Unit 2 Plfsom Jr

Front 1

Define central tolerance

Back 1

tolerance acquired when lymphocytes first encounter self antigens in central lymphoid organs (bone marrow and thymus)

Front 2

Define peripheral tolerance

Back 2

tolerance acquired when lymphocytes first encounter self antigens in peripheral tissues

Front 3

Explain Central Tolerance (Negative Selection) of B cells

Back 3

Immature B cells that bind too strongly to self antigens in bone marrow (central lymphoid organ) will die by apoptosis or undergo receptor editing (reactivate RAG genes, generate a new light chain, change specificity)

Front 4

Explain Central Tolerance (negative selection) of T cells

Back 4

In the maturation process of T cells, T cell progenitors migrate from bone marrow to the thymus. There they rearrange TCR-Beta and TCR-alpha, and begin to express CD4 and CD8 (double +). Double + T cells must bind self MHC with self peptides weakly or they will undergo apoptosis (positive selection). Also, Double + T cells must not bind self MHC with self peptides too strongly or they will undergo apoptosis in thymus (central lymphoid organ) (negative selection). The double-positive T cells lose expression of the unused co-receptor to become CD4 or CD8 single-positive T cells.

Front 5

Explain Central Tolerance (Negative Selection): T cells: AIRE gene

Back 5

Aire is an autoimmune regulator transcription factor expressed in the thymus. It is responsible for thymic expression of otherwise peripherally-restricted protein antigens (self peptides). Mutations in AIRE cause lapse in negative selection which leads to autoimmune disease, especially Autoimmune Polyendocrine Syndrome (APSI).

Front 6

CD4+ Regulatory T cells

Back 6

Some CD4+ autoreactive T cells do not undergo apoptosis, but instead develop into regulatory T cells (T regs). These T regs inhibit immune responses in the periphery.

Front 7

T regs and IL-2

Back 7

T regs are dependent on IL-2 for development and function

Front 8

Foxp3

Back 8

Expressed by CD4+ Treg cells. Mutations in Foxp3 cause an autoimmune disease called X-linked polyendocrinopathy and enteropathy (IPEX)

Front 9

TGF-B and CD4+ T regs

Back 9

CD4+ require IL-2 along with TGF-B for their development and maintenance

Front 10

What do CD4+ T regs produce?

Back 10

IL-10 and TGF-B (inhibitory cytokines) which will block lymphocyte/macrophage activation

Front 11

What are the features of Central tolerance? (3)

Back 11

Negative selection, BCR light chain editing, Development of T regs

Front 12

What are the features of Peripheral Tolerance? (3)

Back 12

Suppression by T regs, Anergy, Activation Induced Cell Death (AICD) (deletion by apoptosis)

Front 13

Define Anergy as it relates to Peripheral Tolerance

Back 13

Anergy is T cell inactivation that occurs when T cells recognize peptide:MHC on resiting APCS with inadequate expression of costimulators (B7, etc). (The second signal indicative of accompanying innate immune response is lacking.) The T cells become "anergic" or unresponsive to the antigen, but DO NOT UNDERGO APOPTOSIS.

Front 14

Describe the role of CTLA-4 in anergy

Back 14

Too few activating B7:CD28 interactions or too many B7:CTLA-4 or PD-1inhibitory interactions (PD-1binds a ligand related to B7) cause anergy

Front 15

Is the operation of anergy well understood?

Back 15

No

Front 16

Mechanism 1 for T cell apoptosis triggered by inadeuqte costimulation by B7:CD28, peptide/MHC:TCR

Back 16

mitochondrial proteins activate caspase-9 which induces apoptosis (anti-apoptotic proteins are lacking, due to inadequate costimulation)

Front 17

Mechanism 2 for T cell apoptosis triggered by inadeuqte costimulation by B7:CD28, peptide/MHC:TCR

Back 17

T cells normally express Fas. If inadequate costimulation, then repeated peptide/MHC:TCR interaction causes them to express FasL. Fas: FasL interaction activates caspase-8 which induces apoptosis

Front 18

Describe three features of antigens that influence the choice between T cell tolerance and activation

Back 18

"1- Presence in lymphoid organs: central (generative) vs. peripheral lymphoid organs. 2- Second signals: absence vs. presence. 3- Exposure: long vs. short.

Front 19

Describe peripheral tolerance as it relates to B lymphocytes

Back 19

"Lacking help, T-dependent B cells become anergic. They leave the lymph node follicles, can't re-enter, lack survival stimuli, and die.

Front 20

Describe the natural decline of an immune response including the role of antibody feedback

Back 20

Even desirable immune responses diminish (return to homeostasis). Memory cells persist, but effector cells do not. During the immune response, IL-2 and B7:CD28 interactions maintain T cell survival/proliferation. 1-2 weeks after infection is cleared, activation stimunli wane, effector T/B cells, deprived of survival signals, die by apoptosis. But the Memory Cells live on!

