Final week Flashcards
Define Self-antigens:
An individual own antigens (blood type antigens)
Define immunologic tolerance:
Unresponsiveness to self-antigens (negative selection process)
Define tolerogens:
Antigens that induce tolerance
Define Immunogens:
Antigens that induce an immune response
Define Autoimmunity:
Failure of self-tolerance and resulting immune reaction to self-antigens
What is central tolerance?
- Immature developing lymphocytes encountering self-antigens in generative lypmhoid organs
- T cells: deletion and regulatory T cells
- B cells: receptor editing, deletion, anergy
What is peripheral tolerance?
- Mature lymphocytes encounter self-antigens in secondary lymphoid organs
- T cells: anergy, suppression, deletion
- B cells: anergy, suppression, deletion
What are the 2 main pathways for central tolerance in T cells?
- Negative selection (deletion)
- Development of regulatory T cells
- The tolerance of T cells usually influences B cell tolerance
Where do DN thymocytes enter the thymus?
Right at the border of the medulla, where they then venture into the cortex for maturation
What is AIRE?
- AutoImmune Regulator Protein (AIRE)
- Expressed in thymic medullary epithelial cells
- Presents peripheral tissue antigens to thymus
- Without AIRE, there is no regulation and autoimmunity results!
What is APECED and its classic triad?
- Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy
- Classic Triad: mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism
What is the mode of inheritance for APECED?
- Autosomal recessive
- Mutations in AIRE gene
Which T cells do not depend on AIRE for their development?
Regulatory T cells
Where is icos expressed and what is its function?
- Expressed on activated T cells
- Costimulation of T cells & generation of T follicular helper cells
Where is CTLA-4 expressed and what is its function?
- Activated T cells
- Negative regulation of immune response & self-tolerance
Where is PD-1 expressed and what is its function?
- T cells, B cell, and myeloid cells (activated)
- Negative regulation of effector T cells & self tolerance
What are the two forms of T cell anergy?
After recognition of self-antigen
- Signaling block
- OR
- Engagement of inhibitory receptors
What is CD25?
Alpha chain for IL2 receptor
What is the difference between natural and induced T regs?
- Natural develop in the thymus
- Induced develop in the peripheral tissues (TGF-beta)
What are the 3 main ways T regs suppress the immune response?
- Production of inhibitory cytokines (IL-10 & TGF-beta)
- Expression of CTLA-4
- Expression of IL-2 receptor and capture of IL-2
What is IPEX and its classic triad?
- Immune Dysregulation, Polendocrinopathy, Enteropathy, X-linked Syndrome
- Classic Triad: enteropathy (diarrhea), dermatitis (eczema), endocrine disease (diabetes/thyroid)
What is the difference between intrinsic and extrinsic in peripheral T lymphocyte deletion?
- Intrinsic- cell death caused by deficiency of survival genes (mitochondria releases inducers of apoptosis)
- Extrinsic- cell death caused by engagement of death receptors (FasL and Fas interaction)
What is ALPS and its common mutations?
- Autoimmune Lympho-Proliferation Syndrome
- Disorder of apoptosis
- Dominant mutation: Fas, FasL, caspase 8, caspase 10
Which antigens are nonprotein and T-independent?
- Polysaccharides
- Lipids
- Nucleic Acids
What immunoglobulin isotype responds to T-independent antigens?
IgM (short-lived plasma cells)
What are the pathways for central B cell tolerance?
- If self-reactive, can form new light chain to avoid
- If self-reactivity continues, apoptosis
- If responds to self-antigen with low-avidity, it can enter anergy
What are the two main forms of peripheral B cell tolerance?
- Anergy and deletion (in absence of T cell co-stimulation)
- Regulation by inhibitory receptors
What are the common steps in autoimmunity development?
- Inheritance of susceptibility gene and failure of self-tolerance
- Tissue injury and inflammation
- Activation of tissue APCs and self-reactive lymphocytes
- Self-reactive effector lymphocytes cause tissue injury
What are some common polymorphisms (Non-HLA) and their associated autoimmune disease?
- PTPN22 (RA and others)
- NOD2 (Crohn’s Disease)
- CD25 (MS, Type 1 diabetes, others)
- C2, C4 (SLE)
- FCGRIIB (SLE)
What are some single-gene defects that cause autoimmunity?
- AIRE (APECED)
- Foxp3 (IPEX)
- FAS (ALPS)
What are the 2 main form of environmental factors that lead to autoimmunity?
- Induction of costimulators on APCs
- Molecular mimicry
In what disease are both B lymphocyte and T lymphocyte tolerance defective?
Systemic Lupus Erythematosus
What are some common environemntal factors associated with SLE?
- UV radiation
- Viral infection
- Drugs and chemicals
What are some common Anti-__ antibodies involved in SLE?
