Autoimmune diseases(that you need to know for year 1)

• Immunological Tolerance:Unresponsiveness of the immune system to an antigen

(Not only self-antigens, but also foetus, gut flora, plant pollens etc.)

• Antigen:Substance capable of generating an immune response

Definitions:

Immunological tolerance- How does it occur?

• Central tolerance: Targets immature lymphocytes that recognise self-antigens

Develops in thymus (T) & bone marrow (B)

1) “clonal deletion” (by apoptosis)2) “clonal anergy” (inactivated by regulatory T lymphocytes)

• Peripheral tolerance: Targets mature lymphocytes that recognise self or benign antigens

1) “clonal suppression” supressed by other T and B cells Active throughout life

Autoimmunity

1) An immune response to self antigens

2) Due to a failure of immunological tolerance

3) Usually due to a combination of genetic & environmental factors

4) Leading to immune-mediated damage to specific tissues

Definitions:

Autoimmunity- How can it occur ?

Loss of immunological tolerance usually due to a combination of genetic & environmental issues

Genetic:Twin studies identified that genetic issues are involved in the loss of immunological tolerance

What is the gene type that has been implicated? MHC (HLA) genesGive some examples? • HLA-B27 : ankylosing spondylitis, reactive arthritis• HLA-DR2 : systemic lupus erythematosus (SLE)• HLA-DR3 : autoimmune hepatitis, Sjögren’s syndrome, T1DM, SLE• HLA-DR4 : rheumatoid arthritis, Type 1 diabetes mellitus (T1DM)

MHC class I and II Proteins

What is the chromosome number that codes for MHC's? 6

MHC class I- HLA-A + HLA-B + HLA-CExpressed on all nucleated cells

Their function is to display fragments of proteins from within the cell to T cells. Healthy cells will be ignored, while cells containing foreign proteins will be attacked by the immune system.

Alternatively if MHC I is missing or foreign, NK cells destroy the cell.

MHC Class II- HLA-DP + HLA-DQ + HLA-DRExpressed by APC cells

Macrophages, B lymphocytes, dendritic cells and Langerhans cells in skin.Present foreign antigens to Immune system to stimulate immune response

Environmental:Due to “molecular mimicry” of self antigensSequence similarities between foreign and self-peptides are sufficient to result in the activation of T or B cells.

  

Triggered by environmental causes. What are the 4 categories: TINCTrauma Infections : streptococcal infection, gastroenteritis , campylobacter Neoplasm Chemicals : antibiotics , Halothane

Autoimmunity- How can it occur ?

Explain how the following could lead to autoimmune disease:

(a)Streptococcal infection → Rheumatic fever (2 marks)

Streptococcal bacterium present protein on cell surface which mimic membrane proteins in heart/skin & connective tissue. Leading to immune-mediated damage to these tissues.An example of molecular mimicry

(b) Trauma to eye (2 marks)

Trauma causes antigens to be revealed which are normally sequestered from immune system. Body has NOT developed tolerance to these self-antigens, so autoantibodies react.

Diagnosis and treatment

Diagnosis:Diagnosis often confirmed by identifying specific auto-antibodies.May also be diagnosed by HLA-typing (eg. HLA-B27)

Treatment:1) Steroids : anti-inflammatory & immunosuppressive

2) Disease modifying drugs : anti-inflammatory & immunosuppressive

3) Monoclonal antibodies :More specific actionsInfliximab = anti-TNF cytokine used in RA, Crohn’s, ank. spond. Rituximab = anti-CD20 on B lymphocytes used in leukaemia, rejection, RA, SLE etc.

What do you need to know?

• Grave’s disease

• Rheumatoid arthritis

• SLE (Systemic lupus erythematous)

• Sjögren’s syndrome

Grave’s disease

• Commonest form of thyrotoxicosis

• Stupidly common (both in Nuneaton and in exams)

• Heavy familial link; Female > Male

• Signs and symptoms:• Increased BMR

• Tachycardia, Tachypnoea, weight loss, sweating, tremor, heat intolerance, hair thinning

• Goitre (Can lead to horner’s syndrome)

• Exopthalmus

Scary pictures of Grave’s

Pathophysiology (what’s actually happening?)

• TSI (auto-immune antibody) stimulates thyroid gland by binding to TSH receptor

• Induces T3 and T4 production

• This leads to –ive feedback onto pituitaryand hypothalamus to reduce TSH

• TSH is reduced as a result but TSI will stillkeep churning out T3 and T4.

• Result Increased T3 and T4. Low TSH

Investigations and Treatment

• Investigations:• T3 and T4

• TSH

• Anti-TSH receptor antibody (TSI)

• Biopsy

• Treatment:• Beta-blocker

• Anti-thyroid drugs (carbimazole. Prevents thyroid peroxidase from coupling and iodinating the tyrosin resides on thyroglobulin. i.e. less T3 and T4)

• Thyroidectomy

BOLLOCKS!

