Immunol Res (2015) 61:104–106 DOI 10.1007/s12026-014-8611-3
GUEST EDITORIAL
Diagnostics and environmental factors Elias Toubi
Published online: 31 December 2014 Ó Springer Science+Business Media New York 2014
This volume of Immunological Research focuses on some of the environmental factors that are relevant to immune mediated/autoimmune diseases. It also presents the modern diagnostic approach including automatic tools for the diagnosis of autoimmune diseases. One of these factors is vitamin D, proven in many studies to be involved in many diseases including cardiovascular, cancer and immune mediated in origin. Vitamin D deficiency was linked by many to be associated with systemic lupus erythematosus (SLE) disease activity or the development of atherosclerosis. Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for the above spectrum of diseases [1–3]. With this in mind, vitamin D deficiency is reported by Yehuda Shoenfeld to be in association with autoimmune thyroid diseases (AITD). Here, low serum levels of 25 (OH) D are found in Hashimoto thyroiditis when compared to that in normal individuals. In this respect, low serum levels of 25 (OH) D were also correlated with disease duration, thyroid volume and antibody levels. Additionally, low serum levels of vitamin D were also found in Grave’s disease and to be associated with diseases severity. These findings are a further clue to how vitamin D deficiency and autoimmune diseases are linked and to the possible role of vitamin D supplementation in these diseases. In another study by Y. Shoenfeld, vitamin D deficiency was also found to exist in patients with primary biliary cirrhosis (PBC) in association with diseases activity and to be reversible following the treatment with ursodeoxycholic acid [4–6]. E. Toubi (&) Division of Allergy and Clinical Immunology, Faculty of Medicine, Technion, Haifa, Israel e-mail: [email protected]
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Elias Toubi
In another case report study, Y. Shoenfeld discusses some of the mechanisms that underlie tocilizumab (TCZ)-induced neutropenia in rheumatoid arthritis patients. Of these mechanisms is the possibility that TCZ may increase neutrophil apoptosis. The other possible explanation for this neutropenia is that IL-6 blockage may shift neutrophils from the circulating pool to the marginal neutrophil pool. Of interest to notice that in this described case, the temporary decrease in the TCZ dosage by 10–20 % leads to the recovery of neutropenia without influencing TCZ efficacy [7, 8]. Moving to another issue, Luisa Costa evaluated the influence of metabolic syndrome on decreasing the chances of achieving minimal disease activity in psoriatic arthritis patients treated with anti-tumor necrosis factor (TNF) therapy. An inverse association was found between presence of metabolic syndrome and the probability of achieving disease improvement. This notice strengthens the beneficial effect of treating metabolic syndrome in order to achieve a better improvement in the treatment of psoriatic arthritis. The importance of intestinal microenvironment in the development of arthritis is elegantly discussed by Anna Bazso’. She points to the fact that 10–15 % of inflammatory bowel diseases (IBD) are associated with different forms of spondyloarthropaties. Anna Bazso’ discusses the role of colonization of microbiomes on the surface of the gut, the development of mucosal inflammation and their relation to the development of arthritis [9, 10]. Among environmental factors, infectious agents and particularly Epsstein-Barr virus (EBV) have been largely investigated in RA during the last decade. Almost 80 % of RA sera contain antibodies to citrullinated peptides (ACPA). Among them, the autoantibodies to citrullinated human fibrinogen (AhFibA) are composed of two noncross-reactive subsets directed to immunodominant epitopes borne by the a36-50Cit and b60-74Cit fibrin
Diagnostics and Environmental Factors (2015) 61:104–106
peptides. Using a large cohort of RA patients and controls, L.Nogueria shows in her study that in ACPA positive RA patients have also antibodies toward the citrullinated EBNA35-58Cit peptide derived from the EBNA-1 protein of EBV. Using competition assays, anti-EBNA35-58 Cit antibodies were shown to be highly cross-reactive with the b60-74Cit peptide. The demonstration that a citrullinated peptide derived from EBNA-1 protein of EBV presents a molecular mimicry with human citrullinated fibrin constitutes a further argument for the role of EBV in RA pathophysiology [11–13]. The role of infectious diseases was also reported in respect of many diseases. Here, Eric Rosenthal describes a case of a 66-year-old male with hepatopulmonary syndrome and a rare expression of visceral leishmaniasis, presenting as an autoimmune systemic disease namely neutropenia and