- Antinuclear antibody
- Anti-dsDNA antibody
- Anti-Smith antibody
- Anti-Ro (SSA) antibody
- Anti-La (SSB) antibody
- Anti-RNP antibody
- Anti-histone antibody
A malar rash is associated with what disease?
Lupus
What hormonal factors are associated with SLE?
- Increased in women during child bearing years
- Estrogen-induced flares
Define hypersensitivity
Overreaction of normally protective response that results in tissue injury and disease
What are the 3 common triggers of hypersensitivity?
- “self” antigens- autoimmunity
- Microbial antigens- excessive inflammation
- Environmental antigens- allergy/atopy
What is the most common type of hypersensitivity?
Type 1
How is type 1 hypersensitivity characterized?
- Allergy or atopy
- Rapid onset (minutes)
- Antigen-specific IgE
- Mast cell (histamine) and eosinophil involvement
- Vasoactive mediators, lipid mediators, cytokines
What are some common examples of Type 1 hypersensitivity?
- Allergic rhinitis
- Atopic asthma
- Anaphylaxis
What antibodies mediate type 2 and 3 hypersensitivity?
IgG and IgM
Which type(s) of hypersensitivity often involve auto-antibodies or foreign antigens?
Type 2 and 3
What is the role of the antibodies in type 2 hypersensitivity?
- Antibody directly binds the target
- Antigens are specific cells or extracellular matrix
- Local, tissue specific
What is the role of the antibodies in type 3 hypersensitivity?
- Immune complex deposition
- Antigens present in circulation
- Systemic
Which class of immunoglobulins has the most subtypes?
- IgG (1-4)
- IgA has 2 subtypes
How is type 2 hypersensitivity characterized?
- Cytotoxic hypersensitivity
- Onset in minutes-hours
- Complement and Fc receptor mediated (involves opsonization/phagocytosis or hormone signaling)
- Neutrophils can cause direct tissue injury
What are some examples of Type 2 hypersensitivity?
- Goodpasture’s Syndrome
- Idopathic thrombocytopenic purpura (ITP)
- Autoimmune hemolytic anemia (AIHA)
- Grave’s (antibody stimulates TSH receptor)
- Myasthenia gravis (antibody inhibits Ach receptor)
In what disease are antibodies against the basement membrane of the kidney and lung made?
Goodpasture’s syndrome (type 2)
How is type 3 hypersensitivity characterized?
- Immune complex hypersensitivity
- Onset within hours
- Complement and Fc receptor mediated
- Complexes deposited in vascular basement membrane
- Lysosomal enzymes and ROS cause damage, neutrophils (vasculitis)
What is “serum sickness”?
- A type 3 hypersensitivity response
- Body makes antibodies against foreign antibodies (diptheria and horse antibodies)
- Complex formation and deposition causes symptoms (fever, hives, joint pain)
How is type 4 hypersensitivity characterized?
- Delayed type hypersensitivity
- Onset of hours to days
- Involved CD4+ and CD8+ T cells, macrophage activation, and direct target cell lysis
- Non-transferrable by serum (not antibodies)
What are some examples of Type 4 hypersensitivity?
- Poison ivy contact dermatitis (urushiol is lipid soluble and is presented on MHC 1 molecules)
- TB test
What are some examples of type 3 hypersensitivity?
- SLE
- Serum sickness
- Vasculitis
What are the general steps that lead to immediate hypersensitivity?
- First exposure to antigen (activate Th2 cells and stimulate IgE class switch in B cells)
- Production of IgE & binding to mast cells (FcR)
- Repeat exposure to antigen
- Activation of mast cell (release mediators)
- Immediate reaction (minutes after repeat exposure)
- Late Phase Reaction
What is the role of IgE in hypersensitivity?
- Sensitize mast cells
- Recognition of antigen
What is the difference between immediate and late phase response in hypersensitivity reaction?
- Immediate- minutes after exposure and result of vasoactive amines/lipid mediators
- Late- happens a few hours after exposure and result of cytokine release
Where are mast cells mainly located?
GI tract, skin, and respiratory
What is a pruritic rash?
Itchy rash (allergic response)
What are the most common food allergies?
- Milk, egg, peanut, wheat, soy
- To a lesser extent: fish, shellfish, tree nuts
What are common candidate genes that cause asthma?
- Cytokine gene clusters (IL4, IL5, IL13), CD14, and B-adrenergic receptor
- ADAM33
How does ADAM33 cause asthma?
Metalloproteinase involved in airway remodeling
What is a gene candidate for atopic dermatitis?
Filaggrin- component of terminall differentiated keratinocytes important for epithelial barrier function
What are the general steps in mast cell activation?
