07-11-23 – Immunology - the immune response, auto-immunity, white blood cells

Question 1

Learning outcomes

Answer 1

• Describe the main features of the autoimmune disease Rheumatoid Arthritis, and how is is usually treated.
• Describe the common sites/organs affected by autoimmune conditions
• Describe the main ways in which tolerance to self antigens is thought to be lost
• Describe the main features of common autoimmune diseases

Question 2

What are the 3 different types of Disorders of the Immune system?

Answer 2

• 3 different types of Disorders of the Immune system:
  1) Immunodeficiency – too little
  2) Hypersensitivity – too much
  3) Autoimmunity – misdirected

Question 3

How many autoimmune diseases are there?

What factors contribute to autoimmune diseases?

What is the prevalence of autoimmune diseases in western populations?

What sex is the prevalence of autoimmune diseases greater in?

Answer 3

• There are around 80 chronic inflammatory (autoimmune) conditions
• Genetic predisposition and environmental modulators/ triggers contribute to autoimmune diseases
• 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

Question 4

Do single gene mutations lead to autoimmune diseases?

What are 2 examples where that a single gene mutation leads to a single autoimmune disease?

Answer 4

• The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION, not the rule
• Autoimmune disease are complex, interplay between multiple genes, and external factors
• 2 examples where that a single gene mutation leads to a single autoimmune disease:

1) Autoimmune polyglandular syndrome type 1 (APS-1)
* AIRE gene – low expression of some self-antigens in thymus – some autoreactive T cells not deleted.

2) Autoimmune lymphoproliferative syndrome (ALPS)
* FAS, FASL genes – failure of apoptosis of some self-reactive T and B cells.

Question 5

What are 12 examples of Organs commonly affected by autoimmune conditions?

Answer 5

1) Autoimmune uveitis –eyes

2) Sjogrens syndrome – mouth

3) Rheumatic fever –heart and others

4) Autoimmune hepatitis – liver

5) Autoimmune oophoritis –ovaries

6) Rheumatoid arthritis – joints

7) MS – nerves

8) Pemphigus –skin and muscosa

9) Goodpasture’s – lung

10) Diabetes – pancreas

11) Ulcerative Colitis – large intestine

12) Autoimmune hemolytic anemia – blood

Question 6

What is tolerance?

Describe deletional and regulatory tolerance.

Answer 6

• Tolerance is the process that keeps the immune system from attacking “self”

1) Regulatory tolerance (dominant)
* T cell specific for self-antigen becomes a regulatory T cell (Treg)
* Cytokines (IL-10 and TGF-B produced by Treg inhibit other self-reactive T cells

2) Deletional tolerance (recessive)
* Self-reactive T cells are deleted in the thymus
* Occasionally, Self-reactive T cells may escape deletion
* In the periphery, such escaped self-reactive T cells can cause tissue damage

Question 7

What are 9 mechanisms thought to be involved in breakdown of tolerance?

Answer 7

• 9 mechanisms thought to be involved in breakdown of tolerance:
  1) Failure to delete autoreactive lymphocytes
  2) Central or peripheral tolerance failure
  3) Molecular mimicry
  4) Abnormal presentation of self antigens
  5) Aberrant expression of HLA class II molecules
  6) Release of sequestered self antigens
  7) Overproduction of self antigens
  8) Cyptic T cell epitopes
  9) Epitope spreading

Question 8

What is rheumatic fever an example of?

What bacteria causes it?

Describe the mechanism behind rheumatic fever.

What damage does rheumatic fever lead to?

Answer 8

• Rheumatic fever is a classic example of molecular mimicry
• Caused by Group A Streptococcus infection, typically in throat
• Mechanism behind rheumatic fever:
• Antibodies generated against Strep carbohydrate GlcNAc
• These antibodies cross react on cardiac myosin
• T cells also produced
• Rheumatic fever leads to heart valve damage, but also brain/neuronal damage possible

Question 9

What is SLE?

What structures does it affect?

What are 8 signs/symptoms of SLE?

What are 4 treatments for SLE?

