Measuring IP-One to assess autoimmune hypoparathyroidism
When the immune system develops self-antibodies directed against its own healthy cells and tissues, it leads to chronic and severe diseases. Many organs can be targeted by such aberrant immune response, impairing their normal physiological functions in the organism. The phenomenon is termed autoimmunity.
Auto-antibodies are abnormally raised against proteins exposed at the surface of cells and, once bound to their target, they modify the target’s functions. This is the case for the calcium-sensing receptor (CaSR), which plays a pivotal role in regulating parathyroid hormone (PTH) secretion and systemic calcium homeostasis.
In this article, Mina Chamberlin carried out a study to characterize the molecular mechanism and monitor the effect of an immunosuppressive treatment in a patient suffering from autoimmune hypoparathyroidism. She set-up an in-vitro assay using HEK cells transfected with a CaSR-FLAG construct and then assessed the presence of anti-CaSR antibody in the serum. Incubation of HEK- CaSR-FLAG cells with IgG purified from the patient’s serum elicited a rise in both calcium response, quantified by measuring IP1 accumulation, and activation of the MAP-kinase cascade, quantified by the level of ERK1/2 phosphorylation. When the patient was treated with immunosuppressive drugs, both responses reverted to normal in comparison to responses observed with control serum from healthy volunteers.
The pivotal role of CaSR in parathyroid function is now fully assessed at the molecular level. Simple readouts, such as IP1 and ERK1/2, can be used at the clinical level to assess the efficacy of immunosuppressive treatment in patients suffering from autoimmune hypoparathyroidism.
Activating antibodies directed at the extracellular calcium-sensing receptor (CaSR) have been described in autoimmune hypoparathyroidism in the setting of isolated hypoparathyroidism or autoimmune polyglandular syndrome type 1.
A 34-year-old female presented with hypocalcaemia (6.0 mg/dL) and hypomagnesaemia (1.1 mg/dL) accompanied by low serum PTH (2.4 pg/mL) as well as urinary calcium and magnesium wasting. She was diagnosed with hypoparathyroidism, which was refractory to standard therapy. She was started on 60 mg prednisone and 150 mg azathioprine treatment daily on suspicion of an autoimmune aetiology. The patient was tested for CaSR antibodies.
The patient was positive for CaSR antibodies of the IgG1 subtype, which stimulated phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and inositol phosphate (IP) accumulation. Post-treatment with prednisone and azathioprine, her serum calcium and magnesium normalized, as did her CaSR antibody titre and antibody-mediated stimulation of ERK1/2 phosphorylation and IP accumulation.
This is the first demonstration of CaSR antibody-mediated hypoparathyroidism responsive to immunosuppressive therapy, adding to the evidence that autoimmune hypoparathyroidism can be, in some cases, reversible and not the result of autoimmune parathyroid destruction.
Clinical Endocrinology, 2019 Jan;90(1):214-221.