Systemic Lupus Erythematous (SLE)

• Seriously rare (But there is one in UHCW right now)

• Butterfly rash!

• Associated with Anti-phospholipid syndrome• Blah blah blah.

• Activates system of coagulation thrombosis and PVD (peripheral vascular disease)

• Recurrent miscarriage

• Blah blah blah

Investigations and Treatment

• Investigations:• Lower Hb, WCC and platelets, Raised ESR, Raised CRP

• ANA

• dsDNA

• Anti-phospholipid antibodies

• Treament:

• Steroids

• NSAIDs

• DMDs

• mAbs

• You will learn DMDs and mAbs in more detail later in block 4 with RA treatments

Sjorgen’s Syndrome (Sicca syndrome)

• Rare; Women > Men;

• Affects the mucus-secreting tissues

• Can be Primary or Secondary• Primary: Idiopathic w/o another AI disease. Associated with anti-Ro

and anti-La

• Seondary: Secondary to another AI disease

•

Investigations and Treatments

• Investigations:• Test the mucus secreting glands (tear glands, salivary glands etc)

• Saliva flow test (Salivary); Schirmer’s test (tear glands)

• USS of salivary glands

• Biopsy

• Treatment:• Artificial tears/saliva

• Autoantibody (Anti-La)

• DMDs

Autoimmunity

Quiz

Question 4a Name the following signs of autoimmune conditionsA B C

1 mark 1 mark 3 marks

i

ii

iii

Autoimmunity Quiz

Question 4b Identify the likely autoimmune condition from the signA B C

1 mark 1 mark 1 mark

Autoimmunity Quiz

Question 4c Identify an autoantibody raised in this condition

A B C

1 mark 1 mark 1 mark

Question 4 : Answers

A B C

Sign: Exopthalmos Disease: Grave’s Disease AA: TSHR autoantibodies

Sign: Butterfly rash (note nasolabial groove sparing)

Disease: Systemic Lupus Erythematosus AA: ANA e.g. anti-dsDNA,anti-cardiolipin

Signs: (i) Boutonnière deformity(ii) Ulnar deviation of MCP(iii) Swan-neck deformityDisease: Rheumatoid arthritisAA: RhF, anti-CCP

A ‘fun’ list

Autoimmune condition

Rheumatoid arthritis

Systemic Lupus Erythematosus

Sjögren’s / Sicca syndrome

Myasthenia Gravis

Grave’s Disease

Hashimoto’s thyroiditis

Coeliac Disease

Elevated antibodies

RhF (rheumatoid factor), anti-CCP (anti cyclic citrullinated protein)

ANA (anti-nuclear antibody) e.g. anti-dsDNA (anti double-stranded DNA),

anti-cardiolipin

RhF, ANA e.g. anti-Ro, anti-La

nAChR (nicotinic acetylcholine receptor)

antibodies

TSHR (thyroid stimulating hormone

recepetor) antibodies

Anti-thyroid perioxidase

Antigliadin

N.B. I’ve used acronyms: remember in an exam WRITE EVERYTHING OUT IN FULL!

Question 5Describe the joint position of a finger in: (a)Swan neck deformity(b) Boutonnière deformity

Question 6a A patient with Rheumatoid arthritis presents with:- Dry mouth- Scratchy, dry eyes- RashesSjögren’s Syndrome / Sicca Syndrome

Bonus Marks

List TWO diagnostic tests

• Schirmer’s test • Slit lamp examination • Saliva flow test• Autoantibodies (anti-La = most specific)• Ultrasound of salivary glands (hypoechoic lesions & loss

of tissue)• Biopsy of lip or salivary gland (lymphocytic infiltration

tissue damage & loss)

Which secondary autoimmune condition should be suspected?

XerostomiaXerophthalmia

N.B. Sjorgren’s / Sicca can also present on its own, i.e. as a primary condition

N.B. Be able to describe these (just a sentence)

Medical terms

Autoimmunity Quiz

Question 6bSicca / Sjögren’s Syndrome:State THREE treatments/management

CONSERVATIVE

MEDICAL

SURGICAL

Artificial tears, regular sips of fluid, artificial saliva, (awareness of lymphoma risk)

DMDs: Topical cyclosporin

Lacrimal plugs

Autoimmunity Quiz

Question 7Grave’s Disease:State THREE treatments/management

CONSERVATIVE

MEDICAL

SURGICAL

N/A

1. Thioamides: Carbimazole or propylthiouracil (inhibt thyroid peroxidase enzyme required to convert iodine → thyroid hormone)

2. Radioiodine

Partial or total thyroidectomy

Autoimmunity Quiz

Clarifications

Exopthalmos = “appearance of protruding eyes” caused by proptosis (eye protrudes beyond orbit) and lid retraction

Thyrotoxicosis = excess thyroid hormone

Usually due to hyperthyroidism

Most common cause is Grave’s disease