Natural killer cell receptor expression reflects the role of human cytomegalovirus in the pathogenesis of a subset of CD4+ T-cell large granular lymphocytosis.

A high frequency of CD4(+) T-cell large granular lymphocyte (T-LGL) lymphocytosis occurs in human leukocyte antigen (HLA) -DRB1*0701 individuals displaying monoclonal expansions of Vß13.1+ CD4(+) T-cell clones, which specifically respond to human cytomegalovirus (HCMV) antigens. We previously reported the expression of natural killer (NK)-cell associated receptors (NKR) by HCMV-specific cytolytic CD4(+) T cells from healthy donors. In the present study a high expression of different NKR (i.e., NKG2D, killer Ig-like receptors (KIR), CD94, ILT2) was observed in CD4(+) T cells from both Vß13.1- and Vß13.1+ CD4(+) T-LGL cases. Remarkably, elevated numbers of CD94/NKG2C+ NK cells, previously shown to expand in association to HCMV infection, were preferentially found in Vß13.1+ T-LGL, further supporting its role in the pathogenesis of a subset of CD4(+) T-LGL.

A polymorphism in the interleukin-10 promoter affects the course of disease in patients with clear-cell renal carcinoma.

In the tumor microenvironment, interleukin (IL)-10 production has a pleiotropic ability to positively and negatively influence the function of innate and adaptive immunity against cancer. This study investigated whether IL-10 genetic polymorphisms that influence gene expression levels play a role in the risk and clinical course of clear-cell renal cell carcinoma (RCC). We analyzed the allelic and haplotype frequency formed by alleles at -1082(G/A), -819(C/T), and -592(C/A) of the IL-10 gene in RCC (n = 126) and healthy individuals (n = 176). The frequency of IL-10 polymorphic variants was similar between patients and controls. However, -1082 G/A IL-10 genotype showed a significant association with three prognostic indicators: advanced disease stage (p = 0.002), higher tumor size (p = 0.001), and presence of adenopathy (p = 0.006). Our results can be explained by the contradictory antitumor or pro-tumorigenic relationship between this molecule and cancer. Genotypes associated with high or low levels of IL-10 gene expression (GG or AA-1082 IL-10) were both associated with a more favorable course of the disease. We propose the hypothesis that the -1082 GA medium expression genotype confers a tumor-promoting phenotype, likely resulting from the immunosuppressive effects of anti-tumor Th-1 responses in conjunction with the insufficient inhibition of tumor angiogenesis at this intermediate level of IL-10 expression.

Genetic polymorphisms of RANTES, IL1-A, MCP-1 and TNF-A genes in patients with prostate cancer.

BACKGROUND: Inflammation has been implicated as an etiological factor in several human cancers, including prostate cancer. Allelic variants of the genes involved in inflammatory pathways are logical candidates as genetic determinants of prostate cancer risk. The purpose of this study was to investigate whether single nucleotide polymorphisms of genes that lead to increased levels of pro-inflammatory cytokines and chemokines are associated with an increased prostate cancer risk. METHODS: A case-control study design was used to test the association between prostate cancer risk and the polymorphisms TNF-A-308 A/G (rs 1800629), RANTES-403 G/A (rs 2107538), IL1-A-889 C/T (rs 1800587) and MCP-1 2518 G/A (rs 1024611) in 296 patients diagnosed with prostate cancer and in 311 healthy controls from the same area. RESULTS: Diagnosis of prostate cancer was significantly associated with TNF-A GA + AA genotype (OR, 1.61; 95% CI, 1.09-2.64) and RANTES GA + AA genotype (OR, 1.44; 95% CI, 1.09-2.38). A alleles in TNF-A and RANTES influenced prostate cancer susceptibility and acted independently of each other in these subjects. No epistatic effect was found for the combination of different polymorphisms studied. Finally, no overall association was found between prostate cancer risk and IL1-A or MCP-1 polymorphisms. CONCLUSION: Our results and previously published findings on genes associated with innate immunity support the hypothesis that polymorphisms in proinflammatory genes may be important in prostate cancer development.

Evaluation of functional single nucleotide polymorphisms of different genes coding for the immunoregulatory molecules in patients with monoclonal large granular lymphocyte lymphocytosis.

