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The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

The pentraxin C-reactive protein (CRP) is a pentameric protein now known to be able to undergo dissociation into a monomeric, modified isoform, referred to as mCRP. In carefully assessing the bioactivities of each isoform, mCRP has strong pro-inflammatory activities while pCRP has mild anti-inflammatory activities. Systemic lupus erythematosus (SLE) is a disease characterized by a vast number of autoantibodies, including anti-CRP autoan-tibodies which have been associated with SLE disease activity and lupus nephritis. The origin of these autoan-tibodies is currently unknown. Extracellular vesicles (EVs) have been implicated in SLE pathogenesis as they can expose nuclear antigens on their outside surface, thereby being a potential adjuvant for the generation of au-toantibodies. Herein, we studied exposure of both pCRP and mCRP on EVs in SLE plasma and the implications of each in disease activity, organ damage and clinical manifestations. We used flow cytometry to detect CRP iso-forms on EV surfaces in 67 well-characterized SLE patients and 60 sex-and age-matched healthy controls. Au-toantibodies against mCRP were measured using ELISA. We found an abundance of both pCRP and mCRP on SLE EVs compared to controls. Furthermore, mCRP+ but not pCRP+ EVs were elevated in patients with active disease and in anti-CRP positive patients. The proportions of mCRP+ EVs were lower in patients with acquired organ damage, especially in patients with lupus nephritis (LN), and displayed an inverse relationship with disease duration in LN and patients with active disease. Speculatively, these data suggest EV-bound mCRP as a relevant factor in SLE pathogenesis, which could contribute to development of anti-CRP autoantibodies by stimulating an immune response.

The pentraxin C-reactive protein (CRP) is a pentameric protein now known to be able to undergo dissociation into a monomeric, modified isoform, referred to as mCRP. In carefully assessing the bioactivities of each isoform, mCRP has strong pro-inflammatory activities while pCRP has mild anti-inflammatory activities. Systemic lupus erythematosus (SLE) is a disease characterized by a vast number of autoantibodies, including anti-CRP autoan-tibodies which have been associated with SLE disease activity and lupus nephritis. The origin of these autoan-tibodies is currently unknown. Extracellular vesicles (EVs) have been implicated in SLE pathogenesis as they can expose nuclear antigens on their outside surface, thereby being a potential adjuvant for the generation of au-toantibodies. Herein, we studied exposure of both pCRP and mCRP on EVs in SLE plasma and the implications of each in disease activity, organ damage and clinical manifestations. We used flow cytometry to detect CRP iso-forms on EV surfaces in 67 well-characterized SLE patients and 60 sex-and age-matched healthy controls. Au-toantibodies against mCRP were measured using ELISA. We found an abundance of both pCRP and mCRP on SLE EVs compared to controls. Furthermore, mCRP+ but not pCRP+ EVs were elevated in patients with active disease and in anti-CRP positive patients. The proportions of mCRP+ EVs were lower in patients with acquired organ damage, especially in patients with lupus nephritis (LN), and displayed an inverse relationship with disease duration in LN and patients with active disease. Speculatively, these data suggest EV-bound mCRP as a relevant factor in SLE pathogenesis, which could contribute to development of anti-CRP autoantibodies by stimulating an immune response.

The pentraxin C-reactive protein (CRP) is a pentameric protein now known to be able to undergo dissociation into a monomeric, modified isoform, referred to as mCRP. In carefully assessing the bioactivities of each isoform, mCRP has strong pro-inflammatory activities while pCRP has mild anti-inflammatory activities. Systemic lupus erythematosus (SLE) is a disease characterized by a vast number of autoantibodies, including anti-CRP autoan-tibodies which have been associated with SLE disease activity and lupus nephritis. The origin of these autoan-tibodies is currently unknown. Extracellular vesicles (EVs) have been implicated in SLE pathogenesis as they can expose nuclear antigens on their outside surface, thereby being a potential adjuvant for the generation of au-toantibodies. Herein, we studied exposure of both pCRP and mCRP on EVs in SLE plasma and the implications of each in disease activity, organ damage and clinical manifestations. We used flow cytometry to detect CRP iso-forms on EV surfaces in 67 well-characterized SLE patients and 60 sex-and age-matched healthy controls. Au-toantibodies against mCRP were measured using ELISA. We found an abundance of both pCRP and mCRP on SLE EVs compared to controls. Furthermore, mCRP+ but not pCRP+ EVs were elevated in patients with active disease and in anti-CRP positive patients. The proportions of mCRP+ EVs were lower in patients with acquired organ damage, especially in patients with lupus nephritis (LN), and displayed an inverse relationship with disease duration in LN and patients with active disease. Speculatively, these data suggest EV-bound mCRP as a relevant factor in SLE pathogenesis, which could contribute to development of anti-CRP autoantibodies by stimulating an immune response.

The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

The pentraxin C-reactive protein (CRP) is a pentameric protein now known to be able to undergo dissociation into a monomeric, modified isoform, referred to as mCRP. In carefully assessing the bioactivities of each isoform, mCRP has strong pro-inflammatory activities while pCRP has mild anti-inflammatory activities. Systemic lupus erythematosus (SLE) is a disease characterized by a vast number of autoantibodies, including anti-CRP autoan-tibodies which have been associated with SLE disease activity and lupus nephritis. The origin of these autoan-tibodies is currently unknown. Extracellular vesicles (EVs) have been implicated in SLE pathogenesis as they can expose nuclear antigens on their outside surface, thereby being a potential adjuvant for the generation of au-toantibodies. Herein, we studied exposure of both pCRP and mCRP on EVs in SLE plasma and the implications of each in disease activity, organ damage and clinical manifestations. We used flow cytometry to detect CRP iso-forms on EV surfaces in 67 well-characterized SLE patients and 60 sex-and age-matched healthy controls. Au-toantibodies against mCRP were measured using ELISA. We found an abundance of both pCRP and mCRP on SLE EVs compared to controls. Furthermore, mCRP+ but not pCRP+ EVs were elevated in patients with active disease and in anti-CRP positive patients. The proportions of mCRP+ EVs were lower in patients with acquired organ damage, especially in patients with lupus nephritis (LN), and displayed an inverse relationship with disease duration in LN and patients with active disease. Speculatively, these data suggest EV-bound mCRP as a relevant factor in SLE pathogenesis, which could contribute to development of anti-CRP autoantibodies by stimulating an immune response.

