Association of killer cell immunoglobulin-like receptor polymorphisms with chronic hepatitis C and responses to therapy in Brazil

ABSTRACT: Soroprevalence for Hepatitis C virus is reported as 2.12% in Northern Brazil, with about 50% of the patients exhibiting a sustained virological response (SVR). Aiming to associate polymorphisms in Killer Cell Immunoglobulin-like Receptors (KIR) with chronic hepatitis C and therapy responses we investigated 125 chronic patients and 345 controls. Additionally, 48 ancestry markers were genotyped to control for population stratification. The frequency of the KIR2DL2 and KIR2DL2+HLA-C^Asp80 gene and ligand was higher in chronic infected patients than in controls (p < 0.0009, OR = 3.4; p = 0.001, OR = 3.45). In fact, KIR2DL3 is a weaker inhibitor of NK activity than KIR2DL2, which could explain the association of KIR2DL2 with chronic infection. Moreover, KIR2DS2 and KIR2DS2+HLA-C^Asp80 (p < 0.0001, OR = 2.51; p = 0.0084, OR = 2.62) and KIR2DS3 (p < 0.0001; OR = 2.57) were associated with chronic infection, independently from KIR2DL2. No differences in ancestry composition were observed between control and patients, even with respect to therapy response groups. The allelic profile KIR2DL2/KIR2DS2/KIR2DS3 was associated with the chronic hepatitis C (p < 0.0001; OR = 3). Furthermore, the patients also showed a higher mean number of activating genes and a lower frequency of the homozygous AA profile, which is likely secondary to the association with non-AA and/or activating genes. In addition, the KIR2DS5 allele was associated with SVR (p = 0.0261; OR = 0.184).The ancestry analysis of samples ruled out any effects of population substructuring and did not evidence interethnic differences in therapy response, as suggested in previous studies.

HLA-Bw4-B*57 and Cw*18 alleles are associated with plasma viral load modulation in HIV-1 infected individuals in Salvador, Brazil

Host genetic factors play an important role in mediating resistance to HIV-1 infection and may modify the course of infection. HLA-B alleles (Bw4 epitope; B*27 and B*57) as well as killer cell immunoglobulin-like receptors have been associated with slow progression of HIV-1 infection. OBJECTIVE: To evaluate the association between serological epitopes HLA-Bw4 and HLA-Bw6 and prognostic markers in AIDS. METHODS: 147 HIV-infected individuals in Bahia, Northeast Brazil, were genotyped for HLA class I locus. HLA class I genotyping was performed by hybridization with sequence-specific oligonucleotide probes following amplification of the corresponding HLA-A, HLA-B and HLA-C genes. Statistical analysis was performed using Fisher's exact and ANOVA tests for categorical and continuous variables, respectively. RESULTS: We detected a significant association (χ2 = 4.856; p = 0.018) between the presence of HLA-Bw4 and low levels of viremia. Eighteen out of the 147 HIV-infected individuals presented viremia <1,800 copies/mL and 129 presented viremia > 2,000 copies/mL. Ninety and four percent (17/18) of all individuals with viremia < 1,800 copies/mL carried HLA-Bw4, compared to 67.4% (87/129) of individuals with viremia > 2,000 copies/mL. Additionally, we found a significantly higher frequency of B*57 (OR = 13.94; 95% CI = 4.19-46.38; p < 0.0001) and Cw*18 (OR = 16.15; 95% CI = 3.46-75.43; p < 0.0001) alleles, favoring the group with lower viremia levels, in comparison with those with higher viral load. CONCLUSION: HLA-Bw4-B*57 and Cw*18 alleles are associated with lower level of viral load in HIV-infected Brazilian patients. These findings may help us in understanding the determinants of HIV evolution in Brazilian patients, as well as in providing important information on immune response correlates of protection for such population.

Polimorfismos do complexo de genes KIR predispõem à hanseníase e modulam seu desenvolvimento para a forma paucibacilar

A hanseníase é uma infecção crônica e granulomatosa da pele e nervos periféricos, que infecta principalmente macrófagos e células de Schwann. A Organização Mundial de Saúde classifica a hanseníase em duas formas polares: multibacilar e paucibacilar, de acordo com o índice baciloscópico e a resposta imune do hospedeiro. As células natural killer (NK) têm um importante papel na infecção, sendo a primeira forma de defesa contra organismos intracelulares. As células NK utilizam muitos tipos de receptores de superfície celular, como os receptores imunoglobulina-símiles de célula NK (KIR), que podem inibir ou ativar a resposta citolítica de NK, através do reconhecimento de moléculas do complexo de histocompatibilidade principal (MHC) de classe I na célula alvo. Nesse estudo caso controle, a presença ou ausência de 15 genes KIR e seus ligantes HLA-C foram investigadas, na intenção de se descrever sua variabilidade genotípica, associação com a hanseníase e sua evolução clínica. A genotipagem do complexo de genes KIR e dos grupos NK1 e NK2 de HLA-C foi feita por PCR-SSP em 105 pacientes e 104 controles. KIR2DL2 e KIR2DL3, na presença do seu ligante HLA-Cw parece predispor à hanseníase (p=0,046; X²= 3,97; OR=1,99; IC 95%= 1,00-3,97). Além disso, a prevalência da hanseníase ao redor do mundo e as freqüências de KIR2DL2 se correlacionaram positivamente. Esse achado, juntamente com a associação entre KIR2DL3 e a tuberculose, descrita por outros autores, sugere que esses genes de receptores inibitórios predispõem à doença. Adicionalmente, o gene KIR2DS2 foi associado com o desenvolvimento da hanseníase paucibacilar (p=0,009; X²= 7,23; OR=3,97; IC 95%= 1,37-9,96), possivelmente modulando o desenvolvimento para a forma mais branda da doença.

Influence of melatonin on the development of functional nicotinic acetylcholine receptors in cultured chick retinal cells

The influence of melatonin on the developmental pattern of functional nicotinic acetylcholine receptors was investigated in embryonic 8-day-old chick retinal cells in culture. The functional response to acetylcholine was measured in cultured retina cells by microphysiometry. The maximal functional response to acetylcholine increased 2.7 times between the 4th and 5th day in vitro (DIV4, DIV5), while the Bmax value for 125I-a-bungarotoxin was reduced. Despite the presence of a8-like immunoreactivity at DIV4, functional responses mediated by a-bungarotoxin-sensitive nicotinic acetylcholine receptors were observed only at DIV5. Mecamylamine (100 µM) was essentially without effect at DIV4 and DIV5, while dihydro-ß-erythroidine (10-100 µM) blocked the response to acetylcholine (3.0 nM-2.0 µM) only at DIV4, with no effect at DIV5. Inhibition of melatonin receptors with the antagonist luzindole, or melatonin synthesis by stimulation of D4 dopamine receptors blocked the appearance of the a-bungarotoxin-sensitive response at DIV5. Therefore, a-bungarotoxin-sensitive receptors were expressed in retinal cells as early as at DIV4, but they reacted to acetylcholine only after DIV5. The development of an a-bungarotoxin-sensitive response is dependent on the production of melatonin by the retinal culture. Melatonin, which is produced in a tonic manner by this culture, and is a key hormone in the temporal organization of vertebrates, also potentiates responses mediated by a-bungarotoxin-sensitive receptors in rat vas deferens and cerebellum. This common pattern of action on different cell models that express a-bungarotoxin-sensitive receptors probably reflects a more general mechanism of regulation of these receptors.