- IgE coating (occurs on Fc receptor)
- Antigen activated mast cell (needs cross-linking of antigen & IgE-FcR)
- Histamine/lipid mediators (immediate)
- Cytokines (late)
What is systemic anaphylaxis?
Systemic immediate hypersensitivity reaction characterized by edema in many tissues & decrease in blood pressure (secondary to vasodilation)
What is a wheal and flare reaction?
- Result of intradermal injection of antigen
- Vasodialation on edge of lesion
- Vasodilation and congestion in “wheal” (mast cells, edema)
What is the value of a skin prick test (or in vitro serum test)?
Excellent negative predictive value (positive predicitive value is ~50%)
Who are “atopic” individuals?
- Susceptible to immediate hypersensitivity
- Have more IgE in blood and more IgE-specific Fc receptors per mast cell
How are eosinophils recruited and activated?
- Recruited by chemokines and IL4
- Activated by IL5
What is the role of biogenic amines and lipid mediators?
Rapid vascular and smooth muscle reactions (vasodilation, vascular leakage, edema, brochoconstriction, gut hypermotility)
Is asthma an immediate or late-phase reaction?
Both
Is susceptibility to allergic disease inherited?
Yes
What are Eicosanoids?
- Made by oxidation of 20C FA
- Inflammation and Immunity processes
- Include prostaglandins and leukotrienes
What is the main precursor for Eicosanid synthesis?
Arachidonic Acid (synthesized by Phospholipase A2)
What enzyme is used to synthesize Leukotrienes from Arachidonic acid?
Lipoxygenase
What enzyme is used to synthesize prostaglandins and thromboxanes from Arachidonic acid?
Cyclooxygenase (COX)
What is the difference between COX-1 and COX-2?
- COX-1: Constitutive expression, ubiquitis location, “houskeeping” functions
- COX-2: Inducible (pro-inflammatory signals), Inflammatory site location, proinflammatory functions
What is the downside of Cox inhibitors?
- Cox inhibitors are used to decrease inflammtory response
- However, most of the drugs act on both Cox-1 and Cox-2 (causing GI problems)
- Need Cox-2 selective drugs!
What is the mechanism of NSAIDs?
Inhibition of prostraglandin production and interferes with physiological roles of molecules
Frequently leads to erosion of GI mucosal protection
What is the generic name of Aspirin and its MoA?
- Acetylsalicylic acid
- Transfers functional group onto COX enzyme (irreversible inhibition)
- Leukotriene pathway remains unaffected
What are some of the major problems with aspirin use?
- GI disturbance (direct effect on mucosa)
- Prolonged bleeding (decreased platelet function for 4-6 days)
- Tinnitus (aspirin toxicity)
What is the relationship between therapeutic effects and dose in aspirin?
- Low dose (30-100mg): antiplatelet
- Medium dose (.3-.6g): analgesic and antipyretic
- High dose (3-5g): anti-inflammatory
What is Kawasaki disease?
- Persistenet fever with increased risk of CAD (must meet criteria)
- Risk of vasculitis
- Treatment is IVIG with aspirin (initially high dose, then low)
What is Reye’s Syndrome?
- Result of giving aspirin to lower fever following viral infection
- Five clinical stages (lead to coma and seizure)
- Use ibuprofen or acetaminophen instead
What are the signs of acute vs chronic poisoning with aspirin?
- Acute- respiratory depressoin and acidosis
- Chronic- Nausea, tinnitus, hyperglycemia
What is it called when aspirin leads to nasal congestion and acute, sever bronchospasm?
(also increased risk for anaphylaxis and angiodema)
Aspirin Sensitive Asthma
What is the most frequently used and quickest acting NSAID?
- Ibuprofen
- Sold as: advil, motrin, nuprin
- Also has longer duraction of action compared to acetaminophen
What are some properties of Ibuprofen?
- Peak plasma levels in 15-30 minutes
- Half-life of about 2 hours
- Anti-inflammatory regimen requires 2400-3200mg daily
- Take with food (GI problems)
What drug is chemically similar to Ibuprofen with a longer half-life?
- Naproxen (Naprosyn, Aleve)
- Half-life of about 12 hours (take twice a day)
- Peak plasma within 2-4 hours
- Higher rate of GI bleeding
What is Indomethacin (Indocin) mainly used to treat?
Gout (has sever side effects, so not much else)
What is the significance of Nabumetone (Relafen)?
- Only nonacid NSAID currently available
- Take once-a-day (halflife 24 hours)
What is the significance of Rofecoxib (Vioxx)?
- Highly selective COX-2 inhibitor
- Taken off market in 2004 due to increased risk of MI and stroke
What is the significance of Celecoxib (Celebrex)?
- COX-2 inhibitor
- Does not appear to cause more heart problems
What is the significance of Ketorolac (Toradol)?
