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Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance.

ABSTRACT: The transformation from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is thought to be associated with changes in immune processes. We have therefore used serologic analysis of recombinant cDNA expression library to screen the sera of MGUS patients to identify tumor-associated antigens. A total of 10 antigens were identified, with specific antibody responses in MGUS. Responses appeared to be directed against intracellular proteins involved in cellular functions, such as apoptosis (SON, IFT57/HIPPI), DNA and RNA binding (ZNF292, GPATCH4), signal transduction regulators (AKAP11), transcriptional corepressor (IRF2BP2), developmental proteins (OFD1), and proteins of the ubiquitin-proteasome pathway (PSMC1). Importantly, the gene responsible for the oral-facial-digital type I syndrome (OFD1) had response in 6 of 29 (20.6%) MGUS patients but 0 of 11 newly diagnosed MM patients. Interestingly, 3 of 11 (27.2%) MM patients after autologous stem cell transplantations showed responses to OFD1. We have confirmed T-cell responses against OFD1 in MGUS and observed down-regulation of GLI1/PTCH1 and p-beta-catenin after OFD1 knock-down with specific siRNA, suggesting its functional role in the regulation of Hh and Wnt pathways. These findings demonstrate OFD1 as an important immune target and highlight its possible role in signal transduction and tumorigenesis in MGUS and MM.

SUBMITTER: Blotta S

PROVIDER: S-EPMC2759650 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance.

Blotta Simona S Tassone Pierfrancesco P Prabhala Rao H RH Tagliaferri Piersandro P Cervi David D Amin Samir S Jakubikova Jana J Tai Yu-Tzu YT Podar Klaus K Mitsiades Constantine S CS Zullo Alessandro A Franco Brunella B Anderson Kenneth C KC Munshi Nikhil C NC

Blood 20090708 15

The transformation from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is thought to be associated with changes in immune processes. We have therefore used serologic analysis of recombinant cDNA expression library to screen the sera of MGUS patients to identify tumor-associated antigens. A total of 10 antigens were identified, with specific antibody responses in MGUS. Responses appeared to be directed against intracellular proteins involved in cellular functio ...[more]

PMID: 19587378

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Project description:ImportanceMultiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). Risk models that estimate the risk of progression from MGUS to multiple myeloma use data from a single time point, usually the initial workup.ObjectiveTo longitudinally investigate the alterations of serum immune markers with stable vs progressive MGUS.Design, setting, and participantsThis prospective cross-sectional cohort study included 77 469 adult participants aged 55 to 74 years in the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnosis of progressing MGUS (n = 187) or stable MGUS (n = 498), including light-chain subtype, from November 1993, through December 2011. For each participant, all available serially stored prediagnostic serum samples (N = 3266) were obtained. Data analysis was performed from April 2018, to December 2018.Main outcomes and measuresSerum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class were measured.ResultsOf 685 individuals included in the study, 461 (67.3%) were men; the mean (SD) age was 69.1 (5.6) years. In cross-sectional modeling, risk factors associated with progressive MGUS were IgA isotype (adjusted odds ratio [OR], 1.80; 95% CI, 1.03-3.13; P = .04), 15 g/L or more monoclonal spike (adjusted OR, 23.5; 95% CI, 8.9-61.9; P < .001), skewed (<0.1 or >10) serum free light chains ratio (adjusted OR, 46.4; 95% CI, 18.4-117.0; P < .001), and severe immunoparesis (≥2 suppressed uninvolved immunoglobulins) (adjusted OR, 19.1; 95% Cl, 7.5-48.3; P < .001). Risk factors associated with progressive light-chain MGUS were skewed serum free light chains ratio (adjusted OR, 44.0; 95% CI, 14.2-136.3; P < .001) and severe immunoparesis (adjusted OR, 48.6; 95% CI, 9.5-248.2; P < .001). In longitudinal analysis of participants with serial samples prior to progression, 23 of 43 participants (53%) had high-risk MGUS before progression; 16 of these 23 (70%) experienced conversion from low-risk or intermediate-risk MGUS within 5 years. Similar results were found for light-chain MGUS.Conclusions and relevanceThe findings of evolving risk patterns support annual blood testing and risk assessment for patients with MGUS or light-chain MGUS.

Dataset Information

Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance.

Publications

Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance.

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