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DeCure for Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency

DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.

Disease module1 genesLead labNephrology
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NephrologyDOID:0111967$DeCureNephro

The disease map

Disease modulePrimary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.

Research record

01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash

Current lead

No approved-drug candidate for primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.

What the evidence adds up to

In 28 patients with congenital adrenal hyperplasia, 27 after bilateral adrenalectomy for Cushing’s syndrome, and 21 with Addison’s disease, all on a stable glucocorticoid replacement regimen (median 25 mg hydrocortisone per day), natural killer cell cytotoxicity was reduced in every subgroup compared to 52 healthy controls. The smallest reduction was seen in congenital adrenal hyperplasia. The degranulation marker CD107a was upregulated in patients after bilateral adrenalectomy and in Addison’s disease, but not in congenital adrenal hyperplasia. The NK-cell inhibiting receptor CD94 was upregulated in the bilateral adrenalectomy and Addison’s disease groups, but not in congenital adrenal hyperplasia. These immunophenotypic differences appeared despite identical glucocorticoid preparation and dose, suggesting disease-specific immune alterations rather than a simple consequence of replacement therapy.

The percentage of T helper cell subsets was downregulated in Addison’s disease patients compared to controls (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001). Cytotoxic T cell subsets were reduced in Addison’s disease (Tc1 p = 0.0075, Tc2 p = 0.0154) and in congenital adrenal hyperplasia (Tc1 p = 0.0055, Tc2 p = 0.0012). No major intergroup differences in clock gene expression were detected. The study was cross-sectional, single-centre, and did not include patients with primary immunodeficiency and NK-cell deficiency as a separate group; the NK-cell abnormalities reported are in the context of adrenal insufficiency of known aetiology, not in patients with a primary NK-cell deficiency syndrome.

Earlier literature on adrenal insufficiency in AIDS noted that more than 50% of AIDS patients have pathological evidence of necrotizing adrenalitis, though the degree of adrenal destruction is usually less than 50%. Adrenal cortical insufficiency in that population was linked to cytomegalovirus infection and ketoconazole therapy, with hypoglycaemia from pentamidine and hyponatraemia from diverse causes being the most serious endocrine abnormalities. These observations come from a different disease context and do not address primary NK-cell deficiency.

What is still missing is a dedicated study of immune function, particularly NK-cell number and cytotoxicity, in patients with the specific combination of primary immunodeficiency with NK-cell deficiency and adrenal insufficiency. No trial has tested any intervention to restore NK-cell function in this population. Patient stratification by genetic aetiology of the NK-cell defect and by type of glucocorticoid replacement regimen would be needed before any rational treatment hypothesis could be formed. Funding for such rare-disease immunophenotyping and for the development of NK-cell functional assays suitable for multicentre use is lacking.

Evidence

Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.

Archives of Internal Medicine · 1989 · 71 citations

Endocrine Complications of the Acquired Immunodeficiency Syndrome

AbstractAcquired immunodeficiency syndrome (AIDS) is a multisystem disorder characterized by defects in the immune system that result in opportunistic infections and neoplasms. While endocrine dysfunction has not been a prominent clinical feature of AIDS, all endocrine glands may be affected by the opportunistic infections and neoplasms or by agents used in their treatment. Adrenal cortical insufficiency related to cytomegalovirus and ketoconazole therapy, hypoglycemia related to pentamidine therapy, and hyponatremia secondary to diverse causes are the most serious endocrine abnormalities that commonly occur. As the numbers of patients with AIDS increase, the development of these and other endocrine complications will occur more often. Because the clinical manifestations of endocrine dysfunction may be nonspecific or subtle, they may be overlooked, particularly in the setting of chronically and severely ill patients. Recognition and prompt therapy for endocrine dysfunction is essential for optimal treatment of these patients.

https://doi.org/10.1001/archinte.1989.00390020058012
Annals of Internal Medicine · 1997 · 34 citations