Answer 9

• Systemic lupus erythematosus (SLE), is the most common type of lupus.
• SLE is an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs.
• It can affect the joints, skin, brain, lungs, kidneys, and blood vessels.
• 8 signs/symptoms of SLE:
  1) Butterfly rash
  2) Raised red patches on skin
  3) Light sensitivity
  4) Mouth ulcers
  5) Heart/lung lining inflammation
  6) Seizures/nerves problems
  7) Proteinuria
  8) ANA - antinuclear antibodies
• 4 treatments for SLE:
  1) systemic corticosteroids
  2) Steroid creams
  3) Antimalarials (hydroxychloroquine)
  4) Monoclonal antibodies (rituximab)

Question 10

What is Sjogren’s syndrome?

What are the 8 symptoms/signs of Sjogren’s syndrome?

What are 4 treatments for Sjogren’s syndrome?

What is there an increased risk of in those with Sjogren’s syndrome?

Answer 10

• Sjögren’s syndrome, also known as Sjögren’s and Sjögren’s disease, is a chronic (long-lasting) autoimmune disorder that happens when the immune system attacks the glands that make moisture in the eyes, mouth, and other parts of the body.
• 8 Symptoms/signs of Sjogren’s syndrome:
  1) Dry eyes
  2) Dry mouth (dry eyes and dry mouth are the main ones)
  3) Dry skin
  4) Tiredness
  5) Vaginal dryness
  6) Muscle or joint pain
  7) Swelling between the jaw and ears (swollen salivary glands)
  8) Rashes (especially after being in the sun)
• 4 treatments for Sjogren’s syndrome:
  1) Eye drops
  2) Antifungals
  3) NSAIDS
  4) Hydroxychloroquine methotrexate
• Be aware – 5x increased risk of non-Hodgkin lymphoma in these patients – swollen glands night sweats, unexplained weight loss)

Question 11

What are 2 autoimmune conditions of the thyroid?

Answer 11

• 2 autoimmune conditions of the thyroid:
  1) Graves’ disease
  2) Hashimoto’s thyroiditis

Question 12

What causes Graves’ disease?

What are 3 treatment option for Graves’ disease?

Answer 12

• Graves’ disease is caused by overstimulation of the thyroid due to Antibodies being generated against TSH receptors which mimics TSH
• 3 treatment option for Graves’ disease:
  1) Radioactive Iodine
  2) Methimazole
  3) Thyroidectomy

Question 13

What does Hashimoto’s thyroiditis cause?

What is the mechanism behind Hashimoto’s?

What are 5 signs/symptoms of Hashimoto’s thyroiditis?

How is it treated?

Answer 13

• Hashimoto’s thyroiditis causes autoimmune hypothyroidism
• In Hashimoto’s antibodies to thyroglobulin and thyroid peroxidase are produced
• 5 Signs/symptoms of Hashimoto’s thyroiditis:
  1) Fatigue
  2) Feeling cold
  3) TSH increase
  4) Weight gain
  5) Enlarged thyroid
• Treatment for Hashimoto’s is replacement therapy (levothyroxine)

Question 14

What is Autoimmune Pernicious Anemia?

What is it caused by?

What deficiency does this lead to?

What is the treatment for Autoimmune Pernicious Anemia?

Answer 14

• Autoimmune Pernicious Anemia is an Autoimmune condition affecting stomach
• Antibodies are generated to intrinsic factor,and parietal cells
• Deficiency in vitamin B12 results as no binding to intrinsic factor and absorption
• Treatment for Autoimmune Pernicious Anemia is – vitamin B12 injections

Question 14

What is Myasthenia Gravis caused by?

What does this lead to?

What are 3 signs/symptoms of Myasthenia Gravis?

What are 3 treatments for Myasthenia Gravis?