The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

The pentraxin C-reactive protein (CRP) is a pentameric protein now known to be able to undergo dissociation into a monomeric, modified isoform, referred to as mCRP. In carefully assessing the bioactivities of each isoform, mCRP has strong pro-inflammatory activities while pCRP has mild anti-inflammatory activities. Systemic lupus erythematosus (SLE) is a disease characterized by a vast number of autoantibodies, including anti-CRP autoan-tibodies which have been associated with SLE disease activity and lupus nephritis. The origin of these autoan-tibodies is currently unknown. Extracellular vesicles (EVs) have been implicated in SLE pathogenesis as they can expose nuclear antigens on their outside surface, thereby being a potential adjuvant for the generation of au-toantibodies. Herein, we studied exposure of both pCRP and mCRP on EVs in SLE plasma and the implications of each in disease activity, organ damage and clinical manifestations. We used flow cytometry to detect CRP iso-forms on EV surfaces in 67 well-characterized SLE patients and 60 sex-and age-matched healthy controls. Au-toantibodies against mCRP were measured using ELISA. We found an abundance of both pCRP and mCRP on SLE EVs compared to controls. Furthermore, mCRP+ but not pCRP+ EVs were elevated in patients with active disease and in anti-CRP positive patients. The proportions of mCRP+ EVs were lower in patients with acquired organ damage, especially in patients with lupus nephritis (LN), and displayed an inverse relationship with disease duration in LN and patients with active disease. Speculatively, these data suggest EV-bound mCRP as a relevant factor in SLE pathogenesis, which could contribute to development of anti-CRP autoantibodies by stimulating an immune response.

The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

Rapidly progressive immune complex-mediated glomerulonephritis (RPGNMN II) is a clinical syndrome characterized by severe deterioration of renal function associated with hematuria, edema, and oliguria. It is histologically characterized as a crescentic glomerulonephritis, with the presence of granular deposits on immunofluorescence. Although it is a rare condition, it is a potentially serious disease that may progress to chronic renal disease, therefore its early identificationis essential. Here we present a review of this form of glomerulonephritis, with emphasis on its etiology and the currently available therapeutic options., La glomerulonefritis rápidamente progresiva mediada por complejos inmunes (GMNRP II) es un síndrome clínico caracterizado por el rápido deterioro de la función renal asociado a hematuria, edemas y oliguria. Histológicamente se manifiesta como una glomerulonefritis crescéntica, con la presencia de depósitos granulares en la inmunofluorescencia. Aunque es una enfermedad rara, es grave y puede evolucionar a una enfermedad renal crónica, por lo cual es fundamental su identificación temprana. A continuación, se presenta una revisión sobre este tipo de glomerulonefritis, con énfasis en su etiología y en las opciones terapéuticas existentes en la actualidad.

We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-alpha 2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-alpha 2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.

Systemic Lupus Erythematosus (SLE) is a chronic immune complex (IC)-mediated disease with variable prevalence worldwide, reported to be more common in Africans, Hispanics and Asians than in Caucasian populations. Expression of autoantibodies might vary between different ethnic populations due to environmental and genetic factors. Antiphospholipid antibodies (aPL) react with several antigenic targets of negatively charged phospholipids and/or associated plasma proteins. In this thesis we have studied the immunological and clinical characteristics of SLE in patients from Sudan and Sweden using an identical methodology. We have also investigated the occurrence of aPL during healthy pregnancies in both countries. Sudanese patients with SLE were younger, had shorter disease duration and suffered from more organ damage compared to Swedish patients. Neurological involvement, predominantly in young patients, was the main contributor to organ damage among the Sudanese patients. When comparing anti-nuclear antibody (ANA) specificities in IC between Sudanese and Swedish patients, different results from ANA detected in serum was observed. While serum ANA levels were mainly higher in Swedish SLE patients, levels of most ANA specificities in IC, particularly anti-chromatin specificities, were increased in Sudanese patients. In both cohorts, ANA in IC associated with more active SLE. Sudanese SLE patients had a higher prevalence of IgA aPL using common assay cut-off points. However, aPL levels among controls were also higher in Sudan, and when cut-offs were adjusted based on national controls the difference in prevalence between the patient groups was no longer evident. A more recently defined test measuring antibody against the phosphatidylserine/prothrombin complex was the best aPL predictor of thrombosis in Swedish SLE patients, independent of cardiovascular risk factors and antiphospholipid antibody syndrome criteria tests. Levels of IgA aPL, particularly anti-β2 glycoprotein

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by immune complexes. Because these complexes contain mitochondrial components, we assessed the presence of antibodies to whole mitochondria (wMITO) using an ELISA in which mitochondria from mouse liver are bound to microtiter plates pre-coated with poly-L-lysine. Studies with this ELISA demonstrated that SLE plasmas contain abundant anti-wMITO activity. While digestion with DNase 1 did not affect anti-wMITO activity, adsorption of plasma on DNA affinity columns could reduce binding activity. Assay for anti-mitochondrial antibodies (AMA) by immunofluorescence and an ELISA with the M2 antigen (2-oxo-acid dehydrogenase protein complex) showed a low frequency of positivity, indicating that AMA and anti-wMITO are distinct specificities. In the study of 204 patients with SLE, the levels of anti-wMITO were higher in active SLE and correlated with levels of anti-DNA. These findings suggest that anti-wMITO can form immune complexes with mitochondria which may drive pathogenesis.

