Tolerance and Autoimmunity Flashcards
Define autoimmunity
Adaptive immune responses with specificity for self “antigens” (autoantigens)
What are the criteria for disease to be ‘autoimmune’?
Evidence of disease-specific adaptive immune response in the affected target tissue, organ or blood
Passive transfer of autoreactive cells or antibodies replicates the disease
Elimination of the autoimmune response modifies disease
History of autoimmune disease (personal or family), and/or MHC associations
Give examples of genetic and environmental factors that contribute to autoimmune disease
Women more susceptible Inflammatory environments Obesity, high fat Stress Microbiome
Describe the epidemiology of autoimmune diseases
~5% of people in developed countries are affected by autoimmune disease.
~75% of these are female
The incidence of autoimmunity, like hypersensitivity/allergy, is increasing (via the hygeine hypothesis).
What are the major autoimmune diseases
Rheumatoid arthritis (RA)
Type I diabetes mellitus (T1DM)
Multiple sclerosis (MS)
Systemic lupus erythematosus (SLE / lupus)
Autoimmune thyroid diseases e.g. Hashimoto’s and Graves’ disease
Describe the mechanisms of autoimmune reactions
Autoimmune reactions use the same mechanisms as immune responses to pathogens.
This involves breaking T cell tolerance
As ‘self’ tissue is always present, autoimmune diseases are always chronic conditions.
The effector mechanisms resemble type II, III, and IV hypersensitivity.
Describe the role of autoantibodies in autoimmune diseases using an example
Autoantibodies (aAbs) and levels thereof have a direct link with autoimmune disease.
Autoantibodies to RBCs are responsible for haemolytic anaemia via clearance and also complement activation, which causes systemic effects beyond a lack of RBCs.
Type II and type III hypersensitivity pathways are both involved in this
Give examples of immune reactions that are known to play a direct role in the pathology of human autoimmune disease
Antibody response to cellular or extracellular matrix antigen (Type II)
Immune complex formed by antibody against soluble antigen (Type III)
T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV)
Give an example of a disease that is due to type II hypersensitivity and describe it
Graves’
Autoantibodies bind to the TSH receptor on thyroid follicular cells, causing hyperthyroidism
Give an example of a disease that is due to type IV hypersensitivity and describe it
T1DM
cell-mediated
T cells react to pancreatic beta-cell antigens and kill the cells
What is the role of MHC in antigen presentation
Antigens are presented to T cells by MHC expressed on the surface of antigen-presenting cells
What is the role of HLA/MHC
Dominant genetic factor affecting susceptibility to autoimmune disease.
Define immunological tolerance
Inability to respond to an antigenic stimulus
What are the criteria for immunological tolerance (3A)
Acquired: tolerance involves cells of the acquired/adaptive immune system and is ‘learned’
Antigen-specific
An active process in neonates, the learnings of which are maintained through life
Describe the selection of T cells in central tolerance
Immature T cells in the thymus recognise peptides presented on MHCs.
Those that can’t recognise any peptides die by apoptosis
Those that recognise ‘self’ strongly are actively signalled to die by apoptosis (-ve selection)
Those that see MHC weakly are signalled to survive.
What percentage of thymocytes survive selection
~5% of immature T cells
Describe the selection of B cells in central tolerance
Cross-linking of B cell surface immunoglobulins by polyvalent antigens on bone marrow stromal cells facilitates deletion versus survival
Give an example of a disease resulting from failure of central tolerance
APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy)
Describe APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy)
Rare
Results from the thymus failing to delete self- reactive T cells
Caused by genetic mutations in a transcription factor called AIRE (autoimmune regulator) which stop it working, so other tissue-specific genes for tolerance-building aren’t expressed.
Which tissues are affected by APECED
Endocrine glands Thyroid Kidneys Chronic mucocutaneous candidiasis Gonadal failure Diabetes mellitus Pernicious anaemia
What is the importance of development of tolerance in the periphery
Some antigens may not be expressed in the thymus or bone marrow, and may be expressed only after the immune system has matured
What are the mechanisms of preventing mature lymphocytes becoming auto-reactive and causing disease (peripheral tolerance)
Anergy
Suppression by regulatory T cells
(Ignorance of antigen)
What is anergy
Absence of costimulation
Most cells on the body lack costimulatory molecules like CD80/86/40 (found on APCs)
Without costimulation, T cells do not proliferate or produce factors.
When does immunological ignorance occur
When antigen concentration is too low in the periphery
When the antigen presenting molecule is absent (most cells have no MHC class II)
