A participação dos alelos HLA na manifestação da hanseníase dimorfa em amostra de população do Estado de São Paulo
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Data
2014-05-31
Autores
Souza, Fabiana Covolo de [UNIFESP]
Orientadores
Tomimori, Jane [UNIFESP]
Tipo
Tese de doutorado
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Introdução: A hanseníase é uma doença infecciosa de evolução crônica, causada pelo Mycobacterium leprae. Trata-se de uma doença cujo patógeno é intracelular obrigatório, com predileção pela pele e sistema nervoso periférico (células de Schwann), o que torna a resposta imune celular do hospedeiro o principal mecanismo de resistência ao agente agressor. A doença pode se manifestar através de diferentes formas clínicas. O complexo HLA parece influenciar na resposta imune do hospedeiro ao bacilo. O consenso na literatura é a associação do HLA-DRB1*02/DRB1*03 com a hanseníase tuberculóide (TT) e HLA-DQB1*01 com a hanseníase virchowiana (LL), entretanto, não existe estudo que demonstre a associação do complexo HLA com a hanseníase dimorfa (B). Objetivo: O objetivo do presente estudo foi verificar a possível associação dos alelos HLA de classe I e II nas formas clínicas B (BB, BT e BL) e a participação desses alelos quanto à manifestação das reações hansênicas. Identificar a frequência dos haplótipos HLA envolvidos na forma B na amostra de população do estado de São Paulo. Métodos: As amostras de DNA de 202 pacientes com diagnóstico de hanseníase B, distribuídos entre as formas BB, BT e BL e 478 indivíduos controles foram obtidas pela técnica de Salting-out. Os alelos HLA de classe I (loci A*, B*, C*), e de classe II (loci DRB1* e DQB1*) foram determinados em baixa resolução através da técnica de PCR-SSO empregando-se o kit Labtype-SSO (One Lambda, CA, USA). Os dados clínicos e evolutivos foram obtidos através de revisão de prontuários. Resultados: Através da análise caso-controle os resultados obtidos mostraram associação significante entre a hanseníase B e os alelos HLA-C*05 (5,94% vs 14,02%, p= 0,002, OR=0,38, IC 95%= 0,20 – 0,73, pc= 0,032) e HLA-DRB1*07 (16,34% vs 26,77%, p= 0,003, OR= 0,53, IC 95%= 0,3 – 0,8, pc= 0,039). Os pacientes BL apresentaram associação protetora com o alelo HLA-DQB1*02 (18,18% vs 39,53%, p= 0,005, OR=0,34, IC95%= 0,15-0,75, pc= 0,025). Nos pacientes reacionais, associação significante dos alelos HLA-B*15 (25,96% vs 12,76%, p= 0,021, OR=2,40, IC95%= 1,13-5,06, pc= 0,672) e HLA-DQB1*04 (13,46% vs 5,32%, p= 0,057, OR=2,77, IC95%= 0,96- 8,01, pc=0,285), foram observadas na predisposição a manifestação das reações. Os pacientes B com a reação de Mitsuda ≥ 5,0mm apresentaram associação positiva com o alelo HLA-A*33 (14,28% vs 1,02%, p= 0,001, OR= 16,17, IC95%= 1,96-133,0, pc= 0,02). A análise dos haplótipos HLA evidenciou A*02-B*07-C*07-DRB1*15-DQB1*06 (2,97% vs 1,04%, p= 0,015) e A*02-B*40-C*03-DRB1*13-DQB1*06 (1,73% vs 0,10%, p= 0,0011), associados a suscetibilidade na hanseníase B. A presença do haplótipo HLA-DRB1*02 ou HLA-DRB1*03/HLA-DQB1*01 simultâneamente foi observada nos pacientes B (33,0% vs 22,05%, p= 0,005) sugerindo o envolvimento desses haplótipos na manifestação clínica dessa forma da doença. Conclusão: Os resultados encontrados sustentam a hipótese de que os alelos HLA desempenham papel na patogênese da hanseníase B com efeito protetor na manifestação da forma clínica B, na predisposição das reações hansênicas e os haplótipos HLA influenciam na suscetibilidade a forma clínica B.
BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It is a disease whose pathogen is an obligate intracellular parasite with a predilection for cutaneous and peripheral nervous system (Schwann cells), which makes the cellular immune response of the host the first mechanism of resistance to the aggressor. The disease can manifest through different clinical forms. The HLA complex seems to influence the host immune response to bacillus. The consensus in the literature is the association of HLA-DRB1*02/DRB1*03 with tuberculoid leprosy (TT) and HLA-DQB1*01 with lepromatous leprosy (LL), however, there is no study demonstrating the association of HLA with borderline leprosy (B). OBJECTIVE: The aim of this study was to investigate the possible association of HLA class I and II in clinical forms B (BB, BT and BL) and the participation of these alleles in leprosy reactions. To identify the frequency of HLA involved in form B in a sample population of São Paulo state. METHODS: DNA samples from 202 patients diagnosed with B leprosy distributed in BB, BT and BL; and 478 control subjects were obtained by the technique of saltingout. The HLA class I (A*, B*, C* loci) and class II (DRB1* and DQB1*loci) were determined by low resolution PCR-SSO by Labtype-SSO kit (One Lambda, CA, USA). RESULTS: The case-controled analysis results showed a significant association between B leprosy and HLA-C*05 (5,94% vs. 14,02%, p = 0,002, OR = 0,38, 95% CI = 0,20-0,73, pc = 0,032) and HLA-DRB1*07 (16,34% vs. 26.77%, p = 0,003, OR = 0,53, 95% CI = 0,3 – 0,8, pc= 0,039). BL patients showed protective association with the HLA-DQB1*02 (18,18% vs. 39,53%, p = 0,005, OR = 0,34, 95% CI = 0,15- 0,75, pc = 0,025). Among reactional patients, a significant association of HLA-B*15 (25,96% vs. 12,76%, p = 0,021, OR = 2,40, 95% CI = 1,13-5,06, pc = 0,672) and HLA-DQB1*04 (13,46% vs. 5,32%, p = 0,057, OR = 2,77, 95% CI = 0,96-8,01, pc =0,285) demonstrated predisposition for leprosy reaction manifestations. B patients with Mitsuda reaction ≥ 5.0 mm showed a positive association with HLA-A*33 (14,28% vs. 1,02%, p = 0,001, OR = 16,17, 95% CI = 1,96 -133,0, pc = 0,02). The haplotype analysis showed A*02-B*07-C*07-DRB1*15-DQB1*06 (2,97% vs 1,04%, p= 0,015) and A*02-B*40-C*03-DRB1*13-DQB1*06 (1,73% vs 0,10%, p= 0,0011) associated with the susceptibility in B form. The presence of the HLA haplotype HLADRB1*02 ou HLA-DRB1*03/HLA-DQB1*01 simultaneously in B patients (22,05% vs. 33,0%, p = 0.005) suggested the involvement of these haplotypes in this clinical form of the disease. CONCLUSION: The results support the hypothesis that the HLA alleles makes a role in the pathogenesis of B leprosy with a protective effect on the clinical manifestation in B form, on the predisposition of leprosy reactions, and HLA haplotypes influence on the susceptibility to B form.
BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It is a disease whose pathogen is an obligate intracellular parasite with a predilection for cutaneous and peripheral nervous system (Schwann cells), which makes the cellular immune response of the host the first mechanism of resistance to the aggressor. The disease can manifest through different clinical forms. The HLA complex seems to influence the host immune response to bacillus. The consensus in the literature is the association of HLA-DRB1*02/DRB1*03 with tuberculoid leprosy (TT) and HLA-DQB1*01 with lepromatous leprosy (LL), however, there is no study demonstrating the association of HLA with borderline leprosy (B). OBJECTIVE: The aim of this study was to investigate the possible association of HLA class I and II in clinical forms B (BB, BT and BL) and the participation of these alleles in leprosy reactions. To identify the frequency of HLA involved in form B in a sample population of São Paulo state. METHODS: DNA samples from 202 patients diagnosed with B leprosy distributed in BB, BT and BL; and 478 control subjects were obtained by the technique of saltingout. The HLA class I (A*, B*, C* loci) and class II (DRB1* and DQB1*loci) were determined by low resolution PCR-SSO by Labtype-SSO kit (One Lambda, CA, USA). RESULTS: The case-controled analysis results showed a significant association between B leprosy and HLA-C*05 (5,94% vs. 14,02%, p = 0,002, OR = 0,38, 95% CI = 0,20-0,73, pc = 0,032) and HLA-DRB1*07 (16,34% vs. 26.77%, p = 0,003, OR = 0,53, 95% CI = 0,3 – 0,8, pc= 0,039). BL patients showed protective association with the HLA-DQB1*02 (18,18% vs. 39,53%, p = 0,005, OR = 0,34, 95% CI = 0,15- 0,75, pc = 0,025). Among reactional patients, a significant association of HLA-B*15 (25,96% vs. 12,76%, p = 0,021, OR = 2,40, 95% CI = 1,13-5,06, pc = 0,672) and HLA-DQB1*04 (13,46% vs. 5,32%, p = 0,057, OR = 2,77, 95% CI = 0,96-8,01, pc =0,285) demonstrated predisposition for leprosy reaction manifestations. B patients with Mitsuda reaction ≥ 5.0 mm showed a positive association with HLA-A*33 (14,28% vs. 1,02%, p = 0,001, OR = 16,17, 95% CI = 1,96 -133,0, pc = 0,02). The haplotype analysis showed A*02-B*07-C*07-DRB1*15-DQB1*06 (2,97% vs 1,04%, p= 0,015) and A*02-B*40-C*03-DRB1*13-DQB1*06 (1,73% vs 0,10%, p= 0,0011) associated with the susceptibility in B form. The presence of the HLA haplotype HLADRB1*02 ou HLA-DRB1*03/HLA-DQB1*01 simultaneously in B patients (22,05% vs. 33,0%, p = 0.005) suggested the involvement of these haplotypes in this clinical form of the disease. CONCLUSION: The results support the hypothesis that the HLA alleles makes a role in the pathogenesis of B leprosy with a protective effect on the clinical manifestation in B form, on the predisposition of leprosy reactions, and HLA haplotypes influence on the susceptibility to B form.
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SOUZA, Fabiana Covolo de. A participação dos alelos HLA na manifestação da hanseníase dimorfa em amostra de população do Estado de São Paulo. 2014. Tese (Doutorado) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2014.