All Title Author
Keywords Abstract

Cryoglobulins as Potential Triggers of Inflammation in Schizophrenia

DOI: 10.1155/2013/125264

Full-Text   Cite this paper   Add to My Lib


This case study aimed to investigate effects of type III cryoglobulins isolated from the blood of patients with schizophrenia on the production of proinflammatory cytokines interleukin(IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α), anti-inflammatory cytokine IL-10, and chemotactic cytokines IL-8 and monocyte chemoattractant protein-1 (MCP-1) by peripheral blood mononuclear cells (PBMCs). The experiments were performed in vitro using PBMCs healthy subjects and the blood of patients whit schizoprenia. The enzyme-linked immunosorbent assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay were used upon study. The results obtained indicated significant increase ( ) in IL-1β, IL-6, TNF-α, IL-8, and MCP-1 production by cultured PBMCs when incubating for 24 hours with cryoglobulins, beginning from 0.4?mg/mL. The gender difference does not affect the cryoglobulins-induced production of these cytokines by PBMCs. No influence of cryoglobulins on production of IL-10 by PBMCs was observed. Also, it was shown that cryoglobulins in concentration ≤4?mg/mL possessed no cytotoxic effect towards cultured PBMCs. Based upon the results obtained, we concluded that type III cryoglobulins are implicated in schizophrenia-associated alterations in the immune response through induction of the expression of proinflammatory and chemotactic cytokines by PBMCs. 1. Introduction A considerable evidence suggests a role for upregulated immune response in the pathogenesis of schizophrenia (SCZ), since alterations in both the innate and adaptive immunity including autoimmune and inflammatory components were described in this pathology at both central and peripheral levels [1–7]. Moreover, according to a genetic-vascular-inflammatory hypothesis based upon a number of epidemiologic, clinical, and experimental studies, SCZ generates from a damage of the brain microvascular system initiated by genetically induced upregulated inflammatory reactions developed in response to ubiquitous environmental factors [8]. The results of our previous study revealed the detectable blood levels of type III cryoglobulins (Cgs) in SCZ and found the presence of complement activation split products in these complexes [9]. The presence of Cgs in the blood is detected in lymphoproliferative, autoimmune and infectious diseases and considered as a marker of the immune system chronic activation, inflammation, and autoimmune sensitization [10, 11]. Cgs can cause immune complex vacuities by depositing in the blood vessels, bind complement components, activate the complement system, and induce


