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HLA-B27: The Facts

HLA-B27 is an abbreviation for "Human Leukocyte Antigen B27", a class I surface antigen that is encoded in the B locus in the major histocompatibility complex (MHC) on the short arm of chromosome 6. One of the functions of HLA-B27 is to present antigenic peptides to T-cells.

HLA-B27 gene loci on chromosome 6

HLA-B27 was discovered in 1969 and is distributed worldwide but with variable prevalence [1, 2]. Four years later HLA-B27 was found to show a remarkable association with a rheumatic disease called ankylosing spondylitis (AS), and later also with the related group of diseases called spondyloarthropathies (SpA) [3–5]. But the strength of this association varies not only among the various forms of SpA but also among the many ethnic and racial groups worldwide [5, 6]. For example, whereas only 8% of the populations of northwestern European descent possess HLA-B27, more than 90% of AS patients possess this gene (Table 1). In contrast, among African Americans 2% to 4% of the general population and 50% of patients with AS possess this gene [5, 6].

The presence of HLA-B27 influences the clinical manifestations of AS because, although there are many similarities, the HLA-B27–positive patients have a significantly younger age at onset of their disease and a higher prevalence of episodes of eye inflammation (acute anterior uveitis) and hip joint involvement [23–26]. Of interest, HLA-B27 homozygosity does not affect the clinical manifestations of AS, but it does triple the risk of disease occurrence [26–28]. The precise biological explanation for this remarkable association remains elusive, and in the general population more than 95% of the individuals with this gene never develop these diseases.

HLA-B27 shows a remarkable polymorphism, with an ever-increasing number of alleles [5, 10–17]. Thus far, there are 75 known alleles of HLA-B27 based on nucleotide sequence differences [5, 10] (Table 2). However, at the translated protein level, there are 62 subtypes of HLA-B27 based on amino acid sequence differences because some of the mutations are located within introns and thus are silent, or they occur in exons but do not cause amino acid changes [5, 10].. These 62 subtypes can be encompassed by the numbering system HLA-B*2701 to HLA-B*2763 because one of the assignments—HLA-B*2722—was subsequently withdrawn when it was found to be identical to HLA-B*2706 [10].

The various subtypes of HLA-B27 show an extremely varied racial and ethnic prevalence throughout the world, and it has now been established that not all of them are disease associated, although some of them may differ from the disease-associated subtype by only a single amino acid [5, 6, 13, 15]. A table showing amino acid sequence variations in a1 and a2 domains among the various HLA-B27 subtypes have recently been published [5]. HLA-B*2705 (specifically the HLA-B*270502 allele) is the most widely distributed disease-associated subtype in the world and has been the subject of most studies. The other common disease-associated subtypes are HLA-B*2702 (Mediterranean Caucasian populations) and HLA-B*2704 (Chinese and other Asian populations). Among the remaining subtypes, HLA-B*2701, HLA-B*2703, HLA-B*2707, HLA-B*2708, HLA-B*2710, HLA-B*2713, HLA-B*2714, HLA-B*2715, HLA-B*2719, HLA-B*2723, HLA-B*2724, and HLA-B*2725 are also known to be disease associated, or at least one or more AS patients possessing these subtypes have been observed [5]. Most of the remaining subtypes are too rare or too recently described to have been evaluated for disease presence or association.

There are also differences among some of the HLA-B27 subtypes when it comes to disease association [5, 11–16, 18–21]. Thus, whereas HLA-B*2705 and HLA-B*2702 seem to confer equal susceptibility to AS in Caucasian populations, HLA-B*2706 (a common subtype in south-east Asia) and HLA-B*2709 (a rare subtype found primarily on the Italian island of Sardinia) seem to lack association with AS [5, 12]. On the other hand, among Chinese populations, HLA-B*2704 has been clearly demonstrated to show a stronger association with AS than HLA-B*2705 [21].

In conclusion, HLA-B27 represents a family of closely related proteins encoded by an ever-increasing number of alleles; not all of them are disease associated and an overwhelming majority of patients with this gene remain unaffected.

The HLA-B27 gene is strongly associated with a certain immune mediated inflammatory diseases which are classified as "seronegative spondyloarthropathies". Seronegative means that they are not associated with rheumatoid factor, an autoantibody that is common in about 70% of patients with rheumatoid arthritis, a different immune mediated inflammatory disease.