antigens-containing immune complex deposition in biopsy. In another report, Sami Lakhal shows that sera from adult patients with signs of autoimmune disease present antinuclear autoantibodies that cross-react with Leishmania infantum conserved proteins. This is why higher precautions must be taken to confirm the presence of visceral leishmaniasis in front of positive serology in antinuclear antibodies positive sera. Higher precautions should take into account regional aspects of course. F.M. Ribero reported on three Brazilian patients whose SLE disease was inactive but flared following the infection with leprosy. In this respect, it was shown that shared epitopes among idiotypes derived from 8E7 and TH9 lepromatous antibodies and these obtained from SLE patients could partially explain the triggering phenomenon of SLE caused or triggered by M. lepra [14]. The issue of autoimmune diagnosis was also discussed in this volume. Autoimmune diagnostics has undergone major changes over the past 10 years. In his review, Nicola Bizzaro describes in detail the innovative and affordable technologies that have been developed and which most importantly are automated and have a high throughput to meet both clinical needs and to cope with the growing demand for autoantibody tests. An important role in this scenario was assumed by the laboratory autoimmunologist, whose task is not only to govern the analytical part, but also to assist physicians in correctly choosing the most suitable test for each specific disease and give the proper interpretation of each test [15]. Aiming to evaluate a novel automated chemiluminescent immunoassay, QUANTA flash CTD screen plus, Chelsea Bentow tested sera from patients with systemic autoimmune rheumatic diseases along with disease and healthy controls using the CTD CIA and NOVA Life HEp-2 ANA, using both the manual method of reading (IFA slides) and the NOVA View instrument. Here, IFA with NOVA View digital image interpretation had higher sensitivity, while the CTD CIA showed higher specificity [16, 17]. She concludes that with
105
the added benefits of full automation, the new assay is an attractive alternative to traditional ANA screening. Indirect immunofluorescense (IIF) is the main technique for the detection of antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA) [18]. The fully automated IIF processor HELIOS is the first IIF processor that is able to automatically prepare slides and perform automatic reading. ANA detection by visual IIF or HELIOS was performed on 425 sera samples including 218 consecutive samples submitted to a reference laboratory for routine ANA testing, 137 samples from healthy subjects and 70 ANA/ENA samples. There was 95 % agreement between the ANCA IIF performed by automated and visual IIF on the investigation of routine samples. Based on these results, HELIOS demonstrates a high diagnostic performance for the automated ANA and ANCA IIF interpretation that was similar to a visual reading in all groups of samples [19]. Further studies will prove automated diagnostic tools to take over and become the favorite assay in the diagnosis of autoimmune diseases.
References 1. Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia, and mortality—a review of recent evidence. Autoimmun Rev. 2013;12:976–89. 2. Kriegel MA, Manson JE, Costenbader KH. Does vitamin D effect risk of developing autoimmune disease?: a systemic review. Semin Arthritis Rheum. 2011;40:512–31. 3. Antico A, Tampoia M, Tozzoli R, Bizzaro N. Can supplementation with vitamin D reduce the risk or modify the course of autoimmune disease? A systematic review of the literature. Autoimm Rev. 2012;12:127–36. 4. Delvin E, Souberbielle JC, Viard JP, Salle B. Role of vitamin D in acquired immune and autoimmune diseases. Crit Rev Clin Lab Sci. 2014;51:232–47. 5. Sternberg Z. Autonomic dysfunction: a unifying multiple sclerosis theory, linking chronic cerebrospinal venous insufficiency, vitamin D (3), and EBV. Autoimmun Rev. 2012;12:250–9. 6. Bozkut NC, Karbek B, Ucan B, Sahin M, Cakal E, Ozbek M, Delibasi T. The association between severity of vitamin D deficiency and Hashimoto’s thyroiditis. Endocr Pract. 2013;19:479– 84. 7. Atzeni F, Benucci M, Salli S, Bongiovanni S, Boccassini L, Sarzi-Puttini P. Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev. 2013;12:575–9. 8. Wroght HL, Cross AL, Edwards SW, Moots RJ. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (Oxford). 2014;53:1321–31. 9. Toussirot E, Aubin F, Dumoulin G. Relationships between adipose tissue and psoriasis with or without arthritis. Front Immunol. 2014;5:368. 10. Costells ME, Elewaut D, Kenna TJ, Brown MA. Microbes the gut and ankylosing spondylitis. Arthritis Res Ther. 2013;15:214. 11. Bartoloni E, Alunno A, Bistoni O, Bizzaro N, Migliorini P, Morozzi G, et al. Diagnostic value of anti-mutated citrullinated
123
106
12.
