Role of HLA, KIR, MICA, and Cytokines Genes in Leprosy

Many genes including HLA, KIR, and MICA genes, as well as polymorphisms in cytokines have been investigated for their role in infectious disease. HLA alleles may influence not only susceptibility or resistance to leprosy, but also the course of the disease. Some combinations of HLA and KIR may result in negative as well as positive interactions between NK cells and infected host cells with M. leprae, resulting in activation or inhibition of NK cells and, consequently, in death of bacillus. In addition, studies have demonstrated the influence of MICA genes in the pathogenesis of leprosy. Specifically, they may play a role in the interaction between NK cells and infected cells. Finally, pro- and anti-inflammatory cytokines have been influencing the clinical course of leprosy. Data from a wide variety of sources support the existence of genetic factors influencing the leprosy pathogenesis. These sources include twin studies, segregation analyses, family-based linkage and association studies, candidate gene association studies, and, most recently, genome-wide association studies (GWAS). The purpose of this brief review was to highlight the importance of some immune response genes and their correlation with the clinical forms of leprosy, as well as their implications for disease resistance and susceptibility

Killer Cell Immunoglobulin-like Receptors and Their HLA Ligands are Related with the Immunopathology of Chagas Disease.

The aim of this study was to investigate the influence of killer cell immunoglobulin-like receptor (KIR) genes and their human leucocyte antigen (HLA) ligands in the susceptibility of chronic Chagas disease. This case-control study enrolled 131 serologically-diagnosed Chagas disease patients (59 men and 72 women, mean age of 60.4 ± 9.8 years) treated at the University Hospital of Londrina and the Chagas Disease Laboratory of the State University of Maringa. A control group was formed of 165 healthy individuals - spouses of patients or blood donors from the Regional Blood Bank in Maringa (84 men and 81 women, with a mean age of 59.0 ± 11.4 years). Genotyping of HLA and KIR was performed by PCR-SSOP. KIR2DS2-C1 in the absence of KIR2DL2 (KIR2DS2+/2DL2-/C1+) was more frequent in Chagas patients (P = 0.020; Pc = 0.040; OR = 2.14) and, in particular, those who manifested chronic chagasic cardiopathy-CCC (P = 0.0002; Pc = 0.0004; OR = 6.64; 95% CI = 2.30-18.60) when compared to the control group, and when CCC group was compared to the patients without heart involvement (P = 0.010; Pc = 0.020; OR = 3.97). The combination pair KIR2DS2+/2DL2-/KIR2DL3+/C1+ was also positively associated with chronic chagasic cardiopathy. KIR2DL2 and KIR2DS2 were related to immunopathogenesis in Chagas disease. The combination of KIR2DS2 activating receptor with C1 ligand, in the absence of KIR2DL2, may be related to a risk factor in the chronic Chagas disease and chronic chagasic cardiopathy

Human platelet antigen polymorphisms and the risk of chronic Chagas disease cardiomyopathy

Human platelet antigen (HPA) polymorphisms are considered to be a risk factor for cardiac and vascular diseases, but the role of HPA in chronic Chagas disease cardiomyopathy (CCC) is not available. Therefore, the aim of this study was to investigate the association of HPA polymorphisms, HPA-1, HPA-2, HPA-3, HPA-5 and HPA-15, in the severity of left ventricular systolic dysfunction (LVSD) in CCC patients. For this, 229 CCC patients were separated into three groups: without LVSD, mild/moderate LVSD and severe LVSD. PCR-SSP was performed for HPA genotyping and the risk was assessed using SNPStats software. HPA-1 allele and genotype frequencies were lower in mild/moderate LVSD patients compared to other groups, without statistical significance. After stratified analyzes, the HPA-3a/3b genotype frequency was lower in women with severe LVSD compared to those without LVSD (OR:0.29; 95% CI: 0.10–0.84). In conclusion, HPA-3 variant could be a protection factor for CCC in the female patients

Characteristics of the chronic Chagas disease patients and control individuals.

<p>CCD: chronic Chagas disease patients; NC: without heart involvement patients, CCC: chronic chagasic cardiopathy patients.</p><p>*mixed population (white + mulatto + black) = 165 controls and 131 patients</p><p>Characteristics of the chronic Chagas disease patients and control individuals.</p

MHC Class I Chain-Related Gene A Polymorphisms and Linkage Disequilibrium with HLA-B and HLA-C Alleles in Ocular Toxoplasmosis.