Systemic Lupus Erythematosus (SLE) is a chronic immune complex (IC)-mediated disease with variable prevalence worldwide, reported to be more common in Africans, Hispanics and Asians than in Caucasian populations. Expression of autoantibodies might vary between different ethnic populations due to environmental and genetic factors. Antiphospholipid antibodies (aPL) react with several antigenic targets of negatively charged phospholipids and/or associated plasma proteins. In this thesis we have studied the immunological and clinical characteristics of SLE in patients from Sudan and Sweden using an identical methodology. We have also investigated the occurrence of aPL during healthy pregnancies in both countries. Sudanese patients with SLE were younger, had shorter disease duration and suffered from more organ damage compared to Swedish patients. Neurological involvement, predominantly in young patients, was the main contributor to organ damage among the Sudanese patients. When comparing anti-nuclear antibody (ANA) specificities in IC between Sudanese and Swedish patients, different results from ANA detected in serum was observed. While serum ANA levels were mainly higher in Swedish SLE patients, levels of most ANA specificities in IC, particularly anti-chromatin specificities, were increased in Sudanese patients. In both cohorts, ANA in IC associated with more active SLE. Sudanese SLE patients had a higher prevalence of IgA aPL using common assay cut-off points. However, aPL levels among controls were also higher in Sudan, and when cut-offs were adjusted based on national controls the difference in prevalence between the patient groups was no longer evident. A more recently defined test measuring antibody against the phosphatidylserine/prothrombin complex was the best aPL predictor of thrombosis in Swedish SLE patients, independent of cardiovascular risk factors and antiphospholipid antibody syndrome criteria tests. Levels of IgA aPL, particularly anti-β2 glycoprotein

We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-alpha 2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-alpha 2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.

We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-alpha 2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-alpha 2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.

Calf bronchopneumonia is accompanied by increased level of circulating immune complexes (CIC), and we analysed size, and protein and lipid constituents of these CIC with an attempt to elucidate the connection between the CIC structural properties and their capacity to modulate leukocyte function. CIC of heathy calves (CICH) and calves with naturally occurring bronchopneumonia (CICD) were isolated by PEG precipitation and analysed by electrophoresis and chromatography. The predominant CIC proteins were IgG, albumin, and transferrin. Affinity isolated serum and CIC IgG coprecipitated several proteins, but only 75 and 80 kDa proteins bound CIC IgG, exclusively. 60 and 65 kDa proteins co-precipitated with CICD IgG, unlike CICH IgG. In both CICH and CICD, oleic acid-containing phospholipids predominated. In CICD, the content of oleic and vaccenic acid was higher than in CICH, while myristic, palmitic, stearic, linoleic and arachidonic acid showed lower content. Dynamic light scattering displayed difference in particle size distribution between CICH and CICD; 1280 nm large particles were present only in CICD. The effect of CICH and CICD on mononuclear cells (MNC) and granulocytes was analysed in vitro. CICH and CICD, with slight difference in intensity, stimulate MNC apoptosis, promote cell cycle arrest of unstimulated MNC, and cell cycle progression of PHA stimulated MNC. Both CIC reduced granulocyte apoptosis after 24 h while after 48 h this effect was detected for CICD only. These results indicate that structural differences of CICH and CICD might interfere with the CIC functional capacity, which we consider important for evaluation of CIC immunoregulatory function.

Calf bronchopneumonia is accompanied by increased level of circulating immune complexes (CIC), and we analysed size, and protein and lipid constituents of these CIC with an attempt to elucidate the connection between the CIC structural properties and their capacity to modulate leukocyte function. CIC of heathy calves (CICH) and calves with naturally occurring bronchopneumonia (CICD) were isolated by PEG precipitation and analysed by electrophoresis and chromatography. The predominant CIC proteins were IgG, albumin, and transferrin. Affinity isolated serum and CIC IgG coprecipitated several proteins, but only 75 and 80 kDa proteins bound CIC IgG, exclusively. 60 and 65 kDa proteins co-precipitated with CICD IgG, unlike CICH IgG. In both CICH and CICD, oleic acid-containing phospholipids predominated. In CICD, the content of oleic and vaccenic acid was higher than in CICH, while myristic, palmitic, stearic, linoleic and arachidonic acid showed lower content. Dynamic light scattering displayed difference in particle size distribution between CICH and CICD; 1280 nm large particles were present only in CICD. The effect of CICH and CICD on mononuclear cells (MNC) and granulocytes was analysed in vitro. CICH and CICD, with slight difference in intensity, stimulate MNC apoptosis, promote cell cycle arrest of unstimulated MNC, and cell cycle progression of PHA stimulated MNC. Both CIC reduced granulocyte apoptosis after 24 h while after 48 h this effect was detected for CICD only. These results indicate that structural differences of CICH and CICD might interfere with the CIC functional capacity, which we consider important for evaluation of CIC immunoregulatory function.

We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-alpha 2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-alpha 2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.

Calf bronchopneumonia is accompanied by increased level of circulating immune complexes (CIC), and we analysed size, and protein and lipid constituents of these CIC with an attempt to elucidate the connection between the CIC structural properties and their capacity to modulate leukocyte function. CIC of heathy calves (CICH) and calves with naturally occurring bronchopneumonia (CICD) were isolated by PEG precipitation and analysed by electrophoresis and chromatography. The predominant CIC proteins were IgG, albumin, and transferrin. Affinity isolated serum and CIC IgG coprecipitated several proteins, but only 75 and 80 kDa proteins bound CIC IgG, exclusively. 60 and 65 kDa proteins co-precipitated with CICD IgG, unlike CICH IgG. In both CICH and CICD, oleic acid-containing phospholipids predominated. In CICD, the content of oleic and vaccenic acid was higher than in CICH, while myristic, palmitic, stearic, linoleic and arachidonic acid showed lower content. Dynamic light scattering displayed difference in particle size distribution between CICH and CICD; 1280 nm large particles were present only in CICD. The effect of CICH and CICD on mononuclear cells (MNC) and granulocytes was analysed in vitro. CICH and CICD, with slight difference in intensity, stimulate MNC apoptosis, promote cell cycle arrest of unstimulated MNC, and cell cycle progression of PHA stimulated MNC. Both CIC reduced granulocyte apoptosis after 24 h while after 48 h this effect was detected for CICD only. These results indicate that structural differences of CICH and CICD might interfere with the CIC functional capacity, which we consider important for evaluation of CIC immunoregulatory function.

