Immunology: the immune response, auto-immunity, white blood cells Flashcards
What are the 3 different disorders of the immune system ?
1). Immunodeficiency
- Too little immunity
- Can be induced by HIV, genetics or a drug with temporary immunodeficiency
2). Hypersensitivity
- Too much immunity
- Where you react to something you wouldn’t normally respond to
3). Autoimmunity
- Misdirected
- Make an immune response to a tissue or organ that you would normally ignore
What are the features of Autoimmune diseases?
Autoimmune diseases;
- Group of 80 or so chronic inflammatory conditions
- Genetic predisposition and environmental modulators/triggers
- Prevalence of 5-8% in most western populations
- Prevalence greater for females - account for 75% of cases and 4th largest class of disease in females
Are Autoimmune Diseases caused by single genes?
The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION, not the rule (rare if you did find some)
- Autoimmune disease are complex, interplay between multiple genes and external factors
What are some Exceptions where a single gene is involved?
- Autoimmune polyglandular syndrome type 1 (APS-1), AIRE - low expression of some self antigens in thymus - some auto reactive T cells not deleted (thymus where t cells educated before leave)
- Autoimmune lymphoproliferative syndorme (ALPS) FAS, FASL - failure of apoptosis of some self reactive T and B cells
What are the 2 autoimmune conditions that don’t affect females more than males?
Ulcerative colitis: affects both sex’s the same amount
Diabetes mellitus: Affects men more than women
What body parts can be affected by autoimmune disease?
Body parts that can be affected by autoimmune disease;
* Trachea
* Blood
* Blood vessels
* Heart
* Skin
* Oesophagus
* Liver
* Kidney
* Ovary
* Brain
* Eyes
* Mouth
* Spinal cord
* Thyroid
* Lung
* Joints
* Pancreas
* Gut
What are some common autoimmune conditions in each of these systems?
Don’t remember all of this, not examinable
- Autoimmune uveitis —eyes
- Sjogrens syndrome — mouth
- Rheumatic fever —heart and others
- Autoimmune hepatitis — liver
- Autoimmune oophoritis —ovaries
- Rheumatoid arthritis — joints
- MS — nerves
- Pemphigus —skin and muscosa
- Goodpasture’s — lung
- Diabetes — pancreas
- Ulcerative Colitis — large intestine
- Autoimmune hemolytic anemia - blood
What is tolerance?
Tolerance is the process tat keeps the immune system from attacking itself
- Failure of tolerance is thought to cause an autoimmune response
- Central tolerance - express lots of these proteins and deleted in thymus
- Peripheral tolerance - keep under control
These can go wrong!
E.g thymus deletion of autoreactive cells and T regulatory cells
T cells go from bone marrow to thymus where they undergo thymic education before being released into periphery. Idea is that you select a bunch of T cells that recognise your own MHC and HLA molecules but are sensitive enough to ignore your self peptides and activate when see protein from pathogen or bacteria
Thymic epithelial cells express almost every gene in your genome. Contradictory as usually cells for that organ are only found in that organ. But thymic epithelial cells are capable of expressing every gene and protein in your body. Meaning the T cells in your thymus can see every gene product in your body, in an environment where if they are autoreactive then they are deleted. Unique set of cells in Thymus that expresses almost every protein that allows to delete most autoreactive T cells and prevent developing autoimmune disease.
But some escape into periphery and undergo peripheral tolerance, whereby secreted cytokines can prevent them from becoming a bulk population of cells which will drive autoimmunity
What are the mechanisms thought to be involved in the breakdown of Tolerance?
Mechanisms thought to be involved in the breakdown of Tolerance;
- Failure to delete autoreactive lymphocytes (T cells)
- Central or peripheral tolerance failure
- Molecular mimicry (Seen in glandular fever - immune response mead but its the immune response pathway that causes the problem)
- Abnormal presentation of self antigens
- Aberrant expression of HLA class II molecules
- Release of sequestered self antigens (e.g eye keeps away but damage release self antigens)
- Overproduction of self antigens
What happens in Rheumatic Fever?
Rheumatic Fever - a classic example of molecular mimicry (Classic presentation of heart valve damage)
- Group A streptococcus infection, typically in throat
- Antibodies generated against Strep carbohydrate G1cNAc
- These antibodies cross react on cardiac myosin (Antibodies start to cause damage to heart valve)
- T cells also produced
- Heart valve damage, but also brain/neuronal damage possible
Antibodies don’t only bind to pathogen, also a part of your body !
What happens in Systemic Lupus Erythematosus (SLE)?