PREVALENCE In the general population, the HLA-B27 antigen is present in about 8% of Caucasians, 4% of individuals of African descent, between 2% to 9% of Chinese, and only 0.1-0.5% of the Japanese.

In some populations (i.e. Northern Scandinavia) up to 24% of the general population are HLA-B27 positive, yet only 1.8% have associated ankylosing spondylitis (AS). Therefore, although typing for the histocompatibility antigen (HLA)-B27 has been suggested as a clinically valuable diagnostic test for ankylosing spondylitis, the presence of this antigen is not necessarily predictive of future development of the disease.

Diagnoses can be made in most patients with ankylosing spondylitis on the basis of the history, physical examination, and radiographic (x-ray) findings. The HLA-B27 test cannot be used to screen an asymptomatic population to detect these diseases, and the test should not be used as a routine diagnostic test. In certain patients the B27 test, when used properly, is of clinical value as an aid to confirming a diagnosis of AS. The HLA-B27 test result does not absolutely confirm or exclude the presence of AS; it merely provides a statement of increased probability of the existence of AS in the symptomatic patient. The test is therefore most useful to physicians who understand the use of probability reasoning in clinical decision making.

REFERENCE FOR PREVALENCE SECTION: Diagnostic Value of HLA-B27 Testing in Ankylosing Spondylitis and Reiter's Syndrome. M.A. Khan, M.K. Khan. Annals of internal Medicine January 1, 1982 vol. 96 no. 1 70-76

OTHER REFERENCES:

References 1. Thorsby E: HL-A antigens and genes. I. A study of unrelated Norwegians. Vox Sang 1969, 17:81–92.

2. Khan MA: HLA-B27 and its pathogenic role. J Clin Rheumatol 2008, 14:50–52.

3. Brewerton DA, Hart FD, Nicholls A, et al.: Ankylosing spondylitis and HL-A 27. Lancet 1973, 1:904–907. 4. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM: High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 1973, 288:704–706.

5. **Khan MA: HLA and spondyloarthropathies. In: The HLA Complex in Biology and Medicine. Edited by Mehra N. New Delhi, India: Jaypee Brothers Medical Publishers; 2010:422–446. It is a comprehensive review on the association between HLA-B27and ankylosing spondylitis, and polymorphism of HLA-B27 in a book just published.

6. Akkoc N, Khan MA: Epidemiology of ankylosing spondylitis and related spondyloarthropathies. In Ankylosing Spondylitis and the Spondyloarthropathies: A Companion to Rheumatology. Edited by Weisman MH, Reveille JD, van der Heijde D. London: Mosby-Elsevier; 2006:117–131.

7. Brown MA, Jepson A, Young A, et al.: Ankylosing spondylitis in West Africans—evidence for a non-HLA-B27 protective effect. Ann Rheum Dis 1997, 56:68–70.

8. Lopez-Larrea C, Mijiyawa M, Gonzalez S, et al.: Association of ankylosing spondylitis with HLA-B*1403 in a West African population. Arthritis Rheum 2002, 46:2968–2971

9. Diaz-Pena R, Blanco-Gelaz MA, Njobvu P, et al.: Influence of HLA-B*5703 and HLA-B*1403 on susceptibility to spondyloarthropathies in the Zambian population. J Rheumatol 2008, 35:2236–2240.

10. Khan MA: Ankylosing spondylitis and heterogeneity of HLA-B27. Semin Arthritis Rheum 1988, 18:134–141.

11. Khan MA: HLA-B27 and its subtypes in world populations. Curr Opin Rheumatol 1995, 7:263–269.

12. Khan MA: Update: the twenty subtypes of HLA-B27. Curr Opin Rheumatol 2000, 12:235–238.

13. Khan MA, Mathieu A, Sorrentino R, Akkoc N: The pathogenic role of HLA-B27 and its subtypes in ankylosing spondylitis. Autoimmun Rev 2007, 6:183–189.

14. Taurog JD: The mystery of HLA-B27: if it isn’t one thing, it’s another. Arthritis Rheum 2007, 56:2478–2481.

15. Ziegler A, Loll B, Misselwitz R, Uchanska-Ziegler B: Implications of structural and thermodynamic studies of HLA-B27 subtypes exhibiting differential association with ankylosing spondylitis. Adv Exp Med Biol 2009, 649:177–195.