Calf bronchopneumonia is accompanied by increased level of circulating immune complexes (CIC), and we analysed size, and protein and lipid constituents of these CIC with an attempt to elucidate the connection between the CIC structural properties and their capacity to modulate leukocyte function. CIC of heathy calves (CICH) and calves with naturally occurring bronchopneumonia (CICD) were isolated by PEG precipitation and analysed by electrophoresis and chromatography. The predominant CIC proteins were IgG, albumin, and transferrin. Affinity isolated serum and CIC IgG coprecipitated several proteins, but only 75 and 80 kDa proteins bound CIC IgG, exclusively. 60 and 65 kDa proteins co-precipitated with CICD IgG, unlike CICH IgG. In both CICH and CICD, oleic acid-containing phospholipids predominated. In CICD, the content of oleic and vaccenic acid was higher than in CICH, while myristic, palmitic, stearic, linoleic and arachidonic acid showed lower content. Dynamic light scattering displayed difference in particle size distribution between CICH and CICD; 1280 nm large particles were present only in CICD. The effect of CICH and CICD on mononuclear cells (MNC) and granulocytes was analysed in vitro. CICH and CICD, with slight difference in intensity, stimulate MNC apoptosis, promote cell cycle arrest of unstimulated MNC, and cell cycle progression of PHA stimulated MNC. Both CIC reduced granulocyte apoptosis after 24 h while after 48 h this effect was detected for CICD only. These results indicate that structural differences of CICH and CICD might interfere with the CIC functional capacity, which we consider important for evaluation of CIC immunoregulatory function.

We investigated whether belimumab treatment impacts on levels of autoantibodies and cytokines of interest in systemic lupus erythematosus (SLE). Longitudinally collected serum samples from 78 belimumab-treated Swedish SLE patients were analysed. Serum cytokine levels were determined using Luminex xMAP technology, and nuclear antigen autoantibody specificities using addressable laser bead immunoassay. In patients with detectable levels at baseline, interferon (IFN)-alpha 2 levels were lower at month 6 (median; interquartile range (IQR): 8.9; 1.5-54.9 pg/mL) versus baseline (28.4; 20.9-100.3 pg/mL; p = 0.043). Interleukin (IL)-6 (baseline: 7.1; 2.9-16.1 pg/mL) decreased from month 6 (0.5; 0.5-6.3 pg/mL; p = 0.018) and throughout a 24 month follow-up. IL-10 (baseline: 12.6; 2.8-29.7 pg/mL) showed more rapid decreases from month 3 (1.8; 0.6-9.1 pg/mL; p = 0.003). Levels of anti-dsDNA (p < 0.001), anti-Smith antigen (Sm) (p = 0.002), anti-U1 small nuclear ribonucleoprotein (U1RNP) (p < 0.001), anti-Sm-U1RNP complex (p = 0.028), and anti-ribosomal P (p = 0.012) antibodies decreased from month 3 and remained decreased. Anti-Sm positivity at baseline was associated with higher probability and/or shorter time to achieve sustained SLE responder index-4 response (hazard ratio (HR): 2.52; 95% CI: 1.20-5.29; p = 0.015), independently of other factors. Decline of IL-6 levels through month 3 was greater in responders. In summary, belimumab treatment lowered IFN-alpha 2, IL-6, and IL-10 levels, as well as levels of multiple autoantibodies, however after different time spans. Notably, anti-Sm positivity and early decline in IL-6 levels were associated with favorable treatment outcome.

Introduction: Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in circulating IC might be of prognostic value. Methods: A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment. Results: High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1-2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers. Conclusion: Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lu

Introduction: Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in circulating IC might be of prognostic value. Methods: A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment. Results: High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1-2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers. Conclusion: Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lu

Introduction: Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in circulating IC might be of prognostic value. Methods: A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment. Results: High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1-2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers. Conclusion: Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lu

Immune complex (IC) vaccines have been successfully used to increase immune responses against various pathogens, including HIV-1. Additionally, IC vaccines can induce qualitatively different antibody responses, with distinct antigenic specificities compared to the same antigens used alone. Here we measured the HIV-1-specific antibody responses in female New Zealand White rabbits after immunization with ICs made from BG505 SOSIP.664 trimers (BG505 trimers) and three rabbit monoclonal antibodies (MAbs) with different neutralization profiles. Two of the MAbs were specific for a hole in the glycan shield of the BG505 trimer, while the third, which bound less avidly, was specific for determinants at the gp41-gp120 interface. We found that immunization with one of the glycan-hole-specific ICs resulted in lower levels of trimer-binding antibodies compared to vaccination with the uncomplexed trimer, and that ICs made using either of the glycan-hole-specific MAbs resulted in lower rates of anti-trimer antibody decay. We concluded that ICs based on MAbs that bound to the immunodominant glycan hole epitope likely diverted antibody responses, to some extent, away from this site and to other regions of the trimer. However, this outcome was not accompanied by a widening of the breadth or an increase in the potency of neutralizing antibody responses compared with uncomplexed trimers.IMPORTANCE Immunodominant epitopes may suppress immune responses to more desirable determinants, such as those that elicit potentially protective neutralizing antibody responses. To overcome this problem, we attempted to mask immunodominant glycan holes by immunizing rabbits with ICs consisting of the BG505 SOSIP.664 gp140 trimer and MAbs that targeted the glycan holes. We found that IC vaccination likely diverted antibody responses, to some extent, away from the glycan holes and toward other regions of the trimer. IC vaccination resulted in slower decay of HIV-1-specific antibodies than did immunizati