- Only NSAID for IM or IV injection
- Used mainly in postoperative patients
- Risk of renal effects
How to Corticosteroid drugs suppress the immune system?
- Regulate the transcription of molecules
- Increase lipcortin
- Decrease IL1, IL2, TNF-alpha, INF-gamma
What are the two pathways of corticosteroid effects on Eicosanoid production?
- Decrease the activity of Phospholipase A2 (by increasing Lipocortin)
- Decrease the expression of COX-2
What part of the immune response to glucocorticoids affect most?
- There is more inhibition of the cell-mediated arm over the humoral arm
- Also induce apoptosis in rapidly-dividing leukocytes
What are some of the common uses corticosteroids?
- Graft rejection and delayed hypersensitivity
- Transplant rejection
- suppress hypersensitivity/allergies
What is one of the negatives of corticosteroid use?
- Increase risk of infection (espcecially CMI)
- Cannot use live virus vaccines during regimen
- Longterm use can cause Cushing’s Syndrome (fat face)
- Impaired wound healing
Do NSAIDs ameliorate the ongoing immune reaction?
No, just address the symptoms
Is acetaminophen an NSAID?
No, because it does not decrease inflammation
What is RICEM and when is it used?
- Rest
- Ice
- Compression
- Elevation
- Medication (anti-inflammatory)
Use with acute inflammation caused by trauma!
What is he main problem with the results and science behind herbals?
Most only show in vitro activities
What is one of the exceptions to the problem with herbal supplement studies for inflammation?
Cat’s claw has clinical trials showing improvement of osteoarthritis
What are the 3 main mechanisms for immunosuppressant drugs?
- Cytotoxic (cause cell death)
- Inhibit proliferation or fxn of lymphocytes
- Prevent lymphocyte proliferation (via nucleotides)
What does DMARDS stand for?
- Disease Modifying Anti-Rheumatic Drugs
- RA is a systmic inflammatory disease
What is Methotrexate MoA, usage, and adverse effects?
- Inhibits DHFR (folate metabolism)-> no DNA
- Use high dose in chemo, low dose in autoimmune
- Can cause liver and bone marrow effects
What is the MoA, usage, and adverse effects in Mycophenolate Mofetil (CellCept)?
- Inhibits IMPDH (purine/DNA synthesis)
- Used to prevent graft rejection and for autoimmune
- Can effect GI and bone marrow
What is the difference between conventional and biologics as immunosuppressant drugs?
- Conventional- interfere with combinations of pathways
- Biologics- selectively inhibit a cytokine or receptor
What immunosuppressants are used to prevent transplant rejection, but not in kidneys due to nephrotoxicity?
- Cyclosporin and Tacrolimus
- Both are calcineurin inhibitors and prevent IL2 transcription
What immunosuppressant is an mTOR inhibitor that can cause cytopenias?
- Sirolimus
- Prevents IL2 response
- Used to prevent renal transplant rejection
What immunosuppressant blocks nucleotide synthesis and can cause cytopenias?
- Azathioprine (Imuran)
- Inhibits lymphocyte proliferation
- Prevents transplant rejection, RA, Chrohn’s
How do glucocorticoids prevent transplant rejection?
Inhibit NFkB (which decreases cytokine transcription)
What is a biologic that ends with -ximab?
Chimera (mostly human, but mouse derived)
What is a biologic that ends with -zumab?
Mostly human (humanized!)
What is a biologic that ends with -umab?
100% human
Which biologic targets the Jak1/Jak3 pathway?
Tofacitinib (Xeljanz)
Why is Etanercept (Enbrel) not considered a mAb?
Because it is a man made fusion protein
What do Etanercept (Enbrel), Infliximab (Remicade), Adalimumab (Humira) all inhibit?
TNF-alpha
What is Sreptococcus pyogenes (GABHS)?
- Group A Beta Hemolytic Streptococcus
- Causes acute rheumatic fever
What is one of the big concerns with acute rheumatic fever (ARF)?
- Inflammation of the heart, joints, brain, and vascular connective tissue
- Due to cross-reactive antibody and/or CMI
- Treat with corticosteroids (Salicylates too)
What is autoinflammatory disease?
- Errors in innate immune system
- Perioidic fever, joint pains, abdominal pains
- Common in USA is PFAPA
What kind of immune reaction if caused by TH2 activation?
Humoral immunity (not CMI)
What kind of response does a live virus vaccine cause?
A CD8+ T cell response (this will be intracellular processing)
What is the classic sign of Chediak-Hegashi Syndrome?
Giant cytoplasmic granules in mononuclear cells
What do you call the atypical lymphocytes reacting to the EBV-infected B cells?
Downey cells (CD8+ T cells target them infected B cells)