#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Immunogenetic and hormonal markers of predisposition to systemic rheumatic diseases - particularly systemic lupus erythematosus


Authors: M. Fojtíková
Authors‘ workplace: Revmatologický ústav Praha
Published in: Čes. Revmatol., 20, 2012, No. 1, p. 30-38.
Category: Review

Overview

Background:
Several factors like genetic susceptibility are required for the development of systemic rheumatic diseases. Prolactin (PRL) is an effective immunomodulator which supports the development of autoimmunity. 

Objectives:
1. To detect the immunogenetic background (HLA class I and II alleles and alleles of microsatellite polymorphism of the transmembrane part exon 5 of MIC-A gene (MIC-A)) in SLE and PsA.2. To detect PRL levels in serum and synovial fluid with regard to clinical and laboratory activity of RA. 3. To examine the role of the functional polymorphism -1149G/T SNP of extrapituitary promoter of PRL gene in the development and phenotype of SLE, RA, PsA, SSc and inflammatory myopathies. 

Methods:
Genetic analyses were performed in patients with SLE (n=156), RA (n=173), PsA (n=100), SSc (n=75), PM (n=47), DM (n=68) and 123 healthy individuals using PCR-SSP (HLA class I and II), PCR-fragment analysis (MIC-A) and PCR-RFLP (-1149 G/T SNP PRL). In 29 RA and 26 OA PRL serum and synovial fluid concentrations were detected using immunoradiometric assay. 

Results:
1. The allele HLA-DRB1*03 (pc=0.008; OR 2.5) and haplotype HLA-DRB1*03-DQB1*0201 (pc <0.001; OR 4.54) were determined as risk immunogenetic markers for SLE in the Czech population. The allele MIC-A5.1 was increased in SLE compared to controls (pc =0.005; OR 1.88). MIC-A5.1 together with HLA-DRB1*03 significantly increases the risk for the development of SLE, pc <0.000001; OR 9.71. The allele HLA-Cw*0602 occurs more frequently in PsA with psoriasis type I compared to controls, pc <0.05; OR 3.33. 2. Serum and synovial fluid PRL levels were increased in RA (299.55±27.28 and 338.85± 33.49 mIU/l, respectively) compared to OA (230.59±16.61 and 245.97±21.88 mIU/l, respectively, both p<0.05). Synovial fluid PRL levels correlate with DAS-28 (p=0.010) and serum PRL levels correlate with structural damage (p=0.014). 3. Genotype GT -1149 G/T SNP PRL is more frequent in RA than in controls, pc =0.039; OR 1.82. Genotype GG is more common in patients with onset of SLE at the age of 21 – 40 years compared to other disease onsets, pc =0.023; OR 2.94. Similarly, the TT genotype seems to be rare in SSc with disease onset after 45th year of age compared to patients with disease onset prior 45 years of age, pc =0.02; OR 0.13. 

Conclusion:
This is the first immunogenetic study in two severe rheumatic diseases - SLE and PsA in the Czech population. We detected that the allele MIC-A5.1 incerases the risk for the development of SLE in HLA-DRB1*03 individuals. The allele HLA-Cw*0602 is a risk factor for PsA with psoriasis type I. PRL modulates the course of systemic rheumatic diseases: PRL reflects the activity and severity of RA, and alleles of -1149G/T SNP PRL gene show differences associated with the age at disease onset of SLE and SSc. 

Key words:
systemic lupus erythematosus, psoriatic arthritis, polymorphism, allele, gene, prolactin


Sources

1. International Consortium for Systemic Lupus erythematosus Genetics (SLEGEN), Harley JB, Alercon-Riquelme ME, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008; 40: 204-10.

2. Bronson PG, Komorowski LK, Ramsay PP, et al. Analysis of Maternal–Offspring HLA Compatibility, Parent-of-Origin Effects, and Noninherited Maternal Antigen Effects for HLA–DRB1 in Systemic Lupus Erythematosus. Arthritis Rheum 2010; 62: 1712-1717.