16. Reveille J, Maganti R: Subtypes of HLA-B27: history and implications in the pathogenesis of ankylosing spondylitis. Adv Exp Med Biol 2009, 649:159–176.

17. European Bioinformatics Institute: IMGT/HLA Database. Available at: http://www.ebi.ac.uk/cgi-bin/imgt/hla/allele.cgi. Accessed July 13, 2010.

18. Mou Y, Wu Z, Gu J, et al.: HLA-B27 polymorphism in patients with juvenile and adult onset ankylosing spondylitis in Southern China. Tissue Antigens 2010, 75:56–60.

19. Liu X, Hu LH, Li YR, et al.: The association of HLA-B*27 subtypes with ankylosing spondylitis in Wuhan population of China. Rheumatol Int 2010, 30:587–590.

20. *Tam LS, Gu J, Yu D: Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol 2010, 6:399–405.

It is a comprehensive review on the pathogenetic aspects of ankylosing spondylitis.

21. Liu Y, Jiang L, Cai Q, et al.: Predominant association of HLA-B*2704 with ankylosing spondylitis in Chinese Han patients. Tissue Antigens 2010, 75:61–64.

22. Varnavidou-Nicolaidou A, Karpasitou K, Georgiou D, et al.: HLA-B27 in the Greek Cypriot population: distribution of subtypes in patients with ankylosing spondylitis and other HLA-B27-related diseases: The possible protective role of B*2707. Hum Immunol 2004, 65:1451–1454.

23. Khan MA, Kushner I, Braun WE: Comparison of clinical features in HLA-B27 positive and negative patients with ankylosing spondylitis. Arthritis Rheum 1977, 20:909–912.

24. Feldtkeller E, Khan MA, van der Linden S, et al.: Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int 2003, 23:61–66.

25. * Khan MA: Ankylosing Spondylitis. New York: Oxford University Press; 2009. It is a recently published concise book on ankylosing spondylitis and related spondyloarthropathies.

26. Kim TJ, Na KS, Lee HJ, et al.: HLA-B27 homozygosity has no influence on clinical manifestations and functional disability in ankylosing spondylitis. Clin Exp Rheumatol 2009, 27:574–579.

27. Khan MA, Kushner I, Braun WE, et al.: HLA-B27 homozygosity in ankylosing spondylitis: relationship to risk and severity. Tissue Antigens 1978, 11:434–438.

28. Jaakkola E, Herzberg I, Laiho K, et al.: Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis. Ann Rheum Dis 2006, 65:775–780.

29. **Thomas GP, Brown MA: Genetics and genomics of ankylosing spondylitis. Immunol Rev 2010, 233:162–180. It is a comprehensive review summarizing recent state-of-the-art knowledge about the genetic aspects of ankylosing spondylitis.

30. Kollnberger S, Bowness P: Role of B27 heavy chain dimer immune receptor interactions in spondyloarthritis. Adv Exp Med Biol 2009, 649:277–285.

31. François RJ, Braun J, Khan MA: Entheses and enthesitis: a histopathological review and relevance to spondyloarthritides. Curr Opin Rheumatol 2001, 13:255–264.

32. Adams DD, Knight JG, Ebringer A: Autoimmune diseases: solution of the environmental, immunological and genetic components with principles for immunotherapy and transplantation. Autoimmun Rev 2010, 9:525–530.

33. Stone MA, Payne U, Schentag C, et al.: Comparative immune responses to candidate arthritogenic bacteria do not confirm a dominant role for Klebsiella pneumonia in the pathogenesis of familial ankylosing spondylitis. Rheumatology (Oxford) 2004, 43:148–155.

34. Cragnolini JJ, Garcia-Medel N, Lopez de Castro J: Endogenous processing and presentation of T-cell epitopes from chlamydia trachomatis with relevance in HLA-B27-associated reactive arthritis. Mol Cell Proteomics 2009, 8:1850–1859.

35. Carter JD, Gerard HC, Espinoza LR, et al.: Chlamydiae as etiologic agents in chronic undifferentiated spondylarthritis. Arthritis Rheum 2009, 60:1311–1316.