Introduction: Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in circulating IC might be of prognostic value. Methods: A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment. Results: High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1-2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers. Conclusion: Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lu

Introduction: Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in circulating IC might be of prognostic value. Methods: A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment. Results: High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1-2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers. Conclusion: Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lu

Experimental studies have shown that the size and infectious-stage of viral inoculum influence disease outcomes in rhesus macaques infected with simian immunodeficiency virus. The possible contribution to disease outcome of antibody developed after transmission and/or present in the inoculum in free or bound form is not understood. In this study, we develop a mathematical model of virus-antibody immune complex formation and use it to predict their role in transmission and protection. The model exhibits a bistable switch between clearance and persistence states. We fitted it to temporal virus data and estimated the parameter values for free virus infectivity rate and antibody carrying capacity for which the model transitions between virus clearance and persistence when the initial conditions (in particular the ratio of immune complexes to free virus) vary. We used these results to quantify the minimum virus amount in the inoculum needed to establish persistent infections in the presence and absence of protective antibodies.

Experimental studies have shown that the size and infectious-stage of viral inoculum influence disease outcomes in rhesus macaques infected with simian immunodeficiency virus. The possible contribution to disease outcome of antibody developed after transmission and/or present in the inoculum in free or bound form is not understood. In this study, we develop a mathematical model of virus-antibody immune complex formation and use it to predict their role in transmission and protection. The model exhibits a bistable switch between clearance and persistence states. We fitted it to temporal virus data and estimated the parameter values for free virus infectivity rate and antibody carrying capacity for which the model transitions between virus clearance and persistence when the initial conditions (in particular the ratio of immune complexes to free virus) vary. We used these results to quantify the minimum virus amount in the inoculum needed to establish persistent infections in the presence and absence of protective antibodies.

Experimental studies have shown that the size and infectious-stage of viral inoculum influence disease outcomes in rhesus macaques infected with simian immunodeficiency virus. The possible contribution to disease outcome of antibody developed after transmission and/or present in the inoculum in free or bound form is not understood. In this study, we develop a mathematical model of virus-antibody immune complex formation and use it to predict their role in transmission and protection. The model exhibits a bistable switch between clearance and persistence states. We fitted it to temporal virus data and estimated the parameter values for free virus infectivity rate and antibody carrying capacity for which the model transitions between virus clearance and persistence when the initial conditions (in particular the ratio of immune complexes to free virus) vary. We used these results to quantify the minimum virus amount in the inoculum needed to establish persistent infections in the presence and absence of protective antibodies.

Experimental studies have shown that the size and infectious-stage of viral inoculum influence disease outcomes in rhesus macaques infected with simian immunodeficiency virus. The possible contribution to disease outcome of antibody developed after transmission and/or present in the inoculum in free or bound form is not understood. In this study, we develop a mathematical model of virus-antibody immune complex formation and use it to predict their role in transmission and protection. The model exhibits a bistable switch between clearance and persistence states. We fitted it to temporal virus data and estimated the parameter values for free virus infectivity rate and antibody carrying capacity for which the model transitions between virus clearance and persistence when the initial conditions (in particular the ratio of immune complexes to free virus) vary. We used these results to quantify the minimum virus amount in the inoculum needed to establish persistent infections in the presence and absence of protective antibodies.

Experimental studies have shown that the size and infectious-stage of viral inoculum influence disease outcomes in rhesus macaques infected with simian immunodeficiency virus. The possible contribution to disease outcome of antibody developed after transmission and/or present in the inoculum in free or bound form is not understood. In this study, we develop a mathematical model of virus-antibody immune complex formation and use it to predict their role in transmission and protection. The model exhibits a bistable switch between clearance and persistence states. We fitted it to temporal virus data and estimated the parameter values for free virus infectivity rate and antibody carrying capacity for which the model transitions between virus clearance and persistence when the initial conditions (in particular the ratio of immune complexes to free virus) vary. We used these results to quantify the minimum virus amount in the inoculum needed to establish persistent infections in the presence and absence of protective antibodies.

Деформація копитець у корів супроводжується дистрофічно-запальними змінами в структурах копитець, у виникненні і перебігу яких вирішальну роль відіграють циркулюючі імунні комплекси, внаслідок чого при запущеній деформації копитець виникає імунокомплексний дифузний пододерматит., Деформация копытец у коров сопровождается дистрофическими и воспалительными изменениями в структурах копытец, в возникновении и течение которых решающую роль играют циркулирующие иммунные комплексы, вследствие чего при запущенной деформации копытец возникает иммуннокомплексный диффузный пододерматит., The deformation of cows hooves deformation is accompanied by degenerative and inflammatory changes in their structures, in origin and coarse of which the decisive role play the circulating immune complexes, and as a result in case of advanced hooves deformation it follows by immune complexes diffuse pododermatitis.

Деформація копитець у корів супроводжується дистрофічно-запальними змінами в структурах копитець, у виникненні і перебігу яких вирішальну роль відіграють циркулюючі імунні комплекси, внаслідок чого при запущеній деформації копитець виникає імунокомплексний дифузний пододерматит., Деформация копытец у коров сопровождается дистрофическими и воспалительными изменениями в структурах копытец, в возникновении и течение которых решающую роль играют циркулирующие иммунные комплексы, вследствие чего при запущенной деформации копытец возникает иммуннокомплексный диффузный пододерматит., The deformation of cows hooves deformation is accompanied by degenerative and inflammatory changes in their structures, in origin and coarse of which the decisive role play the circulating immune complexes, and as a result in case of advanced hooves deformation it follows by immune complexes diffuse pododermatitis.

