J of IMAB. 2012; 18(3):315-322
ANTI-COLLAGEN TYPE IV ANTIBODIES AND THE DEVELOPMENT OF MICROVASCULAR COMPLICATIONS IN DIABETIC PATIENTS WITH ARTERIAL HYPERTENSION
Asparuh G. Nikolov¹, Georgi Nicoloff², Ivan Tsinlikov¹,  Ivanka Tsinlikova¹, 
1) Department of Propedeutics of Internal Diseases, Medical University, Pleven
2) Division of Biology, Medical University, Pleven, Bulgaria.

ABSTRACT:
Background and Aims: Thickening of basement membrane in capillaries and small vessels is a well-known finding and important in the progression of diabetic microangiopathy. Patients with diabetes mellitus and arterial hypertension are at higher risk of vascular disease.
Material and methods: To monitor the metabolism of the basement membrane protein collagen type IV (CIV) in type 2 diabetes mellitus (T2DM), serum levels of antibodies to CIV (ACIV) IgG, IgM and IgA were measured using an ELISA method in 93 patients with type 2 diabetes mellitus and arterial hypertension (AH) (mean age 61,4±11,3 years, diabetes duration 9,88±3,12 years; hypertension duration 9,28±4,98). These values were compared to serum antibodies to CIV in 42 age and sex matched controls. Diabetics were divided in two groups according to presence- Group 1 (n=67) or absence- Group 2 (n=26) of microangiopathy.
Results: Patients with T2DM and AH showed statistically significant higher levels of ACIV IgG  in comparison to healthy controls (0.30±0.12 vs. 0.21±0.08) (p=0.0001). Group 1 showed significantly hihger levels of  ACIV IgG  than Group 2 (0.32±0.13vs. 0.24±0.08) (p=0.009) and healthy controls (0.32±0.13vs. 0.21±0.08) (p=0.0001). ACIV IgG are statistically significant higher in diabetics with retinopathy than this without (0.33±0.10 vs. 0.26±0.13) (р=0.04). ACIV IgG correlates with diabetes duration (r=0.49); (p=0.0004), retinopathy (r=0.20); (p=0.05) and BMI (r=-0.24); (p=0.05). Serum ACIV IgM and IgA levels in patients with T2DM and AH were lower than these in controls, but the differences are not statistically significant.
Conclusion: Our study showed a relationship between elevation of  serum levels of ACIV IgG in diabetics and development of microangiopathy.

Key words: Diabetes mellitus, arterial hypertension, anti-collagen type IgG, micrangiopathy.

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Please cite this article as: Nikolov AG, Nicoloff G, Tsinlikov I, Tsinlikova I. ANTI-COLLAGEN TYPE IV ANTIBODIES AND THE DEVELOPMENT OF MICROVASCULAR COMPLICATIONS IN DIABETIC PATIENTS WITH ARTERIAL HYPERTENSION. J of IMAB. 2012; 18(3):315-322. doi: 10.5272/jimab.2012183.315.