Purchase Ankylosing Spondylitis: The Facts by Muhammad Asim Khan, MD, Oxford University Press

Other Published Scientific Articles by Professor Khan on Ankylosing Spondylitis

Other Useful Links

Book on Ankylosing Spondylitis for patients, their families, and allied health professionals

Other Published Scientific Articles by Professor Khan on Ankylosing Spondylitis

PHYSICIANS ONLY



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	HLA-B27: The Facts HLA-B27 is an abbreviation for "Human Leukocyte Antigen B27", a class I surface antigen that is encoded in the B locus in the major histocompatibility complex (MHC) on the short arm of chromosome 6. One of the functions of HLA-B27 is to present antigenic peptides to T-cells. HLA-B27 was discovered in 1969 and is distributed worldwide but with variable prevalence [1, 2]. Four years later HLA-B27 was found to show a remarkable association with a rheumatic disease called ankylosing spondylitis (AS), and later also with the related group of diseases called spondyloarthropathies (SpA) [3–5]. But the strength of this association varies not only among the various forms of SpA but also among the many ethnic and racial groups worldwide [5, 6]. For example, whereas only 8% of the populations of northwestern European descent possess HLA-B27, more than 90% of AS patients possess this gene (Table 1). In contrast, among African Americans 2% to 4% of the general population and 50% of patients with AS possess this gene [5, 6]. The presence of HLA-B27 influences the clinical manifestations of AS because, although there are many similarities, the HLA-B27–positive patients have a significantly younger age at onset of their disease and a higher prevalence of episodes of eye inflammation (acute anterior uveitis) and hip joint involvement [23–26]. Of interest, HLA-B27 homozygosity does not affect the clinical manifestations of AS, but it does triple the risk of disease occurrence [26–28]. The precise biological explanation for this remarkable association remains elusive, and in the general population more than 95% of the individuals with this gene never develop these diseases. HLA-B27 shows a remarkable polymorphism, with an ever-increasing number of alleles [5, 10–17]. Thus far, there are 75 known alleles of HLA-B27 based on nucleotide sequence differences [5, 10] (Table 2). However, at the translated protein level, there are 62 subtypes of HLA-B27 based on amino acid sequence differences because some of the mutations are located within introns and thus are silent, or they occur in exons but do not cause amino acid changes [5, 10].. These 62 subtypes can be encompassed by the numbering system HLA-B2701 to HLA-B2763 because one of the assignments—HLA-B2722—was subsequently withdrawn when it was found to be identical to HLA-B2706 [10]. The various subtypes of HLA-B27 show an extremely varied racial and ethnic prevalence throughout the world, and it has now been established that not all of them are disease associated, although some of them may differ from the disease-associated subtype by only a single amino acid [5, 6, 13, 15]. A table showing amino acid sequence variations in a1 and a2 domains among the various HLA-B27 subtypes have recently been published [5]. HLA-B2705 (specifically the HLA-B270502 allele) is the most widely distributed disease-associated subtype in the world and has been the subject of most studies. The other common disease-associated subtypes are HLA-B2702 (Mediterranean Caucasian populations) and HLA-B2704 (Chinese and other Asian populations). Among the remaining subtypes, HLA-B2701, HLA-B2703, HLA-B2707, HLA-B2708, HLA-B2710, HLA-B2713, HLA-B2714, HLA-B2715, HLA-B2719, HLA-B2723, HLA-B2724, and HLA-B2725 are also known to be disease associated, or at least one or more AS patients possessing these subtypes have been observed [5]. Most of the remaining subtypes are too rare or too recently described to have been evaluated for disease presence or association. There are also differences among some of the HLA-B27 subtypes when it comes to disease association [5, 11–16, 18–21]. Thus, whereas HLA-B2705 and HLA-B2702 seem to confer equal susceptibility to AS in Caucasian populations, HLA-B2706 (a common subtype in south-east Asia) and HLA-B2709 (a rare subtype found primarily on the Italian island of Sardinia) seem to lack