Rheumatoid arthritis (RA) patients with early elevations of antibodies against collagen type II (CII) have a distinct acute onset phenotype, associated with cytokine induction by surface-bound anti-CII-containing immune complexes (ICs) and high C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Polymorphonuclear granulocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) are abundant in the vicinity of CII in RA joints, and both PMN and PBMC reactivity against anti-CII IC individually relate to early joint destruction and early elevation of CRP and ESR in RA. We searched for CII-dependent mechanisms that might attract PMNs and PBMCs to RA joints. Human PBMCs and PMNs were stimulated with anti-CII ICs and control ICs, either individually or in cocultures. Cocultured PMNs and PBMCs stimulated with anti-CII ICs synergistically augmented production of the chemokines CXCL8, RANTES and MCP-1, whereas downregulation was seen with control IC. This upregulation was unique to chemokines, as TNF-α, IL-1β, and GM-CSF were downregulated in anti-CII IC-stimulated cocultures. The coculture-associated chemokine upregulation depended on endogenous TLR4 ligand(s) and functionally active PMN enzymes, and was partially mediated by GM-CSF. As anti-CII levels peak around the time of RA diagnosis, this mechanism can attract inflammatory cells to joints in early RA and intensify the anti-CII-associated acute onset RA phenotype.

Rheumatoid arthritis (RA) patients with early elevations of antibodies against collagen type II (CII) have a distinct acute onset phenotype, associated with cytokine induction by surface-bound anti-CII-containing immune complexes (ICs) and high C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Polymorphonuclear granulocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) are abundant in the vicinity of CII in RA joints, and both PMN and PBMC reactivity against anti-CII IC individually relate to early joint destruction and early elevation of CRP and ESR in RA. We searched for CII-dependent mechanisms that might attract PMNs and PBMCs to RA joints. Human PBMCs and PMNs were stimulated with anti-CII ICs and control ICs, either individually or in cocultures. Cocultured PMNs and PBMCs stimulated with anti-CII ICs synergistically augmented production of the chemokines CXCL8, RANTES and MCP-1, whereas downregulation was seen with control IC. This upregulation was unique to chemokines, as TNF-α, IL-1β, and GM-CSF were downregulated in anti-CII IC-stimulated cocultures. The coculture-associated chemokine upregulation depended on endogenous TLR4 ligand(s) and functionally active PMN enzymes, and was partially mediated by GM-CSF. As anti-CII levels peak around the time of RA diagnosis, this mechanism can attract inflammatory cells to joints in early RA and intensify the anti-CII-associated acute onset RA phenotype.

Rheumatoid arthritis (RA) patients with early elevations of antibodies against collagen type II (CII) have a distinct acute onset phenotype, associated with cytokine induction by surface-bound anti-CII-containing immune complexes (ICs) and high C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Polymorphonuclear granulocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) are abundant in the vicinity of CII in RA joints, and both PMN and PBMC reactivity against anti-CII IC individually relate to early joint destruction and early elevation of CRP and ESR in RA. We searched for CII-dependent mechanisms that might attract PMNs and PBMCs to RA joints. Human PBMCs and PMNs were stimulated with anti-CII ICs and control ICs, either individually or in cocultures. Cocultured PMNs and PBMCs stimulated with anti-CII ICs synergistically augmented production of the chemokines CXCL8, RANTES and MCP-1, whereas downregulation was seen with control IC. This upregulation was unique to chemokines, as TNF-α, IL-1β, and GM-CSF were downregulated in anti-CII IC-stimulated cocultures. The coculture-associated chemokine upregulation depended on endogenous TLR4 ligand(s) and functionally active PMN enzymes, and was partially mediated by GM-CSF. As anti-CII levels peak around the time of RA diagnosis, this mechanism can attract inflammatory cells to joints in early RA and intensify the anti-CII-associated acute onset RA phenotype.

Neutrophils have traditionally been thought to play only a peripheral role in the genesis of many autoimmune and inflammatory diseases. However, recent studies in a variety of animal models suggest that these cells are central to the initiation and propagation of autoimmunity. The use of mouse models, which allow either deletion of neutrophils or the targeting of specific neutrophil functions, has revealed the many complex ways these cells contribute to autoimmune/inflammatory processes. This includes generation of self antigens through the process of NETosis, regulation of T-cell and dendritic cell activation, production of cytokines such as BAFF that stimulate self-reactive B-cells, as well as indirect effects on epithelial cell stability. In comparing the many different autoimmune models in which neutrophils have been examined, a number of common underlying themes emerge - such as a role for neutrophils in stimulating vascular permeability in arthritis, encephalitis and colitis. The use of animal models has also stimulated the development of new therapeutics that target neutrophil functions, such as NETosis, that may prove beneficial in human disease. This review will summarize neutrophil contributions in a number of murine autoimmune/inflammatory disease models.

Neutrophils have traditionally been thought to play only a peripheral role in the genesis of many autoimmune and inflammatory diseases. However, recent studies in a variety of animal models suggest that these cells are central to the initiation and propagation of autoimmunity. The use of mouse models, which allow either deletion of neutrophils or the targeting of specific neutrophil functions, has revealed the many complex ways these cells contribute to autoimmune/inflammatory processes. This includes generation of self antigens through the process of NETosis, regulation of T-cell and dendritic cell activation, production of cytokines such as BAFF that stimulate self-reactive B-cells, as well as indirect effects on epithelial cell stability. In comparing the many different autoimmune models in which neutrophils have been examined, a number of common underlying themes emerge - such as a role for neutrophils in stimulating vascular permeability in arthritis, encephalitis and colitis. The use of animal models has also stimulated the development of new therapeutics that target neutrophil functions, such as NETosis, that may prove beneficial in human disease. This review will summarize neutrophil contributions in a number of murine autoimmune/inflammatory disease models.

