Aspectos genéticos da esclerose múltipla: II. sistema HLA

Rezende, Patrícia Almeida de; Arruda, Walter Oleschko

doi:10.1590/S0004-282X1996000300013

Resumos

Foi feita análise e revisão de estudos populacionais de associação entre antígenos HLA e a esclerose múltipla (EM). Há evidências de que os genes HLA, principalmente os de classe II, das sub-regiões DR e DQ possam estar envolvidos. O haplótipo DRB1*1501.DQA1*0102.DQB1*0602 referente ao fenótipo DR2.Dw2.DQ6 foi encontrado em associação positiva em vários estudos realizados em populações caucasóides. O desequilíbrio de ligação entre os genes DR e DQ dificulta o reconhecimento da contribuição individual de cada alelo. A heterogeneidade de critérios diagnósticos da EM constitui importante fator metodológico que dificulta a comparação entre os diversos estudos. A padronização dos critérios diagnósticos e dos métodos laboratoriais empregados, assim como a análise individual de grupos de pacientes com formas clínicas diferentes, são medidas que provavelmente permitirão avaliação mais precisa dos fatores genéticos envolvidos no desenvolvimento da EM.

esclerose múltipla; sistema HLA; genética

Review of studies about HLA antigens and multiple sclerosis (MS). The HLA system, in special class II antigens, subregions DR and DQ, is probably involved in the immunopathogenesis of MS. Haplotype DRB1*1501.DQA1*0102.DQB1*0602, corresponding to phenotype DR2.Dw2.DQ6, is positively associated with MS in several caucasoid populations. Clinical heterogeneity of MS, as well as different diagnostic criteria adopted by investigators are potential sources of confusion and may lead to discrepant results. A better standardization of clinical and laboratorial methodology, appropriate subdivision of patients with different clinical forms of MS, may allow a more accurate evaluation of the role of genetic factors in the pathogenesis of MS.

multiple sclerosis; HLA system; genetics

Aspectos genéticos da esclerose múltipla: II. sistema HLA

Genetic aspects in multiple sclerosis: HLA system

Patrícia Almeida de Rezende^I; Walter Oleschko Arruda^II

^IMestre em Genética, Universidade Federal do Paraná (UFPR)

^IINeurologista

RESUMO

Foi feita análise e revisão de estudos populacionais de associação entre antígenos HLA e a esclerose múltipla (EM). Há evidências de que os genes HLA, principalmente os de classe II, das sub-regiões DR e DQ possam estar envolvidos. O haplótipo DRB1*1501.DQA1*0102.DQB1*0602 referente ao fenótipo DR2.Dw2.DQ6 foi encontrado em associação positiva em vários estudos realizados em populações caucasóides. O desequilíbrio de ligação entre os genes DR e DQ dificulta o reconhecimento da contribuição individual de cada alelo. A heterogeneidade de critérios diagnósticos da EM constitui importante fator metodológico que dificulta a comparação entre os diversos estudos. A padronização dos critérios diagnósticos e dos métodos laboratoriais empregados, assim como a análise individual de grupos de pacientes com formas clínicas diferentes, são medidas que provavelmente permitirão avaliação mais precisa dos fatores genéticos envolvidos no desenvolvimento da EM.

Palavras-chave: esclerose múltipla, sistema HLA, genética.

ABSTRACT

Review of studies about HLA antigens and multiple sclerosis (MS). The HLA system, in special class II antigens, subregions DR and DQ, is probably involved in the immunopathogenesis of MS. Haplotype DRB1*1501.DQA1*0102.DQB1*0602, corresponding to phenotype DR2.Dw2.DQ6, is positively associated with MS in several caucasoid populations. Clinical heterogeneity of MS, as well as different diagnostic criteria adopted by investigators are potential sources of confusion and may lead to discrepant results. A better standardization of clinical and laboratorial methodology, appropriate subdivision of patients with different clinical forms of MS, may allow a more accurate evaluation of the role of genetic factors in the pathogenesis of MS.

Key words: multiple sclerosis, HLA system, genetics.

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Agradecimentos - Ao apoio financeiro de CAPES, ao Sr. Armando Guedes Vicentini pelo seu inestimável apoio na elaboração deste estudo.

Aceite: 14-março-1996.

Dr Walter O. Arruda - Rua Gonçalves Dias 713 - 80240-340 Curitiba PR - Brasil.