13.
14.
15.
Diagnostics and Environmental Factors (2015) 61:104–106 vimentin in comparison to anti-cyclic citrullinated peptide and anti-viral citrullinated peptide 2 antibodies in rheumatoid arthritis: an Italian multicentric study and review of the literature. Autoimmun Rev. 2012;11:815–20. Pratesi F, Petit Teixeira E, Sidney J, Michou L, Puxeddu I, et al. HLA shred epitope and ACPA: just a marker or an active player? Autoimmun Rev. 2013;12:1182–11827. Trouw LA, Mahler M. Closing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis. Autoimmun Rev. 2012;12:318–22. Nozzi M, Del Torto M, Chiarelli F, Breda L. Leishmaniasis and autoimmune diseases in pediatric age. Cell Immunol. 2014;292: 9–13. Op De Beeck K, Vermeersch P, Verschueren P, Westhovens R, Marien G, Blockmans D, Bossuyt X. Antinuclear antibody detection by automated multiplex immunoassay in untreated patients at the time of diagnosis. Autoimmun Rev. 2012;12:137– 43.
123
16. Maenhout TM, Bonroy C, Verfaillie C, Stove V, Devreese K. Automated indirect immunofluorescence microscopy enables the implementation of a quantitative internal quality control system for anti-nuclear antibody (ANA) analysis. Clin Chem Lab Med. 2014;52:989–98. 17. De Beeck Op. K, Vermeersch P, Verschueren P, Westhovens R, Marien G, Blockmans D, Bossuyt X. Detection of antinuclear antibodies by indirect immunofluorescence and by solid phase assay. Autoimmun Rev. 2011;10:801–8. 18. Melegari A, Bonaguri C, Russo A, Luisita B, Trenti T, Lippi G. A comparative study on the reliability of a automated system for the evaluation of cell-based indirect immunofluorescence. Autoimmun Rev. 2012;11:713–6. 19. Sowa M, Grossman K, Knutter I, Hiemann R, Rober N, Anderer U, et al. Simultaneous automated screening and confirmatory testing for vasculitis-specific ANCA. PLoS One. 2014;9:e107743.
GUEST EDITORIAL
Diagnostics and environmental factors Elias Toubi
Published online: 31 December 2014 Ó Springer Science+Business Media New York 2014
This volume of Immunological Research focuses on some of the environmental factors that are relevant to immune mediated/autoimmune diseases. It also presents the modern diagnostic approach including automatic tools for the diagnosis of autoimmune diseases. One of these factors is vitamin D, proven in many studies to be involved in many diseases including cardiovascular, cancer and immune mediated in origin. Vitamin D deficiency was linked by many to be associated with systemic lupus erythematosus (SLE) disease activity or the development of atherosclerosis. Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for the above spectrum of diseases [1–3]. With this in mind, vitamin D deficiency is reported by Yehuda Shoenfeld to be in association with autoimmune thyroid diseases (AITD). Here, low serum levels of 25 (OH) D are found in Hashimoto thyroiditis when compared to that in normal individuals. In this respect, low serum levels of 25 (OH) D were also correlated with disease duration, thyroid volume and antibody levels. Additionally, low serum levels of vitamin D were also found in Grave’s disease and to be associated with diseases severity. These findings are a further clue to how vitamin D deficiency and autoimmune diseases are linked and to the possible role of vitamin D supplementation in these diseases. In another study by Y. Shoenfeld, vitamin D deficiency was also found to exist in patients with primary biliary cirrhosis (PBC) in association with diseases activity and to be reversible following the treatment with ursodeoxycholic acid [4–6]. E. Toubi (&) Division of Allergy and Clinical Immunology, Faculty of Medicine, Technion, Haifa, Israel e-mail: [email protected]
123
Elias Toubi
In another case report study, Y. Shoenfeld discusses some of the mechanisms that underlie tocilizumab (TCZ)-induced neutropenia in rheumatoid arthritis patients. Of these mechanisms is the possibility that TCZ may increase neutrophil apoptosis. The other possible explanation for this neutropenia is that IL-6 blockage may shift neutrophils from the circulating pool to the marginal neutrophil pool. Of interest to notice that in this described case, the temporary decrease in the TCZ dosage by 10–20 % leads to the recovery of neutropenia without influencing TCZ efficacy [7, 8]. Moving to another issue, Luisa Costa evaluated the influence of metabolic syndrome on decreasing the chances of achieving minimal disease activity in psoriatic arthritis patients treated with anti-tumor necrosis factor (TNF) therapy. An inverse association was found between presence of metabolic syndrome and the probability of achieving disease improvement. This notice strengthens the beneficial effect of treating metabolic syndrome in order to achieve a better improvement in the treatment of psoriatic arthritis. The importance of intestinal microenvironment in the development of arthritis