The endocrine autoimmune diseases (type 1 diabetes, Hashimoto's thyroiditis, Addison's disease) may be the fragility cost of a beneficial physiological mechanism: 'autoimmune surveillance of hyper-secreting mutants' (ASHM), in which autoreactive T cells preferentially eliminate endocrine cells that hyper-secrete hormones because of missensing mutations that also make them hyper-proliferate (Korem Kohanim, Tendler, Mayo, Friedman and Alon, Immunity 2020). The hypothesis is supported by indirect evidence — endocrine autoantigens are secretion-pathway proteins, autoreactive T-cell receptors occur in the public repertoire of healthy individuals, and immune killing can discriminate antigen dose — but its critical experimental tests have not been performed. This problem asks for direct in vivo validation or refutation of ASHM: does removing T cells increase the expansion of hyper-secreting mutants in endocrine organs, and do tissue-resident autoreactive T cells in healthy organisms preferentially kill hyper-secreting cells? It further asks for the mechanistic basis (participating T-cell subsets, antigen-presentation pathway, checkpoint and regulatory T-cell control) and the tissue-level tuning of the mechanism (why parathyroid, pituitary, and renin-secreting tissues show weak or absent ASHM). As of mid-2026 the hypothesis remains theoretically extended but experimentally untested.

Background

Many endocrine glands — thyroid, pancreatic islets, adrenal cortex, gastric parietal cells — are frequent targets of organ-specific autoimmune diseases (AIDs), such as type 1 diabetes (T1D), Hashimoto's thyroiditis, and Addison's disease, while other hormone-secreting tissues (parathyroid, pituitary, renin-secreting juxtaglomerular cells of the kidney) almost never develop AID and instead frequently develop benign tumors of hyper-secreting mutant clones (for example hyperparathyroidism and toxic pituitary adenomas). Why this partition exists, and why healthy people carry self-reactive T cells against endocrine autoantigens without disease, are long-standing puzzles.

Korem Kohanim, Tendler, Mayo, Friedman and Alon (Immunity 52(5):872–884.e5, 2020; preprint bioRxiv 10.1101/845750) addressed these puzzles from the viewpoint of feedback control. Endocrine tissues regulate their own mass: the controlled blood-borne signal (glucose for beta cells, thyroid-stimulating hormone for the thyroid, calcium for the parathyroid) drives both cell proliferation and secretion. Such feedback loops are unstable against 'missensing' mutants — cells that mis-read the signal (for example, sensing uu times more signal than wild type) and therefore both hyper-proliferate and hyper-secrete. When hypersecretion is acutely lethal (hypoglycemia from insulin, thyrotoxicosis), these mutants are life-threatening. The authors hypothesize that each such organ maintains 'autoimmune surveillance of hyper-secreting mutants' (ASHM): autoreactive T cells, recognizing peptides from abundant secretion-pathway proteins (the classical endocrine autoantigens) presented on MHC class I molecules (the cell-surface molecular platform that displays intracellular peptides to cytotoxic CD8+ T cells), preferentially kill cells presenting more antigen than their neighbors — that is, the hyper-secretors. The fragility of this mechanism is organ-specific autoimmune disease when it over-activates.

Indirect support assembled in the paper includes: (i) the major endocrine autoantigens are indeed secretion-pathway proteins; (ii) T-cell receptor beta-chains reactive with these autoantigens occur in the 'public' T-cell repertoire (TCR sequences shared by most healthy individuals), consistent with a physiological role rather than being mere escapees of tolerance; (iii) T-cell killing is cooperative in antigen level (a Hill-type dose response), enabling differential elimination of high presenters at low overall killing rates; and (iv) a mathematical model showing ASHM can remove all missensing mutants while killing few normal cells, provided killing is ratiometric (proportional to antigen level relative to the tissue mean, plausibly implemented via regulatory T cells (Tregs) — the suppressive T-cell lineage — or immune checkpoints (inhibitory pathways such as PD-1 that restrain T-cell effector function)). The model predicts a tradeoff: organs in which the fitness cost of hypersecretion exceeds the cost of autoimmunity (estimated via lethality thresholds of the regulated factor, FhyperF_{\text{hyper}} versus FhypoF_{\text{hypo}}) evolve ASHM and get AID; the others get mutant-expansion disease. It also predicts that in advanced autoimmune disease the tissue is not fully destroyed but retains slow-growing, poorly secreting (hypo-secreting) cells that evade ratiometric killing, as observed in T1D.

The authors state explicitly that ASHM 'can be experimentally tested' and propose critical tests: (1) systemic T-cell deficiency (or depletion of specific subsets) should increase the prevalence of hyper-secreting mutant expansion in endocrine organs; (2) introducing marked hypersensing mutant cells at low density into healthy tissue — they should be removed in wild-type backgrounds but proliferate in T-cell-deficient backgrounds; (3) healthy organisms should harbor active tissue-resident autoreactive T cells against secretion-pathway proteins in the target organ and draining lymph nodes, preferentially killing high-secreting cells; (4) people with HLA (human leukocyte antigen — the human MHC gene region) variants protective for autoimmune disease should show increased prevalence of hyper-secreting adenomas. Related open questions include why some organs have weak or absent ASHM (possibilities: AIRE — the autoimmune regulator gene that drives thymic expression of tissue-specific antigens, trimming reactive T cells from the repertoire — or reduced antigen presentation in those tissues), and the molecular identity of the participating T cells and their regulation by checkpoints and Tregs.