CORREÇÃO. Duas correções são necessárias no artigo Rezende PA, Arruda WO. Aspectos genéticos da esclerose múltipla: II. Sistema HLA. Arq Neuropsiquiatr 1996; 54(3): 439-450. A primeira, na Figura 1 (página 441): onde consta "proteínas do comportamento" leia-se "proteínas do complemento". A segunda, no título da Tabela 2 (página 446): onde consta "de diversas rocedências", leia-se "de diversas procedências". Essas incorreções foram notadas por Patrícia Almeida de Rezende, a primeira autora do artigo, cuja cooperação o Editor agradece.

1. Abbas AK, Lichtman AH, Pober JS. Cellular and molecular immunology. Philadelphia: Saunders. 1994.
2. Allen M, Sandberg-Wollheim M, Sjogren K, Erlich H, Petterson U, Gyllensten U. Association of susceptibility to multiple sclerosis in Sweden with HLA class IIDRB1 and DQB1 alleles. Hum Immunol 1994;39:41-48.
3. Atkins G, Daly E, Sheahan B, Higgins D, Sharp P. MS and molecular mimicry. Neuropathol Appl Neurobiol 1990; 16:179.
4. Begovich AB, Helmuth RC, Oksenberg JR et al. HLA-DP beta and susceptibility to multiple sclerosis: an analysis of Caucasoid and Japanese patient population. Hum Immunol 1990;28:365-372.
5. Bertrams J, Kuweit E. HL-A antigen frequencies in multiple sclerosis: significant increase of HL-A3, HL-A10 and WS and decrease of HL-A12. Eur Neurol 1972,7:74.
6. Ebers GC. Genetics and multiple sclerosis: an overview. Ann Neurol 1994;36(Suppl): 12-14.
7. Fugger L, Ryder LP, Morling N, Odum N, Friis J, Pedersen FK, Heilmann C, Sandberg-Wollheim M, Svejgaard A. DNA typing for HLA-DPB1 *02 and DPB1 *04 in multiple sclerosis and juvenile rheumatoid arthritis. Immunogenetics 1990;32:150-156.
8. Fukazawa T, Hamada T, Tashiro K, Moriwaka F, Yanagihara T, Sugyiama K, Tsukada Y. HLA profiles of multiple sclerosis in Hokkaido, the northernmost island of Japan. Acta Neurol Scand 1992;86:517-520.
9. Gomes MM, Almeida GFG. Esclerose múltipla e doenças correlatas: tendências diagnosticas no Brasil (capitais), 1979-1987. Rev Bras Neurol 1991;27:187-192.
10. Graeber MB, Streit WJ, Buringer D, Sparks DL, Kretzberg GW. Ultrastructural location of major histocompatibility complex (MHC) class II positive perivascular cells in histologically normal human brain. J Neuropathol Exper Neurol 1992;5 1:303-311.
11. Haegert DG, Francis GS. HLA-DQ polymorphisms do not explain HLA class II associations with multiple sclerosis in two Canadian patient groups. Neurology 1993;43:1207-1210.
12. Hillert J. Human leukocyte antigen studies in multiple sclerosis. Ann Neurol 1994;36(Suppl):15-17.
13. Hillert J, Gronning M, Nyland H, Link H, Olerup O. An immunogenetic heterogeneity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1992;55:887-890.
14. Hillert J, Olerup O. Multiple sclerosis is associated with genes within or close to the HLA-DR-DQ subregion on a normal DR15,DQ6,DW2 haplotype. Neurology 1993;43:163-168.
15. Howell WM, Sage DA, Evans PR, Smith JL, Francis GS, Haegert DG. No association between susceptibility to multiple sclerosis and HLA-DPB1 alleles in the French Canadian population. Tissue Antig 1991 ;37:156-160.
16. Kellar-Wood HF, Powis SH, Gray J, Compston DAS. MHC-encoded TAP1 and TAP2 dimorphisms in multiple sclerosis. ' Tissue Antig 1994;43:129-132.
17. Kelly MA, Jacobs KH, Penny MA, Mijovic CH, Nightingale S, Barnet AH, Francis DA. An investigation of HLA-encoded genetic susceptibility to multiple sclerosis in subjects of Asian Indian and Afro-Caribbean ethnic origin. Tissue Antig 1995;45:197-202.
18. Kurdi A, Ayesh I, Abdallat A, Maayta U, McDonald WI, Compston, DAS, Batchelor JR. Different B lymphocyte alloantigens associated with multiple sclerosis in Arabs and North Europeans. Lancet 1977;28:1123-1125.
