Overactive immune and immune suppressants

Question 1

Allergens

Answer 1

Small soluble proteins, normally innocuous, to which the mounts an immune defense.

Question 2

Type 1 hypersensitivity

Answer 2

Mediated by IgE. Trend towards Th2 response.

Question 3

Mast Cells and IgE

Answer 3

Mast cells bind to the Fc region of antibodies. Mast cell discharges granulates containing cytotoxic and inflammatory mediators (histamine, TNF, . Histamine, causes expansion of blood vessels, bronchii restriction.

Question 4

Allergy activation: 3 stages

Answer 4

Sensitization:
 -B cell processes antigen
 -T cells activate (Th2)
 -IgE binds FcR on mast cells
Subsequent exposure:
 -Occurs within minutes of exposure.
     -Allergen recognized by IgE on mast cells.
     -Mast cells release granulates.
     -Release histamine, prostaglandin. 
Late response:
  -Cytokines released
        -recruit inflammatory cells. Eosinophils.

Question 5

Type of T cells and in regards to allergies.

Answer 5

T helper cells release cytokines that mediate the immune response. However, during proliferation, T cells become many different types, each of which produces different cytokines (ILs), thereby mediating a different response. Allergic response depends greatly on the type of T helper cells.

Question 6

Hypersensitivity classification

Answer 6

Antibody dependent: types 1,2,3. Evident within hours. Quick response.

 - Type 1: IgE -asthma, allergies, 
 - Type 2: IgG -drug allergies
 - Type 3: IgG

Type 4 is T cell mediated. Delayed sensitivity, requires at least a day to develop.

Question 7

Fc Receptors and IgG/IgE

Answer 7

Antibody based hypersensitivity involves the binding of an immune cell to the FC region of an antibody.

Type 1 hypersensivity is the result if IgE binding to immune cells. Granulocytes (mast cells, basophils, and eosinophils) have FcRs that bind to IgE.

Type 2 and 3 are the result of IgG binding to immune cells. FcRs that bind to IgG are expressed on macrophages, neutrophils, natural killer cells, and dendritic cells.

Question 8

Type 2 hypersensitivity

Answer 8

Antibody dependent. IgG. Recruits macrophages and natural killer cells.

Generally drug allergies. Eg. penicillin.

Question 9

Type 3 hypersensitivity

Answer 9

Antibody dependent. IgG. Recruits inflammatory cells and complement activation, driving granulate release.

Deposition in joints. Arthritis. Fibrosis.

Question 10

Type 4 hypersensitivity

Answer 10

T cell driven. Take longer to mount.

Contact dermatitis. Antigen usually bind with proteins on epithelial cells. T Cells cells against allergen will kill skin cells. Release of cytokines promotes inflammation.

Poison oak.

Question 11

Autoimmunity

Answer 11

When tolerance to self goes wrong. A complex range of disorders. They can be organ specific or systemic.

Organ specific: Type 1 diabetes, Multiple sclerosis, Myasthenia gravia.

Systemic: Rheumatoid arthritis, lupus.

Question 12

Self-Tolerance

Answer 12

B and T cells that recognize self are killed, both during their development and while in the periphery.

Central tolerance:

 - occurs in primary lymphoid organs
     - bone marrow, thymus
 - Cells that react to self are killed by negative selection. 

Peripheral tolerance:

 - some auto reactive T/B cells escape detection are either the peripheral system. 
 - They are suppressed by T regulatory cells, which secrete immunosuppressive cytokines (IL 10, TGF).

Question 13

T regulatory cells

Answer 13

They are a type of T cell that act to suppress activation of immune system, preventing activation in response to self-antigens. they work by secreting immunosuppressive cytokines (IL 10, TGF).

Question 14

How does autoimmunity develop?

Answer 14

Genetic predisposition in genes that activate or turn off immune system.

Question 15

Types of autoimmunities (2)

Answer 15

• Autoantibodies

- Cell mediated immunity (T cell activation)

Question 16

Antibody driven autoimmunity (autoantibodies)

Answer 16

Can change function by blocking interactions.
-myasthenia gravis
Or can drive type 2/3 hypersensitivities.
-Lupus, type 3 systemic.

