DeCure for Immunodeficiency 121 with autoinflammation
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for immunodeficiency 121 with autoinflammation — 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 121 with autoinflammation 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
approvedBortezomibApproved drug
Structures already discussed alongside immunodeficiency 121 with autoinflammation in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of the Lon-like protease MtaLonC — Bortezomib has a real, experimentally solved structure in complex with this target (PDB 4FWD, 2.03 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet bo2drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4FWD · 2.03 Å · ligand Bortezomib (BO2). Experimental structure, not a prediction.
What the evidence adds up to
Primary immunodeficiency disorders are frequently complicated by autoimmune and inflammatory conditions, creating diagnostic and therapeutic challenges. Mechanisms linking immunodeficiencies to autoimmunity include increased homeostatic proliferation in lymphopenic states and defects in regulatory T cells, as seen in Wiskott-Aldrich syndrome. Immunodeficiencies affecting the innate immune system can impair negative regulatory mechanisms, leading to inappropriate inflammation. Systemic autoinflammatory diseases are inherited monogenic disorders of dysregulated innate immunity, and molecular mechanisms typical of autoinflammation have been recognised in the pathogenesis of several autoimmune and immunodeficiency states.
A 24-year-old Australian woman with relapsing and remitting multiple sclerosis, atopy, lymphocytic enteritis, recurrent lower respiratory tract infections, and other conditions was commenced on daclizumab, a monoclonal antibody blocking CD25, after failing several prior treatments. During a hospital admission she was incidentally diagnosed with combined immunodeficiency with hypogammaglobulinaemia and declined intravenous immunoglobulin. After six months of daclizumab she presented with febrile neutropenia; bone marrow biopsy showed agranulocytosis with a maturation block at the myeloblast stage. Neutrophil recovery occurred after stopping daclizumab and starting corticosteroids and methotrexate. Whole exome sequencing revealed a novel heterozygous missense variant in CTLA4, leading to a diagnosis of CTLA-4 haploinsufficiency with autoimmune infiltration. This case demonstrates that autoimmune disease can be the presenting feature of primary immunodeficiency, and genetic clarification may alter the safety of proposed immunotherapy.
HIV infection is associated with autoimmune manifestations as well as immunodeficiency and immune dysregulation. With highly active antiretroviral therapy and restoration of immunity, multiple immune-mediated diseases have resurfaced in the HIV population. The 2024 review of autoinflammatory diseases notes that the concept has evolved from an interleukin-1-centred paradigm to recognition of other signalling pathways, including inflammasome, interferon, and NF-κB pathways, and classifies systemic autoinflammatory diseases into inflammasomopathies, interferonopathies, relopathies, protein misfolding syndromes, other cytokine-signalling disorders, and complementopathies.
What is still missing are prospective trials that stratify patients by underlying genetic immunodeficiency before starting immunomodulatory therapy, and systematic diagnostic pathways to identify monogenic autoinflammatory or immunodeficiency syndromes in patients presenting with autoimmune or inflammatory symptoms. The cost and availability of whole exome sequencing and targeted immunological testing remain barriers to routine implementation.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Rheumatology · 2008 · 71 citations · open access
Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders
AbstractPURPOSE OF REVIEW: Although it may seem paradoxical, primary immunodeficiency disorders are frequently complicated by autoimmune and inflammatory conditions. These conditions pose significant diagnostic and therapeutic challenges for clinicians caring for these patients. There have been a number of new insights into how immunodeficiencies can predispose to autoimmunity, and rheumatologists should understand the basis for and manifestations of autoimmunity in primary immunodeficiency disorders to more effectively care for these patients. RECENT FINDINGS: A number of mechanisms have recently been found to link primary immunodeficiencies and autoimmunity, including increased homeostatic proliferation in primary immunodeficiencies associated with lymphopenia and defects in regulatory T cells in the Wiskott-Aldrich syndrome. Primary immunodeficiencies that affect the innate immune system can also lead to inappropriate inflammation through impairing negative regulatory mechanisms in innate immune cells. SUMMARY: The realization that primary immunodeficiencies can also impair negative regulation of immune responses has provided a new framework for the understanding of autoimmunity associated with these conditions. These insights may lead to new, more targeted therapies for autoimmune complications in primary immunodeficiency patients.