19. Lamm LU, Olaisen B. Report of the comittee consitution of chromosomes 5 and 6. Cytog Cell Genet 1985;40:128.
20. Liblau R, Endert PN, Sandberg-Wollheim M, Patel SD, Lopez MT, Land S, Fugger L, McDevitt HO. Antigen processing gene polymorphisms in HLA-DR2 multiple sclerosis. Neurology 1993 ;43:1192-1197.
21. Marrosu MG, Muntoni F, Spinicci G, Pischedda MP, Goddi F, Cossu P, Pirastu M. Sardinian multiple sclerosis is associated with HLD-DR4: a serologic and molecular analysis. Neurology 1988;38:1749-1753.
22. McAlpine D, Lumsden CE, Acheson ED. Multiple sclerosis, a reappraisal. Ed2. Edinburgh: Churchill-Livingstone, 1972.
23. McDonald WI, Halliday AM. Diagnosis and classification of multiple sclerosis. Br Med Bull 1977;33:4.
24. Muntoni F, Murru MR, Costa G, Congia M, Cueca F, Cossu P, Cao A, Dessalvi L, Pirastu M, Marros MG. Different HLA DR2-DQwl haplotypes in Sardinian and northern Italian populations: implications for multiple sclerosis susceptibility. Tissue Antig 1991 ;38:34-36.
25. Naito S, Kurdiwa Y, Itoyama T, Tsubaki T, Horikawa A, Sakazuki T, Noguchi S, Ohtsuki S, Tokuomi H, Miyatake T, Takahata N, Kawanami S, McMichael AJ. HLA and Japanese MS. Tissue Antig 1978;12:19-24.
26. Naito S, Manerow N, Mickey MR, Terasaki PI. Multiple sclerosis: association with HL-A3. Tissue Antig 1972;2:1-4.
27. Odum N, Hyldig-Nielsen J, Morling N, Sandberg-Wollheim M, Platz P, Svejgaard A. HLA-DP antigens are involved in susceptibility to multiple sclerosis. Tissue Antig 1988,31:235-237.
28. Olerup O, Hillert J, Fredrikson S, Olsson T, Kam-Hansen S, Moller E, Carlsson B, Wallin J. Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci USA 1989;86:7113-7117.
29. Olerup O, Hillert J. HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antig 1991,38:1-15.
30. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231.
31. Rezende PA. Aspectos imunogenéticos da esclerose múltipla. Dissertação de Mestrado, UFPR - Curitiba, 1995.
32. Rose AS, Ellison GW, Myers LM, Tourtellotte WW. Criteria for the clinical diagnosis of multiple sclerosis. Neurology 1976;26(Suppl):20-22.
33. Schumacher G A, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F, Nagler B, Sibley WA, Tourtellotte WW, Willmon TL. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965;122:552-568.
34. Smith ME, Sommer MA. Association between cell-mediated demyelination and astrocyte stimulation. Progr Brain Res 1992;94:411-422.
35. Spurkland A, TabiraT, Ronningen KS, Vandvik B, Thorsby E, Vartdal F. HLA-DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 in Japanese multiple sclerosis patients. Tissue Antig 1991;37:171-173.
36. Spurkland A, Knutsen I, Undlien DE, Vartdal F. No association of multiple sclerosis to alleles at the TAP2 locus. Hum Immunol 1994;39:299-301.
37. Stites DP, Terr Al.Basic and clinical immunology. Los Altos, CA: Lange, 1991.
38. Stites DP, Terr AI. Imunologia básica. Rio de Janeiro:PHB, 1992.
39. Tienari PJ, Wikstrom J, Koskimies S, Partanen J, Palo J, Peltonen L. Reappraisal of HLA in multiple sclerosis: close linkage in multiplex families. Eur J Hum Genet 1993; 1:257-268.
40. Vartdal F, Sollid LM, Vandvik B, Markussen G, Thorsby, E. Patients with multiple sclerosis carry DQB1 genes which encode shared polymorphic amino acid sequences. Hum Immunol 1989;25:103-110.
41. Weber F, Meinl E, Aloisi F, Nevinny-Stickel C, Albert E, Wekerle H, Hohlfeld R. Human astrocytes are only partially competent antigen presenting cells: possible implications for lesion development in multiple sclerosis. Brain 1994; 117:59-69.
42. Wucherpfennig KW. Autoimmunity in the central nervous system: mechanisms of antigen presentation and recognition. Clin Immunol Immunopathol 1994;72:293-306.

