# Insights into erythropoietin homeostasis: Identifying the autoantigen targeted in the TEMPI syndrome

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $262,935

## Abstract

Project Summary
The TEMPI syndrome is a rare disorder characterized by five features: (1) Telangiectasias, (2) elevated
Erythropoietin and erythrocytosis, (3) Monoclonal gammopathy, (4) Perinephric fluid collections and
(5) Intrapulmonary shunting. This is a syndrome that we first identified and described in 2011 and have since
found 27 patients worldwide. The TEMPI syndrome is an acquired disorder that appears to be driven by the
presence of an abnormal autoantibody, i.e., the monoclonal gammopathy. In patients who have required
treatment, therapies that target plasma cells and eradicate the antibody have led to a complete resolution of
the other features of the TEMPI syndrome, implicating the antibody as a pathogenic driver of the disease.
Patients with TEMPI syndrome present with serum erythropoietin (EPO) levels that can range as high as 500x
the upper limit of normal. This suggests that the pathway of hypoxia sensing, and EPO production are
dramatically dysregulated. Taken together, this further implicates the abnormal autoantibody as a pathogenic
driver of EPO production. In this proposal we aim to identify the antigenic target of the monoclonal
gammopathy. Understanding how this antibody-antigen interaction can drive both EPO production from the
kidneys and drive neovascularization within the endothelium of the skin (telangiectasias) and lungs (shunting)
has the potential to identify an entirely new signaling mechanism triggered by extracellular antibody binding.
We will couple multiple approaches to antigen identification with gene expression and mutational profiling of
the monoclonal plasma cells. Our approach takes advantage of available patient samples that have been
carefully and longitudinally banked from patients of this ultra-rare disease. Our preliminary data demonstrates
that we can successfully identify and clone the heavy and light chain monoclonal antibody sequences, and
this has permitted the in vitro production of recombinant antibody from one patient already. In an exciting
recent experiment, we have demonstrated that this recombinant antibody is capable of driving erythrocytosis
when introduced into mice, lending strong support to our hypothesis that the monoclonal gammopathy is
pathogenic. In this proposal, we will build on this preliminary data, and generate recombinant monoclonal
antibodies from additional patients with the TEMPI syndrome will the goal of using these antibodies as tools
for antigen identification. Pilot attempts using crude patient serum as a source of antibody for antigen
identification have been unsuccessful, leading us to surmise that the antibody-antigen interaction may be of
low-affinity. Thus, we are proposing a multi-pronged approach using both traditional immunology approaches
as well as a new approach of proximity labeling. If successful, our proposal will identify the antigenic target of
the monoclonal gammopathy in patients with TEMPI syndrome and in doing so will identify a novel antibody-
a...

## Key facts

- **NIH application ID:** 10511508
- **Project number:** 1R21AI171732-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David B Sykes
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $262,935
- **Award type:** 1
- **Project period:** 2022-07-06 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10511508

## Citation

> US National Institutes of Health, RePORTER application 10511508, Insights into erythropoietin homeostasis: Identifying the autoantigen targeted in the TEMPI syndrome (1R21AI171732-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10511508. Licensed CC0.

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