type 1 diabetes Ovarian failure
How does tolerance is induced in Treg cells?
Some T cells recognize self antigens in the thymus but do not die
Instead T cells develop CD 25+ regulatory T cells
What are the functions of Treg cells?
Protect host from self reactive lymphocytes by secreting IL-10 and TGF beta
Down regulate B7 co stimulatory molecule on dendritic cells
Suppress TH1,TH2,TH17 and macrophages
How is anergy induced in T cells?
T cell interacts with an APC that lack B7
B7 is a co stimulatory molecule on APCs
Most body cells lack B7 so tolerance to self issue is the norm
What are the immunological privilege tissues?
Brain Anterior chamber of the eye Placenta Pregnant uterus Testis
What is the mechanism of B cell selection?
No T cell help lead to B cell being anergic
Immature B cell binds to self antigen in bone marrow can be deleted or go through receptor editing
Immature B cells binds to a soluble self antigen can go through anergy or through receptor editing
What are the factors influencing autoimmunity ?
Inheritance of HLA and other susceptibility genes
Environmental: infection ( molecular mimicry), injury,inflammation
Physical trauma that breaks immunological privilege
Gender: females more affected than males
What are the diseases associated with HLA-B27?
Psoriasis
Ankylosing spondylitis
Inflammatory bowel disease
Reiters syndrome
What are the diseases associated with HLA-DR2?
Multiple sclerosis
Systemic lupus erythematous
Goodpasture syndrome
Hay fever
What are the disease associated with HLA-DR3/DR4?
Type 1 diabetes
HLA-DR4- Rheumatoid arthritis
What are the characteristics of pernicious anemia?
Megaloblastic anemia caused by vitamin B12 (cobalamin) malabsorption organ target is the stomach
Molecular target is intrinsic factor
Cellular target is parietal cells
Associated with chronic H.pylori infection
Type 2 hypersensitivity
What is the presentation of a patient with pernicious anemia?
Usual onset40-70 years
Weakness, sore tongue, paresthesia
Beefy red tongue appearance
Increase risk of gastric adenocarcinoma (3x)
How is pernicious anemia diagnosed?
What is the treatment ?
Circulating antibodies to intrinsic factor and other parietal cell components
Treated with vitamin B12
What are the characteristics of Goodpasture syndrome ?
Organ targets are the lungs and the kidneys
Glomerulonephritis and pulmonary hemorrhage
Complement fixing antibodies against type 4 collagen (molecular target)
Type 2 hypersensitivity
What is the presentation of Goodpasture syndrome?
Onset: 20-30 and 60-70 years old
Smoking and solvent inhalation is a precipitating event
Pulmonary hemorrhage can lead to respiratory failure and eventually death
How is Goodpasture syndrome diagnosed?
Detection of circulating anti glomerular basement membrane antibodies
Kidney biopsy shows linear deposition of antibody and complement
HLA-DR2 linkage
What is the treatment for Goodpasture syndrome?
Acute phase: intubation, assisted ventilation, hemodialysis
Long term: plasmapheresis, high dose corticosteroids, immunosuppression with cyclophosphamide, reduce exposure to irritants
ESRD: hemodialysis, kidney transplant
What are the characteristics of type 1 diabetes?
Insulin dependent
Cell mediated killing of beta cells (cellular target) of pancreas (organ target)
GAD is the molecular target
Type 4 hypersensitivity
What is the presentation of type 1 diabetes patient?
Most common in juveniles Thin stature despite good appetite Hyperglycemia Ketoacidosis RuQ pain from fatty liver
How is type 1 diabetes diagnosed?
Presentation and history
Fasting glucose tests greater than 5mg/dL in an asymptomatic patient
Any random glucose test greater or equal 200 mg/dL with symptoms
Circulating autoantibodies to insulin and beta cell components
How is type 1 diabetes treated?