Front 21

B cell activation blocking

Back 21

B cell activation can be blocked by antibody feedback. B cells FcyRIIB with ITIM are inhibited when the BCR binds antigen with IgG bound, and activation is blocked

Front 22

Describe two principle factors that contribute to the development of autoimmunity

Back 22

1- Inheritance of susceptibility genes, 2- environmental triggers (infections)

Front 23

Ankylosing spondylitis

Back 23

Autoimmune disease due to a defect in the MHC allele HLA-B27. RR=90.

Front 24

Rheumatoid Arthritis

Back 24

Autoimmune disease due to a defect in the MHC allele HLA-DR4. RR=4.

Front 25

Type 1 Diabetes Mellitus

Back 25

Autoimmune diesease due to a defect in the MHC allele HLA-DR3/DR4. RR=25.

Front 26

Pomphigus vulgaris

Back 26

Autoimmune disease due to a defect in the MHC allele HLA-DR4. RR=14.

Front 27

How can infection precede autoimmunity? (1)

Back 27

Microbes may contain peptides/epitopes similar and cross-reactive with self antigens, "molecular mimicry"

Front 28

How can infection precede autoimmunity? (2)

Back 28

Tissue injured by infection may expose "sequestered" antigens (normally hidden from the immune system), allowing immune system to react.

Front 31

Describe the mechanism of action and the most important adverse effects of methotrexate when used for treatment of rheumatoid arthritis [prototype: methotrexate]

Back 31

Methotrexate inhibits dihydrofolate reductase activation of folate to tetrahydrofolate, required in synthesis of thymidine and purines for DNA synthesis. Lymphocyte proliferation in bone marrow is particularly sensitive to the antimetabolite effect. Used continuously at much lower doses than cancer chemotherapy, methotrexate results in reduction of rheumatoid factor and cytokine production, and impairs chemotaxis of leucocytes into joints where they attack the synovial membrane and bone. Methotrexate causes myelosuppression, and can damage the epithelial lining of mouth and GI tract.

Front 32

Describe the mechanism of action and the most important adverse effects of an anti-tumor necrosis factor-alpha agent when used for treatment of rheumatoid arthritis [prototype: infliximab]

Back 32

TNF is one of the proinflammatory cytokines produced by macrophages and activated T cells. It is found in high concentration in the synovial fluid of joints. It seems to be involved in both the inflammation and joint destructive pathologic processes of rheumatoid arthritis. Infliximab is probably the least attractive of many anti-TNF¥á inhibitors currently approved for treatment of RA, but my purpose in assigning it as the prototype is so you will become familiar with its disadvantages in relation to therapeutic choices. Most other anti-TNF¥á inhibitors are fully humanized, but infliximab is a chimeric human-mouse monoclonal antibody which is antigenic. Infliximab is administered intravenously in cycles; with each cycle the induction of antibodies increases potential for hypersensitivity infusion reactions. Drug-neutralizing antibodies lead to progressive dose escalation. Pre-treatment with glucocorticoids and antihistamines reduces hypersensitivity reactions and induction of neutralizing antibodies.

Front 33

Recognize the clinical relevance of distinguishing gout (monosodium urate crystal arthropathy) from pseudogout (calcium pyrophosphate crystal arthropathy), based on the pathogenesis of crystal arthropathies, and why drug choices for chronic gout may not be appropriate for acute gout. [prototype: probenecid]

Back 33

high dose inhibits urate reabsorption by the uric acid transporter (URAT-1) on the luminal side of the tubular epithelium; however, low doses compete with urate secretion into the filtrate by the organic acid transporter (OAT-1). Aspirin at low doses (but not NSAIDs) inhibits OAT-1 and should be avoided in patients with gout. Low doses of aspirin and probenecid can paradoxically increase urate retention, because they are highly protein bound in plasma. Plasma proteins, and therefore drugs bound to plasma proteins, are not filtered. Only the free-fraction (about 1% of the plasma concentration) is filtered. The drug reaches its intended URAT-1 site of action from the luminal side, so high dose increases the filtered concentration at the receptor. Low doses achieve a sufficient concentration on the interstitial side (from the outside) to inhibit OAT-1 located on the basolateral membrane.

Front 34

Recognize the clinical relevance of distinguishing gout (monosodium urate crystal arthropathy) from pseudogout (calcium pyrophosphate crystal arthropathy), based on the pathogenesis of crystal arthropathies, and why drug choices for chronic gout may not be appropriate for acute gout. [prototype: allopurinol]

Back 34

Xanthine oxidase catalyzes the two terminal steps of purine catabolism, so inhibitors are a rational way to reduce the margin that urate overproduction exceeds renal capacity to excrete urate. Many patients discontinue allopurinol because of hypersensitivity reactions, rash, vasculitis, GI intolerance and other adverse effects. It is contraindicated in patients with renal insufficiency, but februxostat can be used in patients with renal insufficiency and patients who are intolerant. As with all urate-lowering therapies, initiation of therapy with februxostat can induce paradoxical gout flares. Februxostat has not been associated with hypersensitivity reactions. It is associated with higher rates of cardiovascular events.