Answer 14

• Myasthenia Gravis is caused by the production of antibodies against acetylcholine receptors
• This leads to long-term neuromuscular problems
• 3 signs/symptoms of Myasthenia Gravis:
  1) Double vision (diplopia)
  2) Drooping eyelids (ptosis) and other face muscles
  3) Skeletal muscle weakness, especially after exercise
• 3 treatments for Myasthenia Gravis?
  1) Thymectomy
  2) Immunosuppressive drugs
  3) Plasmapheresis to remove circulating antibodies

Question 15

What causes Autoimmune hemolytic anemia?

What does this lead to?

What is Autoimmune hemolytic anemia induced by?

What are 6 symptoms/signs of Autoimmune hemolytic anemia?

What are 3 treatments for Autoimmune hemolytic anemia?

Answer 15

• Autoimmune hemolytic anemia is caused by Antibodies binding to RBC
• This leads to lysis, clumping, and clearance by spleen
• Autoimmune hemolytic anemia is Induced by drug or agent modifying RBC cell surface, leading to a neo-antigen (foreign protein absent in normal tissues) being created.
• 6 symptoms/signs of Autoimmune hemolytic anemia:
  1) Chills
  2) Tachycardia
  3) Pale
  4) Fatigue
  5) Dark urine
  6) Jaundice
• 3 treatments for Autoimmune hemolytic anemia:
  1) Avoid activating drug
  2) Plasmapheresis
  3) Splenectomy

Question 16

What causes Multiple Sclerosis (MS)?

What are 8 signs/symptoms of MS?

What are 3 treatments for MS?

Answer 16

• Multiple Sclerosis (MS) is caused by CD4 and CD8 T cells that recognise and attack CNS, causing Damage to myelin sheath surrounding nerves
• 8 signs/symptoms of MS:
  1) Fatigue
  2) Difficulty walking
  3) Vision problems, such as blurred vision
  4) Problems controlling the bladder
  5) Numbness or tingling in different parts of the body
  6) Muscle stiffness and spasms
  7) Problems with balance and co-ordination
  8) Problems with thinking, learning and planning
• 3 treatments for MS:
  1) Steroids
  2) Muscle relaxant for spasm
  3) Stem cell transplant

Question 17

What is Rheumatoid Arthritis (RA)?

How many people does it affect in the UK?

What is it mainly characterized by?

What long-term problems can it lead to?

Answer 17

• Rheumatoid Arthritis (RA) is chronic, systemic autoimmune disease that affects over 350,000 people in UK
• It is mainly characterized by inflammation of the lining, or synovium, of the joints.
• RA may lead to long-term joint damage, which would result in chronic pain, loss of function, and disability

Question 18

What sex is RA more common in?

What is the most common age of onset?

What ethnic groups does it occur in?

Answer 18

• RA is 3 times more common in women than in men
• Commonly strikes between the ages of 30 and 50, but can also affect young children
• Occurs in all ethnic groups and in all parts of the world, ie not linked to ‘damp climate’

Question 19

Describe the Joints Affected by RA.

Which ones are affected in virtually all people with RA?

Answer 19

• Joints Affected by RA:

1) Foot and Ankle, Knee
* Effusions and synovial thickening of the knee usually are detected easily.

2) Hip
* involvement is common in RA, but early manifestations are not apparent.

3) Hands and wrists
* Affected in virtually all people with RA

4) Elbow
* Effusion difficult to detect on physical exam. Only objective finding is loss of motion.

5) Shoulders
* Neck stiffness and general loss of motion

Question 20

Describe how the following organs are affected by RA:
1) Blood
2) Nerves
3) Heart
4) Lungs
5) Eyes Skin

Answer 20

• How the following organs are affected by RA:

1) Blood (tissue not organ)
* Hypochromatic-microcytic anemia with low serum ferritin and low or normal iron-binding capacity almost universal in patients with active RA.

2) Nerves
* Results from cervical spine instability, peripheral nerve entrapment, and vasculitis resulting in mononeuritis multiplex.

3) Heart
* Pericardial effusion present in almost 50% of patients, but clinical symptoms are rare.