Symptoms are treated with insulin
Diet and exercise will help control the disease
What are the characteristics of Myasthenia gravis?
IgG autoantibodies form against acetylcholine receptors at neuromuscular junctions
Only skeletal muscles are affected
Symptoms do not appear until acetylcholine receptors reduced to less than 30% of normal
Type 2 hypersensitivity
How does a patient with myasthenia gravis present?
Onset is 28 years in women and 42 in men
Progressive muscle weakness with exercise
Strength is recovered after a period of rest
Weakness least severe in the morning
Ptosis
Worsened with sunlight, stress ans medications
What is neonatal myasthenia?
Generalized muscle weakness in infants born to myasthenia gravis women
Due to IgG passively crossing the placenta
Symptoms resolve in days to weeks as antibody titers decline
How is myasthenia gravis diagnosed?
Circulating anti acetylcholine receptor antibodies
Thymoma on Xray or CT
Administration of edrophonium resolves symptoms
What is the treatment for myasthenia gravis?
Cholinesterase inhibitors Corticosteroids Immunosuppressive drugs Intravenous immune globulin Plasmapheresis Thymectomy
What are the characteristics of Addison disease?
Adrenocortical insufficiency when 90% of adrenal cortices are destroyed
Inadequate secretion of corticosteroids
Mixed type 2 and 4 hypersensitivity
How is the presentation of a patient with Addison disease?
Most common in children and females
Adult onset 30-50 years
Hyperpigmentation of skin and mucous membranes
Overproduction of corticotropin and melanocyte stimulating hormone
Vitiligo
Acute adrenal crisis
How is Addison disease diagnosed and treated ?
Rapid ACTH stimulation test shows no rise in plasma cortisol and aldosterone after ACTH injection
Treated with hormone replacement ie prednisone
What are the characteristics of Bullous pemphigoid?
Chronic subepithelial blistering skin disease
Rarely involves mucous membrane
IgG antibodies are specific for the hemidesmosomal antigens BPAg1 and 2
Exacerbated by UV, Xray, NSAIDs, antibiotics
How does a patient with bullous pemphigoid present?
Average age is 65 years
Blisters are tense and preceded by urticaria
How is bullous pemphigoid diagnosed?
DIF shows IgG and complement in linear band at demal epidermal junction
IgG id on blister roof
Circulating antibodies to BPag1 and 2
How is bullous pemphigoid treated?
Prednisone
Immunosuppressives
Tetracycline
Rituximab
What are the characteristics of of pemphigus vulgaris?
Erosion of skin and mucous membanes
IgG are specific for keratinocyte surface desmogleins
How does a pemphigus vulgaris patient present?
Mean age is 50-60 years
Flaccid blisters are painful but do not itch
Treatment similar to bullous pemphigoid
What are the characteristics of Graves disease?
Autoimmune disease characterized by hyperthyroidism
Autoantibodies against receptor to TSH continuously stimulate thyroid
Type 2 hypersensitivity
How is Graves’ disease presentation?
Goiter Exophthalmos/proptosis Pretibial myxedema Heat intolerance Tachycardia Weight loss despite increased appetite
How is Graves disease diagnosed?
Anti TSH receptor antibodies
Free T3 and T4 are elevated
TSH levels are low
Radioactive iodine uptake increased
What is the treatment for Graves disease?
Radioactive iodine
Anti thyroid drugs
Thyroid surgery
What are the characteristics of Hashimoto thyroiditis?
TH1 infiltration destroys thyroid gland leading to hypothyroidism
Type 4 hypersensitivity
How is the presentation of Hashimoto?
Hoarseness due to goiter Cold intolerance Bradycardia Constipation, weight gain Decreased sweating
How is Hashimoto diagnosed?
Elevated TSH level
Antibodies to thyroid peroxidase and thyroglobulin
How is Hashimoto treated?
Levothyroxine replacement therapy
Surgery for goiter or malignant nodules
What are the characteristics of psoriasis ?
