Autoimmunity Flashcards
Define tolerance
“state of immunologic unresponsiveness to a particular antigen”
- maintain unresponsive state toward self/ mount a response against non-self
Establishment of Tolerance
Thymus: positive and negative selection
Bone Marrow: self reactive mIg results in clonal deletion
Secondary Lymphoid: T cells that bind to self MHC in absence of co-stimulation = anergy
mIg = membrane bound form of immunoglobulins
T regulatory cells
CD4+ CD25+ T regulatory cells (Treg):
- Express ↑ IL-2R α-chains (CD25) = low affinity for IL-2
- Found in secondary lymph tissues and sites of inflammation
- Secrete IL-10, IL-35, (TGFβ) = anti-inflammatory and
suppress nearby responses - Inhibit APCs by binding CD80/86 (via CTL4-A on T cell)
- Bind APC along with other T cells = suppressing their activity = linked suppression (opposite of cross-presentation)
Regulatory CD8+ T cells
Regulatory CD8+ T cells:
- poorly understood
- apparently NOT generated in thymus, but in the periphery during CD8+ T-cell activation induction events
— appear after Ag-MHC I stimulation in the presence of TGF-β cytokine - Most likely use a range of mechanisms (similar to CD4+ Treg cells) to suppress activity
— Lysis of APCs
— Inhibition of APC function
— Regulation of effector cells that bind the same Ag
Factors for Autoimmunity
- Genetics
- specific HLA genes
- Gender; more common in female
- Environmental factors (Drugs, Infections, Diet ? Chemicals/ toxins ?)
Are identical twins guaranteed to have the same autoimmunity ?
No, although genetics can play a role in immunity, there is 30 - 70% variability between identical twins due to other factors (ie. environmental)
Drugs that cause autoimmunity
- Procainamide, Hydralazine = Lupus
- Methyldopa, quinidine = AIHA
Proposed mechanism of autoimmunity
- Most likely multifactorial
- Several “hits” likely required to induce autoimmunity:
— molecular mimicry
— Infections that induce genetic changes
— Damage/stress events that expose sequestered Ag
— Foods that alter gut microbial balance, promoting chronic
inflammation and hypersensitivity reactions
— Exposure to immune privileged sites
— inappropriate Th1 vs Th2 response
How is Autoimmune Disease acquired ?
- multi factorial
- genetics and ENVIRONMENT
- increased autoimmunity
- decreased regulation of autoimmunity
How is Hashimoto’s thyroiditis an autoimmune disease ?
Hypothyroidism:
- anti-TPO forms against thyroid
- macrophages and NK cells = antibody-dependent cytotoxicity
- histology = non-functional, non-smooth, non-magenta cells
- TSH = high bc body is trying to compensate/ activate thryoid
Is autoimmunity always detrimental ?
No, autoimmunity is not always detrimental
— it can be benign
— does not always cause Autoimmune Disease
Autoimmunity in Grave’s Disease
Hyperthyroidism:
- Auto-Ab binds thyroid cell receptors
= Stimulates thyroid to produce T3 and T4
= Patient becomes energetic, hot, loses weight
= Sensitivity to light
SLE Pathogenesis
-
Autoantibodies against nuclear, cytoplasmic or phospholipid
components - Immune complex formation deposits on tissue, or tissue-specific antibody damage
- Neutrophil tries to clear immune complex = frustrated phagocytosis releases enzymes = systemic inflammation
= Acute and chronic inflammation
Lab Diagnosis for SLE
- ANA (anti-nucleic antibody) = no longer performed
- Indirect immunofluorescence (low specificity)
Treatment for SLE
- challenging to balance immune suppression:
- anti-inflammatory drugs (corticosteroids)
- pain control (acetaminophen)
- immunosuppressive drugs (azathiaprine, cyclophosphamide, cyclosporin)
- monoclonal therapy; targets chemokines
- antibody removal (plasmapheresis)
- IVIg; saturates binding sites for macrophages to prevent binding to immune complexes
How does Hashimoto’s cause autoimmunity ?
Hypothyroidism:
- anti-TPO forms against thyroid
- macrophages and NK cells = antibody-dependent cytotoxicity
- histology = non-functional, non-smooth, non-magenta cells
- TSH = high bc body is trying to compensate/ activate thyroid