4) Lungs
* Interstitial lung disease common, but may be asymptomatic
* An umbrella term used for a large group of diseases that cause scarring (fibrosis) of the lungs

5) Eyes
* Keratoconjunctivitis sicca
* Episcleritis
* Scleritis

6) Skin
* Rheumatoid nodules in 50% of RA patients; dermal vasculitic lesions

Question 21

Which genes have an association with RA?

Which one is responsible for two-thirds of Caucasians with RA?

Where does it reside?

How can the risk of increased severity of disease by increased?

What are 3 potential roles of HLA-DR genes?

Answer 21

• Specific human leukocyte antigen (HLA)-DR genes have been found to be associated with RA
• HLA-DR4 is responsible for two-thirds of Caucasians with RA
• It resides in the MHC (Major histocompatibility complex) and participates in antigen presentation
• Higher risk of severity of disease is increased by homozygosity
• 3 potential roles of HLA-DR genes:
  1) Binds to arthritogenic peptides
  2) Serves as a target for autoreactive T cells
  3) Closely linked to other genes in the MHC

Question 22

What is the definite test for RA?

What are 3 parts used in the diagnosis of RA?

What 3 blood tests are used for RA diagnosis?

Answer 22

• No definite test for RA diagnosis
• 3 parts used in the diagnosis of RA:

1) Medical history
* –i.e. do you have joint pain in many joints? symmetrical pain?

2) Physical examination
* Look for common features reported in RA

3) Lab tests
* Imaging studies – Erythrocyte Sedimentation Rate (ESR)
* Blood tests – C-reactive Protein (CRP)
* Rheumatoid factor – Antinuclear Antibodies (ANA)

Question 23

What are 3 sources of information that allows RA treatment to be tailored to individuals?

What are 4 focuses of RA treatment?

Answer 23

• 3 sources of information that allows RA treatment to be tailored to individuals:
  1) Severity of arthritis
  2) Other medical conditions
  3) Lifestyle
• 4 focuses of RA treatment:
  1) Relieving pain
  2) Reducing inflammation
  3) Stopping or slowing joint damage
  4) Improving functioning and sense of well-being

Question 24

What are 3 types of symptomatic medications used in RA?

What are 6 disease modifying drugs used for RA?

What are 2 drugs used as biological modifiers in RA?

Answer 24

• 3 types of symptomatic medications used in RA:
  1) Nonsteroidal anti-inflammatory drugs (NSAIDs)
  2) Analgesics
  3) Corticosteroids
• 6 disease modifying drugs used for RA:
  1) Methotrexate
  2) Sulfasalazine
  3) Azathioprine
  4) Cyclosporine
  5) Hydroxychloroquine
  6) Minocycline
• Combination DMARD Therapy (Disease-modifying anti-rheumatic drugs) may be used with the above drugs
• Drugs used as biological modifiers in RA:
  1) Infliximab (anti-TNF)
  2) Rituximab (anti-CD20)

Question 25

What is coeliac disease?

What is it driven by?

What is the incidence of coeliac disease in the UK?

What groups is it higher in?

What is the typical onset of coeliac disease?

What are 3 signs/symptoms of coeliac disease?

What are 4 complications of coeliac disease?

What are the genetic links for coeliac disease?

Answer 25

• Coeliac disease is a gut condition where small intestines become inflamed
• It is driven by autoimmune reaction to gluten (wheat, barley, rye)
• Incidence around 1 in 100 in UK. 2-3 x higher in females.
• In children, the onset is often within the first year (diagnosis may take long)
• The onset in adulthood is often between 40-60 years
• 3 signs/symptoms of coeliac disease:
  1) Diarrhoea
  2) Abdominal pain
  3) Bloating
• 4 Complications of coeliac disease:
  1) Osteoporosis
  2) Iron, vitamin B12-, folate-deficiency
  3) Anaemia
  4) Bowel cancer
• Coeliac disease has a genetic link to HLA-DQ genes (Human leukocyte antigen), which code for HLA class 2 molecules
• DQ 2.5 (most common), DQ8 and DQ2.2 (less common)

Question 26

Coeliac disease diagram

Answer 26

Question 27

Coeliac disease diagram

Answer 27