association with AS [5, 12]. On the other hand, among Chinese populations, HLA-B2704 has been clearly demonstrated to show a stronger association with AS than HLA-B2705 [21]. In conclusion, HLA-B27 represents a family of closely related proteins encoded by an ever-increasing number of alleles; not all of them are disease associated and an overwhelming majority of patients with this gene remain unaffected. The HLA-B27 gene is strongly associated with a certain immune mediated inflammatory diseases which are classified as "seronegative spondyloarthropathies". Seronegative means that they are not associated with rheumatoid factor, an autoantibody that is common in about 70% of patients with rheumatoid arthritis, a different immune mediated inflammatory disease. PREVALENCE In the general population, the HLA-B27 antigen is present in about 8% of Caucasians, 4% of individuals of African descent, between 2% to 9% of Chinese, and only 0.1-0.5% of the Japanese. In some populations (i.e. Northern Scandinavia) up to 24% of the general population are HLA-B27 positive, yet only 1.8% have associated ankylosing spondylitis (AS). Therefore, although typing for the histocompatibility antigen (HLA)-B27 has been suggested as a clinically valuable diagnostic test for ankylosing spondylitis, the presence of this antigen is not necessarily predictive of future development of the disease. Diagnoses can be made in most patients with ankylosing spondylitis on the basis of the history, physical examination, and radiographic (x-ray) findings. The HLA-B27 test cannot be used to screen an asymptomatic population to detect these diseases, and the test should not be used as a routine diagnostic test. In certain patients the B27 test, when used properly, is of clinical value as an aid to confirming a diagnosis of AS. The HLA-B27 test result does not absolutely confirm or exclude the presence of AS; it merely provides a statement of increased probability of the existence of AS in the symptomatic patient. The test is therefore most useful to physicians who understand the use of probability reasoning in clinical decision making. REFERENCE FOR PREVALENCE SECTION: Diagnostic Value of HLA-B27 Testing in Ankylosing Spondylitis and Reiter's Syndrome. M.A. Khan, M.K. Khan. Annals of internal Medicine January 1, 1982 vol. 96 no. 1 70-76 OTHER REFERENCES: References 1. Thorsby E: HL-A antigens and genes. I. A study of unrelated Norwegians. Vox Sang 1969, 17:81–92. 2. Khan MA: HLA-B27 and its pathogenic role. J Clin Rheumatol 2008, 14:50–52. 3. Brewerton DA, Hart FD, Nicholls A, et al.: Ankylosing spondylitis and HL-A 27. Lancet 1973, 1:904–907. 4. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM: High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 1973, 288:704–706. 5. *Khan MA: HLA and spondyloarthropathies. In: The HLA Complex in Biology and Medicine. Edited by Mehra N. New Delhi, India: Jaypee Brothers Medical Publishers; 2010:422–446. It is a comprehensive review on the association between HLA-B27and ankylosing spondylitis, and polymorphism of HLA-B27 in a book just published. 6. Akkoc N, Khan MA: Epidemiology of ankylosing spondylitis and related spondyloarthropathies. In Ankylosing Spondylitis and the Spondyloarthropathies: A Companion to Rheumatology. Edited by Weisman MH, Reveille JD, van der Heijde D. London: Mosby-Elsevier; 2006:117–131. 7. Brown MA, Jepson A, Young A, et al.: Ankylosing spondylitis in West Africans—evidence for a non-HLA-B27 protective effect. Ann Rheum Dis 1997, 56:68–70. 8. Lopez-Larrea C, Mijiyawa M, Gonzalez S, et al.: Association of ankylosing spondylitis with HLA-B1403 in a West African population. Arthritis Rheum 2002, 46:2968–2971 9. Diaz-Pena R, Blanco-Gelaz MA, Njobvu P, et al.: Influence of HLA-B5703 and HLA-B1403 on susceptibility to spondyloarthropathies in the Zambian population. J Rheumatol 2008, 35:2236–2240. 10. Khan MA: Ankylosing spondylitis and heterogeneity of HLA-B27. Semin Arthritis Rheum 1988, 18:134–141. 11. Khan MA: HLA-B27 and its subtypes in world populations. Curr Opin Rheumatol 1995, 7:263–269. 12. Khan MA: Update: the twenty subtypes of HLA-B27. Curr Opin Rheumatol 2000, 12:235–238. 13. Khan MA, Mathieu A, Sorrentino R, Akkoc N: The pathogenic role of HLA-B27 and its subtypes in ankylosing spondylitis. Autoimmun Rev 2007, 6:183–189. 