Most common autoimmune disease of the skin
Keratinocytes are induced by TH1 and TH17 cytokines
Scaly red plaques affecting elbows, knees’ scalp, lower back
Can also affect eyes and joints
How is psoriasis diagnosed?
RF negative
Elevated uric acid
Sterile pistule fluid with many PMNs
Auspitz sign: removal of scales causes small bleeding
How to treat psoriasis?
Topical creams
Anti inflammatory, biologicals
Light therapy
Stress reduction
What are the characteristics of Rheumatoid Arthritis (RA)?
Destructive disease of the joints
Type 4 hypersensitivity
Classic signs are morning stiffness, arthritis of 3 or more joints, rheumatoid nodules
HLA-DR4 linkage
How is RA diagnosed?
ESR and CRP elevated
Circulating RF( not pathognomonic)
Anti cyclic citrullinated peptide (CCP) antibodies specific ( arg—>citrulline)
What is the treatment for RA?
NSAIDs
Corticosteroids (prednisone )
Anti TNF alpha: infliximab,adalimumab
Soluble TNF receptor: Etanercept/Enbrel
What are the characteristics of SLE?
Chronic inflammatory disease that follows a relapsing and remitting course
Immune complexes of self DNA are seposited in the skin, kidneys and joints
Deficiency in C1,C2 and C4 contributes to development
How does SLE present?
Erythema- butterfly rash
Glomerulonephritis
Arthritis
Raynaud phenomenon
Bacterial infections are the most common cause of death early on
Accelerated arteriosclerosis leading to kidney and heart failure are the most common cause of late mortality
How is SLE diagnosed?
Lumpy bumpy pattern on IF
Anti dsDNA antibodies correlated with kidney damage and disease severity
Anti Smith antibodies detected by Elisa indicate renal involvement
How is SLE treated?
Avoid sunlight to prevent flares
NSAIDs
Steroids
Rituximab
What are the characteristics of Sjogren syndrome?
Chronic inflammatory disease mediated by CD4+ infiltrate affecting the exocrine glands primarily the lacrimal and salivary
How does Sicca syndrome present?
Xerophthalmia
Xerostomia with poor oral health
Xeroderma, urticaria, purpura
Parotid swelling most common sign in children
Usually associated with another CT disease ie SLE or RA
How is Sicca syndrome diagnosed?
Anti SS-A/Ro
Schirmer test for tear production
Biopsy suspicious parotid glands and lymph nodes
What are the characteristics of GBS?
Ascending paralysis that affects the peripheral nerves
Follows infection or vaccination
Most important cause of acute flaccid paralysis in countries without polio
Lipid antigens of microbes dmonstrate molecular mimicry
How is GBS diagnosed?
Elevated CSF protein greater than 0.55g/L without elevated WBCs
Abnormal nerve conduction test
How is GBS treated?
Treated as medical emergency
Closely monitor
No corticosteroids- worsen the outcome
What are the characteristics of multiple sclerosis?
Destruction of myelinated axons in the CNS Primary progressive (PPMS)and relapsing remitting (RRMS) forms Most common neurologic disease of young adults
How does MS present?
Peak onset 35
Charcot triad: dysarthria, ataxia, tremor
Poor judgment
Heat makes it worse
How is MSdiagnosed?
Plaques of demyelination primarily in the white matter
Abnormal CSF in majority of patients
How to treat MS?
Natalizumab prevents entry of leukocytes into CNS
Ocrelizumab binds to CD20 useful for PPMS and RRMS
Drug to control seizures
Regular exercise and physical therapy
ABC therapy- reduces relapse frequency and delays disability
What are the ABC drugs for MS?
Avonex and Betaserone
Copaxone
What is the role of Avonex and Betaserone?
Down regulate expression of B7 and adhesion molecules
Promote TGF beta synthesis
What is the role of copaxone?
Induces Treg cells that down regulate inflammatory response