Datas de Publicação

Publicação nesta coleção
23 Nov 2010
Data do Fascículo
Set 1996

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Abbas AK, Lichtman AH, Pober JS. Cellular and molecular immunology. Philadelphia: Saunders. 1994.

[2] 2. Allen M, Sandberg-Wollheim M, Sjogren K, Erlich H, Petterson U, Gyllensten U. Association of susceptibility to multiple sclerosis in Sweden with HLA class IIDRB1 and DQB1 alleles. Hum Immunol 1994;39:41-48.

[3] 3. Atkins G, Daly E, Sheahan B, Higgins D, Sharp P. MS and molecular mimicry. Neuropathol Appl Neurobiol 1990; 16:179.

[4] 4. Begovich AB, Helmuth RC, Oksenberg JR et al. HLA-DP beta and susceptibility to multiple sclerosis: an analysis of Caucasoid and Japanese patient population. Hum Immunol 1990;28:365-372.

[5] 5. Bertrams J, Kuweit E. HL-A antigen frequencies in multiple sclerosis: significant increase of HL-A3, HL-A10 and WS and decrease of HL-A12. Eur Neurol 1972,7:74.

[6] 6. Ebers GC. Genetics and multiple sclerosis: an overview. Ann Neurol 1994;36(Suppl): 12-14.

[7] 7. Fugger L, Ryder LP, Morling N, Odum N, Friis J, Pedersen FK, Heilmann C, Sandberg-Wollheim M, Svejgaard A. DNA typing for HLA-DPB1 *02 and DPB1 *04 in multiple sclerosis and juvenile rheumatoid arthritis. Immunogenetics 1990;32:150-156.

[8] 8. Fukazawa T, Hamada T, Tashiro K, Moriwaka F, Yanagihara T, Sugyiama K, Tsukada Y. HLA profiles of multiple sclerosis in Hokkaido, the northernmost island of Japan. Acta Neurol Scand 1992;86:517-520.

[9] 9. Gomes MM, Almeida GFG. Esclerose múltipla e doenças correlatas: tendências diagnosticas no Brasil (capitais), 1979-1987. Rev Bras Neurol 1991;27:187-192.

[10] 10. Graeber MB, Streit WJ, Buringer D, Sparks DL, Kretzberg GW. Ultrastructural location of major histocompatibility complex (MHC) class II positive perivascular cells in histologically normal human brain. J Neuropathol Exper Neurol 1992;5 1:303-311.

[11] 11. Haegert DG, Francis GS. HLA-DQ polymorphisms do not explain HLA class II associations with multiple sclerosis in two Canadian patient groups. Neurology 1993;43:1207-1210.

[12] 12. Hillert J. Human leukocyte antigen studies in multiple sclerosis. Ann Neurol 1994;36(Suppl):15-17.

[13] 13. Hillert J, Gronning M, Nyland H, Link H, Olerup O. An immunogenetic heterogeneity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1992;55:887-890.

[14] 14. Hillert J, Olerup O. Multiple sclerosis is associated with genes within or close to the HLA-DR-DQ subregion on a normal DR15,DQ6,DW2 haplotype. Neurology 1993;43:163-168.

[15] 15. Howell WM, Sage DA, Evans PR, Smith JL, Francis GS, Haegert DG. No association between susceptibility to multiple sclerosis and HLA-DPB1 alleles in the French Canadian population. Tissue Antig 1991 ;37:156-160.

[16] 16. Kellar-Wood HF, Powis SH, Gray J, Compston DAS. MHC-encoded TAP1 and TAP2 dimorphisms in multiple sclerosis. ' Tissue Antig 1994;43:129-132.

[17] 17. Kelly MA, Jacobs KH, Penny MA, Mijovic CH, Nightingale S, Barnet AH, Francis DA. An investigation of HLA-encoded genetic susceptibility to multiple sclerosis in subjects of Asian Indian and Afro-Caribbean ethnic origin. Tissue Antig 1995;45:197-202.

[18] 18. Kurdi A, Ayesh I, Abdallat A, Maayta U, McDonald WI, Compston, DAS, Batchelor JR. Different B lymphocyte alloantigens associated with multiple sclerosis in Arabs and North Europeans. Lancet 1977;28:1123-1125.

[19] 19. Lamm LU, Olaisen B. Report of the comittee consitution of chromosomes 5 and 6. Cytog Cell Genet 1985;40:128.

