DeCure for Immunodeficiency 36 with lymphoproliferation
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for immunodeficiency 36 with lymphoproliferation — 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 moduleImmunodeficiency 36 with lymphoproliferation 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 immunodeficiency 36 with lymphoproliferation 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.
Molecular view
phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) — PIK3R1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 1rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8W9A · 2.7 Å · ligand 6-chloranyl-3-[[(1R)-1-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)-3,6-dimethyl-4-oxidanylidene-quinazolin-8-yl]ethyl]amino]pyridine-2-carboxylic acid (UEX). Experimental structure, not a prediction.
What the evidence adds up to
In 17 patients with late-onset immunodeficiency, 94% had autoimmunity and 65% had lymphoproliferation. Somatic mutations in immune-associated genes were found in 65% of all immunodeficiency patients and in 75% of those with common variable immunodeficiency, compared to 48% of healthy controls. Mutations occurred in STAT5B, C5AR1, KRAS, and NOD2, among others. Clonal hematopoiesis-associated variants appeared in 24% of patients. Common variable immunodeficiency patients also showed increased frequencies of T-cell receptor clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences, indicating repertoire perturbation.
In three AIDS patients with very high IgE and near-complete CD4+ depletion, IgE synthesis was still inhibited by anti-IL-4. CD8+ T cell lines and clones from these patients produced IL-4, IL-5, and IL-6, and 44% of CD8+ clones expressed CD40 ligand. Their supernatants induced IgE synthesis by normal B cells. These CD8+ cells functionally mimicked Th-2 cells and may account for hyper-IgE and eosinophilia in the absence of CD4+ cells.
Six AIDS-related lymphoma-derived antibodies were tested for binding to HIV and cell surface epitopes. Five expressed IgM, one IgG. Their V genes were 3% to 15% diversified from germline. None showed reactivity against HIV recombinant proteins or native HIV epitopes on infected cells. Two bound strongly to non-HIV-infected cells of various tissue origins, suggesting the transformed B cells arose from B cells responding to other antigens, including self-antigens, not from anti-HIV specific B cells.
A review notes that lymphoproliferative disease incidence is higher in congenital, acquired, or iatrogenic immunodeficiency. Three WHO categories are discussed: LPD in primary immune disorders, post-transplant LPD, and LPD in HIV infection. The review describes monoclonal antibody treatment as potentially effective for some types, but provides no new trial data or survival numbers. What is missing is prospective data linking specific somatic mutations to treatment response, a trial design that stratifies patients by mutation or T-cell clonality status, and funding for such stratified studies rather than further descriptive sequencing.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Experimental Medicine · 1995 · 105 citations · open access
CD8+ T lymphocytes provide helper activity for IgE synthesis in human immunodeficiency virus-infected patients with hyper-IgE.
AbstractIncreased levels of serum IgE and eosinophilia have been described in human immunodeficiency virus (HIV) infection, almost exclusively in patients with CD4+ cell count < 200 cells/microliters. IgE production is regulated by CD4+ T helper type 2 (Th-2) lymphocytes, producing interleukin 4 (IL-4) and expressing a ligand for the B cell-specific CD40 molecule (CD40 ligand [L]). A shift to a Th-2-like pattern of cytokine secretion has been postulated to be associated with progression toward acquired immunodeficiency syndrome (AIDS). We studied three AIDS patients with very high levels of IgE and almost complete depletion of CD4+ lymphocytes, suggesting that IgE synthesis could not be driven by CD4+ cells. IgE in vitro synthesis by cells from such patients was, however, inhibited by anti-IL-4. We show that both CD8+ T cell lines and the majority of CD8+ T cells clones derived from these patients produce IL-4, IL-5, and IL-6 in half of the cases together with interferon gamma (IFN-gamma). 44% of CD8+ T cell clones expressed a CD40L, and the supernatants of the clones were capable of inducing IgE synthesis by normal B cells costimulated with anti-CD40. CD8+ T cells in these patients therefore functionally mimic Th-2 type cells and may account for hyper-IgE and eosinophilia in the absence of CD4+ cells. The presence of such CD8+ cells may also provide a source of IL-4 directing the development of predominant Th-2 responses in HIV infection.
Somatic mutations and T-cell clonality in patients with immunodeficiency
AbstractCommon variable immunodeficiency and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is however implicated. To study whether somatic mutations in CD4+ and CD8+ T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset common variable immunodeficiency and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor beta sequencing was used to characterize CD4+ and CD8+ T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in common variable immunodeficiency and 48% in controls. Clonal hematopoiesis-associated variants in both CD4+ and CD8+ cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immune- and proliferative functions, such as STAT5B (two patients), C5AR1 (two patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, common variable immunodeficiency patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4+ and CD8+ cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.
Evidence that immunoglobulin specificities of AIDS-related lymphoma are not directed to HIV-related antigens
AbstractChronic B-cell stimulation may be a predisposing event in the early pathogenesis of the acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL). ARL-derived immunoglobulin (Ig) genes are significantly diversified from germline, suggesting that antigenic stimulation via Ig receptors may occur prior to malignant transformation. We have evaluated 6 ARL-derived antibodies for binding to human immunodeficiency virus (HIV) and cell surface epitopes. Five cases expressed IgM, and 1 case expressed IgG. Expressed V genes were significantly diversified (3%-15%) from known germline V genes. A non-Ig producing mouse myeloma cell line was transfected with expression vectors containing the lymphoma-derived V genes. By enzyme-linked immunosorbent assay and Western blot assay, the lymphoma-derived Ig's showed no reactivity against HIV recombinant proteins. Also, no specific HIV reactivity was observed by flow cytometry with lymphoma-derived Ig's against the T-cell line infected with T-tropic HIV-1 or peripheral blood mononuclear cells infected with M-tropic HIV strains, indicating lack of binding to native HIV epitopes. However, 2 of the lymphoma-derived Ig's (ARL-7 and ARL-14) bound strongly to non-HIV-infected cells of various tissue origins. Thus, these findings suggest that the transformed B cells of AIDS-associated lymphomas may not arise from the pool of anti-HIV specific B cells but, rather, may develop from B cells responding to other antigens, including self-antigens. (Blood. 2000;95:1393-1399)
Lymphoproliferative Disorders in Immunocompromised Individuals and Therapeutic Antibodies for Treatment
AbstractThe incidence of lymphoproliferative disease (LPD) is significantly higher in individuals who have congenital, acquired or iatrogenically induced immunodeficiency. Although there are a wide range of LPDs including lymphoma and leukemia, this article only covers LPDs in patients with impaired immune function, which are called immunodeficiency-associated LPDs (ID-LPDs). Three of the four ID-LPD categories recognized by WHO have been selected for discussion: LPD in primary immune disorders, post-transplant LPD and LPD in HIV infection. Because of the high incidence and mortality of ID-LPDs, careful evaluation of the morphology, immunophenotype, genotype, viral status and clinical history is required for accurate diagnosis and treatment. Recently, treatment with monoclonal antibodies (mAbs) has been widely used and developed because of its potential benefits. The aim of this review is to describe new information concerning mAb treatment in LPDs and to draw physicians' attention to mAb therapy, which should be effective for some types of LPD.
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.