Front 35

Recognize the clinical relevance of distinguishing gout (monosodium urate crystal arthropathy) from pseudogout (calcium pyrophosphate crystal arthropathy), based on the pathogenesis of crystal arthropathies, and why drug choices for chronic gout may not be appropriate for acute gout. [prototype: pegloticase]

Back 35

This is a new drug, a polyethylene glycolated recombinant mammalian urate oxidase. In man, urate is the final product of purine catabolism, but other mammals have another enzyme, urate oxidate, which further metabolizes urate to allantoin. Allantoin is more soluble than urate and therefore much less likely to precipitate proinflammatory crystals in joints, kidney and soft tissues.

Front 36

Recognize the clinical relevance of distinguishing gout (monosodium urate crystal arthropathy) from pseudogout (calcium pyrophosphate crystal arthropathy), based on the pathogenesis of crystal arthropathies, and why drug choices for chronic gout may not be appropriate for acute gout. [prototype: colchicines]

Back 36

a 2nd-line agent for gout and pseudogout. Colchicine inhibits microtubules and may thereby inhibit neutrophil chemotaxis, mobility, phagocytosis and synthesis of eicosanoids such as prostaglandins and leukotrienes. A single oral dose may abort an attack if given at the earliest twinge, also effective in treating an attack, and can be used prophylactically to reduce flares that are commonly associated with starting urate-lowering therapies (allopurinol or uricosurics). Due to frequent toxicities, it is considered a 2nd-line drug: Diarrhea and vomiting occur in 80% of patients; bone marrow suppression, renal and hepatic toxicity, serious skin reactions and peripheral neuropathy are among the most serious.

Front 37

Describe the mechanism of action and the most important adverse effects of non-steroidal anti-inflammatory drugs used for symptomatic relief of arthritic pain [prototype: ibuprofen]

Back 37

Arthritis occurs at all ages but prevalence is much higher in the elderly. NSAIDs are required long-term for chronic disease, and toxicity increases with dose and duration. The most serious adverse effect is NSAID-induced nephropathy; that risk is reduced by insisting that the patient remains exceptionally well hydrated throughout treatment. Best avoid NSAIDs in patients with pre-existing impairment of renal function. Consequence: dialysis or renal transplant¡¦serious! The second most most serious and more common adverse effect is NSAID-induced gastropathy: by inhibiting cox-1, NSAIDs inhibit prostaglandin E2 synthesis. PGE2 plays a key gastroprotective physiological role by stimulating gastric blood flow and gastromucosal secretion of the mucous bicarbonate barrier that shields gastroduodenal epithelial cells from the aggressive factors, acidity in particular.

Front 38

Describe the mechanism of action and the most important adverse effects of glucocorticosteroids used for symptomatic relief of arthritic pain [prototype: prednisone]

Back 38

Glucocorticosteroids inhibit synthesis and release of inflammatory cytokines, incl. IL-1, leucotrienes, and PGE2 by inducing synthesis of annexin-1 (lipocortin) ¨  ¡ésynthesis of phospholipase (PLA2) and so inhibits release of arachidonic acid as substrate for prostaglandin synthesis. Glucocorticosteroids also induce I¥êB, which then inhibits NF¥êB from switching on genes that encode for cox-2, PLA2, IL- 1 and others. The adverse effects increase with dose and duration: of most concern: adrenal suppression (failure to synthesize endogenous glucocorticosteroids, which are necessary for survival, Osteoporosis, osteonecrosis of femoral head and other joints (requires joint replacement), infections secondary to immunosuppression, provoke and exacerbate diabetes mellitus, but there are many more potential adverse effects that are less serious or uncommon.

Front 39

Describe the mechanism of action and the most important adverse effects of calcineurin/FKBP drugs used for symptomatic relief of arthritic pain [prototype: cyclosporine]

Back 39

Cyclosporine A is the prototype, tacrolimus and sirolimis are alternatives (all antibiotics derived from Streptomyces). These drugs form a complex with a class of intracellular protein (neurophilins such as cyclophilin) which in turn binds and inhibits calcineurin. Calcineurin is the gene transcription-regulating phosphatase for IL-2 production. IL-2 is required for activation of cytotoxic T lymphocytes, which lead the attack on alloantigens in joints of other tissues. Cyclosporine is nephrotoxic.

Front 40

CD25+

Back 40

CD25=IL2R-alpha chain, required to convert IL-2R into its high affinity form

Front 41

Explain T cells coming out of anergy and causing an autoimmune deficiency

Back 41

APCs activated at infection site (express B7) may stimulate self-reactive T cells and break anergy