T2-L2: Autoimmunity Flashcards
What is the difference between adaptive and innate immune mediated inflammation?
Innate Immunity:
- Macrophages, Dendritic cells, Mast cells, Neutrophils and Complement - There is no learning. The cells just recognise a pathogen using pattern recognition complexes e.g. a pattern seen on common bacteria rather than a specific one - When they are recognised you get the same response: there is no memory, amplification
Adaptive immunity:
- B cells and T cells - Highly specific - it is against a specific pathogen the immune system has encountered in the past - There is strong memory and amplification components (e.g. vaccines, previous infection) - Mainly regulatory - More affective
Define autoinflammation.
Autoinflammation is quite rare disease, examples include TRAPS, FMF, CAPS and HIDS. In this case there is no adaptive immune response. There is no learned component or antibodies, it is just over amplification of inflammation.
What are the characteristics of acute inflammation mediated by the innate immune system.
- It is very fast
- It has a short duration
- There is no learning. The cells just recognise a pathogen using pattern recognition complexes e.g. a pattern seen on common bacteria rather than a specific one
- When they are recognised you get the same response: there is no memory, amplification
- Phagocytosis, cytotoxicity (such as complement), inflammatory mediators etc.
What are key cells involved in innate immunity?
Phagocytic cells
• Neutrophils: eat and destroy pathogens
• Macrophages: also produce chemokines to attract other immune cells
• Dendritic cells: also present antigen to adaptive immune system
Histamine-producing cells
• Mast cells, basophils, eosinophils: produce histamine and other chemokines and cytokines
• Vasodilatation, attract other immune cells
• Defense against parasites, wound healing but also allergy and anaphylaxis
Complement
• Directly attacks pathogens via alternative and lectin pathways
• May be activated by adaptive immune system via antibodies
Cytokines
• Signal between different immune cells (e.g. innate to adaptive, adaptive to innate)
Chemokines
• Attract other immune cells to sites of inflammation
Give a definition of autoimmunity.
Autoimmunity is adaptive immune response against the bodies own cells.
What are main differences between autoimmunity and auto-inflammation?
Autoinflammation
- Innate immunity
- Neutrophils and macrophages
- Few or no antibodies
- Recurrent, often seemingly unprovoked attacks
- Cause by tissue specific factors/danger signals
- Cytokine and bacterial pathways are main genetic susceptibility
- Therapy includes anti-cytokines (IL1, TNF and IL6)
Autoinflammation:
- Adaptive immunity
- B and T cell mediated
- Autoantibodies involved
- Continuous progression of autoimmunity
- MHC class II associations and adaptive response genes lead to genetic susceptibility
- Treatment is anti B and T cell
What are mechanisms of autoimmunity?
Failure of Central tolerance
• T cell selection in the thymus
• B cell selection in the bone marrow
When these cells are made they are selected so that any auto-immune cells are deleted and those that aren’t are kept. There may be an issue with this.
Genetic predisposition • Certain HLA (MHC) types select for certain self-antigens • Other genes that regulate immune functions Antigenic factors • Infections that trigger autoimmune responses • Environmental triggers: UV light, smoking • Alterations in self-proteins that increase their immunogenicity
How can MHC Class be involved in autoimmunity?
MHC only has a finite number of types. T cells have an infinite amount of receptors.
MHC types are different shaped, they will be better/more efficient at presenting certain antigen. They are inherited and can predispose to an autoimmune disease e.g. inherited a family of MHC class that presents better autoimmune antigens.
Give examples of HA-DRB1 associations.
Type 1-diabetes - DR3, DR4
Graves Disease - DR3
Multiple sclerosis - DR2
SLE - DR2, DR3
RA - DR1, DR4
There is usually one genetic predisposition, it runs with family. It may be one gene, but it is usually a combination. Even though you have the predisposition you are not born with the disease, it usually kicks in later in life. There therefore must be an environment factor. The immune system also has regulator functions to shut down.
What are causative associations with autoimmunity?
- Seen in women more than men
- Autoimmunity more common in elderly, may be due to more exposure to environment
- Environment - infection, trauma-tissue damage and smoking
- Sequestered antigens - may be recognised as foreign by the immune system since not regulatory seen by the immune system
- Infections
- Molecular mimicry - e.g. rheumatic fever antibodies against M Streptococcus also react against glycoproteins of the heartChanges in the amount or nature of auto-antigens may cause autoimmunity - Citrullination of proteins make more immunogenetic - citrulline is another amino acid. It swaps with alaluine and so seen as more foreign. This is seen in rheumatoid arthritis. - Tissue transglutamase alters gluten to help it bind to HLA-DQ (leads to coeliac disease) - Failure to clear apoptotic debris increases availability of sequestered antigens inside the cell (leads to systemic lupus erythematosus)
What is the difference between organ specific and systemic autoimmunity?
Organs specific autoimmunity:
- Affect a single organ e.g. the thyroid - Autoimmunity restricted to autoantigens of that organ - Overlap with other organ specific diseases - Autoimmune thyroid disease is typical Systemic autoimmunity: - Affect several organs simultaneously - Autoimmunity associated with autoantigens found in most cells of body - Overlap with other non-organ specific diseases - Connective tissue diseases are typical E.g. Lupus
What is the likely diagnosis of the following case?
History
A 28-year-old woman with recent tiredness and difficulty concentrating had experienced a decline in memory over the last several months. She also noted decreased frequency of bowel movements and an increased tendency to gain weight. She felt chilled without light sweater, even in warm weather.
Examination
She was 5’5” tall and weighed 125 lb. Her pulse rate was 58 beats per minute and her blood pressure was 138/88. She had a slightly puffy face and her eyebrows were sparse, especially at the lateral margins. The deep tendon reflexes were normally contractive, but showed delay.
Hashimotos thyroiditis (Hypothyroidism)
- Destruction of thyroid follicles by autoimmune process
- Associated with autoantibodies to thyroglobulin to thyroid peroxidase
- Leads to hypothyroidism
What is the likely diagnosis of the following case?
58 yrs old man presents with difficulty keeping his eyes open, speaking and swallowing. His family have noticed he hardly smiles any more. He finds that his problems are worse as the day progresses.
Myasthenia gravis - The antibody is interfering with the neuromuscular junction.
What is the pathogenesis of pernicious anaemia?
In pernicious anaemia there is a deficiency of vitamin B12. You have plenty of haemoglobin but not enough have enough cells to put them in and so cells become macrocytic. This means that they are over stuffed and the cells end up larger than they need to be. This is organs specific also. Vitamin B12 needs intrinsic factor to be absorbed - this is made by parietal cells. If your autoimmune cells targets this cells, intrinsic factor is not made and so B12 is not absorbed.
What are signs and symptoms of Lupus?
- Red rash
- Mouth ulcers
- Pain in the joints
- Losing hair
- Most are skin related featuresSunlight is a key trigger. You also get internal organ features such as pleural effusion due to cytokines and chemokines coming in to treat the inflammation leading to fluid build up and therefore pleuric pain. The keys, brain, gut and so many other parts are infected. The individual will have anti-nuclear antibodies. Such as antibodies to: - ddDNA - dsDNA - Ribosomes - Histones
