Immunosuppression: Corticosteroids and autoimmune conditions

Question 1

Glucocorticoids vs corticosteroids

Answer 1

Glucocorticoids = endogenous steroids regulating glucose metabolism: hydrocortisone, corticoeterone.

Corticosteroids = glucocorticoids + mineralocorticoids + artificial steroids used in therapy e.g dexamethasone

Question 2

Glucocorticoid receptor

Answer 2

Major form: GCRα
Present in the cytoplasm complexed with other proteins e.g hsp90.
On ligand binding, receptor dissociates & is translocated to nucleus- where acts as a transcriptional regulator:
- direct activation of transcription
- directly enhancing activation of other TFs
- indirectly enhancing activation of other TFs.

Question 3

Anti-inflammatory proteins up-regulated by glucocorticoids

Answer 3

lipocortin-1
secretory leukocyte inhibitory protein
IL-1 receptor antagonist
IκB

Question 4

Pro-inflammatory proteins down-regulated by glucocorticoids

Answer 4

IL-1
TNF-α
iNOS
COX2

Question 5

Production of glucocorticoids

Clinical significance?

Answer 5

Anterior pituitary releases ACTH in response to neuronal stimulation
ACTH stimulated conversion of cholesterol to glucocorticoids in the adrenal cortex.
Glucocorticoids exert strong negative feedback on their own production. Therefore prolonged treatment by corticosteroids shuts down endogenous production. Sudden withdrawal of corticosteroid treatment could therefore be fatal.

Question 6

Cushing’s syndrome

Answer 6

Due to side effects of corticosteroid treatment

• ‘buffalo hump’
• moon face, with red (plethoric) cheeks
• deposition of abdominal dat

Question 7

Side effects of corticosteroid treatment

Answer 7

Suppression of HPA axis
Polyphagia
Diabetes
Muscle weakness
Thinning of skin
Increased risk of infection
Poor wound healing
External signs: Cushing's syndrome

Question 8

Corticosteroids in treatment of respiratory diseases

Answer 8

In asthma, treatment with inhaled corticosteroids: reduce production of acute inflammatory mediators, & cytokins, homing of T cells to the lungs, prevent dendritic cell maturation

Inhaled corticosteroids are ineffective in COPD, possible due to high levels of oxidative stress.

Question 9

Multiple sclerosis

Answer 9

Autoimmune

Immune attack on oligodendrocytes

Question 10

Type I diabetes

Answer 10

Autoimmune

Immune attack on pancreatic beta cells

Question 11

Rheumatoid arthritis

Answer 11

Autoimmune
Immune attack on synovium surrounding joints
~1% human population

Joint changes typically appear in proximal phalanges or small bones in hands, feet, also in cervical regions of the spine. Involve inflammation, proliferation of synovium, erosion of cartilage & bone.
Also effects on heart, lungs, kidney, skin, sclera of eye

Question 12

Hyperthyroidism

Answer 12

Autoimmune

= Graves disease

Question 13

Hypothyroidism

Answer 13

Autoimmune

= Hashimoto’s thyroiditis

Question 14

Vitiligo

Answer 14

Autoimmune
Immune attack on melanocytes, causing uneven skin pigmentation.

No major consequences- not treated

Question 15

Lupus

Answer 15

Autoimmune

Skin inflammation due to attack on blood vessels

Question 16

Systemic lupus erythematosus (SLE)

Answer 16

Autoimmune
More serious condition than lupus
Immune attack on blood vessels in internal organs

Question 17

Behcet’s disease

Answer 17

Autoimmune

Immune attack on blood vessels & anterior chamber of eye

Question 18

Ulcerative colitis, Crohn’s disease

Answer 18

Autoimmune

Immune attack on large bowel.