DeCure for Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation — 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 moduleAutoinflammation-PLCG2-associated antibody deficiency-immune dysregulation 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 autoinflammation-plcg2-associated antibody deficiency-immune dysregulation 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
phospholipase C gamma 2 (PLCG2) — PLCG2 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 gspdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2W2X · 2.3 Å · ligand 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE (GSP). Experimental structure, not a prediction.
What the evidence adds up to
A 2024 study identified a novel de novo PLCG2 variant, p.D993Y, in a single patient with colitis, pansinusitis, skin rash, oedema, recurrent respiratory infections, B-cell deficiencies, and hypogammaglobulinaemia. In vitro experiments in HEK293T, COS-7, and PLCG2 knock-out THP-1 cell lines showed that this variant increased PLCγ2 phosphorylation, raised inositol-1,4,5-trisphosphate production and intracellular calcium release, and activated the MAPK, NF-κB, and NFAT signalling pathways compared to controls. The variant disrupted the interaction between the catalytic and autoinhibitory domains of PLCγ2, causing autoactivation. The same abstract notes the patient was responsive to a TNF inhibitor, but provides no numbers on response duration, dosing, or sample size beyond the single case.
Two review articles from 2024 discuss the broader landscape of inborn errors of immunity with autoinflammation. One review states that primary immunodeficiency diseases affect approximately six million people worldwide and that targeted treatments such as rituximab are used for common variable immunodeficiency cases that do not respond to standard therapy. It also notes that IL-1 inhibitors have shown promise in managing monogenic autoinflammatory disorders such as cryopyrin-associated periodic syndromes and familial Mediterranean fever, reducing flare frequency and improving quality of life. The other review emphasises that immune deficiency and autoinflammation are interconnected rather than opposing, and calls for better diagnostic clues and future research.
No controlled trial data exist for any drug in APLAID syndrome. The evidence for TNF inhibitor response rests on a single patient report with no comparator, no blinding, and no long-term follow-up published. What is still missing is a dedicated clinical trial, any form of patient registry that could aggregate outcomes across rare genotypes, and systematic stratification by specific PLCG2 variant to determine whether TNF inhibition or alternative pathways (such as IL-1 blockade) are more broadly effective.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Characterization of a Novel Pathogenic <scp><i>PLCG2</i></scp> Variant Leading to APLAID Syndrome Responsive to a TNF Inhibitor
AbstractObjective Autoinflammation and phospholipase C (PLC) γ2–associated antibody deficiency and immune dysregulation (APLAID) syndrome is an autoinflammatory disease caused by gain‐of‐function variants in PLCG2 . This study investigates the pathogenic mechanism of a novel variant of PLCG2 in a patient with APLAID syndrome. Methods Whole‐exome sequencing and Sanger sequencing were used to identify the pathogenic variant in the patient. Single‐cell RNA sequencing, immunoblotting, luciferase assay, inositol monophosphate enzyme‐linked immunosorbent assay, calcium flux assay, quantitative PCR, and immunoprecipitation were used to define inflammatory signatures and evaluate the effects of the PLCG2 variant on protein functionality and immune signaling. Results We identified a novel de novo variant, PLCG2 p.D993Y, in a patient with colitis, pansinusitis, skin rash, edema, recurrent respiratory infections, B‐cell deficiencies, and hypogammaglobulinemia. The single‐cell transcriptome revealed exacerbated inflammatory responses in the patient's peripheral blood mononuclear cells. Expression of the D993Y variant in HEK293T, COS‐7, and PLCG2 knock‐out THP‐1 cell lines showed heightened PLCγ2 phosphorylation; elevated inositol‐1,4,5‐trisphosphate production and intracellular Ca 2+ release; and activation of the MAPK, NF‐κB, and NFAT signaling pathways compared with control‐transfected cells. In vitro experiments indicated that the D993Y variant altered amino acid properties, disrupting the interaction between the catalytic and autoinhibitory domains of PLCγ2, resulting in PLCγ2 autoactivation. Conclusion Our findings demonstrated that the PLCG2 D993Y variant is a gain‐of‐function mutation via impairing its autoinhibition, activating multiple inflammatory signaling pathways, thus leading to APLAID syndrome. This study further broadens the molecular underpinnings and phenotypic spectrum of PLCγ2‐related disorders.
DOAJ (DOAJ: Directory of Open Access Journals) · 2024 · 0 citations · open access
Immune Deficiency and Autoinflammation, the " Yin" and " Yang" of the Immune System
AbstractInborn errors of immunity (IEI) are immune system disorders caused by genetic mutations, often presenting with varying degrees of infection, immune dysregulation, lymphoproliferation, and tumor susceptibility. Initially, IEIs were typically diagnosed in patients with recurrent and unusual infections. However increasing research has shown that noninfectious manifestations can also be the initial or even primary presentation of IEI. Over the past ten years, more and more IEIs associated with autoinflammatory symptoms have been identified. Although these diseases are rare, relevant research suggests that immune deficiency and autoinflammation are not opposing conditions but rather interconnected aspects of the immune system, influencing each other in a complementary and inseparable manner. This article reviews the mechanisms involved in IEI with autoinflammation, and proposes some clues for identifying IEI manifested as autoinflammation. It also summarizes the current progress in the diagnosis and treatment of IEI manifested as autoinflammation, and presents prospects for future research on IEI.
Malaysian Journal of Paediatrics and Child Health · 2024 · 0 citations · open access
Exploring Recent Developments in Immunodeficiency and Autoinflammatory Diseases
AbstractPrimary immunodeficiency diseases (PIDs) and autoinflammatory disorders present major challenges in clinical medicine due to their complexity and varied symptoms. PIDs heighten the risk of infections, autoinflammatory conditions, allergies, and cancers, impacting approximately six million people worldwide. This article reviews recent developments in the understanding and management of antibody deficiencies particularly Common Variable Immunodeficiency (CVID), which is a condition caused by genetic abnormalities especially those involving the NFKB2 gene. Clinical cases highlight the challenges in managing CVID and underscore the necessity of targeted treatments, such as rituximab, for cases that do not respond to standard therapies. Autoinflammatory diseases characterized by episodes of unprovoked inflammation are also explored, with a focus on monogenic disorders such as Cryopyrin-Associated Periodic Syndromes (CAPS) and Familial Mediterranean Fever (FMF). Advances in targeted therapies particularly IL-1 inhibitors, have shown significant promise in managing the conditions, reducing the frequency of flare-ups, and improving quality of life. This article concluded by emphasizing the need for ongoing research into the pathophysiology of these disorders, creating novel biomarkers for early identification, and international collaboration to enhance patient care and outcomes.
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.