Question 17

Myasthenia gravis

Answer 17

Antibodies against nAChRs at NMJ block their function.

Question 18

Systemic Lupus Erythematous

Answer 18

SLS is a chronic, multi organ disease affecting mainly women.

Characterized by the production of antibodies against DNA/RNA binding proteins (anti-nuclear proteins).

Question 19

T Cell driven autoimmunity

Answer 19

• Th cell driven, releases inflammatory cytokines. Rheumatoid arthritis, MS
• Cytotoxic T Cell driven - Type 1 diabetes.

Question 20

Type 1 diabetes

Answer 20

Cytotoxic T cell driven autoimmunity of islet beta cells.

Question 21

What are the T helper cells and cytokines involved in Th Cell driven autoimmunity?

Answer 21

Th1 and Th17, and IL17.

Question 22

What are the T cells and cytokines involved in regulating immunity?

Answer 22

Treg and Th2, with IL10.

Question 23

Rheumatoid Arthritis key features

Answer 23

• Symptoms >6 weeks
• Synovitis; swollen joints (not distal phalangeal)
• Symmetrical and polyarticular
• Morning stiffness
• High serum rheumatoid factor
• may be mild or severe and may progesss.
• flareups.

Question 24

RA vs OA

Answer 24

RA:
    -responds to NSAIDs
    -not distal joint
    -stiffness last for hours
    -improves with use
    -loss of function
    -Redness and warmth
    -vasculitis (blod blisters)
OA:
    -Not responsive to NSAIDs
    -distal joint
    -Stiffness lasts mintutes
    -worsens with use

Question 25

RA therapeutic approach

Answer 25

• Analgesics
• Immunosuppressants
  
  • COX2 NSAIDs for symptomatic relief.
  • Steroids-prednisone.
  • intra articular steroids for flareups
• Disease Modifying Anti-Rheumetic Drugs
  
  • Tripple Rx
    
    • methotraxate
    • hydrochloroquine
    • sulfasalazine
• Newer biologics
  
  • Anti TNF alfa
  • B cell inhibitors
  • IL1 receptor agonist
• Joint replacement

Question 26

DMARDs, triple therapy

Answer 26

Disease Modifying Anti-Rheumetic Drugs

 - Tripple Rx works better than any single therapy. 
      - methotraxate
      - hydrochloroquine
      - sulfasalazine

Require frequent monitoring.

Question 27

Methotrexate

Answer 27

Best single DMARD. Low doses. Good risk/benefit ratio. Used in Psoriasis, RA and post transplant. Give folic acid supplementation.

Different mechanism than in cancer: Inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine; inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells; selective down-regulation of B cells; and the inhibition of the binding of IL1 to its cell surface receptor.

Adverse reactions include: pulmonary damage, myelosupression, GI problems (nausea, stomach upset, and loose stools), Stomatitis and soreness of mouth, infection, alopecia.

Question 28

Multiple Sclerosis

Answer 28

Multiple sclerosis (MS) is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems.

Question 29

MS treatment

Answer 29

Fingolimod is an immunomodulating drug, mostly used for treating multiple sclerosis (MS). Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.

Natalizumab is a monoclonal antibody against the cell adhesion molecule α4-integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn’s disease. Natalizumab appears to reduce the transmission of immune cells into the central nervous system by interfering with the α4β1-integrin receptor molecules on the surfaces of cells.

Question 30

IgE

Answer 30

IgE plays a role in parasitic worm diseases via the Th2 immune response. Eosinophils have Fc receptors for IgE and binding of eosinophils to IgE-coated helminths results in killing of the parasite.

Question 31

Transplant drug

Answer 31

Tacrolimus is an immunosuppressant that works by inhibiting the expression of IL-2 by T cells. This suppress T-cell activation and activity. A side effect of this medication may be vasoconstriction of the afferent and efferent arterioles of the kidneys, reducing renal blood flow and GFR.

Tacrolimus is a very effective immunosuppressant. As the patient is 5 years post-transplant, it is likely that a lower dose of Tacrolimus can still achieve the same effectiveness, but reduce the deterioration of renal damage.