[20] 20. Liblau R, Endert PN, Sandberg-Wollheim M, Patel SD, Lopez MT, Land S, Fugger L, McDevitt HO. Antigen processing gene polymorphisms in HLA-DR2 multiple sclerosis. Neurology 1993 ;43:1192-1197.

[21] 21. Marrosu MG, Muntoni F, Spinicci G, Pischedda MP, Goddi F, Cossu P, Pirastu M. Sardinian multiple sclerosis is associated with HLD-DR4: a serologic and molecular analysis. Neurology 1988;38:1749-1753.

[22] 22. McAlpine D, Lumsden CE, Acheson ED. Multiple sclerosis, a reappraisal. Ed2. Edinburgh: Churchill-Livingstone, 1972.

[23] 23. McDonald WI, Halliday AM. Diagnosis and classification of multiple sclerosis. Br Med Bull 1977;33:4.

[24] 24. Muntoni F, Murru MR, Costa G, Congia M, Cueca F, Cossu P, Cao A, Dessalvi L, Pirastu M, Marros MG. Different HLA DR2-DQwl haplotypes in Sardinian and northern Italian populations: implications for multiple sclerosis susceptibility. Tissue Antig 1991 ;38:34-36.

[25] 25. Naito S, Kurdiwa Y, Itoyama T, Tsubaki T, Horikawa A, Sakazuki T, Noguchi S, Ohtsuki S, Tokuomi H, Miyatake T, Takahata N, Kawanami S, McMichael AJ. HLA and Japanese MS. Tissue Antig 1978;12:19-24.

[26] 26. Naito S, Manerow N, Mickey MR, Terasaki PI. Multiple sclerosis: association with HL-A3. Tissue Antig 1972;2:1-4.

[27] 27. Odum N, Hyldig-Nielsen J, Morling N, Sandberg-Wollheim M, Platz P, Svejgaard A. HLA-DP antigens are involved in susceptibility to multiple sclerosis. Tissue Antig 1988,31:235-237.

[28] 28. Olerup O, Hillert J, Fredrikson S, Olsson T, Kam-Hansen S, Moller E, Carlsson B, Wallin J. Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci USA 1989;86:7113-7117.

[29] 29. Olerup O, Hillert J. HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue Antig 1991,38:1-15.

[30] 30. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231.

[31] 31. Rezende PA. Aspectos imunogenéticos da esclerose múltipla. Dissertação de Mestrado, UFPR - Curitiba, 1995.

[32] 32. Rose AS, Ellison GW, Myers LM, Tourtellotte WW. Criteria for the clinical diagnosis of multiple sclerosis. Neurology 1976;26(Suppl):20-22.

[33] 33. Schumacher G A, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F, Nagler B, Sibley WA, Tourtellotte WW, Willmon TL. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann NY Acad Sci 1965;122:552-568.

[34] 34. Smith ME, Sommer MA. Association between cell-mediated demyelination and astrocyte stimulation. Progr Brain Res 1992;94:411-422.

[35] 35. Spurkland A, TabiraT, Ronningen KS, Vandvik B, Thorsby E, Vartdal F. HLA-DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 in Japanese multiple sclerosis patients. Tissue Antig 1991;37:171-173.

[36] 36. Spurkland A, Knutsen I, Undlien DE, Vartdal F. No association of multiple sclerosis to alleles at the TAP2 locus. Hum Immunol 1994;39:299-301.

[37] 37. Stites DP, Terr Al.Basic and clinical immunology. Los Altos, CA: Lange, 1991.

[38] 38. Stites DP, Terr AI. Imunologia básica. Rio de Janeiro:PHB, 1992.

[39] 39. Tienari PJ, Wikstrom J, Koskimies S, Partanen J, Palo J, Peltonen L. Reappraisal of HLA in multiple sclerosis: close linkage in multiplex families. Eur J Hum Genet 1993; 1:257-268.

[40] 40. Vartdal F, Sollid LM, Vandvik B, Markussen G, Thorsby, E. Patients with multiple sclerosis carry DQB1 genes which encode shared polymorphic amino acid sequences. Hum Immunol 1989;25:103-110.

[41] 41. Weber F, Meinl E, Aloisi F, Nevinny-Stickel C, Albert E, Wekerle H, Hohlfeld R. Human astrocytes are only partially competent antigen presenting cells: possible implications for lesion development in multiple sclerosis. Brain 1994; 117:59-69.

[42] 42. Wucherpfennig KW. Autoimmunity in the central nervous system: mechanisms of antigen presentation and recognition. Clin Immunol Immunopathol 1994;72:293-306.