Submitted by Lúcia Brandão (lucia.elaine@live.com) on 2015-12-11T19:01:49Z No. of bitstreams: 1 Dhêmerson - Dhêmerson Souza de Lima.pdf: 2134258 bytes, checksum: 027d2a19329c1030eb634da31db37ae6 (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2016-01-19T14:57:53Z (GMT) No. of bitstreams: 1 Dhêmerson - Dhêmerson Souza de Lima.pdf: 2134258 bytes, checksum: 027d2a19329c1030eb634da31db37ae6 (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2016-01-19T15:02:05Z (GMT) No. of bitstreams: 1 Dhêmerson - Dhêmerson Souza de Lima.pdf: 2134258 bytes, checksum: 027d2a19329c1030eb634da31db37ae6 (MD5) / Made available in DSpace on 2016-01-19T15:02:05Z (GMT). No. of bitstreams: 1 Dhêmerson - Dhêmerson Souza de Lima.pdf: 2134258 bytes, checksum: 027d2a19329c1030eb634da31db37ae6 (MD5) Previous issue date: 2015-05-08 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Tuberculosis (TB) is a serious public health problem, considered as a priority by the government of Brazil since 2003. This disease is endemic in low and middle-income countries, mainly affecting the population living in urban peripheries when associated with poor living conditions, malnutrition and drug abuse. Brazil is one of 22 countries contributing to the global high TB burden; it is on 16th position in number of TB cases. In 2014, Amazonas state had the highest national incidence rate of TB (68.4 per 100.000 inhabitants). Poverty, social exclusion, operational difficulties for diagnosis and treatment of TB are crucial to maintaining the high rate of incidence. In addition, the host immunogenic factors are associated with TB. Human Leukocyte Antigen (HLA) genes are associated with susceptibility or resistance to TB. This study verifies the frequency of HLA-DRB1*04 allele and subtypes in 622 subjects (316 patients with pulmonary TB and 306 controls). HLA-DRB1*04 was more frequent in TB patients (187/316; 59,2%) than control group (101/306; 33,0%). In this study, nine subtypes of HLA-DRB1*04 were identified. The subtype HLA-DRB1*04:11:01 was associated with susceptibility to pulmonary TB (p = 0.0019; OR = 2.23; 95% CI = 1.34 to 3.70), while HLA-DRB1*04:07:01 was associated with protection (p < 0.0001; OR = 0.02; 95% CI = 0.001 to 0.33) and HLA-DRB1*04:92 was associated with transmission to pulmonary TB disease (p = 0.0112; OR = 8.62; 95% CI = 1.63 to 45.5). These results suggest three subtypes of HLA-DRB1*04 as potential immunogenetic markers in TB and can help in better understanding of mechanisms involved in disease, as well as the reasons for high rates of TB incidence in Amazonas state. / A tuberculose (TB) é um grave problema de saúde pública, considerada como prioridade pelo governo do Brasil desde 2003. A doença é endêmica nos países de baixa e média renda, acometendo principalmente a população que reside nas periferias urbanas (favelas e invasões), estando associada às más condições de moradia, à alimentação, ao saneamento básico e ao uso de drogas. O Brasil é um dos 22 países que contribuem com as maiores cargas de TB no mundo, ocupando a 16.a posição em número absoluto de casos. O Estado do Amazonas, em 2014, apresentou o maior coeficiente de incidência nacional de casos de TB (68,4 por 100 mil habitantes). Miséria, exclusão social, dificuldades operacionais de diagnósticos e tratamento da TB são preponderantes para manutenção da alta taxa de incidência. Além disso, os fatores imunogenéticos do hospedeiro são descritos e associados à suscetibilidade ou à resistência da doença. Dentre os genes mais fortemente associados à TB, estão os do Antígeno Leucocitário Humano (HLA). No presente estudo, foi investigada a frequência do alelo HLA-DRB1*04 em 622 indivíduos, 316 pacientes com TB pulmonar e 306 controles. O HLA-DRB1*04 foi frequente nos pacientes (187/316; 59,2%), quando comparado aos dados dos controles (101/306; 33,0%). Neste estudo, foram identificados nove subtipos de HLADRB1*04; destes, o HLA-DRB1*04:11:01 foi associado à suscetibilidade (p = 0,0019; OR =2,23; IC 95% = 1,34 – 3,70) e à transmissão de TB pulmonar, enquanto o HLA-DRB1*04:07:01 foi associado à proteção (p < 0,0001; OR = 0,02; IC 95% = 0,001 – 0,33), e o HLA-DRB1*04:92 foi associado à transmissão da doença (p = 0,0112; OR = 8,62; IC 95% = 1,63 – 45,5). Esses resultados sugerem três subtipos do HLA-DRB1*04 como potenciais marcadores imunogenéticos na TB, os quais podem ajudar na compreensão dos mecanismos envolvidos na doença, bem como esclarecer os motivos das altas taxas de incidência de TB no Estado do Amazonas.

Indiana University-Purdue University Indianapolis (IUPUI) / Background: Bacterial adherence to the acquired dental pellicle, important in caries, is mediated by receptor-adhesin interactions such as Streptococcus mutans antigen I/II (I/II). Ten I/II epitopes from the A, V, P and C regions were chosen to determine their reactivity in human saliva. Underlying the body’s ability to immunologically respond to bacteria that lead to caries are the human leukocyte antigen (HLA) genes, specifically HLA class II (HLA-II) genes that control antigen presentation. Previous studies suggested that a specific HLA biomarker group (HLA-DRB1*04) may have differential control of immune responses to I/II. However, it was not known whether secretory IgA (SIgA) responses to the selected epitopes from HLA-DRB1*04 positive subjects were different compared to their non-biomarker counterparts (negative), or across other caries factors, since no study to date had thus assessed these questions. Methods: Per IRB approval, the study population was divided into age, sex and race matched DRB1*04 positive (n=16) and negative groups (n=16). SIgA-epitope (and whole cell) reactivity was determined using ELISA. Other caries factors were measured. Subjects received a clinical exam by a trained examiner. ix Differences between DRB1*04 positive and negative groups were examined using a two-sided, two-sample t-test. Results: DRB1*04 positive subjects had numerically, but not statistically, higher reactivity to 9 out of 10 epitopes, the exception being residues 834-853 from the V and P regions of I/II across multiple measures. Though statistically insignificant, DRB1*04 positive subjects also exhibited 25-30 μg mL-1 less total IgA (TIgA) than negative counterparts. All clinical caries data proved inconclusive when comparing groups, likely due to exogenous factors and sample size. Conclusion: DRB1*04 positive subjects showed a trend toward lower TIgA. Moreover, they also showed a lower SIgA response across multiple measures to 834-853, the I/II V and P region epitope. This region forms a sort of functional epicenter involved in collaboration between domains along the entire I/II antigen, and governs the region involved in initial attachment to the acquired dental pellicle. This region may be involved in an in vivo discontinuous conformationally specific immunogenic epitope that serves as an HLA-II binding motif which remains elusive.