Allergy Asthma and Clinical Immunology · 2018 · 13 citations · open access
Pitfalls of immunotherapy: lessons from a patient with CTLA-4 haploinsufficiency
AbstractDaclizumab is a humanized monoclonal antibody that blocks CD25, the high affinity alpha subunit of the interleukin-2 receptor. Daclizumab therapy targets T regulatory cell and activated effector T cell proliferation to suppress autoimmune disease activity, in inflammatory conditions like relapsing and remitting multiple sclerosis. Here, we present the first report of agranulocytosis with daclizumab therapy in a patient with relapsing and remitting multiple sclerosis. Our patient was a 24-year-old Australian female with a clinical history of atopy, lymphocytic enteritis complicated by B12 deficiency, relapsing and remitting multiple sclerosis, recurrent lower respiratory tract infections, vulval/cervical intraepithelial neoplasia and melanoma. She was commenced on daclizumab therapy after failing several lines of treatment for relapsing and remitting multiple sclerosis. During a hospital admission for lymphocytic enteritis, she was incidentally diagnosed with combined immunodeficiency with hypogammaglobulinaemia and declined proposed regular intravenous immunoglobulin infusions. Following six months of daclizumab therapy, our patient presented to hospital with febrile neutropenia. No clear infective cause was found, despite numerous investigations. However, bone marrow biopsy revealed agranulocytosis with an apparent maturation block at the myeloblasts stage. Neustrophil recovery occurred following cessation of daclizumab and the initiation of T cell immunosuppressive agents including systemic corticosteroids and methotrexate. The patient was further investigated for combined immunodeficiency and whole exome sequencing revealed a novel heterozygous missense variant in cytotoxic T lymphocyte antigen 4 ( CTLA4 ), leading to a diagnosis of CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI). This case demonstrates that autoimmune disease may be the presenting feature of primary immunodeficiency and should be appropriately investigated prior to the commencement of immunotherapy. Genetic clarification of underlying primary immunodeficiency may provide critical clinical information that alters the safety of the proposed treatment strategy.
Efficacy of Bortezomib for Treating Anti-Interferon-Gamma Autoantibody-Associated Adult-Onset Immunodeficiency Syndrome
AbstractBACKGROUND: Currently, there is no effective treatment for adult-onset immunodeficiency (AOID) syndrome with anti-interferon-gamma autoantibodies (anti-IFN-γ-auto-Abs). This study aimed to investigate the effectiveness of bortezomib (BTZ) for decreasing anti-IFN-γ-auto-Abs. METHODS: A pre- and post-intervention study was conducted from February 2017 through June 2019 at Siriraj Hospital (Bangkok, Thailand). Five patients were invited to receive once-weekly BTZ (1.3 mg/m2 body surface area) subcutaneously for 8 weeks followed by oral cyclophosphamide (1 mg/kg/d) for 4 months. The primary outcomes were the difference in antibody level at 8 and 48 weeks compared with baseline and the incidence of serious adverse events (AEs). The secondary outcome was the occurrence of opportunistic infections (OIs) during the 72 weeks after starting BTZ. RESULTS: The median patient age was 46 years (range, 34-53). All patients had 3-5 OIs prior to enrollment. All patients were receiving antimycobacterial agents for treatment of nontuberculous mycobacterial infection at enrollment. There was no significant difference in the mean optical density of auto-Abs at 8 weeks (3.73 ± 0.72) or 48 weeks (3.74 ± 0.53) compared with baseline (3.84 ± 0.49; P = .336 and P = .555, respectively). However, after serum dilution, the antibody titer nonsignificantly decreased 8-16 weeks after BTZ initiation (P = .345). Ten OIs were observed 24-72 weeks after BTZ initiation. CONCLUSIONS: Treatment with BTZ followed by cyclophosphamide yielded no significant decrease in antibody titer levels, and 10 OIs were observed during 24-72 weeks of BTZ treatment. No serious AEs were observed. Combining rituximab with BTZ is likely necessary to prevent generation of new autoantibody-producing plasma cells. Clinical Trials Registration. NCT03103555.