14. Taurog JD: The mystery of HLA-B27: if it isn’t one thing, it’s another. Arthritis Rheum 2007, 56:2478–2481. 15. Ziegler A, Loll B, Misselwitz R, Uchanska-Ziegler B: Implications of structural and thermodynamic studies of HLA-B27 subtypes exhibiting differential association with ankylosing spondylitis. Adv Exp Med Biol 2009, 649:177–195. 16. Reveille J, Maganti R: Subtypes of HLA-B27: history and implications in the pathogenesis of ankylosing spondylitis. Adv Exp Med Biol 2009, 649:159–176. 17. European Bioinformatics Institute: IMGT/HLA Database. Available at: http://www.ebi.ac.uk/cgi-bin/imgt/hla/allele.cgi. Accessed July 13, 2010. 18. Mou Y, Wu Z, Gu J, et al.: HLA-B27 polymorphism in patients with juvenile and adult onset ankylosing spondylitis in Southern China. Tissue Antigens 2010, 75:56–60. 19. Liu X, Hu LH, Li YR, et al.: The association of HLA-B27 subtypes with ankylosing spondylitis in Wuhan population of China. Rheumatol Int 2010, 30:587–590. 20. Tam LS, Gu J, Yu D: Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol 2010, 6:399–405. It is a comprehensive review on the pathogenetic aspects of ankylosing spondylitis. 21. Liu Y, Jiang L, Cai Q, et al.: Predominant association of HLA-B2704 with ankylosing spondylitis in Chinese Han patients. Tissue Antigens 2010, 75:61–64. 22. Varnavidou-Nicolaidou A, Karpasitou K, Georgiou D, et al.: HLA-B27 in the Greek Cypriot population: distribution of subtypes in patients with ankylosing spondylitis and other HLA-B27-related diseases: The possible protective role of B2707. Hum Immunol 2004, 65:1451–1454. 23. Khan MA, Kushner I, Braun WE: Comparison of clinical features in HLA-B27 positive and negative patients with ankylosing spondylitis. Arthritis Rheum 1977, 20:909–912. 24. Feldtkeller E, Khan MA, van der Linden S, et al.: Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int 2003, 23:61–66. 25. * Khan MA: Ankylosing Spondylitis. New York: Oxford University Press; 2009. It is a recently published concise book on ankylosing spondylitis and related spondyloarthropathies. 26. Kim TJ, Na KS, Lee HJ, et al.: HLA-B27 homozygosity has no influence on clinical manifestations and functional disability in ankylosing spondylitis. Clin Exp Rheumatol 2009, 27:574–579. 27. Khan MA, Kushner I, Braun WE, et al.: HLA-B27 homozygosity in ankylosing spondylitis: relationship to risk and severity. Tissue Antigens 1978, 11:434–438. 28. Jaakkola E, Herzberg I, Laiho K, et al.: Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis. Ann Rheum Dis 2006, 65:775–780. 29. **Thomas GP, Brown MA: Genetics and genomics of ankylosing spondylitis. Immunol Rev 2010, 233:162–180. It is a comprehensive review summarizing recent state-of-the-art knowledge about the genetic aspects of ankylosing spondylitis. 30. Kollnberger S, Bowness P: Role of B27 heavy chain dimer immune receptor interactions in spondyloarthritis. Adv Exp Med Biol 2009, 649:277–285. 31. François RJ, Braun J, Khan MA: Entheses and enthesitis: a histopathological review and relevance to spondyloarthritides. Curr Opin Rheumatol 2001, 13:255–264. 32. Adams DD, Knight JG, Ebringer A: Autoimmune diseases: solution of the environmental, immunological and genetic components with principles for immunotherapy and transplantation. Autoimmun Rev 2010, 9:525–530. 33. Stone MA, Payne U, Schentag C, et al.: Comparative immune responses to candidate arthritogenic bacteria do not confirm a dominant role for Klebsiella pneumonia in the pathogenesis of familial ankylosing spondylitis. Rheumatology (Oxford) 2004, 43:148–155. 34. Cragnolini JJ, Garcia-Medel N, Lopez de Castro J: Endogenous processing and presentation of T-cell epitopes from chlamydia trachomatis with relevance in HLA-B27-associated reactive arthritis. Mol Cell Proteomics 2009, 8:1850–1859. 35. Carter JD, Gerard HC, Espinoza LR, et al.: Chlamydiae as etiologic agents in chronic undifferentiated spondylarthritis. Arthritis Rheum 2009, 60:1311–1316. Purchase Ankylosing Spondylitis: The Facts by Muhammad Asim Khan, MD, Oxford University Press Other Published Scientific Articles by Professor Khan on Ankylosing Spondylitis Other Useful Links Book on Ankylosing Spondylitis for patients, their families, and allied health professionals Other Published Scientific Articles by Professor Khan on Ankylosing Spondylitis PHYSICIANS ONLY



			glutathione immunocal calorad