Lecture 10: Autoimmune Disease: Diabetes and SLE Flashcards
Recall the overview of immunological tolerance.
Tolerance induced during _________.
early life
Why is tolerance important?
- 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.
Recall the overview of T cell tolerance mechanisms.
- 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
Recall the overview of T cell selection in the thymus.
- 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
Recall the overview of peripheral tolerance of T cells.
- 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 (Treg induction)
- negative regulation (engagement of CTLA4)
Recall about B cell tolerance.
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
What is autoimmunity?
- 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
What happens when tolerance fails?
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
Recall the pathogenesis of autoimmunity.
Recall the concept of molecular mimicry in autoimmunity.
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
Recall the role of Treg in autoimmunity.
Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells.
What are Milgrom and Witebsky’s criteria for autoimmune diseases,
Recall the spectrum of autoimmune diseases.
What are pathogenic autoantibodies? How are they classified?
Recall the autoantibody patterns of non-organ specific autoimmune diseases.
Recall the autoantibody patterns of the characteristic of organ-specific autoimmune diseases.
What is diabetes?
- 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
Recall the types of diabetes
Recall the diagram in regards to Type 1 and 2 diabetes.
What is LADA?
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.
Recall the features of LADA.
Recall the pathogenesis of type 1 diabetes.
Recall the pathological features of Type 1 diabetes.
Recall the diagram in regards to islet cell pathology.
Recall the immunological events in diabetes.
Recall the autoantibodies in diabetes.
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
Recall the summary of type I diabetes.
What is systemic lupus erythematosus?
- Multi-system chronic autoimmune disease
- remitting and relapsing
- Acute or insidious in onset
- Many organs affected
- skin
- kidney
Recall the criteria for SLE classification.
Recall the characteristics of typical non-organ specific autoantibodies.
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.
What are anti-nuclear autoantibodies?
Antibodies to Sm antigen and dsDNA are diagnostic of SLE. Others include:
- anti-lymphocyte
- anti-platelet
- anti-phospholipid
Recall the anti-nuclear autoantibody patterns.
Recall the pathogenesis of SLE.
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.
Recall the pathological mechanism of SLE.
What is Type III Hypersensitivity?
Recall the hallmark lesions in SLE.
Recall the clinical course in SLE.
- disease course can be variable
- 90% survival (5 years); 80% 10 years
- Most common cause of death is renal failure
- Treatment:
- Corticosteroids
- Immunosuppressants