3. Gladman DD, Farawell VT, Pellet F, et al. HLA is a candidate region for psoriatic arthritis. evidence for excessive HLA sharing in sibling pairs. Hum Immunol 2003; 64: 887-9.

4. Grant SF, Thorleifsson G, Frigge ML, et al. The inheritance of rheumatoid arthritis in Iceland. Arthritis Rheum 2001; 44: 2247–54.

5. Thorsby E, Lie BA. HLA associated genetic predisposition to autoimmune diseases: genes involved and possible mechanisms. Transplant Immunol 2005; 14: 175-182.

6. Gudjonsson JE, Karason A, Runarsdottir EH, et al. Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients – an analysis of 1019 HLA-C- and HLA-B-typed patients. J Invest Dermatol 2006; 126: 740-745.

7. Fries JF, Wolfe F, Apple R, et al. HLA–DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: Frequency, severity, and treatment bias. Arthritis Rheum 2002; 46: 2320-2329.

8. Queiro R, Gonzalez S, Lopez-Larrea C, et al. HLA-C locus alleles may modulate the clinical expression of psoriatic arthritis. Arthritis Res Ther 2006; 8: R185.

9. McHugh NJ, Owen P, Cox B, et al. MHC class II, tumour necrosis factor α, and lymphotoxin α gene haplotype associations with serological subsets of systemic lupus erythematosus. Ann Rheum Dis 2006; 65: 488-94.

10. So AK, Fielder AH, Warner CA, et al. DNA polymorphism of major histocompatibility complex class II and class III genes in systemic lupus erythematosus. Tissue Antigens 1990; 35: 144–147.

11. Steinle A, Li P, Morris DL, et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics 2001; 53: 279-87.

12. Gambelunghe G, Brozzeti AL, Ghaderi M, et al. MICA A8: a new allele within MHC class I chain-related A transmembrane region with eight GCT repeats. Hum Immunol 2006; 67: 1005–1007.

13. Lockshin MD. Sex differences in autoimmune disease. Lupus 2006; 15: 753-756.

14. Matera L, Mori M, Geuna M, et al. Prolactin in autoimunity and antitumor defence. J Neuroimmunol 2000; 109: 47-55.

15. Chavez-Rueda K, Hernandez J, Zenteno E, et al. Identification of prolactin as a novel immunomodulator on the expression of co-stimulatory molecules and cytokine secretions on T and B human lymphocytes. Clin Immunol 2005; 116: 182–91.

16. Tripathi A, Sodhi A. Production of nitric oxide by murine peritoneal macrophages in vitro on treatment with prolactin and growth hormone: involvement of protein tyrosine kinases, Ca++, and MAP kinase signal transduction pathways. Mol Immunol 2007; 44: 3185.

17. Gerlo S, Davis JR, Mager DL, Kooijman R. Prolactin in man: a tale of two promoters. Bioessays 2006; 28: 1051-5.

18. Gellersen B, Kempf R, Telgmann R, et al. Nonpituitary human prolactin gene transcription is independent of Pit-1 and differentially controlled in lymphocytes and in endometrial stroma. Moll Endocrinol 1994; 8: 356-73.

19. Graham RR, Ortmann WA, Langefeld CD, et al. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am J Hum Genet 2002; 71:543-553.

20. Gambelunghe G, Gerli R, Bartoloni Bocci E, et al. Contribution of MHC class I chain-related A (MICA) gene polymorphism to genetic susceptibility for systemic lupus erythematosus. Rheumatology 2005; 44:287–292.

21. Fernando MM, Stevens CR, Sabeti PC, et al. Identification of two independent risk factors for lupus within the MHC in United Kingdom families. PLoS Genet 2007; 3: e192.

