Autoimmunity Flashcards
Examples of autoimmune disease
State the ways autoimmune diseases are present?
Systemic or organ-specific
State 2 examples of organ-specific autoimmune diseases?
- Graves disease: over activation of TSH receptors in thyroid -> bulging of eyes
- Type 1 diabetes: Targets insulin producing cells of the pancreas
State and describe an example of a systemic autoimmune pathology?
- Systemic lupus erythematosus
- Multi-system disease
- Characterised by autoAB to nuclear antigens (dsDNA) -> Relapse + remission of disease
Basics of tolerance
What is autoimmunity?
- Failure of various regulatory immune system controls
- Immune attack of host components
What is tolerance and describe the 2 types?
- Tolerance: Immunosuppression doesn’t attack self proteins or cells
- Central Tolerance: destroy self-reactive T or B cells before they enter circulation
- Peripheral Tolerance: destroy or control self reactive T or B cells which enters circulation
Describe central tolerance for B cells?
- Immature B cells in bone marrow -> Encounter antigen in form (stromal cell) which crosslinks their IgM -> Apoptosis triggered
What can be the problem behind selecting T-cell receptors which bind to self MHC?
- Binding is too weak -> signalling may not get activated -> when binding to MHC with foreign peptides
- Binding is too strong -> signalling occurs -> whether self or foreign peptide
Describe the factors used for T cell selection in the thymus?
- Useless? -> no self-MHC binding -> death by neglet/apoptosis
- Dangerous? -> binds self MHC too strongly -> apoptosis triggered -> -ve selection
- Useful? -> binds self MHC weakly -> signal to survive -> + ve selection
How can a T cell developing in the thymus encounter MHC bearing peptides expressed in other parts of the body?
- Specialised TF -> known as Autoimmune regulator (AIRE)
- Increase self tolerance by allowing thymic expression of genes from other tissues
- AIRE mutation - autoimmune polyendocrinopathy syndrome type 1 -> multi-organ autoimmunity
Peripheral tolerance
State the mechanisms involved within peripheral tolerance?
- Ignorance
- Anergy
- Regulation
Describe the ignorance mechanism involved within peripheral tolerance?
- Includes: antigen present in Decreased concentrations
- Prevent threshold TCR triggering in immunologically privileged sites (eye, brain)
Describe the anergy mechanism involved within peripheral tolerance?
- Naive T cells require co-stimulatory signals for activation
- Most cells lack co-s + MHC II
- If Naive T cell see MHC/peptide ligand without co-s, it becomes anergic -> Decreased stimulation even if co-s is present
Describe the regulation mechanism involved within peripheral tolerance?
Treg cells (subset of Th) -> inhibit other T cells via cytokines (IL-10 + TGF-beta) -> defective Treg - multiple sclerosis
Name the Treg expression TF and what its mutation can lead to?
- FOXP3
- Mutation - severe + fatal autoimmune disorder
- Immune dysregulation
- Polyendocrinopathy
- Enteropathy X-linked (IPEX) syndrome.
Genetic + environmental factors
Describe genetic factors involved within autoimmunity?
- MHC
- Polymorphism (increased genetic variation) -> associated with disease + autoimmunity
State endocrine factor diseases more common in male than females + vice versa?
- M > F -> Multiple sclerosis, ankylosing spondylitis
- F > M - SLE
- F = M -> diabetes
Describe hypothesis involved within environmental factors of autoimmunity?
- Hygiene hypothesis -> Non-obese diabetic mice + specific pathogen free
- Conditions = no diabetes seen -> Migration + T1d, MS + SLE
- Smoking = rheumatid arthritis
Examples of immune mechanisms
Give 4 mechanisms which might trigger a breakdown of self tolerance?
- Loss of/problem with reg. cells
- Release of sequestered antigen
- Modification of self
- Molecular mimicry
Describe the modification of self mechanisms stating an example?
Citrulline (AA, not via DNA) -> Arginine (+ ve) converted to citrulline (neutral) as post-translational modification by peptidylarginine deiminase (PAD) enzyme + increase via IF -> C residue on peptide = increased degradation chances -> AutoABs to cit. found in RA - clinical diagnosis
Describe the molecular mimicry mechanism with an example?
- Diseases triggered via infection with streptococcus pyogenes
- ABs to stop cell wall antigens cross reacting with cardiac muscle
- Causes rheumatic fever
Describe ABs in autoimmune pathologies outlining 3 examples and describing them?
- Graves disease -> Auto-ABs bind TSHR + stimulate -> hyperthyroidism -> diseases transferred via lqG
- Myasthenia gravis -> AutoABs bind ACHR -> block ACH binding + receptor internalisation & degradation -> muscle weakness
- SLE + vasculitis -> AutoABS to soluble antigen -> immune complex formation -> deposited in tissue -> activation of complement + phagocytic cell -> disposition in kidney = renal failure
How can newborns suffer from autoimmune diseases?
- Patient transfers anti-Autoimmune infection across placenta into fetus
- Newborn suffers autoimmune disease
- Plasmapheresis removes IgG + cures diseases
Describe how T cells can be involved in autoimmune pathology?
- T cell destruction -> Direct killing (CD8+), self destruction (cytokines), Macrophages (- tissue destruction), CD4 provide help for AB + cytotoxicity (non-pathogenic IgM -> pathogenic IgG) -> diseases = multiple sclerosis, insulin
Describe purpose of TH17 cells and state examples of Autoimmune diseases where they become implicated?
Th cells -> produce cytokine IL-17 + highly IF -> immune cells recruitment, migration + activation -> implicated in spondyloarthropathy, MS + diabetes
Describe therapeutic strategies used to deal with Al diseases?
- Anti-inflammatories (NSAIDs, corticosteroids)
- T + B cell depletion (RA: anti-CD4 + CD20-ABs)
- Therapeutic ABs (anti-T,VLA-4 (blocks adhesion))
- Antigen specific therapies in development (glatiramer acetate -> Increase T reg