Congenital infection with cytomegalovirus (CMV) represents the leading cause of maternal fetal infection, also is the leading cause of childhood deafness worldwide. Infected women can present a large number of events or asymptomatic. Most newborns and infants are asymptomatic at birth, but can present late sequelae such as mental retardation, learning disabilities, cerebral palsy, epilepsy, partial or total deafness or blindness and visual deficits. Mother diagnosis is based on the presence of antibodies in blood and fetal diagnosis is based on detection of immunocomplexes in amniotic fluid. Treatment during pregnancy has been used antiviral drugs such as ganciclovir and valganciclovir orally., La infección congénita por el citomegalovirus (CMV) representa la principal causa de infección materna fetal y es la principal causa de sordera infantil a nivel mundial. Las mujeres infectadas pueden presentar un gran número de manifestaciones o ser asintomáticas. La mayoría de recién nacidos y lactantes se encuentran asintomáticos al nacer, pero pueden presentar secuelas tardías como retardo mental, discapacidades en el aprendizaje, parálisis cerebral, epilepsia, sordera total o parcial y déficit visual o ceguera. El diagnóstico de la madre se basa en la presencia de anticuerpos en sangre y el diagnóstico fetal se basa en la detección de inmunocomplejos en líquido amniótico. El tratamiento durante el embarazo se ha utilizado antivirales como el ganciclovir y su forma oral valganciclovir.

Immune complex (IC) deposition in the glomerular basement membrane (GBM) is a key early pathogenic event in lupus nephritis (LN). The clarification of the mechanisms behind IC deposition will enable targeted therapy in the future. Circulating cell-derived microparticles (MPs) have been proposed as major sources of extracellular autoantigens and ICs and triggers of autoimmunity in LN. The overabundance of galectin-3-binding protein (G3BP) along with immunoglobulins and a few other proteins specifically distinguish circulating MPs in patients with systemic lupus erythematosus (SLE), and this is most pronounced in patients with active LN. G3BP co-localizes with deposited ICs in renal biopsies from LN patients supporting a significant presence of MPs in the IC deposits. G3BP binds strongly to glomerular basement membrane proteins and integrins. Accordingly, MP surface proteins, especially G3BP, may be essential for the deposition of ICs in kidneys and thus for the ensuing formation of MP-derived electron dense structures in the GBM, and immune activation in LN. This review focuses on the notion of targeting surface molecules on MPs as an entirely novel treatment strategy in LN. By targeting MPs, a double hit may be achieved by attenuating both the autoantigenic fueling of immune complexes and the triggering of the adaptive immune system. Thereby, early pathogenic events may be blocked in contrast to current treatment strategies that primarily target and modulate later events in the cellular and humoral immune response.

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease. HTLV-1 Related Endogenous Sequence (HRES-1), a human endogenous retrovirus, produces 2 retroviral-like Gag capsid proteins (p8 and p15) that share significant sequence homology to the U1-subunit of the small ribonucleoprotein complex (U1sn-RNP), an autoantigen of lupus. The central hypothesis is that molecular mimicry between HRES-1 and U1sn-RNP serves as a priming event in SLE via the production of cross-reactive autoantibodies. Anti-HRES-1/U1sn-RNP serological responses in subjects with SLE and comparison populations were characterized. An overlapping peptide set mapping the HRES-1 p8 and p15 proteins was used. SLE subjects produce IgG to several regions of HRES-1. Healthy subjects or those with RA, HIV-1 infection, or HTLV-1-infection produced no significant anti-HRES-1 IgG. Anti-HRES-1 antibodies deposited in the kidneys of patients with SLE glomerulonephritis were identified. Our data suggests that HRES-1 plays a role in SLE by means of a molecular mimicry mechanism with U1sn-RNP.

To what extent different autoantibodies accumulate in systemic lupus erythematosus (SLE) immune complexes (ICs), and whether such accumulation is associated with disease activity has been investigated. ICs were isolated from SLE sera by both polyethylene glycol (PEG) precipitation and C1q-binding. Autoantibody specificities were determined using a lineblot assay quantified by densitometry. To compare the relative levels of autoantibodies, levels were normalized to the total levels of IgG measured by ELISA in sera and parallel ICs. Samples were investigated both in a cross-sectional design as well as in a paired design with samples obtained during both active and inactive SLE. All investigated autoantibody specificities except anti-dsDNA were enriched in circulating ICs as compared with parallel sera. The group of antibodies against RNA-associated antigens (anti-RNP/Sm, anti-Sm, anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB/La) all exhibited higher median enrichment than the DNA-associated (anti-dsDNA, anti-histones, anti-nucleosomes) or cytoplasmic (anti-ribosomal P) antigens. In particular autoantibodies against RNP/Sm and SSA/Ro52 had the highest degree of enrichment in SLE PEG precipitates. These findings were corroborated by analysis of autoantibody content in C1q-bound ICs. There was no difference in degree of IC accumulation of the investigated autoantibodies during active and inactive SLE. Our findings demonstrate a difference in enrichment between autoantibodies against RNA- and DNA-associated autoantigens in isolated SLE IC, suggesting that the RNA-associated autoantibodies are more prone to form circulating ICs in SLE, in contrast to antibodies against DNA-associated autoantigens such as dsDNA. These finding have implications in understanding mechanisms of differential autoantibody accumulation in target organs in SLE.

