How is fatigue different from tiredness?
Fatigue is when tiredness that is overwhelming and cannot be easily relieved.
What are some causes of fatigue?
- Anaemia
- Sleep apnoea
- Underactive thyroid
- Coeliac disease
- Chronic fatigue syndrome
- Diabetes
- Glandular fever (mono -> EBV)
- Depression
- Restless Leg syndrome
- Generalised anxiety disorder (GAD)
- Vitamin D deficiency
- Insomnia
- Malignancies
- Chronic Heart failure
- Infections
What relevant investigations can be carried out after history/ physical examination, to find out reason for tiredness?
- FBC
- TFTs
- HbA1c
- Urea and electrolytes
- Vitamin D
- CRP
- Coeliac screen
- Autoimmune screen
- EBV serology (Epstein Barr Virus causes glandular fever)
What are the symptoms of an under active thyroid?
- fatigue
- weight gain
- dry skin
- constipation
- cold intolerance
- bradycardia
What are the normal ranges in TFT?
- TSH: 0.5-5.0 mlU/L
- T3: 0.9-2.8 nmol/L
- T4: 5.0- 12.0 microg/dL
What are the causes of primary hypothyroidism?
- autoimmune (Hashimoto’s)
- iodine deficiency
In Hashimoto’s disease, auto-antibodies against which molecule are produced?
TPO enzyme -> involved in the synthesis of T3/4 (anti-TPO)
What happens to the levels of hormone in Hashimoto’s disease?
- TSH increases (no negative feedback)
- T3/T4 decrease (reduced synthesis of hormones)
Which cells contain MHC I molecules?
All cells in the body
Which cells contain MHC II molecules?
APCs
What receptor in the T cell binds to the MHCII molecule on the APC?
TCR
What cell has the B7 receptor and what does it bind to?
APCs: B7 receptors and they bind to CD28 receptors on T cells
What does the TCR bind to on B cells?
BCR
What cell has the CD40L receptor and what does it bind to?
T cells: CD40L receptor which bind to CD40 receptors on B cells
What cells produce anti-TPO antibodies?
B cells
Describe how T cells recognise non-self antigens.
- APCs present antigen using their MHC II molecules onto the TCRs of T helper cells,
- In order for the T cells to be completely activated, they need to be co-stimulated.
What is T cell co-stimulation?
A secondary signal which activates T cells -> in this case, it is the binding of B7 to CD28 receptors on T cells.
What happens in Hashimoto’s?
- APCs present TPO to T cells which recognise it as an non-self antigen.
- T cells gets co-stimulated (B7 -> CD28)
- Activated T helper cells activate B cells by TCR-BCR binding.
- B cells are co-stimulated.
- B cells differentiate into plasma cells and produce anti-TPO.
What is B cell co-stimulation?
A secondary signal which activates B cells -> in this case, it is the binding of CD40L receptor to CD40 on B cells.
What do the anti-TPO antibodies result in?
They bind to and kill thyrocytes.
What other cells are involved in killing thyrocytes?
Cytotoxic T cells
What is immune tolerance?
Prevention of immune response to self antigens.
How do granulocytes (neutrophils etc.) show immune tolerance?
They only detect
- DAMPs
- PAMPs
so cannot kill self-cells. They are part of the innate immune response.
How do lymphocytes (B + T cells) develop tolerance?
In early development, they are exposed to a microcosm of almost every single protein in the body and are trained not to kill self-proteins.
