Immunology 1: Tolerance and Autoimmunity

Question 1

Location for POSITIVE T cell selection? What is selected for/against?

Answer 1

Cortex of Thymus
Pre-T cells develop into double + cells and interact with MHC I & II molecules, those with moderate affinity progress, others die.

Question 2

Location for NEGATIVE T cell selection? What is selected for/against?

Answer 2

Medulla of Thymus

Question 3

The AIRE gene is responsible for what?

Answer 3

In T cell maturation if the AIRE gene is defective then auto reactive T cells are not induced to apoptosis.

Question 4

Defect in AIRE gene leads to which syndrome?

Answer 4

Autoimmune polyendocrine syndrome

Question 5

Where to Treg cells come from? What controls their development (2 things).

Answer 5

Treg cells are CD4+ cells that recognize self antigens but are allowed to develop into CD25+ cells.
Controlled by Foxp3 which is induced by TFGb

Question 6

What is the function of Treg cells?

Answer 6

Regulate self-reactive lymphocytes (TH1, TH2, TH17) by secreting TGFb and IL-10.
Also down regulates B7 on dendritic cells.

Question 7

How is anergy induced in T cells

Answer 7

T cells are inactive by interacting with an antigen presented by an APC lacking the B7 co-stimulator (caused by IL-10).

Question 8

Mutations in HLA-B27 can lead to which disease?

Answer 8

Psoriasis, ankylosing spondylitis, IBS, Reiter’s syndrome

Question 9

Mutations in HLA-DR2 can lead to which disease?

Answer 9

MS, SLE, Goodpasture syndrome, hayfever

Question 10

Mutations in HLA-DR3/4 can lead to which disease?

Answer 10

Type 1 DM

Question 11

Mutations in HLA-DR4 alone can lead to which disease?

Answer 11

Rheumatoid Arthritis

Question 12

Disease caused by trauma to the eye and induction of self-reactive antigens.

Answer 12

Sympathetic Ophthalmia

Question 13

Pernicious anemia

Answer 13

Caused by lack of IF secretion by Parietal Cells in stomach, results in decreased B12 absorption.

Sx:Assoication with H. pylori infection.
Triad of weakness, sore tongue, parasthesias
“Megaloblastic Madness”
3x rate of gastric adenocarcinoma

Dx: circulating antibodies to IF and other parietal cell components

Tx: B12

Question 14

Goodpasture snydrome, anti-glomerular basement membrane (Anti-GBM) disease

Answer 14

Compliment fixing antibodies to Type IV collagen and attack lungs and kidneys basement membranes.

Sx: hemoptysis, pulmonary hemorrhage, malaise, chills, fever.

Dx: circulating anti-glomerular basement membrane antibodies. Kidney biopsy shows linear deposition of antibody and complement

Tx: Plasmapheresis of antibodies, immunosuppressive therapy, reduce lung irritants, ESRD - dialysis/transplant

Question 15

Insulin-dependent diabetes mellitus type 1

Answer 15

Destruction of beta-cells in the islets of Langerhans of the pancreas. Development of ketoaidosis if insulin is withdrawn.

Sx: typically juvenile but can be 30/40’s. Hyperglycemia (<200 random). Peripheral neuropathy in glove/stocking pattern.

TH1 cells over-balance Treg cells and secrete IFNy which actives macrophages and Tc cells to kill the beta-cells. Beta-cells up regulate Fas during initial phases which allows FasL on Tc cells to target more easily.

Possible link to Coxsackie Virus (molecular mimicry with glutamic acid decarboxylase), also Rubella/Mumps.

HLA-DR3/4 link.

Tx: insulin, diet, excercise

Question 16

Myasthenia Gravis (MG)

Answer 16

IgG antibodies formed against acetylcholine nicotinic postsynaptic receptors (AChRs), results in endocytosis of receptors.

Sx worse later in day, improve w/ rest. Notable ptosis.

Dx: circulating anti-AcR antibodies, CT shows thymoma, abnormal ECG, Anticholinesterase test is positive (sx. improve w/ edrophonium administration).

Tx: cholinesterase inhibitor, corticosteriods, immunosuppressive drugs, thymectomy for thymoma.

Question 17

Addison Disease (adrenal glands)

Answer 17

Adrenocortex insufficiency - particularly cortisol. Onset at 90% bilateral disfunction.

Sx: hyper pigmentation of skin and mucus membranes. Excessive melanin secondary to overproduction of corticotropin and melanocyte-stimulating hormone. Later development of Vitiligo.

Dx: Rapid ACTH stimulation test. Atrophy of adrenal glands on CT.

Tx: hormone replacement, prednisone

Question 18

What is acute adrenal crisis and what is the cause?

Answer 18

Fever, nausea, vomiting, vascular collapse, shock, cyanosis, confusion, flank pain – all leading to coma.

Result of complications from Addison Disease.

Question 19

Bullous pemphigoid

Answer 19

Blistering skin disease, RARELY involving mucosa. IgG antibodies specific for hemidesmosomal antigens (BPAg1 and BPAg2) found in basement membranes. Eotaxin strongly expressed in basal layer of epidermis recruits eosinophils to site.