is elegantly discussed by Anna Bazso’. She points to the fact that 10–15 % of inflammatory bowel diseases (IBD) are associated with different forms of spondyloarthropaties. Anna Bazso’ discusses the role of colonization of microbiomes on the surface of the gut, the development of mucosal inflammation and their relation to the development of arthritis [9, 10]. Among environmental factors, infectious agents and particularly Epsstein-Barr virus (EBV) have been largely investigated in RA during the last decade. Almost 80 % of RA sera contain antibodies to citrullinated peptides (ACPA). Among them, the autoantibodies to citrullinated human fibrinogen (AhFibA) are composed of two noncross-reactive subsets directed to immunodominant epitopes borne by the a36-50Cit and b60-74Cit fibrin
Diagnostics and Environmental Factors (2015) 61:104–106
peptides. Using a large cohort of RA patients and controls, L.Nogueria shows in her study that in ACPA positive RA patients have also antibodies toward the citrullinated EBNA35-58Cit peptide derived from the EBNA-1 protein of EBV. Using competition assays, anti-EBNA35-58 Cit antibodies were shown to be highly cross-reactive with the b60-74Cit peptide. The demonstration that a citrullinated peptide derived from EBNA-1 protein of EBV presents a molecular mimicry with human citrullinated fibrin constitutes a further argument for the role of EBV in RA pathophysiology [11–13]. The role of infectious diseases was also reported in respect of many diseases. Here, Eric Rosenthal describes a case of a 66-year-old male with hepatopulmonary syndrome and a rare expression of visceral leishmaniasis, presenting as an autoimmune systemic disease namely neutropenia and antigens-containing immune complex deposition in biopsy. In another report, Sami Lakhal shows that sera from adult patients with signs of autoimmune disease present antinuclear autoantibodies that cross-react with Leishmania infantum conserved proteins. This is why higher precautions must be taken to confirm the presence of visceral leishmaniasis in front of positive serology in antinuclear antibodies positive sera. Higher precautions should take into account regional aspects of course. F.M. Ribero reported on three Brazilian patients whose SLE disease was inactive but flared following the infection with leprosy. In this respect, it was shown that shared epitopes among idiotypes derived from 8E7 and TH9 lepromatous antibodies and these obtained from SLE patients could partially explain the triggering phenomenon of SLE caused or triggered by M. lepra [14]. The issue of autoimmune diagnosis was also discussed in this volume. Autoimmune diagnostics has undergone major changes over the past 10 years. In his review, Nicola Bizzaro describes in detail the innovative and affordable technologies that have been developed and which most importantly are automated and have a high throughput to meet both clinical needs and to cope with the growing demand for autoantibody tests. An important role in this scenario was assumed by the laboratory autoimmunologist, whose task is not only to govern the analytical part, but also to assist physicians in correctly choosing the most suitable test for each specific disease and give the proper interpretation of each test [15]. Aiming to evaluate a novel automated chemiluminescent immunoassay, QUANTA flash CTD screen plus, Chelsea Bentow tested sera from patients with systemic autoimmune rheumatic diseases along with disease and healthy controls using the CTD CIA and NOVA Life HEp-2 ANA, using both the manual method of reading (IFA slides) and the NOVA View instrument. Here, IFA with NOVA View digital image interpretation had higher sensitivity, while the CTD CIA showed higher specificity [16, 17]. She concludes that with
105
the added benefits of full automation, the new assay is an attractive alternative to traditional ANA screening. Indirect immunofluorescense (IIF) is the main technique for the detection of antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA) [18]. The fully automated IIF processor HELIOS is the first IIF processor that is able to automatically prepare slides and perform automatic reading. ANA detection by visual IIF or HELIOS was performed on 425 sera samples including 218 consecutive samples submitted to a reference laboratory for routine ANA testing, 137 samples from healthy subjects and 70 ANA/ENA samples. There was 95 % agreement between the ANCA IIF performed by automated and visual IIF on the investigation of routine samples. Based on these results, HELIOS demonstrates a high diagnostic performance for the automated ANA and ANCA IIF interpretation that was similar to a visual reading in all groups of samples [19]. Further studies will prove automated diagnostic tools to take over and become the favorite assay in the diagnosis of autoimmune diseases.