The Changing Clinical Spectrum of Adrenal Insufficiency

AbstractEditorials15 December 1997The Changing Clinical Spectrum of Adrenal InsufficiencyRobert M. Carey, MDRobert M. Carey, MDUniversity of Virginia School of Medicine; Charlottesville, VA 22908.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-127-12-199712150-00009 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The clinical spectrum of primary adrenal insufficiency has changed substantially over the past decade as a result of the emergence of new disease patterns, improved understanding of clinical presentations, and the impact of molecular genetics. I comment here on five clinical entities that have emerged as new diagnostic or therapeutic challenges in the 1990s.Adrenal insufficiency is increasingly recognized in patients with AIDS [1-3], and it correlates with stage of progression of HIV infection. More than 50% of patients with AIDS have pathologic evidence of necrotizing adrenalitis, but the degree of adrenal destruction is usually less than 50%. Clinical adrenal ...References1. Piedrola G, Casado JL, Lopez E, Moreno A, Perez-Elias MJ, Garcia-Robles R. Clinical features of adrenal insufficiency in patients with acquired immunodeficiency syndrome. Clin Endocrinol (Oxf). 1996; 45:97-101. Google Scholar2. Freda PU, Wardlaw SL, Brudney K, Goland RS. Primary adrenal insufficiency in patients with the acquired immunodeficiency syndrome: a report of five cases. J Clin Endocrinol Metab. 1994; 79:1540-5. Google Scholar3. Amason JA, Graziano FM. Adrenal insufficiency in the antiphospholipid antibody syndrome. Semin Arthritis Rheum. 1995; 25:109-16. Google Scholar4. Bevilacqua M. Hyponatremia in AIDS. Baillieres Clin Endocrinol Metab. 1994; 8:837-48. Google Scholar5. May ME, Vaughan ED Jr, Carey RM. Adrenocortical insufficiency-clinical aspects. In: Vaughan ED Jr, Carey RM, eds. Adrenal Disorders. New York: Thieme Medical; 1989:171-89. Google Scholar6. Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab. 1985; 14:947-76. Google Scholar7. Chin R. Adrenal crisis. Crit Care Clin. 1991; 7:23-42. Google Scholar8. Siu SC, Kitzman DW, Sheedy PF 2d, Northcutt RC. Adrenal insufficiency from bilateral adrenal hemorrhage. Mayo Clin Proc. 1990; 65:664-70. Google Scholar9. Winqvist O, Gustafsson J, Rorsman F, Karlsson FA, Kampe O. Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease. J Clin Invest. 1993; 92:2377-85. Google Scholar10. Uibo R, Aavik E, Peterson P, Perheentupa J, Aranko S, Pelkonen R, et al. Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease. J Clin Endocrinol Metab. 1994; 78:323-8. Google Scholar11. Winqvist O, Gebre-Medhin G, Gustafsson J, Ritzen EM, Lundkvist O, Karlsson FA, et al. Identification of the main gonadal autoantigens in patients with adrenal insufficiency and associated ovarian failure. J Clin Endocrinol Metab. 1995; 80:1717-23. Google Scholar12. Chen S, Sawicka J, Betterle C, Powell M, Prentice L, Volpato M, et al. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison's disease, and premature ovarian failure. J Clin Endocrinol Metab. 1996; 8:1871-6. Google Scholar13. Furmaniak J, Kominami S, Asawa T, Wedlock N, Colls J, Smith BR. Autoimmune Addison's disease-evidence for a role of steroid 21-hydroxylase autoantibodies in adrenal insufficiency. J Clin Endocrinol Metab. 1994; 79:1517-21. Google Scholar14. Boscaro M, Betterle C, Sonino N, Volpato M, Paoletta A, Fallo F. Early adrenal hypofunction in patients with organ-specific autoantibodies and no clinical adrenal insufficiency. J Clin Endocrinol Metab. 1994; 79:452-5. Google Scholar15. De Bellis A, Bizzarro A, Rossi R, Paglionico VA, Criscuolo T, Lombardi G, et al. Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies. J Clin Endocrinol Metab. 1993; 76:1002-7. Google Scholar16. Moser HW. Adrenoleukodystrophy. Curr Opin Neurol. 1995; 8:221-6. Google Scholar17. Aubourg P. Adrenoleukodystrophy and other peroxisomal diseases. Curr Opin Genet Dev. 1994; 4:407-11. Google Scholar18. Wanders RJ, Schutgens RB, Barth PG. Peroxisomal disorders: a review. J Neuropathol Exp Neurol. 1995; 54:726-39. Google Scholar19. Blevins LS Jr, Shankroff J, Moser HW, Ladenson PW. Elevated plasma adrenocorticotropin concentration as evidence of limited adrenocortical reserve in patients with adrenomyeloneuropathy. J Clin Endocrinol Metab. 1994; 78:261-5. Google Scholar20. Laureti S, Casucci G, Santeusanio F, Angeletti G, Aubourg P, Brunetti P. X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison's disease in young adult male patients. J Clin Endocrinol Metab. 1996; 81:470-4. Google Scholar21. Tsigos C, Arai K, Latronico AC, DiGeorge AM, Rapaport R, Chrousos GP. A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome. J Clin Endocrinol Metab. 1995; 80:2186-9. Google Scholar22. Weber A, Clark AJ. Mutations of the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. Hum Mol Genet. 1994; 3:585-8. Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Virginia School of Medicine; Charlottesville, VA 22908.Corresponding Author: Robert M. Carey, MD, Box 395, University of Virginia Health Sciences Center, Charlottesville, VA 22908. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byNeuromuscular Manifestations of Acquired Metabolic, Endocrine, and Nutritional DisordersSteroid Therapy in Adrenal InsufficiencyClinical implications for biochemical diagnostic thresholds of adrenal sufficiency using a highly specific cortisol immunoassayThe Adrenal CortexNeurologic complications of disorders of the adrenal glandsNeurologic complications of multiple endocrine syndromesCardiovascular Manifestations of Endocrine DysfunctionThe Adrenal CortexNeuromuscular Manifestations of Acquired Metabolic, Endocrine, and Nutritional DisordersAddison's Disease From Non-Hodgkin's Lymphoma With Normal-Size Adrenal GlandsCT diagnosis of acute adrenal insufficiency due to bilateral adrenal haemorrhageNeurohormonal FactorsRecognition and Management of Adrenal EmergenciesAdrenal hemorrhage mimicking an acute abdomenAntiphospholipid syndrome and endocrine damage: why bilateral adrenal thrombosis?Autoantibodies in autoimmune polyendocrine syndrome type IIAdrenal Insufficiency in Critically Ill PatientsPrimary hypoadrenalism assessed by the 1 μg ACTH test in hospitalized patients with active pulmonary tuberculosis 15 December 1997Volume 127, Issue 12Page: 1103-1105KeywordsAIDSAdrenocorticotropic hormoneAutoantibodiesCholesterolEnzymesFatty acidsHemorrhageSteroidogenesisThrombosisType 1 diabetes Issue Published: 15 December 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. 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https://doi.org/10.7326/0003-4819-127-12-199712150-00009
Zurich Open Repository and Archive (University of Zurich) · 2023 · 0 citations · open access

Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology

AbstractINTRODUCTION Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. METHODS This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. RESULTS The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p &lt; 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p &lt; 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p &lt; 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. DISCUSSION In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.

https://doi.org/10.5167/uzh-255577

Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.

DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.