REFERENCES:
1. Di Mario U, Pugliese G. 15th Golgi lecture: from hyperglycemia to the dysregulation of vascular remodelling in diabetes. Diabetologia. 2001 Jun;44(6):674-692. [PubMed] [CrossRef]
2. Toeller M, Buyken AE, Heitkamp G, Berg G, Scherbaum WA. Prevalence of chronic complications, metabolic control and nutritional intake in type 1 diabetes: comparison between different European regions. EURODIAB Complications Study group. HormMetabRes. 1999 Dec;31(12):680-685. [PubMed] [CrossRef]
3. Krolewski AS, Warram JH, Rand LI, Kahn CR. Epidemiological approach in the etiology of type 1 diabetes mellitus and its complications. NEnglJMed. 1987 Nov 26;317(22):1390-1398. [PubMed] [CrossRef]
4. Hanefeld M, Fisher S, Julius U, Schulze J, Schwanebeck U, Schmechel H, et al. The DIS Group. Risk factors for myocardial infarction and death in newly detected NIDDM: Diabetes International Study, 11-year follow-up. Diabetologia. 1996 Dec;39(12):1577-1583. [PubMed]
5. Paulsson M. Basement membrane proteins: structure, assembly, and cellular interactions. Crit RevBiochem Molec Biol. 1992 27(1-2):93-127. [PubMed]
6. Kühn K , Basement membrane (type IV) collagen. Matrix Biol. 1995 Feb;14(6):439-45. Review. [PubMed] [CrossRef]
7. Rosenbloom J, Abrams WR, Mecham R. Extracellular matrix 4: the elastic fiber. FASEB J, 1993
8. Schuppan D, Riecken EO. Molecules of the extracellular matrix: potential role of collagens and glycoproteins in intestinal adaptation. Digestion. 1990; 46(Suppl 2):2-11. [PubMed]
9. Balashova L, Zaitseva N, Teplinskaia L, Koval’chuk L, Gankovskaia L, Obraztsova E, Aronskind M. Antitela k kollagenu II i IV tipov, faktor nekroza opukholi al’fa i tsirkuliruiushchie immunnye kompleksy v sleze i syvorotke krovi u bol’nykh s razlichnymi stadiiami diabeticheskoi angioretinopatii. Vestn Oftalmol 2000; 116, 31-34. [in Russian]
10. Nicoloff G, Baydanoff S, Petrova Ch, Christova P. Serum antibodies to collagen type IV and development of diabetic vascular complications in children with Type 1 (insulin-dependent) diabetes mellitus - a longitudinal study. Vascular Pharmacology. 2002 Mar;38(3):143-147. [PubMed] [CrossRef]
11. Risteli L, Risteli J. Analysis of extracellular matrix proteins in biological fluids. Methods Enzymol. 1987; 145:391-411. [PubMed]
12. Alland A, Hartmann DJ, Loupy G, Lechevalier D, Ville G, Cotisson A, et al. Etude de la fibronectine et ducollagene de type IV plasmatiques chez le diabetique. Path.Biol. (Paris). 1984 Feb;32(2):115-121. [Article in French] [PubMed]
13. Matsumoto E, Matsumoto G, Bessho H, Kikuoka H, Nanjo K. Serum concentrations of intact type IV collagen in diabetics. J.Diabet Complications. 1991; 5:189-190
14. Nicoloff G, Baydanoff S, Stanimirova N, et al. Serum collagen type IV in healthy children and children with insulin-dependent diabetes mellitus. Clin. Appl. Immunol. Invest. 2001; 1:165-168.
15. Hasslacher C, Brocks D, Mann J, Waldherr R. Influence of hypertension on serum concentration of type IV collagen antigens in streptozotocin-diabetic and non-diabetic rats. Diabetologia. 1987 May;30(5):344-347. [PubMed]
16. Yano Y, Ura H, Sumida Y, Gabazza EC, Misaki M, Shima T. Serum 7S domain of type IV collagen levels in essential hypertension and hypertensive type 2 diabetic patients. Diabet Med. 1997 Jun;14(6):466-71. [PubMed]
17. Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation. 1979 Jan;59(1):8-13. [PubMed] [CrossRef]
18. Moreland LW, Gay RE, Gay S. Collagen autoantibodies in patients with vasculitis and systemic lupus erythematosus. ClinImmunImmunopathol. 1991 Sep;60(3):412-418. [PubMed]
19. Yang CL, Brinckmann J, Rui HF, Vehring K, Lehmann H, Kekow J, et al. Autoantibodies to cartilage collagens in relapsing polychondritis. Arch DermatolRes. 1993; 285(5):245-249. [PubMed]
20. Susumu T., Uchugu T., Shoichi T, Measurement of Serum Anti-type IV Collagen Antibody in Diabetic Patients, Annals of Gunma University School of Health Sciences, V24.;87-91(2003) 
21. Nicoloff G, Angelova M, Christova I, Nikolov A, Alexiev A. Serum cobalt in children with essential hypertension, Am J Hum Biol. 2006 Nov-Dec;18(6):798-805. [PubMed] [CrossRef]
22. Daskalova M, Taskov H, Dimitrova E, Baydanoff S. Humoral and cellular immune response to elastin in patients with systemic sclerosis. Autoimmunity. 1997; 25(4):233-241. [PubMed]
23. Sato Y, Kataoka K, Matsumori A, Sasayama S, Yamada T, Ito H, et al. Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy. Heart. 1997 Nov;78(5):505-508. [PubMed]
24. Kaiser WJ, Holbrook LM, Tucker KL, Stanley RG, Gibbins JM. A functional proteomic method for the enrichment of peripheral membrane proteins reveals the collagen binding protein Hsp47 is exposed on the surface of activated human platelets. J Proteome Res. 2009 Jun;8(6):2903-14. [PubMed] [CrossRef]
25. Ameye LG, Deberg M, Oliveira M, Labasse A, Aeschlimann JM, Henrotin Y. The chemical biomarkers C2C, Coll2-1, and Coll2-1NO2 provide complementary information on type II collagen catabolism in healthy and osteoarthritic mice. Arthritis Rheum. 2007 Oct;56(10):3336-46. [PubMed] [CrossRef]
26. Rinaldi N, Willhauck M, Weis D, Brado B, Kern P, Lukoschek M, et al. Loss of collagen type IV in rheumatoid synovia and cytokine effect on the collagen type-IV gene expression in fibroblast-like synoviocytes from rheumatoid arthritis. Virchows Arch. 2001 Nov;439(5):675-82. [PubMed] [CrossRef]
27. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiological study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984 Apr;102(4):520-526. [PubMed]
28. Brownlee M, Pongar S, Cerami A. Covalent attachment of soluble proteins by nonenzymatically glycosylated collagen. Role in the in situ formation of immune complexes. J Exp Med. 1983 Nov 1;158(5):1739-1744. [PubMed]
29. Brownlee M. Glycation products and the pathogenesis of diabetic complications. Diabetes Care. 1992 Dec;15(12):1835-1843. [PubMed]
30. Airaksinen KE, Salmela PI, Linnaluto MK, Ikaheimo MJ, Ahola K, Ryhanen LJ. Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen. Cardiovasc Res. 1993 Jun;27(6):942-945. [PubMed] [CrossRef]
31. Steiner G. Diabetes mellitus, dyslipoproteinaemias and atherosclerosis. Diabetologia. 1997 Jul;40(Suppl. 2):S147-148. [PubMed]
32. Peterszegi G, Mandet C, Texier S, Robert L, Bruneval P. Lymphocytes in human atherosclerotic plaque exhibit the elastin-laminin receptor: potential role in atherogenesis. Atherosclerosis. 1997 Nov;135(1):103 -107. [PubMed]
33. Peterszegi G, Texier S, Robert L. Human helper and memory lymphocytes exhibit an inducible elastin-laminin receptor. Int Arch Allergy Immunol. 1997 Nov;114(3):218-223. [PubMed]
34. Tisheva S. Clinical importance of immunological changes in elastin and collagen turnover in vessel wall in arterial hypertension. Dissertation for acquiring scientific-educational degree „Doctor“, 2004
35. Mekenyan E. Changes of elastin and collagen turnover in development of early cardiovascular complications in patients with metabolic syndrome. Dissertation for acquiring scientific-educational degree „Doctor“, 2012.