L 35 Flashcards
What is tolerance for T1DM?
Prevention of an immune response against an antigen causing a state of immunological unresponsiveness
Why does tolerance exist in T1DM?
Because lymphocytes have self-reactive receptors.
What are self-reactive lymphocytes?
Lymphocytes that recognise self tissue as requiring an immune response
Why do we have self reactive lymphocytes?
T cell and B cell receptors need to identify all pathogens for our survival in this world.
What is somatic recombination?
Random recombination means receptors formed randomly with different diversity by mixing up with different genes. Then they make different types of gene to bind with them and kill pathogens.
How are self-reactive lymphocytes formed? What is the adaptational benefit of this process?
Formed by somatic recombination.
Benefit = huge diversity produced to increase ability to recognise pathogens so we don’t get killed.
What should happen to self reactive lymphocytes? What are the 2 processes that do this?
They should be destroyed or controlled
Done via deletion or tolerance induced (respectively)
What is the process of deletion?
What is deletion also known as?
Aka negative selection or central tolerance.
Process: During early T and B cell development, the most self-reactive lymphocytes undergo apoptosis or die.
Peripheral tolerance: how do they occur?
It usually happens when self reactive cells escape from deletion. 3 ways i)Ignorance ii)Energy iii)Suppression
What are some limitations of the deletion process?
Not all peptides are present in the bone marrow or thymus at this stage, or sometimes only the strongly selective ones are weeded out. B cells mature in the ... T cells mature in the ... B cells mature in the bone marrow T cells mature in the thymus
What is ignorance
Lymphocytes are separated from immune privileged site however the sites also produce immunosuppressive cytokines.
What is anergy?
How does it work?
A lack of response or reactivity due to no costimulatory signal activating the T cell.
T cells need 2 signals to become activated. 1 from the antigen being presented as a result of the infection process. Then the antigen will response and produce antibody
2nd one is if there is no real infection but the antigen presenting cell calculated it mistakenly then, the 2nd signal won’t be occurring therefore there is no response to the self-antigen.
What is suppression/regulation?
Process whereby a suppressive cytokine (turns off immune response) or regulatory lymphocyte acts on a T cell to stop autoimmune reactions from occurring
What is autoimmunity?
Why does …. break down?
Autoimmunity is a breakdown of self tolerance.
Tolerance breaks down due to genetics and environment
What genes are involved in autoimmunity?
Polygenic.
Most important genes: ones involved in determining T cell activation - e.g MHC genes and cytokines.
What are the 2 ways that infection can cause tolerance to breaking down?
- Molecular mimicry
2. Bystander activation
What is molecular mimicry?
Why does it occur?
The peptide presented mimics a self-peptide that is also present in our body. T cell reacts with self-peptide because it is similar to another peptide.
Occurs as the peptides are very short (8-10 aa’s) therefore easy to mimic.
What is bystander activation?
Why does it occur?
The self-peptide cell has not been infected itself but is nearby. Cytokines in the area will activate the T cell because it is nearby and therefore causes self-reactivity.
The T cell must present a self-cell if there is no infectious antigen around to present.
3 types of autoimmune disease.
What is the difference between them?
T cell-mediated
Antibody-mediated
Immune complex-mediated
Difference: the self-reactive molecule being recognized is different (otherwise the process is the same)
T1DM is a … caused by …
T1DM is a chronic autoimmune disease caused by the immune destruction of B islet cells.
Pathogenesis of B islet cell destruction
T cells recognize antigens presented by B islet cells and destroy all B islet cells.
Why are NZ’s T1DM rates increasing so much? + examples
Environmental influences e.g climate, diet, social conditions, vitamin D
What’s the hygiene hypothesis?
Children having less time exposed to microbes = more susceptible to inappropriate immune responses due to less memory among Th1 and Th2 cells for protection.
What are the Treatment/cure for T1DM (x3)
- Insulin therapy
- Transplantation of pancreas of islet cells (e.g from a donor, pigs (islet cells hidden in a capsule from the immune system), genetically engineered liver cells transfected with insulin gene)
- Immunotherapy (stem cell transplant) - needs to be done before B islet cell function is lost.
What is T1DM?
A metabolic/endocrine disorder due to the auto-immune mediated destruction of pancreatic B cells, resulting in hyperglycaemia.
At what % of B cell destruction do signs and symptoms start?
Signs and symptoms begin at 80-90% destruction.
Signs and symptoms of T1DM x8
- Polyuria
- Polydipsia
- Polyphagia
- Fatigue/lethargy
- Blurred vision
- Rapid weight loss
- Healing impairment/recurrent infections
- Poor concentration/performance
What is the meaning of the following terms:
- Polyuria
- Polydipsia
- Polyphagia
- Oliguria
- Polyuria - excessive urination
- Polydipsia - excessive thirst
- Polyphagia - excessive hunger
- Oliguria - low urine output
What are the risk factors for T1DM?