References 1. Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia, and mortality—a review of recent evidence. Autoimmun Rev. 2013;12:976–89. 2. Kriegel MA, Manson JE, Costenbader KH. Does vitamin D effect risk of developing autoimmune disease?: a systemic review. Semin Arthritis Rheum. 2011;40:512–31. 3. Antico A, Tampoia M, Tozzoli R, Bizzaro N. Can supplementation with vitamin D reduce the risk or modify the course of autoimmune disease? A systematic review of the literature. Autoimm Rev. 2012;12:127–36. 4. Delvin E, Souberbielle JC, Viard JP, Salle B. Role of vitamin D in acquired immune and autoimmune diseases. Crit Rev Clin Lab Sci. 2014;51:232–47. 5. Sternberg Z. Autonomic dysfunction: a unifying multiple sclerosis theory, linking chronic cerebrospinal venous insufficiency, vitamin D (3), and EBV. Autoimmun Rev. 2012;12:250–9. 6. Bozkut NC, Karbek B, Ucan B, Sahin M, Cakal E, Ozbek M, Delibasi T. The association between severity of vitamin D deficiency and Hashimoto’s thyroiditis. Endocr Pract. 2013;19:479– 84. 7. Atzeni F, Benucci M, Salli S, Bongiovanni S, Boccassini L, Sarzi-Puttini P. Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev. 2013;12:575–9. 8. Wroght HL, Cross AL, Edwards SW, Moots RJ. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (Oxford). 2014;53:1321–31. 9. Toussirot E, Aubin F, Dumoulin G. Relationships between adipose tissue and psoriasis with or without arthritis. Front Immunol. 2014;5:368. 10. Costells ME, Elewaut D, Kenna TJ, Brown MA. Microbes the gut and ankylosing spondylitis. Arthritis Res Ther. 2013;15:214. 11. Bartoloni E, Alunno A, Bistoni O, Bizzaro N, Migliorini P, Morozzi G, et al. Diagnostic value of anti-mutated citrullinated
123
106
12.
13.
14.
15.
Diagnostics and Environmental Factors (2015) 61:104–106 vimentin in comparison to anti-cyclic citrullinated peptide and anti-viral citrullinated peptide 2 antibodies in rheumatoid arthritis: an Italian multicentric study and review of the literature. Autoimmun Rev. 2012;11:815–20. Pratesi F, Petit Teixeira E, Sidney J, Michou L, Puxeddu I, et al. HLA shred epitope and ACPA: just a marker or an active player? Autoimmun Rev. 2013;12:1182–11827. Trouw LA, Mahler M. Closing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis. Autoimmun Rev. 2012;12:318–22. Nozzi M, Del Torto M, Chiarelli F, Breda L. Leishmaniasis and autoimmune diseases in pediatric age. Cell Immunol. 2014;292: 9–13. Op De Beeck K, Vermeersch P, Verschueren P, Westhovens R, Marien G, Blockmans D, Bossuyt X. Antinuclear antibody detection by automated multiplex immunoassay in untreated patients at the time of diagnosis. Autoimmun Rev. 2012;12:137– 43.
123
16. Maenhout TM, Bonroy C, Verfaillie C, Stove V, Devreese K. Automated indirect immunofluorescence microscopy enables the implementation of a quantitative internal quality control system for anti-nuclear antibody (ANA) analysis. Clin Chem Lab Med. 2014;52:989–98. 17. De Beeck Op. K, Vermeersch P, Verschueren P, Westhovens R, Marien G, Blockmans D, Bossuyt X. Detection of antinuclear antibodies by indirect immunofluorescence and by solid phase assay. Autoimmun Rev. 2011;10:801–8. 18. Melegari A, Bonaguri C, Russo A, Luisita B, Trenti T, Lippi G. A comparative study on the reliability of a automated system for the evaluation of cell-based indirect immunofluorescence. Autoimmun Rev. 2012;11:713–6. 19. Sowa M, Grossman K, Knutter I, Hiemann R, Rober N, Anderer U, et al. Simultaneous automated screening and confirmatory testing for vasculitis-specific ANCA. PLoS One. 2014;9:e107743.
