Lecture 10: Autoimmune Disease: Diabetes and SLE

Question 1

Recall the overview of immunological tolerance.

Answer 1

Question 2

Tolerance induced during _________.

Answer 2

early life

Question 3

Why is tolerance important?

Answer 3

• Specificity of the adaptive immune system is critical
• Tolerance arises as a result of the processes that drive both T and B cell diversity during lymphocyte development
• Self-reactivity can occur and result in host damage

Note: Immune system is in balance between immunity and tolerance.

Question 4

Recall the overview of T cell tolerance mechanisms.

Answer 4

• Central tolerance
  
  • occurs in the thymus
  • positive/negative selection of immature T cells
• Peripheral tolerance
  
  • occurs in peripheral tissues
  • ‘regulatory’ responses involving mature T cells

Question 5

Recall the overview of T cell selection in the thymus.

Answer 5

• occurs as T cell matures
• dependent on the affinity of TCR binding to self-antigen
  
  • high: T cells deleted
  • low: T cells deleted
  • intermediate: selected and enter the periphery

Question 6

Recall the overview of peripheral tolerance of T cells.

Answer 6

• self-reactive T cells that enter the circulation are regulated by peripheral tolerance
• Mechanisms include:
  
  • clonal anergy (lack of costimulation)
  • ignorance (do not encounter their antigen)
  • suppression by cytokines (TNF-beta)
  • specific regulation (T_reg induction)
  • negative regulation (engagement of CTLA4)

Question 7

Recall about B cell tolerance.

Answer 7

It occurs in the bone marrow. It requires T cell tolerance to be intact. Self-reactive B cells:

• Deleted when high affinity for the antigen
• Made anergic when the antigen is soluble and at high concentration
• Ignorance when lacking T cell help or low antigen concentration

Question 8

What is autoimmunity?

Answer 8

• Immune response against self-antigen
• Involve both self-reactive T and B cells
• Presence of autoreactive lymphocytes does not necessarily result in autoimmunity
  
  • naturally occurring autoantibodies

Question 9

What happens when tolerance fails?

Answer 9

Autoimmune disease can occur when mechanisms of immunological tolerance break down. It can be caused by:

• ​Acquisition of T cell help
• Molecular mimicry
• Failure of regulatory networks

Question 10

Recall the pathogenesis of autoimmunity.

Answer 10

Question 11

Recall the concept of molecular mimicry in autoimmunity.

Answer 11

It refers to similar/identical epitopes between microbe and host. It is important when host antigen has an important biological function. e.g. Streptococcal protein and bacterial endocarditis

Question 12

Recall the role of T_reg in autoimmunity.

Answer 12

Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells.

Question 13

What are Milgrom and Witebsky’s criteria for autoimmune diseases,

Answer 13

Question 14

Recall the spectrum of autoimmune diseases.

Answer 14

Question 15

What are pathogenic autoantibodies? How are they classified?

Answer 15

Question 16

Recall the autoantibody patterns of non-organ specific autoimmune diseases.

Answer 16

Question 17

Recall the autoantibody patterns of the characteristic of organ-specific autoimmune diseases.

Answer 17

Question 18

What is diabetes?

Answer 18

• Group of diseases affecting insulin production and/or function
• Organ-specific autoimmune disease (Type I)
• Targets the islets of Langerhans cells of the pancreas
  
  • important for insulin secretion
• Secondary damage to kidneys, eyes, nerves, blood vessels
• Onset from first year of life to older adulthood

Question 19

Recall the types of diabetes

Answer 19

Question 20

Recall the diagram in regards to Type 1 and 2 diabetes.

Answer 20

Question 21

What is LADA?

Answer 21

Latent Autoimmune Diabetes in Adults (LADA) is a form of autoimmune diabetes which is diagnosed in individuals who are older than the usual age of onset of type I diabetes. It also is known as “slow onset type I” diabetes or “type 1.5”. LADA patients often thought to have type 2 diabetes due to their age at diagnosis.

Question 22

Recall the features of LADA.

Answer 22

Question 23

Recall the pathogenesis of type 1 diabetes.

Answer 23

Question 24

Recall the pathological features of Type 1 diabetes.

Answer 24

Question 25

Recall the diagram in regards to islet cell pathology.

Answer 25

Question 26

Recall the immunological events in diabetes.

Answer 26

Question 27

Recall the autoantibodies in diabetes.

Answer 27

Major autoantibodies are reactive to 4 islet autoantigens (termed islet cell autoantibodies, ICA):

• Insulinoma-associated antigen-2 (ICA512)
• Insulin (micro-insulin autoantibodies, IAA)
• Glutamic acid decarboxylase 65 (GAD65)
• Zinc transporter 8 (ZnT8)

Note: these leads toa n important role of B cells in pathogenesis in diabetes type I

Question 28

Recall the summary of type I diabetes.

Answer 28

Question 29

What is systemic lupus erythematosus?

Answer 29

• Multi-system chronic autoimmune disease
  
  • remitting and relapsing
• Acute or insidious in onset
• Many organs affected
  
  • skin
  • kidney

Question 30

Recall the criteria for SLE classification.

Answer 30

Question 31

Recall the characteristics of typical non-organ specific autoantibodies.

Answer 31

Autoantibodies target diverse structures. It can be detected against:

• Nuclear antigens
• Cytoplasmic surfaces
• Cell-surface antigens

It is pathogenic in nature. Main diagnostic feature is the presence of anti-nuclear autoantibodies.

Question 32

What are anti-nuclear autoantibodies?

Answer 32

Antibodies to Sm antigen and dsDNA are diagnostic of SLE. Others include:

• anti-lymphocyte
• anti-platelet
• anti-phospholipid

Question 33

Recall the anti-nuclear autoantibody patterns.

Answer 33

Question 34

Recall the pathogenesis of SLE.

Answer 34

Type III Hypersensitivity Disease

Type III hypersensitivity occurs when there is accumulation of immune complexes (antigen-antibody complexes) that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes.

Question 35

Recall the pathological mechanism of SLE.

Answer 35

Question 36

What is Type III Hypersensitivity?

Answer 36

Question 37

Recall the hallmark lesions in SLE.

Answer 37

Question 38

Recall the clinical course in SLE.

Answer 38

• disease course can be variable
• 90% survival (5 years); 80% 10 years
• Most common cause of death is renal failure
• Treatment:
  
  • Corticosteroids
  • Immunosuppressants