AITD Flashcards
(19 cards)
Types of AITD
A spectrum that can lead to a hypo or hyper thyroid.
1) Graves’ disease (1.12% prevalence of all autoimmune diseases) - hypothyroidism
2) Hashimoto’s disease - hyperthyroidism
(Euthyroid is normal functioning)
Indications of an autoimmune disease
- high titer autoantibodies, so high concentration allow high response
- can transfer disease with autoreactive serum/lymphocytes
- self-reactive, lymphocyte attacking immunopathology
- usually 99% are polygenic. MHC association e.g. FoxP3 a transcription regulator that if mutated, cannot regulate T cells
Process
Hypothalamus releases TrH (Thyrotropin-releasing hormone) that stimulates the release of thyrotropin and prolactin from the anterior pituitary. The release of these TSH (thyroid-stimulating hormones) induces production of T3 and T4 (triiodothyronine and thyroxine) in the thyroid gland.
Negative feedback loop of T3 and T4 to hypothalamus signal if there is sufficient TH.
- high TSH may signal underactive thyroid.
Thyroid gland function
Take body’s iodine and convert it into T3 and T4 hormones. These hormones regulate body’s metabolism
Hashimoto’s disease mechanism/Immunopathology
- autoantibodies and CTL
On thyroid epithelial cell
- ADCC. Cytotoxic T Lympocytes recognize antigens presented by pMHC, induces it to apoptosis with granzyme, perforin release and Fas ligand to induce cell death.
- Complement. CTL also activates classical complement pathway to form MAC complex. and also NK cells.
- T helper cells - th1 recruit macrophages, cell-mediated immunity. th2 secrete inflammatory cytokines, proliferate plasma cells to make antibodies
Lymphocytic infiltration
- has autoantibodies against thyroid peroxidase (TPO) and thyroglobulin (Tg) (which oxidize iodine to add onto tyrosine to form T3 and T4) which gradually destroys follicles in thyroid gland.
Results of hypothyroidism/Immunopathology (4)
1) Increased TSH but because thyroid can’t function well, decreased T4 and T3.
2) Either lack of iodine - which forms inflamed goitre -
3) Or sufficient iodine but still hypothyroid- in which case is atrophic thyroiditis and has inhibitory anti-TSH receptor (TSHR) so TSH cannot function
4) Lymphocytic infiltration - autoantibodies detected. TPO and Tg in 95% and 70% of patients. Even the composition of a thyroid tissue starts to look like a germinal center for plasma B cells (as seen in 2nd lymphoid tissues) as follicles are destroyed and infiltrated.
Symptoms of hypothyroidism
Weight gain but poor appetite Loss of energy Dry skin & hair Feeling cold Altered periods Constipation Goitre
Goitre
Swelling of neck because of enlarged, unfunctioning thyroid gland. Hyperplasia (increase in number of cells) to compensate for decreased efficacy.
Usually because of iodine deficiency.
Thyroid autoantibodies
1) anti-Thyroid peroxidase. Organ specific, binds completely to thyroid epithelial cells in Hashimoto’s.
2) anti-Thyroglobulin.
blocking thyroid activity
3) stimulatory anti-thyroid stimulating hormone receptor antibody
activating thyroid activity
Graves’ Disease
1) Stimulatory anti-TSH receptor (TSHR) autoantibodies act like TSH to stimulate thryoid gland to produce T4 and T3. In 95% patients.
2) Cause both hypertrophy and hyperplasia of the thyroid epithelial cells.
3) Increase in T3 and T4 but decrease in actual TSH.
4) also has anti-TPO and anti-Tg in 95% and 50% patients.
Symptoms of Graves’ disease
Weight loss and increased appetite
Excessive sweating
Tremor and palpitations
Altered periods
Stimulatory anti-TSHR
Typically TSHR is stimulated from regular secretions of hormones from the anterior pituitary.
However anti-TSHR antibody is continually secreted from plasma cell to excessively stimulate the TSHR.
- can cause neonatal thyrotoxicosis.
Neonatal thyrotoxicosis
In which mothers with hyperthyroidism transfers thyroid-stimulating IgG antibodies to baby, supposed to allow them to fight any antigens from mother.
However transfer of autoantibodies such as anti-TSHR stimulates baby’s thyroid to cause hyperthyroidism.
- good thing is that 1/2 life of IgG is 21 days so mother’s antibodies will break down and baby’s thyroid stimulation should return to normal.
Graves’ ophthalmopathy
Inflammation of the orbital tissue, with redness, swelling, bulging eye, conjunctivitis. In 60% patients observed, 90% patient in CAT scan.
- Lymphocyte infiltration into extraoccular muscles and orbital connective tissue
- IgG autoantibodies trigger TSHR and insulin-like growth factor-1 receptors of orbital fibroblasts and activate along with T cells and B cells to release pro-inflammatory cytokines and other tissue/adipocyte/fibroblast cells to expand orbital tissue.
- Recruited Th1 produce IFNy, enhacing secretion of chemokines
Genetics of AITD
35% concordance in monozygotic twins.
Polymorphic disease.
- TSHR, FoxP3, CTLA-4
Foxp3
CTLA-4
FoxP3 - regulates development of Treg cells
CTLA-4 - immune checkpoint that downregulates immune response
Environment AITD
- 5x more prevalent in females, subside during pregnancy and rebound post-partum. (REVIEW said fetal microchimerism might be at play in which fetal cells stay in mother and are activated with weak immune system and invoke autoimmune response like graft v host disease)
- stress affects neuroendocrine pathway affecting immune system
- smoking strongly associated with ophthalmopathy. but not Hashimoto’s
- diet, iodine supplements associated with development of Graves’
Immunopathology of AITD
- Initiated by DCs with MHC II activating naive T helper cells. (CD28 costim receptor for T cell activation activated by CD80/86 ligand from the DC.)
- Exacerbated by abnormal expression of MHC II by IFNy on thyroid epithelial cells when normally MHC II only expressed by dendritic cells, B cells. Thus abnormal activation of Th cells.
- Th1 cells secrete IFNy to cell-mediated immunity, activation of CTL and macrophages (mainly HD)
- Th2 cells secrete Il-6/13 which help thyroid-infiltrating B cells make autoantibodies. (mainly GD)
Treatment for AITDs both hypo and hyper (4)
Hypothyroidism
- thyroxine (T3) replacement therapy. since not enough T3+T4 replace with synthetic hormone
Hyperthyroidism
- anti-thyroid drugs. antagonist to act upon thyroid hormones to reduce. Inhibit Thyroid peroxidase, inhibit conversion to T4, T3.
- Radioactive ablation. Using iodine to destroy/ablate healthy thyroid tissue. Safe but leaves them hypothyroid
- Surgery. sub-total thyroidectomy
While a control, all fail to address the underlying immune problem of antibodies and CTLs, need to reestablish immune control.
Animal models:
- anti-MHC to not activate T cells. peptide blockade to not allow recognition of CD80/86. anti-TCR to not receive signals from stimulatory peptides. etc
