autoimmune polyendocrine syndromes affect more than one endocrine gland, but can also affect non-endocrine organs as well. they are driven by inappropriate MHC-TCR-antigen interactions that encourage the production of aberrant antibody production. here is a summary of how these processes are driven:
Type I AIPS
also known as candidiasis-hypoparathyroidism-Addison’s disease-syndrome, and autoimmune polyendocrine candidiadis ectodermal dystrophy (APECED).
it is an autosomal recessive disorder caused by a mutation in the AutoImmune Regulator AIRe gene. this gene is expressed mainly in the thymus. its protein product is a transcription factor that allows the thymus cells to express tissue-specific genes so that thymus cells can present “self” antigens, normally found outside of the thymus, to maturing T-cells. T-cells with T-cell receptors that react too strongly to both the MHC and the MHC-presented antigen undergo apoptosis, a process called negative selection. in this way, the thymus ensures a pool of T-cells that do not react against the body.
without AIRe, maturing T-cells never encounter extrathymal antigens, and thus are never “deleted” from the T-cell pool. when they circulate in the body later in life, they may react with self-tissue, causing a host of variable tissue-specific autoimmune disorders.
the signs include:
- candidiadis from mild immune deficiency in mucocutaneous areas, which are often susceptible to yeast colonization and infection
- hypoparathyroidism from autoimmune attack of the parathyroid, which can lead to hypocalcemic tetany
- Addison’s disease from formation of antibodies against 21-hydroxylase enzyme, which is normally found in the adrenal cortex (zona glomerulosa)
- later phases include hypothyroidism, hypogonadism, vitiligo, alopecia, malabsorption, pernicious anemia, chronic autoimmune hepatitis, and more!
Type II AIPS
this is known as Schmidt’s Syndrome. unlike Type I AIPS, this has not been linked to one gene, but could be the result of many different genetic differences in HLA regions.
the HLA region is an area used to generate allotype diversity expressed within MHC molecules. allotypes are differences in gene products that vary between individuals. there are 6 significant variable HLA regions (HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, HLA-DR). HLA-A, -B, and -C are associated with MHC I allotypes while HLA-DP, -DQ, and -DR are associated with MHC II allotypes. MHC I is expressed by all nucleated cells – so RBCs have none and platelets have few. MHC II is expressed by Professional Antigen Presenting Cells (macrophages, B-cells, and dendritic cells). there are numerous possible alleles per HLA (up to 50 in some cases), but each person can only get two – one on each chromosome. thus, each person can express up to 12 possible HLA regions.
there are also non-HLA regions that constitute MHC allotypes.
variable MHC allotypes cause changed antigen and TCR interactions. this may lead to decreased negative selection and enhanced positive selection that allows aberrant self-reacting T-cells into the T-cell pool. specific HLA haplotypes are related to specific tissue autoimmune disorders. DQ2 and DQ8 are associated with Schmidt’s syndrome. minor regions are thought to cause slow progressing autoimmune disorders.
signs include:
- Addison’s disease
- hypothyroidism from antibodies generated against thyroglobulin
- diabetes mellitus (type 1) from antibodies generated against glutamate dehydrogenase
- and others, including hypogonadism and vitiligo (the loss of melanocytes)