This study investigated whether polymorphisms of the MICA (major histocompatibility complex class I chain-related gene A) gene are associated with eye lesions due to Toxoplasma gondii infection in a group of immunocompetent patients from southeastern Brazil. The study enrolled 297 patients with serological diagnosis of toxoplasmosis. Participants were classified into two distinct groups after conducting fundoscopic exams according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of the ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping of the MICA and HLA alleles was performed by the polymerase chain reaction-sequence specific oligonucleotide technique (PCR-SSO; One Lambda®) and the MICA-129 polymorphism (rs1051792) was identified by nested polymerase chain reaction (PCR-RFLP). Significant associations involving MICA polymorphisms were not found. Although the MICA*002~HLA-B*35 haplotype was associated with increased risk of developing ocular toxoplasmosis (P-value = 0.04; OR = 2.20; 95% CI = 1.05-4.60), and the MICA*008~HLA-C*07 haplotype was associated with protection against the development of manifestations of ocular toxoplasmosis (P-value = 0.009; OR: 0.44; 95% CI: 0.22-0.76), these associations were not statistically significant after adjusting for multiple comparisons. MICA polymorphisms do not appear to influence the development of ocular lesions in patients diagnosed with toxoplasmosis in this study population

Distribution of KIR and their respective HLA ligands in Chagas disease patients and controls.

<p>CCD: chronic Chagas disease patients; NC: without heart involvement patients, CCC: chronic chagasic cardiopathy patients.</p><p>^<b>a</b><i>P</i> = 0.036; <i>Pc</i> = 0.108; OR = 0.43; 95% CI = 0.24–0.75 (CCD vs Controls)</p><p>^<b>b</b><i>P</i> = 0.037; <i>Pc</i> = 0.10; OR = 0.54; 95% CI = 0.31–0.94 (CCD vs Controls)</p><p>^<b>c</b><i>P</i> = 0.031; <i>Pc</i> = 0.093; OR = 0.23; 95% CI = 0.04–0.89 (CCC vs NC)</p><p>Bw4 = <i>HLA-A*23</i>,<i>*24</i>,<i>*32; HLA-B</i>,<i>*13</i>,<i>*27</i>,<i>*44</i>,<i>*51</i>,<i>*52</i>,<i>*53</i>,<i>*57</i>,<i>*58</i></p><p>Group C1 = <i>HLA-C*01</i>,<i>*03</i>,<i>*07</i>,<i>*08</i>,<i>*12</i>,<i>*14</i>,<i>*16</i></p><p>Group C2 = <i>HLA-C*02</i>,<i>*04</i>,<i>*05</i>,<i>*06</i>,<i>*07</i>,<i>*15</i>,<i>*17</i>,<i>*18</i></p><p>Distribution of KIR and their respective HLA ligands in Chagas disease patients and controls.</p

Distribution of activating KIR plus inhibitory KIR and their respective ligands in chronic Chagas disease and controls.

<p>CCD: chronic Chagas disease patients; NC: without heart involvement patients, CCC: chronic chagasic cardiopathy patients.</p><p>^<b>a</b><i>P</i> = 0.020; <i>Pc</i> = 0.040; OR = 2.14; 95% CI = 1.25–7.88 (CCD vs Controls)</p><p>^<b>b</b><i>P</i> = 0.0002; <i>Pc</i> = 0.0004; OR = 6.64; 95% CI = 2.30–18.60 (CCC vs Controls)</p><p>^<b>c</b><i>P</i> = 0.010; <i>Pc</i> = 0.020; OR = 3.97; 95% CI = 1.34–11.79 (CCC vs NC)</p><p>^<b>d</b><i>P</i> = 0.050; <i>Pc</i> = 0.100; OR = 1.06; 95% CI = 1.1–6.9 (CCD vs Controls)</p><p>^<b>e</b><i>P</i> = 0.040; <i>Pc</i> = 0.080; OR = 3.64; 95% CI = 1.12–11.91 (CCC vs NC)</p><p>^<b>f</b><i>P</i> = 0.004; <i>Pc</i> = 0.008; OR = 5.02; 95% CI = 1.71–14.73 (CCC vs Controls)</p><p>^<b>g</b><i>P</i> = 0.036; <i>Pc</i> = 0.144; OR = 0.54; 95% CI = 0.31–0.94 (CCD vs Controls)</p><p>Distribution of activating KIR plus inhibitory KIR and their respective ligands in chronic Chagas disease and controls.</p

Distribution of <i>KIR</i> genes in healthy controls, chronic Chagas disease patients and in groups of patients with and without heart involvement.

<p>CCD: chronic Chagas disease patients, NC: without heart involvement patients, CCC: chronic chagasic cardiopathy patients.</p><p>^<b>a</b><i>P</i> = 0.017; <i>Pc</i> = 0.27; OR = 0.41; 95% CI = 0.20–0.83 (CCC vs Controls)</p><p>Distribution of <i>KIR</i> genes in healthy controls, chronic Chagas disease patients and in groups of patients with and without heart involvement.</p