Systemic Lupus Erythematosus (SLE);
- Most common in females
Symptoms;
- Butterfly rash
- Raised red patches on skin
- Light sensitivity
- Mouth ulcers
- Heart/lung lining inflammation
- Seizures/nerve problems
- Proteinuria
- ANA - Antinuclear antibodies (Can test for these in blood stream) - Bind onto DNA
Treatments;
- Systemic corticosteroids
- Steroid creams
- Antimalarials (hydroxychloroquine)
- Monoclonal antibodies (rituximab) - Recognises CD20 which is on B cells to deplete B cells and stop producing antibodies
What happens in Sjogren’s Syndrome?
Sjogren’s Syndrome;
- More common in females
- Mulitorgan problems
Treatment;
- Eye drops
- Antifungals
- NSAIDS
- Antimalarials (hydroxychloroquine)
- Methotrexate
Be aware - x5 increased risk of non-Hodgkin lymphoma in these patients;
- Swollen glands
- Night sweats
- Unexplained weight loss
Need to be monitored for this occasionally
What are the features of Graves Disease?
Autoimmune condition of Thyroid
Graves;
- Overstimulation of thyroid
- Antibodies generated against TSH receptor which mimics TSH producing more thyroid hormones (no feedback as antibodies)
Treatment;
- Radioactive iodine (1st line)
- Methimazole (antithyroids - Carbimazole)
- Thyroidectomy
What are the features of Hashimoto’s thyroiditis ?
Autoimmune condition of Thyroid
Hashimoto’s;
- Autoimmune hypothyroidism
- Antibodies bind to thyroglobulin and thyroid peroxidase
- Fatigue, feeling cold, TSH increase, weight gain, enlarged thyroid
Treatment:
- Replacement therapy (Levothyroxine)
What are the features of Myasthenia Graves ?
Myasthenia Graves;
- Antibodies to acetylcholine receptors
- Long term neuromuscular problems
- Double vision (diplopia), drooping eyelids (ptosis) and other face muscles
- Skeletal muscle weakness, esp after exercise
Treatment;
- Thymectomy
- Immunosuppressive drugs
- Plasmapheresis drugs
- Plasmapheresis to remove circulating antibodies
What are the features of Multiple Sclerosis (MS)?
Multiple Sclerosis (MS);
- CD4 and CD8 Cytotoxic T cells that recognise and attack CNS (Can generate antibodies as well)
- Damage to myelin sheath surrounding nerves
Treatment;
- Steroids
- Muscle relaxant for spasm
- Stem cell transplant / bone marrow - high risk tho
Stem cells/bone marrow (deplete patient of own stem cells and give new bone marrow) - hard in MS as its a chronic remitting disease so do you do early when fit and healthy of leave it until later when the disease has taken a significant toll and are weaker and this will take a toll on their body
What happens in the body in Rheumatoid arthritis ?
Mainly characterised by inflammation off lining or synovial, of the joints (classic exam question ;))
What joints are affected by Rheumatoid Arthritis ?
Joints affected by Rheumatoid Arthritis;
Foot and Ankle, Knee - Effusions and synovial thickening of knee usually are detected easily
Hip - Involvement is common in RA, but early manifestations are not apparent
Hands and Wrists - Affected in virtually all people with RA
Elbow - Effusion difficult to detect on physical exam. Only objective finding is loss of motion.
Shoulders: Neck stiffness and general loss of motion
What are the features of Coeliac’ disease?
Coeliac’ disease;
- Gut condition where small intestines become inflamed
- Diarrhoea, abdominal pain, bloating (complications include
osteoporosis, iron-, vitamin B 12-, folate-deficiency anaemia, bowel cancer - increased risk)
- Incidence around 1 in 100 in UK
- 2-3 x higher in females
- Onset within first year (diagnosis may take longer). Adulthood 40-60 years..
- Driven by autoimmune reaction to gluten (wheat, barley, rye)
- No cure — gluten free diet (first degree relatives should also be tested)
- HLA class II link - DQ 2.5 (most common), DQ8 and DQ2.2 (less
common)
What happens molecularly behind coeliacs disease?
Main target is - Alpha-Gliadin molecule
- Its a highly abnormal for protein having so many glutamine in its structure
- Antibodies and T cells recognise and targets the 33-mer peptide binding at the G12 site and drives forwards coeliacs disease
Don’t really need to know this bit downwards;
- Gluten crosses into gut and is modified by tissue transglutaminase and it deaminates the gluten and changes from one peptide to another
- These peptides bind stronger with higher affinity making more likely to activate some T cells, can become TH1 cells - proinflammatory releases cytokines cause damage to gut lining and cause symptoms of coeliacs
Remove gluten from diet nothing to drive forwards T cells