22. Smerdel-Ramoya A, Finholt C, Lilleby V, et al. Systemic lupus erythematosus and the extended major histocompatibility complex - evidence for several predisposing loci. Rheumatology 2005, 44: 1368-1373.

23. Steinsson K, Jónsdóttir S, Arason GJ, et al. A study of the association of HLA DR, DQ, and complement C4 alleles with systemic lupus erythematosus in Iceland. Ann Rheum Dis 1998; 57: 503-505.

24. Hrycek A, Siekiera U, Cieslik P, et al. HLA-DRB1 and -DQB1 alleles and gene polymorphisms of selected cytokines in systemic lupus erythematosus. Rheumatol Int 2005; 26: 1-6.

25. Hashimoto H, Nishimura Y, Dong RP, et al. HLA antigens in Japanese patients with systemic lupus erythematosus. Scand J Rheumatol 1994; 23: 191-6.

26. Tsuchiya N, Kawasaki A, Tsao BP, et al. Analysis of the association of HLA-DRB1, TNFaaa promoter and TNFR2 (TNFRSF1B) polymorphisms with SLE using transmission disequilibrium test. Genes Imm 2001; 2: 317-22.

27. Gambelunghe G, Gerli R, Bartoloni Bocci E, et al. Contribution of MHC class I chain-related A (MICA) gene polymorphism to genetic susceptibility for systemic lupus erythematosus. Rheumatology 2005; 44: 287–292.

28. Sanchez E, Torres B, Vilches JR, et al. No primary association of MICA polymorphism with systemic lupus erythematosus. Rheumatology 2006; 45: 1096-1100.

29. Lopez-Vazquez A, Rodrigo L, Fuentes D, et al. MHC class I chain related gene A (MICA) modulates the development of coeliac disease in patients with the high risk heterodimer DQA1*0501/DQB1*0201. Gut 2002; 50: 336–340.

30. Gauedieri S, Leelayuwat C, Townend DC, et al. Allelic and interlocus comparison of the PERB11 multigene family in the MHC. Immunogenetics 1997; 45: 209-216.

31. Ashiru O, Bennett NJ, Boyle LH, et al. NKG2D ligand MICA is retained in the cis-golgi apparatus by human cytomegalovirus protein UL142. J Virol 2009; 83: 12345-12354.

32. Petersdorf EW, Shuler KB, Longton GM, et al. Population study of allelic diversity in the human MHC-class I-related MIC-A gene. Immunogenetics 1999; 49: 605-12.

33. Alenius GM, Jidell E, Nordmark L, Dahlqvist SR. Disease manifestation and HLA antigens in psoriatic arthritis in Northern Sweden. Clin Rheumatol 2002; 21: 357-6.

34. Valdimarsson H. The genetic basis of psoriasis. Clin Dermatol 2007; 25: 563-567.

35. Sczcerkowska Dobosz A, Rebala K, Szczerkowska Z, et al. HLA-C locus alleles distribution in patients from nothern Poland with psoriatic arthritis: preliminary report. Int J Immunogenet 2005; 32: 389-391.

36. Trembath RC, Clough RL, Rosbotham JL, et al. Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum Mol Genet 1997; 6: 813-820.

37. Gonzalez S, Martinez-Borra J, Torre-Alonso JC, et al. The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to develop psoriatic arthritis, and is independent of the association of Cw*0602 in psoriasis. Arthritis Rheum 1999; 42: 1010-1016.

38. Ho YPCP, Barton A, Worthington J, et al. Investigating the role of the HLA-Cw*06 and HLA-DRB1 genes in susceptibility to psoriatic arthritis: comparison with psoriasis and undifferentiated inflammatory arthritis. Ann Rheum Dis 2008; 67: 677-82.

39. Grubic Z, Peric P, Eeéuk-Jelicic E, et al. The MICA-A4 triplet repeats polymorphism in the transmembrane region confers additional risk for development of psoriatic arthritis in the Croatian population. Eur J Immunogenet 2004; 31: 93-98.