TENSE BLISTERS, preceded by urticarial lesions.

Dx: Direct immunoflourescence shows IgG and C3 deposited in linear band at dermal junct. Salt-splitting - results in IgG in ROOF of blister.

Question 20

Pemphigus vulgaris

Answer 20

Blistering of skin and mucosa. IgG antibodies are specific for keratinocyte surface desmogleins. FLACID Blisters, painful but NOT urticarial.

Dx: DIF shows IgG or IgM and C3 deposition on surface of keratinocytes in and around lesions. Circulating IgG binds to epidermis.

Tx: Prednisone, immunosuppressives, IVIG, Rituximab (CD20 specific)

Question 21

Graves’ Disease / thyrotoxicosis

Answer 21

Hyperthyroidism due to circulating antibodies that stimulate thyrotropin receptors, resulting in release of thyroid hormone. Antibody stimulation of TSH receptor is primary cause.

Dx: positive assay for anti-TSH receptor antibodies. TSH levels low. Free T4/T3 elevation.

Tx: radioactive iodine, anti-thyroid drugs

Question 22

Hashimoto Thyroiditis

Answer 22

Cell mediated immune response results in TH1 infiltration of thyroid and causes its destruction.

Dx: TSH levels are elevated w/ thyroid auto-antibodies present; especially to thyroid peroxidase and thryoglobulin.

Tx: thyroid hormone replacement, goiter or nodules can be surgically removed.

Question 23

Difference between Graves Disease and Hashimoto

Answer 23

TSH depressed in Graves

TSH elevated in Hashimoto

Question 24

Rheumatoid arthritis

Answer 24

Persistent symmetric synovitis that affects hands and feet. More prevalent in females. External triggers could include Mycoplasma, EBV, Parovovirus, Rubella. Genetic component of HLA-DR4. Intracellular infiltrates produce large amounts of TNFa. B cells also make rheumatoid factor (RF) which activates compliment.

Dx: ESR and CRP elevation. Circulating RF. Elevated anti-nuclear antibodies (ANA). XR shows erosion or decalcification.

Tx: NSAIDs, Corticosteriods, COX-2 inhibitor, Xenobiotics, Rituximab, Anti-TNFa agents.

Question 25

Systemic Lupus Erythematosus (SLE)

Answer 25

Chronic inflammatory disease, females 11x prevalence (16-64 y.o.). Butterfly rash over nose and cheeks. Infections are common due to use of immunosuppresants as treatment, also speeds up arteriosclerosis.

Dx: Kidney biopsy (lumpy-bumpy-pattern). Antinuclear antibodies (ANA). Antibody to histones and some have elevated RF titers.

Tx: avoid sunlight to prevent flares, NSAIDs and low dose steroids, Methotrexate

Question 26

Sjogren Syndrome (Sicca Syndrome)

Answer 26

Lymphocytic infiltrates (mostly CD4+ but some B cells and plasma cells) into Exocrine organs, notably the lacrimil and salivary glands. Dry eyes/xerophthalmia, dry mouth/xerostomia present. Swelling of salivary glands. Can affect any mucosal surface. Typically associated w/ another disorder such as RA or SLE.

Increased Non-Hodgkin lymphoma rates.

Dx: AF and ANA present, Anti-SSA or Anti-SSB w/ Ro/La antibodies present in many cases. Schirmer test for tear production is low, salivary gland biopsy shows affrefates of CD4+ cells, enlarge parotid glands and lymphnodes.

Question 27

Guillain-Barrè Syndrome

Answer 27

Ascending weakness or flaccid paralysis following infection. Cause is demyelination of peripheral nerves. #1 cause of acute flaccid paralysis in countries without Polio.

Mechanism: Lipid antigens of infections have molecular mimicry with gangliosides and glycolipids. This causes the body to attack it’s own myelin as a result of attacking the infection.

Dx: abnormal nerve conduction tests, CSF protein elevated above 0.55 g/L w/o WBC elevation. MRI can show nerve root enhancement. Watch for pulmonary function changes as paralysis hits diaphragm.

Tx: NO CORTICOSTERIODS!!
assist respiration as needed, plamsapheresis to remove auto-antibodies.

Question 28

Multiple Sclerosis (MS)

Answer 28

Attack of myelinated axons in CNS. Females 2:1 males w/ peak at 35 yr.

Parastesias, weakness of clumsiness of leg or hand, partial blindness, dysarthria, ataxia, tremors, dysphagia, emotional disturbances. Excess heat (summer) can exacerbate symptoms.

Molecular cause: Imbalance of Treg and TH17 cells, too many TH17 cell increases IL-17 production which stimulate microglial, neutrophils, mast cells and NK cells to target oligodendrocytes (which produce myelin sheath). EBV may stimulate inflammatory process.

Dx: MRI showing demyelination, CSF abnormal w/ Oligoclonal IgG bands (levels correlate to disease progression). Free myelin basic protein in CSF.

Tx: Corticosteriods, ABC therapy (Avonex, Betaserone, Copaxone), Natalizumab, exercise and PT.