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Immunological mechanism of Rheumatoid Arthritis

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L7 Immunology

05. Autoimmunity Tutorial

Dr Siobhan Darrington

Today we will examine…

  • Essay style question
  • Case Study

Section A

Critically evaluate the use of Lymphocyte therapies in the treatment of Autoimmune diseases.                              

(50 marks)

Section B

Case study

A 45 year old female smoker was referred to the clinic by her GP. She suffered from transient joint inflammation, joint stiffness in left knee, shoulder, hand and wrist. Blood tests were normal for: U&E’s (Urea and electrolytes), Liver Function Test, Thyroid Function Test. Antinuclear antibody (ANA) & Antineutrophil Cytoplasmic Antibody (ANCA) were negative. Rheumatoid factor – 31 IU/ml (low level positive). Her mother has RA.

  1. Evaluate the patient history and provide a diagnosis for the patient. Provide reasons for your answer.                                                                                                    (15 marks)
  2. Explain the immunological mechanism of the disease. You may use diagram(s) to support your answer.                                                                                                    (15 marks)
  3. Suggest a treatment for the disease. Explain how the treatment will improve the disease outcome for the patient.                                                                                                    (5 marks)

1.     Critically evaluate the use of Lymphocyte therapies in the treatment of Autoimmune diseases.                                                                                                    (50 marks)

1.     Critically evaluate the use of Lymphocyte therapies in the treatment of Autoimmune diseases.                                                                                                    (50 marks)

Excellent!

 

  1. Critically evaluate the use of Lymphocyte therapies in the treatment of Autoimmune diseases.                                                                                                    (50 marks)

Question asks for a critical evaluation. Critique should be on the therapies and their efficacy in treating disease. Lots of treatment options to choose from (remember that the question is asking for lymphocyte therapies, so don’t include information on steroids, etc.). Question asks for Autoimmune diseases, i.e. more than one.

Could focus on two diseases and a couple of therapies.

An excellent answer (Distinction) will

  • Introduce lymphocyte therapies/targets
    • Antibodies targeting B-cells (explain).
      • CD-20 targeting (explain mechanism)
        • RRMS. Describe mechanism
          • Ocrelizumab (humanised anti-CD20 antibody), well-tolerated, adverse effects nasopharyngitis, upper respiratory tract, urinary tract infections)
          • Rituximab (chimeric monoclonal antibody, so may have some antibody cross-reaction side effects), well tolerated, side effects infections)
          • Include details of studies to support which is superior
  • CAR Tregs
    • SLE. Describe mechanism
    • Explain what they are
    • Different types
    • Design (basic design (antigen recognition domain, Antigen binding domain containing a single chain variable fragment (ScFv),, Spacer (hinge) region, Transmembrane domain)
    • Five generations (could give examples of issues with these, could also use other autoimmune disease examples)
    • Example of successes (Mackensen paper – SLE)

Good!

A good answer (Merit) will

  • Introduce lymphocyte therapies/targets, but omit key details
    • Antibodies targeting B-cells (no or limited explanation).
      • CD-20 targeting (limited or mechanism with errors)
        • RRMS. Omit mechanism or key details of disease
          • Omits key details in the following:
          • Ocrelizumab (humanised anti-CD20 antibody), well- tolerated, adverse effects nasopharyngitis, upper respiratory tract, urinary tract infections)
          • Rituximab (chimeric monoclonal antibody, so may have some antibody cross-reaction side effects), well tolerated, side effects infections)
          • Does include details of studies to support which is superior, but with errors or limited
  • CAR Tregs

•       SLE. (Llimited mechanism or mechanism with errors)

  • Does not explain what they are, or with errorsDifferent typesDesign (basic design (antigen recognition domain, Antigen binding domain containing a single chain variable fragment (ScFv),, Spacer (hinge) region, Transmembrane domain)Does not include five generations (could give examples of issues with these, does not provide other autoimmune disease examples)Example of successes (Mackensen paper – SLE)

Average!

An average answer (pass) will

  • Does not Introduce lymphocyte therapies/targets
    • Antibodies targeting B-cells (no explanation).
      • CD-20 targeting (limited or mechanism with errors)
        • RRMS. Omits mechanism or limited explanation
          • Provides details of only one example, with errors:
          • Ocrelizumab (humanised anti-CD20 antibody), well- tolerated, adverse effects nasopharyngitis, upper respiratory tract, urinary tract infections)
          • Rituximab (chimeric monoclonal antibody, so may have some antibody cross-reaction side effects), well tolerated, side effects infections)
          • Does include details of studies to support which is superior, but with errors or limited

STOPS HERE! Or….

  • CAR Tregs

•       SLE. (Llimited mechanism or mechanism with errors)

  • Does not explain what they are
    • Different types not included
    • Design not included or with errors. (basic design (antigen recognition domain, Antigen binding domain containing a single chain variable fragment (ScFv),, Spacer (hinge) region, Transmembrane domain)
    • Does not include five generations (could give examples of issues with these, does not provide other autoimmune disease examples)
    • No example of successes (Mackensen paper – SLE)

Case Study

A 45 year old female smoker was referred to the clinic by her GP. She suffered from transient joint inflammation, joint stiffness in left knee, shoulder, hand and wrist. Blood tests were normal for: U&E’s (Urea and electrolytes), Liver Function Test, Thyroid Function Test. Antinuclear antibody (ANA) & Antineutrophil Cytoplasmic Antibody (ANCA) were negative. Rheumatoid factor – 31 IU/ml (low level positive). Her mother has RA.

  1. Evaluate the patient history and provide a diagnosis for the patient. Provide reasons for your answer.

(15 marks)

  1. Female patient, 45 years old, possibly post-menopausal. Suffering from transient joint inflammation in joints. Blood tests were recorded as normal for U&E’s, liver function, thyroid function. ANA and ANCA negative. Most likely Rheumatoid Arthritis (RA) due to the fact that patient is RF positive. Risk factors: RA has a strong link to females, family history (supported by fact that mother has RA could mention HLAB27), strong link to smoking.
  • Explain the immunological mechanism of the disease. You may use diagram(s) to support your answer.                                               (15 marks)
  • Type III Hypersensitivity also autoimmune disease, Excess of antigen over a protracted period. APC’s interact with CD4+ cells, cytokine release, activates B cells to produce IgG. Antibody plus antigen forms insoluble complex give rise to acute inflammatory reactions. Complement fixation releases C3a and C5a. Mast cell mediator release. Phagocytes attracted attempt to phagocytose immune complexes. Results in extracellular polymorphonucleocytes release of granular contents and damage to local tissues.

See next slide for figure.

Immunological mechanism of Rheumatoid Arthritis

OPG:

osteoprotegerin RANKL: receptor activator of

NF-κB ligand Tph: peripheral T cells

Tf: Follicular T cells

Rick factors:

  • HLA status (HLA-DRB1)
  • Gender
  • Lifestyle
  • Suggest a treatment for the disease. Explain how the treatment will affect the disease of the patient.                                                                                                    (5 marks)

3.   Cytokine targeting antibody (e.g. Infliximab targeting TNF-a). Blocks TNF-a released from macrophages and neutrophils preventing activation of macrophages releasing RANKL

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