[1]  M. Rothermundt, V. Arolt, and T. A. Bayer, “Review of immunological and immunopathological findings in schizophrenia,” Brain, Behavior, and Immunity, vol. 15, no. 4, pp. 319–339, 2001.
[2]  N. Müller and M. J. Schwarz, “The role of immune system in schizophrenia,” Current Immunology Reviews, vol. 6, no. 3, pp. 213–220, 2010.
[3]  U. Meyer, M. J. Schwarz, and N. Müller, “Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond,” Pharmacology and Therapeutics, vol. 132, no. 1, pp. 96–110, 2011.
[4]  B. J. Miller, P. Buckley, W. Seabolt, A. Mellor, and B. Kirkpatrick, “Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects,” Biological Psychiatry, vol. 70, no. 7, pp. 663–671, 2011.
[5]  A. Boyajyan, R. Zakharyan, and A. Khoyetsyan, “Molecular and genetic indicators of aberrant immunity and apoptosis in schizophrenia,” in Schizophrenia Research: Recent Advances, T. Sumiyoshi, Ed., pp. 183–240, Nova Science, New York, NY, USA, 2012.
[6]  M. D. Richard and N. C. Brahm, “Schizophrenia and the immune system: pathophysiology, prevention, and treatment,” The American Journal of Health-System Pharmacy, vol. 69, no. 9, pp. 757–766, 2012.
[7]  B. García-Bueno, M. Bioque, K. S. Mac-Dowell et al., “Pro-/anti-inflammatory dysregulation in patients with first episode of psychosis: toward an integrative inflammatory hypothesis of schizophrenia,” Schizophrenia Bulletin, 2013.
[8]  D. R. Hanson and I. I. Gottesman, “Theories of schizophrenia: a genetic-inflammatory-vascular synthesis,” BMC Medical Genetics, vol. 6, article 7, 2005.
[9]  A. Boyajyan, A. Khoyetsyan, G. Tsakanova, and R. B. Sim, “Cryoglobulins as indicators of upregulated immune response in schizophrenia,” Clinical Biochemistry, vol. 41, no. 6, pp. 355–360, 2008.
[10]  S. Takada, T. Shimizu, Y. Hadano et al., “Cryoglobulinemia (review),” Molecular Medicine Reports, vol. 6, no. 1, pp. 3–8, 2012.
[11]  M. Ramos-Casals, J. H. Stone, M. C. Cid, and X. Bosch, “The cryoglobulinaemias,” The Lancet, vol. 379, no. 9813, pp. 348–360, 2012.
[12]  U. Kallemuchikkal and P. D. Gorevic, “Evaluation of cryoglobulins,” Archives of Pathology and Laboratory Medicine, vol. 123, no. 2, pp. 119–125, 1999.
[13]  S. M. Weiner, V. Prasauskas, D. Lebrecht, S. Weber, H. H. Peter, and P. Vaith, “Occurrence of C-reactive protein in cryoglobulins,” Clinical and Experimental Immunology, vol. 125, no. 2, pp. 316–322, 2001.
[14]  P. Lamprecht, “Cryoglobulinaemic vasculitis: new aspects,” Clinical and Experimental Rheumatology, vol. 30, no. 1, supplement 70, pp. S3–S5, 2012.
[15]  J. C. Brouet, J. P. Clauvel, F. Danon, M. Klein, and M. Seligmann, “Biologic and clinical significance of cryoglobulins. A report of 86 cases,” The American Journal of Medicine, vol. 57, no. 5, pp. 775–788, 1974.
[16]  L. Mathsson, A. Tejde, K. Carlson et al., “Cryoglobulin-induced cytokine production via FcγRIIa: inverse effects of complement blockade on the production of TNF-α and IL-10. Implications for the growth of malignant B-cell clones,” The British Journal of Haematology, vol. 129, no. 6, pp. 830–838, 2005.
[17]  H. Katila, B. Appelberg, M. Hurme, and R. Rimon, “Plasma levels of interleukin-1β and interleukin-6 in schizophrenia, other psychoses, and affective disorders,” Schizophrenia Research, vol. 12, no. 1, pp. 29–34, 1994.
[18]  M. Maes, L. B. Chiavetto, S. Bignotti et al., “Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor,” Schizophrenia Research, vol. 54, no. 3, pp. 281–291, 2002.
[19]  M. Kunz, K. M. Ceresér, P. D. Goi et al., “Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance,” Revista Brasileira de Psiquiatria, vol. 33, no. 3, pp. 268–274, 2011.
[20]  The International Statistical Classification of Diseases and Related Health Problems, World Health Organization, Geneva, Switzerland, 10th edition, 1992.
[21]  American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Publications, American Psychiatric Association, Washington, DC, USA, 4th edition, 2000.