JCR Journal of Clinical Rheumatology · 2023 · 3 citations
HIV-Associated Rheumatic Diseases
AbstractABSTRACT: Human immunodeficiency virus (HIV) is widely prevalent among the world population. Although, historically, it has been linked to opportunistic infections in keeping with immunodeficiency and immune dysregulation, it has also been associated with a wide variety of autoimmune manifestations. With the introduction of highly active antiretroviral therapy and subsequent restoration of immunity, there have been multiple immune-mediated diseases that have resurfaced in the HIV population. Our review highlights autoimmune diseases in association with HIV and its targeted therapies in detail.
Clinical Spectrum and Challenges of Primary Immunodeficiency disorders in Egyptian children
AbstractPrimary Immunodeficiency Disorders (PID) are inherent defects of the immune system that may present in infants and children. The main presentations include increased susceptibility to infections (a narrow or broad spectrum of pathogens), autoimmunity, autoinflammation, allergy and/or malignancy. PIDs are increasingly diagnosed and may present with different phenotypes that range from subtle to severe ones. They are classified into ten major categories according to the International Union of Immunological Societies (IUIS). Autosomal recessive disorders are noticeably more common because of the high consanguinity rates in the society. The spectrum of PID is highlighted with a brief walk through the challenges of establishing a PID service in a resource limited setting like catching up with the rapidly changing field, provision of state of the art diagnostic services and actual provision of medical care to PID patients. Several opportunities for growth of the field and overcoming obstacles are discussed.
Autoinflammatory diseases. Part 1: concept, classification, immunobiology, diagnosis
AbstractSystemic autoinflammatory diseases (SAIDs) are a group of inherited monogenic diseases characterized by dysregulated innate immunity leading to excessive activation of inflammatory pathways. Recently, some molecular mechanisms typical for autoinflammation have also been recognized in the pathogenesis of several autoimmune and immunodeficiency states. This scientific review aimed to systematize current ideas about autoinflammatory diseases to increase medical professionals’ awareness regarding the issue, which is significantly lower than that of other categories of immune dysfunction. We performed a focused search over the Web of Science, Scopus, PubMed Central®, Google Scholar databases over the past 10 years using the keywords “autoinflammatory diseases”, “autoinflammatory syndromes”, “autoinflammation”. The review reflects the historical evolution of scientific views on the immunopathogenesis of autoinflammation since the introduction of the concept in 1999: from the interleukin (IL)-1-centered paradigm to recognition of the significant role of other signaling pathways. Further, we discuss the place of autoinflammation in the spectrum of immunological disorders and present current scientific data on the immunobiological basis of autoinflammation. In particular, we review how the innate immune system triggers inflammation within the inflammasome, interferon and nuclear factor kappa B (NF-κB) signaling pathways, highlighting the role of intracellular sensor proteins, inflammasomes, gasdermin D, IL-1β, IL-18 and IL-36, NF-κB, tumor necrosis factor, type 1 interferons, and others. Based on the underlying molecular pathogenesis, the following classification categories of SAIDs have been suggested recently: inflammasomopathies and other enhanced IL-1 signaling syndromes, interferonopathies, relopathies, protein misfolding diseases/endoplasmic reticulum stress syndromes, other cytokine-signaling disorders and complementopathies. The review also discusses diagnostic challenges and presents current scientific recommendations for the diagnosis of SAIDs, highlighting the distinguishing features of the classic autoinflammatory disorders and the existing potential of diagnostic tests.
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.