Other autoimmune diseases, environment?, close family history.
Diagnosis of T1DM is done by:
Any of the following:
Random plasma glucose >11mmol/L Polt glucose tolerance test >11mmol/L Fasting plasma glucose >7mmol/L Acute T1DM complications x3 DKA, ketonaemia, hypoglycaemia
Chronic T1DM complications (micro and macro)?
Microvascular: retinopathy, nephropathy, neuropathy.
Macrovascular: coronary artery disease, peripheral vascular disease, cerebrovascular disease
Principles/goals of T1DM treatment?
Regular self monitoring of blood glucose
Diet and lifestyle control Insulin (maintain near normal glucose, prevent hypo and ketoacidosis, reduce long term vascular complications)
Monitoring required in T1DM?
- Glucose (6-8x/day)
- HbA1c (3-6 monthly)
- Urine/blood ketone tests (if unwell)
- Eye and feet examinations (complications)
- BP and lipids for older patients
Non pharmacological treatments?
Education to optimise adherence
Nutritional advice (carb/calorie counting)
Regular physical activity
Moderation of alcohol consumption
Alcohol can cause ….glycaemia
Why?
Hypoglycaemia
When you drink alcohol, the liver focuses on clearing that rather than glycogenolysis into the blood stream.
Alcohol also slows down food digestion, giving a slower glucose breakdown.
Therefore lower blood glucose levels from reduced glycogen breakdown, and low blood glucose from meals, but normal (injected) insulin levels = hypoglycaemia
When do you take the following insulins:?
Rapid acting: Short acting: Intermediate acting: Long acting: Premixed: Rapid acting: just before/with food Short acting: 15-20mins before food Intermediate acting: 1-2x day Long acting: 1x day Premixed: 2x day
What is isophane insulin also known as? (2x terms)
NPH or intermediate acting insulin.
Does Lantus have a peak?
What is its generic name?
No prominent peak, steady for 24 hours
Generic name: Long acting insulin glargine
What is basal-bolus insulin?
An insulin injection regimen that involves taking a longer acting form of insulin to keep blood glucose levels stable through periods of fasting (basal) and separate injections of shorter acting insulin to prevent rises in blood glucose levels resulting from meals (bolus).
When is basal bolus insulin taken?
Multiple injections recommended daily:
Basal = 1-2x daily
Bolus (rapid acting) = prior to meals
What form of insulin administration is continuous?
Insulin infusion pumps.
What is DKA?
Diabetic ketoacidosis
What happens in DKA?
Is it a medical emergency?
Glucose is high, but negligible insulin causes lipolysis and ketone release that decreases pH.
Yes it is very much a medical emergency
Signs/symptoms of DKA
N, V, dehydration, polydipsia, polyuria, hyperventilation, acetone (sweet) breath, hyperglycaemia, ketosis, acidosis, hyperkalemia in blood but then hypokalaemia overall.
Why does DKA cause hyperkalemia but a total decrease in K+?
Insulin causes K+ to be taken into cells. When there is reduced insulin (in DKA), potassium moves out of the cells, but then get cleared in the urine
Treatment for DKA (x5)?
IV fluids, IV insulin, IV glucose, IV K+, and sometimes IV HCO3- to buffer if seriously acidotic.
What is the value of hypoglycemia?
What are the symptoms?
<4mmol/L, and <2.8mmol/L is VERY VERY low.
Shakiness, sweating, fatigue, hunger, headaches, faint, confusion/irritability
Very bad symptoms of hypoglycemia (e.g at very low levels) (x5)
Confusion, loss of consciousness, seizure, coma, death
What is hypoglycemia caused by?
Too much insulin
What can increase insulin levels?
High doses Inadequate food/calories to match Other medications High levels of exercise High temperatures Alcohol Illness can often cause... Illness can often cause hyperglycemia But, often when ill, you eat less so you can balance out.
Hypoglycaemic treatment/steps x4
- Check blood sugar immediately
- Drink/eat 15g carbohydrates (e.g glucose tablets, 6 jelly beans, 1 tbsp of sugar)
- Wait 15 mins and re-check your level
- If unconscious, someone can give you a glucagon injection.
Limitations with the hypoglycaemic treatment options?
- When you are hypo you feel so terrible that you are not making rational decisions.
What is the law in regards to hypos and driving?
If you need to treat a hypo at all, wait 1 hour before driving.
If it is very severe, you have to wait 24 hours before driving.
What is glucagon
A peptide hormone produced by the alpha cells of the pancreas.
It raises the glucose and fatty acid concentration in the bloodstream by stimulating gluconeogenesis.
What should you NOT do when treating someone that is unconscious for hypoglycemia?
- Do not try to feed them anything by mouth
- Do not leave them alone
What are the short-term complications of T1DM?
DKA and hypoglycemia
What are the long-term complications of T1DM? (Vague)
Micro and macrovascular complications