[22]  M. B. First, R. L. Spitzer, M. Gibbon, and J. B. W. Williams, Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Non-Patient Edition (SCID-I/NP), Biometrics Research, New York State Psychiatric Institute, New York, NY, USA, 2001.
[23]  O. H. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall, “Protein measurement with the Folin phenol reagent,” The Journal of Biological Chemistry, vol. 193, no. 1, pp. 265–275, 1951.
[24]  S. Kasugai, N. Hasegawa, and H. Ogura, “A simple in vito cytotoxicity test using the MTT (3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) colorimetric assay: analysis of eugenol toxicity on dental pulp cells (RPC-C2A),” Japanese Journal of Pharmacology, vol. 52, no. 1, pp. 95–100, 1990.
[25]  R. Zakharyan and A. Boyajyan, “Inflammatory cytokine network in schizophrenia,” World Journal of Biological Psychiatry, 2013.
[26]  J. Kowalski, P. Blada, K. Kucia, A. Madej, and Z. S. Herman, “Neuroleptics normalize increased release of interleukin-1β and tumor necrosis factor-α from monocytes in schizophrenia,” Schizophrenia Research, vol. 50, no. 3, pp. 169–175, 2001.
[27]  M. Di Nicola, A. Cattaneo, N. Hepgul et al., “Serum and gene expression profile of cytokines in first-episode psychosis,” Brain, Behavior, and Immunity, vol. 31, pp. 90–95, 2013.
[28]  R. Zanardini, L. Bocchio-Chiavetto, C. Scassellati et al., “Association between IL-1β-511C/T and IL-1RA (86bp)n repeats polymorphisms and schizophrenia,” Journal of Psychiatric Research, vol. 37, no. 6, pp. 457–462, 2003.
[29]  M. Paul-Samojedny, M. Kowalczyk, R. Suchanek et al., “Functional polymorphism in the interleukin-6 and interleukin-10 genes in patients with paranoid schizophrenia—a case-control study,” Journal of Molecular Neuroscience, vol. 42, no. 1, pp. 112–119, 2010.
[30]  B. Almoguera, R. Riveiro-Alvarez, J. Lopez-Castroman et al., “ATA homozigosity in the IL-10 gene promoter is a risk factor for schizophrenia in Spanish females: a case control study,” BMC Medical Genetics, vol. 12, article 81, 2011.
[31]  F. W. Lung, M. C. Yang, and B. C. Shu, “The interleukin 10 promoter haplotype ACA and the long-form variant of the DRD4 uVNTR polymorphism are associated with vulnerability to schizophrenia,” Psychiatry Research, vol. 188, no. 2, pp. 294–296, 2011.
[32]  A. Denys, I. A. Udalova, C. Smith et al., “Evidence for a dual mechanism for IL-10 suppression of TNF-α production that does not involve inhibition of p38 mitogen-activated protein kinase or NF-κB in primary human macrophages,” Journal of Immunology, vol. 168, no. 10, pp. 4837–4845, 2002.
[33]  L. Mathsson, J. Lampa, M. Mullazehi, and J. R?nnelid, “Immune complexes from rheumatoid arthritis synovial fluid induce FcγRIIa dependent and rheumatoid factor correlated production of tumour necrosis factor-α by peripheral blood mononuclear cells,” Arthritis Research and Therapy, vol. 8, no. 3, article R64, 2006.
[34]  F. Bacle, N. Haeffner-Cavaillon, M. Laude, C. Couturier, and M. D. Kazatchkine, “Induction of IL-1 release through stimulation of the C3b/C4b complement receptor type one (CR1, CD35) on human monocytes,” Journal of Immunology, vol. 144, no. 1, pp. 147–152, 1990.
[35]  L. B. Klickstein, S. F. Barbashov, T. Liu, R. M. Jack, and A. Nicholson-Weller, “Complement receptor type 1 (CR1, CD35) is a receptor for C1q,” Immunity, vol. 7, no. 3, pp. 345–355, 1997.
[36]  R. S. Selvan, H. B. Kapadia, and J. L. Platt, “Complement-induced expression of chemokine genes in endothelium: regulation by IL-1-dependent and -independent mechanisms,” Journal of Immunology, vol. 161, no. 8, pp. 4388–4395, 1998.
[37]  K. R. Mayilyan, D. R. Weinberger, and R. B. Sim, “The complement system in schizophrenia,” Drug News and Perspectives, vol. 21, no. 4, pp. 200–210, 2008.
[38]  Z. Khalkhali-Ellis, G. A. Bulla, L. S. Schlesinger, D. A. Kirschmann, T. L. Moore, and M. J. C. Hendrix, “C1q-containing immune complexes purified from sera of juvenile rheumatoid arthritis patients mediate IL-8 production by human synoviocytes: role of C1q receptors,” Journal of Immunology, vol. 163, no. 8, pp. 4612–4620, 1999.


comments powered by Disqus