Patients with primary Sjögren's syndrome (pSS) have an activated type I interferon (IFN) system that contribute to the etiopathogenesis and clinical manifestations of the disease. The type I IFN system consists of the stimuli for type I IFN production, the receptors, cells and transcription factors involved in the synthesis of type I IFNs, the type I IFN-receptor and the effects on target cells. Increased type I IFN activity has been demonstrated in sera from patients with pSS and IFN-α, the main type I IFN, has been detected in the minor salivary glands. Gene expression profiling of peripheral blood mononuclear cells (PBMCs) and minor salivary glands from pSS patients display an up-regulation of type I IFN-induced genes, an "IFN signature". The professional IFN-α producing plasmacytoid dendritic cell (pDC) shows a reduced frequency in the peripheral blood, but has been detected in the salivary glands, possibly due to tissue recruitment. Polymorphisms in the interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) genes in the type I IFN system, are associated with increased risk for pSS. A postulated disease model is that an initial viral infection induces type I IFN production in the salivary glands with subsequent activation of the adaptive immune system resulting in the production of autoantibodies against the RNA-binding proteins SSA/SSB/RNP. Interferogenic immune complexes are formed, which trigger the pDCs to an ongoing type I IFN production, which sustain the disease process. Potential therapeutic targets can be identified within the type I IFN system.

Immune complexes (IC) could have an important role in the pathogenesis of pre-ruminant calves' bronchopneumonia. IC are potent activators of complement and neutrophils and they might be responsible for immune protection, as well as for pulmonary damage. Immunoglobulin G (IgG), as constituents of IC, initiates the effector phase of immune response through binding of Fc gamma and complement receptors. The oligosaccharide moieties expressed on IgG can modulate their antigen affinity and effector function. Structural characteristics of IgG molecules from IC in the pre-ruminant calves have not been studied in detail. The aim of our study was to determine if the glycosylation profile of IgG from circulating IC (CIC) in calves with bronchopneumonia differed from those of healthy control calves. A total number of 13 Holstein-Friesian calves, at the age of three months were included in the study. All calves were clinically examined by a veterinarian. Calves were classified by signs of respiratory disease in two groups: healthy (n = 6) and diseased (n = 7) calves. The CIC from calves' sera were isolated by the polyethylene glycol precipitation (PEG) method. IgG molecules were isolated from PEG precipitates by Protein G affinity method. The level of expression and localization N-acetylglucosamine, galactose, sialic acid, and fucose within the isolated IgG was determined by lectin blot assay. Calves with bronchopneumonia had a statistically significantly increased level of CIC. IgG molecule:, were isolated from CIC of both healthy and diseased calves. Several other proteins in complex with IgG were detected in both groups of animals. The isolated IgG heavy chains of healthy calves expressed N-acetylglucosamine, galactose, sialic acid, and fucose. The light chains of IgG expressed N-acetylglucosamine, sialic acid, and fucose whereas galactose was not detected in healthy calves. In diseased animals, galactose was detected on light chains, and both heavy and light IgG chains were

Immune complexes (IC) could have an important role in the pathogenesis of pre-ruminant calves bronchopneumonia. IC are potent activators of complement and neutrophils and they might be responsible for immune protection, as well as for pulmonary damage. Immunoglobulin G (IgG), as constituents of IC, initiates the effector phase of immune response through binding of Fc gamma and complement receptors. The oligosaccharide moieties expressed on IgG can modulate their antigen affinity and effector function. Structural characteristics of IgG molecules from IC in the pre-ruminant calves have not been studied in detail. The aim of our study was to determine if the glycosylation profile of IgG from circulating IC (CIC) in calves with bronchopneumonia differed from those of healthy control calves. A total number of 13 Holstein-Friesian calves, at the age of three months were included in the study. All calves were clinically examined by a veterinarian. Calves were classified by signs of respiratory disease in two groups: healthy (n = 6) and diseased (n = 7) calves. The CIC from calves sera were isolated by the polyethylene glycol precipitation (PEG) method. IgG molecules were isolated from PEG precipitates by Protein G affinity method. The level of expression and localization N-acetylglucosamine, galactose, sialic acid, and fucose within the isolated IgG was determined by lectin blot assay. Calves with bronchopneumonia had a statistically significantly increased level of CIC. IgG molecule:, were isolated from CIC of both healthy and diseased calves. Several other proteins in complex with IgG were detected in both groups of animals. The isolated IgG heavy chains of healthy calves expressed N-acetylglucosamine, galactose, sialic acid, and fucose. The light chains of IgG expressed N-acetylglucosamine, sialic acid, and fucose whereas galactose was not detected in healthy calves. In diseased animals, galactose was detected on light chains, and both heavy and light IgG chains were mo

Immune complexes (IC) could have an important role in the pathogenesis of pre-ruminant calves bronchopneumonia. IC are potent activators of complement and neutrophils and they might be responsible for immune protection, as well as for pulmonary damage. Immunoglobulin G (IgG), as constituents of IC, initiates the effector phase of immune response through binding of Fc gamma and complement receptors. The oligosaccharide moieties expressed on IgG can modulate their antigen affinity and effector function. Structural characteristics of IgG molecules from IC in the pre-ruminant calves have not been studied in detail. The aim of our study was to determine if the glycosylation profile of IgG from circulating IC (CIC) in calves with bronchopneumonia differed from those of healthy control calves. A total number of 13 Holstein-Friesian calves, at the age of three months were included in the study. All calves were clinically examined by a veterinarian. Calves were classified by signs of respiratory disease in two groups: healthy (n = 6) and diseased (n = 7) calves. The CIC from calves sera were isolated by the polyethylene glycol precipitation (PEG) method. IgG molecules were isolated from PEG precipitates by Protein G affinity method. The level of expression and localization N-acetylglucosamine, galactose, sialic acid, and fucose within the isolated IgG was determined by lectin blot assay. Calves with bronchopneumonia had a statistically significantly increased level of CIC. IgG molecule:, were isolated from CIC of both healthy and diseased calves. Several other proteins in complex with IgG were detected in both groups of animals. The isolated IgG heavy chains of healthy calves expressed N-acetylglucosamine, galactose, sialic acid, and fucose. The light chains of IgG expressed N-acetylglucosamine, sialic acid, and fucose whereas galactose was not detected in healthy calves. In diseased animals, galactose was detected on light chains, and both heavy and light IgG chains were mo