Problem Statement

Establish or refute, by direct experiment, whether endocrine tissues possess autoimmune surveillance of hyper-secreting mutants (ASHM) as a physiological mechanism, and characterize how the mechanism is implemented and tuned. The overarching objective — determining whether preferential immune elimination of hyper-secreting cells exists in healthy endocrine tissue and what causes organ-specific autoimmune disease when it misfires — links the following deliverables drawn from the source (Korem Kohanim et al., Immunity 2020):

  1. Critical population-level test: determine whether systemic T-cell deficiency, or depletion of specific T-cell subsets, increases the prevalence of hyper-secreting mutant expansion (clonal expansion of missensing, hyper-secreting cells) in endocrine organs prone to autoimmune disease.
  2. Critical cell-level test — mutant fate: introduce marked hypersensing mutant endocrine cells at low density into healthy tissue and track their fate — ASHM predicts their removal in wild-type backgrounds but clonal expansion in T-cell-deficient backgrounds.
  3. Critical cell-level test — killing preference: seek active tissue-resident autoreactive T cells against secretion-pathway proteins in the target organs and draining lymph nodes of healthy organisms, and test whether the cells they kill are preferentially the high secreters.
  4. Mechanistic identification: establish the molecular basis of ASHM — the participating T-cell subsets (e.g., cytotoxic CD8+ versus regulatory T cells), the antigen-presentation pathway involved, and how immune checkpoints and Tregs regulate the surveillance strength.
  5. Tissue-level variation: explain why some endocrine organs (parathyroid, pituitary, renin-secreting juxtaglomerular cells) show weak or absent ASHM, discriminating among the candidate mechanisms proposed in the source (AIRE-driven thymic expression of the relevant tissue antigens trimming the reactive T-cell repertoire, elevated levels of tissue-specific regulatory T cells, versus reduced MHC class I antigen presentation in those tissues).
  6. Tradeoff principle: test quantitatively, across more tissues and with better lethality data, the evolutionary principle that the balance between autoimmune disease and mutant-expansion disease is set by the relative fitness costs of hyper- versus hyposecretion.

The source additionally flags two conjectural extensions that remain open questions rather than required deliverables: whether ASHM applies to non-genomic hyper-secretion (e.g., stochastic fluctuations in receptor number) and to slow-turnover tissues (e.g., neurons), and whether the model's prediction of hypo-secreting cell survival in autoimmune disease holds across autoimmune disease models beyond type 1 diabetes. The mandatory deliverables are items 1–3: a valid answer to them in either direction (validation or refutation with adequate controls) resolves the existence question that anchors the problem, and together they are sufficient to complete it. Items 4–6 characterize a validated mechanism, are required only when that existence question is answered positively, and are jointly meaningful only relative to it. The answer form for items 1–3 is a concrete experimental program: model system and genotypes, the immune perturbations such as T-cell deficiency or depletion, the controls, and the predicted readouts that would validate or refute ASHM.

References

  1. Korem Kohanim Y, Tendler A, Mayo A, Friedman N, Alon U (2020). Endocrine Autoimmune Disease as a Fragility of Immune Surveillance against Hypersecreting Mutants. Immunity 52(5):872–884.e5. doi:10.1016/j.immuni.2020.04.022, https://pmc.ncbi.nlm.nih.gov/articles/PMC7237888/
  2. Korem Kohanim Y, Tendler A, Mayo A, Friedman N, Alon U (2019). Endocrine autoimmune disease as a fragility of immune-surveillance against hypersecreting mutants. bioRxiv preprint. doi:10.1101/845750, https://doi.org/10.1101/845750
  3. Milo T, Korem Kohanim Y, Toledano Y, Alon U (2023). Autoimmune thyroid diseases as a cost of physiological autoimmune surveillance. Trends in Immunology 44(5):365–371. doi:10.1016/j.it.2023.03.007, https://doi.org/10.1016/j.it.2023.03.007
  4. Korem Kohanim Y, Milo T, Raz M, Karin O, Bar A, Mayo A, Mendelson Cohen N, Toledano Y, Alon U (2022). Dynamics of thyroid diseases and thyroid-axis gland masses. Molecular Systems Biology 18(8):e10919. doi:10.15252/msb.202210919, https://doi.org/10.15252/msb.202210919
  5. Raz M, Glass DS, Milo T, Korem Kohanim Y, Karin O, Tendler A, Mayo A, Alon U (2025). Unifying regulatory motifs in endocrine circuits. Nature Communications 16:11017. doi:10.1038/s41467-025-65924-4, https://doi.org/10.1038/s41467-025-65924-4
  6. Chai C, Sultan E, Sarkar SR, Zhong L, Nanes Sarfati D, Gershoni-Yahalom O, Jacobs-Wagner C, Thiam HR, Rosental B, Wang B (2026). Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense. Cell 189(14):4342–4358.e8. doi:10.1016/j.cell.2026.05.008, https://doi.org/10.1016/j.cell.2026.05.008