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In immune aplastic anemia (IAA), severe pancytopenia results from the immune-mediated destruction of hematopoietic stem cells. Several autoantibodies have been reported, but no clinically applicable autoantibody tests are available for IAA. We screened autoantibodies using a microarray containing >9000 proteins and validated the findings in a large international cohort of IAA patients (n = 405) and controls (n = 815). We identified a novel autoantibody that binds to the C-terminal end of cyclooxygenase 2 (COX-2, aCOX-2 Ab). In total, 37% of all adult IAA patients tested positive for aCOX-2 Ab, while only 1.7% of the controls were aCOX-2 Ab positive. Sporadic non-IAA aCOX-2 Ab positive cases were observed among patients with related bone marrow failure diseases, multiple sclerosis, and type I diabetes, whereas no aCOX-2 Ab seropositivity was detected in the healthy controls, in patients with non-autoinflammatory diseases or rheumatoid arthritis. In IAA, anti-COX-2 Ab positivity correlated with age and the HLA-DRB1*15:01 genotype. 83% of the >40 years old IAA patients with HLA-DRB1*15:01 were anti-COX-2 Ab positive, indicating an excellent sensitivity in this group. aCOX-2 Ab positive IAA patients also presented lower platelet counts. Our results suggest that aCOX-2 Ab defines a distinct subgroup of IAA and may serve as a valuable disease biomarker.

In immune aplastic anemia (IAA), severe pancytopenia results from the immune-mediated destruction of hematopoietic stem cells. Several autoantibodies have been reported, but no clinically applicable autoantibody tests are available for IAA. We screened autoantibodies using a microarray containing > 9 000 proteins and validated the findings in a large international cohort of IAA patients (n = 405) and controls (n = 815). We identified a novel autoantibody that binds to the C-terminal end of cyclo-oxygenase 2 (COX-2, aCOX-2 Ab). 37% of all adult IAA patients tested positive for aCOX-2 Ab, while only 1.7% of the controls were aCOX-2 Ab positive. Sporadic non-IAA aCOX-2 Ab positive cases were observed among patients with related bone marrow failure diseases, multiple sclerosis, and type I diabetes, whereas no aCOX-2 Ab seropositivity was detected in the healthy controls, in patients with non-autoinflammatory diseases or rheumatoid arthritis. In IAA, anti-COX-2 Ab positivity correlated with age and the HLA-DRB1*15:01 genotype. 83% of the > 40 years old IAA patients with HLA-DRB1*15:01 were anti-COX-2 Ab positive, indicating an excellent sensitivity in this group. aCOX-2 Ab positive IAA patients also presented lower platelet counts. Our results suggest that aCOX-2 Ab defines a distinct subgroup of IAA and may serve as a valuable diagnostic tool.

Ion exchange has not been extensively studied nor industrially used for recovering small amounts of silver from concentrated base metal-chloride solutions. A novel multistep process utilizing a weak anion exchanger with polyamine functionality is proposed and its performance was investigated experimentally. Suitability of a silica based polyamine functional resin WP-1 to the task was demonstrated by comparing Ag uptake and selectivity of several ion exchange resins and adsorbents using batch equilibrium experiments. HCl was found to be the best choice for washing impurities, especially Cu, from the bed after the loading step. Tetrasodium salt of EDTA was found suitable especially for selective desorption of lead from the loaded bed, but also other impurities were scrubbed if still present after the wash. Both thiosulfate and thiourea were shown to be effective for elution of Ag from the WP-1 bed, but thiourea is preferred because of the slight affinity of thiosulfate towards the resin. Stability of the performance of the process was shown in several consecutive adsorption–elution cycles containing all the needed washing and scrubbing steps. With the developed process, 72% pure silver product was obtained. As the washing step can be designed such that no silver is lost, the recovery yield for Ag depends only on the length of the loading step, and even 100% recovery can thus be achieved for the whole process. Post-print / Final draft

Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCR beta) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCR beta signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients. Funding Agencies|European Research CouncilEuropean Research Council (ERC) [M-IMM 647355, STRATIFY 862011, DynaOmics 677943]; Academy of Finland Heal-Art consortium [314442]; ERA PerMed (JAKSTAT-TARGET consortium); Finnish Medical foundation; Instrumentarium Science foundation; Biomedicum Helsinki foundation; Orion research foundation; Juhani Aho foundation; K. Albin Johansson foundation; Paulo foundation; Region Ostergotland (ALF grants); European UnionEuropean Union (EU) [675395]; Tekes the Finnish Funding Agency for InnovationFinnish Funding Agency for Technology & Innovation (TEKES) [1877/31/2016]; Sigrid Juselius FoundationSigrid Juselius Foundation; Finska Lakaresallskapet; Liv ochHalsa Foundation; Maire Lisko foundation