40. Gonzalez S, Brautbar C, Martinez-Borra J, et al. Polymorphism in MICA ether than HLA-B/C genes is associated with psoriatic arthritis in the Jewish population. Hum Immunol 2001; 62: 632-638.

41. Mateo L, Noila JM, Bonnion MR, et al. High serum prolactin levels in men with rheumatoid arthritis. J Rheumatol 1998; 25: 2077-2082.

42. Moszkorzova L, Lacinova Z, Marek J, et al. Hyperprolactinaemia in patients with systemic lupus erythematosus. Clin Exp Rheumatol 2002; 20: 807-8012.

43. Gutierrez MA, Garcia ME, Rodriguez JA, et al. Hypothalamic-pituitary – adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress and prolactin stimulation. J Rheuamtol 199;, 26: 277-281.

44. Eijsbouts AM, Van Den Hoogen FH, Laan RF, et al. Decreased prolactin response to hypoglycaemia in patients with rheumatoid arthritis: correlation with disease activity. Ann Rheum Dis 2005; 64: 433-467.

45. Nagy E, Chalmers IM, Baragas FD, et al. Prolactin deficiency in rheumatoid arthritis. J Rheumatol 1991; 18: 1662-1668.

46. Nagafuchi H, Suzuki N, Kaneko A, et al. Prolactin locally produced by synovium infiltrating T lymphocytes induces excessive synovial cell functions in rheumatoid arthritis. J Rheumatol 1999;, 26: 1890-900.

47. Dimitrov S, Lange T, Ehm HL, Born J. A regulatory role of prolactin, growth hormone, and corticosteroids for human T-cell production of cytokines. Brain Behav Immun 2004; 18: 368-74.

48. Mellai M, Giordano M, DęAlfonso S, et al. Prolactin and prolactin receptor gene polymorphisms in multiple sclerosis and systemic lupus erythematosus. Hum Immunol 2003; 64: 274-284.

49. Montoya-Diaz E, Cervera-Castilo H, Chávez-Sanchéz L, et al. Prolactin promoter polymorphism (-1149G/T) is associated with anti-DNA antibodies in Mexican patients with systemic lupus erythematosus. Immunol Invest 2011; Epub Apr 18.

50. Stevens A, Ray DW, Worthington J, et al. Polymorphisms of the human prolactin gene – implications for production of lymphocyte prolactin and systemic lupus erythematosus. Lupus 2001; 10: 676-683.

51. Zermeňo C, Guznam-Morales J, Macotela Y, et al. Prolactin inhibit the apoptosis of chondrocytes induced by serum starvation. J Endocrinol 2006; 189: R1-R8.

52. Cohen-Solal JF, Jeganathan V, Hill L, et al. Hormonal regulation of B-cell function and systemic lupus erythematosus. Lupus 2008; 17: 528-32.

53. Grimaldi CM. Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells. Curr Opin Rheumatol 2006; 18: 456-61.

54. Novota P, Kolostova K, Pinterova D, et al. Association of MHC class I chain related gene-A microsatellite polymorphism with the susceptibility to T1DM and LADA in Czech adult patients. Int J Immunogenet 2005; 32: 273-275.

55. Cerna M, Kolostova K, Novota P, et al. Autoimmune diabetes mellitus with adult onset and type 1 diabetes mellitus in children have different genetic predispositions. Ann NY Acad Sci 2007; 1110: 140-150.

56. Czuwara-Ladykowska J, Sicinska J, Olszewska M, et al. Prolactin synthesis by lymphocytes from patients with systemic sclerosis. Biomed Pharmacother 2006;, 60: 152-155.

57. Lee YC, Raychaudhuri S, Cui J, et al. The PRL -1149G/T polymorphism and rheumatoid arthritis susceptibility. Arthritis Rheum 2009; 60: 1250-1254.

Labels
Dermatology & STDs Paediatric rheumatology Rheumatology
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#