TCR alpha beta+/CD4+ T-large granular lymphocyte (LGL) lymphocytosis is a subgroup of monoclonal T-LGL lymphoproliferative disorders that are different from the CD8+ TCR alpha beta T-LGL. An increasing evidence supports the involvement of a common antigen-driven mechanism in the etiology of TCR alpha beta+/CD4+ T-LGL. In this study, we tested several polymorphic markers associated with chronic viral infections and autoimmune diseases, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), interferon-gamma (IFN-gamma), RANTES, IL-1 alpha, FAS, FAS-ligand (FASL), and NKG2D, to investigate the potential association of these immunogenetic factors with the development of T-LGL. Overall, 38 patients with CD4+ T-LGL were analyzed and compared with a group of both CD8+/TCR alpha beta+ T-LGL patients (n = 43) and a group of control subjects (n = 176). Our results did not show any clear association between the different single nucleotide polymorphisms (SNPs) analyzed and the development of CD4+/TCR alpha beta T-LGL. An increase in the frequency of -380 (AA/GA) TNF-alpha genotype associated with a greater production of this cytokine was found among CD8+ T LGL patients in comparison to the CD4+LGL patients and the control group. Our results suggest that the frequency of SNP of the genes coding for the studied immunoregulatory molecules are not associated with the development of CD4+/TCR alpha beta+ T-LGL.

Monoclonal TCR-Vbeta13.1+/CD4+/NKa+/CD8-/+dim T-LGL lymphocytosis: evidence for an antigen-driven chronic T-cell stimulation origin.

Monoclonal TCRalphabeta(+)/CD4+ T-large granular lymphocyte (T-LGL) lymphocytosis is a T-cell disorder with a restricted TCR-Vbeta repertoire. In the present study we explored the potential association between the expanded TCR-Vbeta families, the CDR3 sequences of the TCR-Vbeta gene, and the HLA genotype of patients with monoclonal TCRalphabeta(+)/CD4+ T-LGL lymphocytosis. For that purpose, 36 patients with monoclonal TCRalphabeta(+)/CD4+ T-LGL lymphocytosis (15 TCR-Vbeta13.1 versus 21 non-TCR-Vbeta13.1) were selected. For each patient, both the HLA (class I and II) genotype and the DNA sequences of the VDJ-rearranged TCR-Vbeta were analyzed. Our results show a clear association between the TCR-Vbeta repertoire and the HLA genotype, all TCR-Vbeta13.1(+) cases being HLA-DRB1*0701 (P = .004). Interestingly, the HLA-DR7/TCR-Vbeta13.1-restricted T-cell expansions displayed a highly homogeneous and strikingly similar TCR arising from the use of common TCR-Vbeta gene segments, which shared (1) unique CDR3 structural features with a constantly short length, (2) similar combinatorial gene rearrangements with frequent usage of the Jbeta1.1 gene, and (3) a homolog consensus protein sequence at recombination junctions. Overall, these findings strongly support the existence of a common antigen-driven origin for monoclonal CD4+ T-LGL lymphocytosis, with the identification of the exact peptides presented to the expanded T cells deserving further investigations.

Analysis of NK cells and chemokine receptors in tumor infiltrating CD4 T lymphocytes in human renal carcinomas.

Recent data suggest that chemokines and chemokine receptors mediate leukocyte recruitment of all components of the antitumor response. This study aimed to phenotypically characterize the immune lymphocyte infiltrate in human renal cell carcinomas RCCs and at the invasive margin (tumor-host interface) and to define the association of these findings with established prognostic indicators. Tumor infiltrating lymphocytes TILs were obtained from 24 patients with RCC undergoing radical nephrectomy. Peripheral blood cells from 37 patients were also obtained before surgery. Our findings are consistent with the preferential recruitment of CD4+ Th1-polarized effector memory cells that express CXCR3/CCR5. These cells were the main component of TILs and expressed as CXCR3, CCR5, CD45RO, and CD95. Natural killer (NK) cells were found in significantly higher proportions in TILs of RCCs than in peripheral blood lymphocytes (PBLs) or in other tumors studied (colorectal and breast cancers), where these cells were found in small proportions. No differences in nuclear grade or other studied parameters were observed between the TILs and the lymphocytes present at the invasive margin, which showed a similar composition. However, differences were found according to the tumor stage. First, significantly fewer NK cells were observed in PBLs from metastatic patients. Second, a significantly lower proportion of CCR5/CXCR3/CD4+ cells and a higher proportion of CCR4/CD4+ cells were observed in metastatic patients, suggesting that preferential Th1-polarization may gradually change during the progression of renal cancer cells. Finally, the frequency of CD25/CD4+ cells was higher in metastatic patients. Although the sample of patients with metastasis was small, the overall results suggest a change in composition of the TILs that may potentially confer a selective advantage for tumor growth and may account for the suppression of an effective cytotoxic response.

[Cystinosis: diagnosis through the measurement of the leukocyte cystine content by HPLC]. / Cistinosis: diagnóstico mediante la determinación del contenido de cistina intraleucocitaria por cromatografía líquida de alta resolución.

BACKGROUND AND OBJECTIVE: Cystinosis is an autosomal recessive disorder characterized by an accumulation of intralysosomal cystine. Three disease forms exist, infantile, juvenile or late-onset, and ocular nonnephropathic cystinosis, delineated on the basis of severity of symptoms and age of onset. The knowledge of early clinic manifestations and the onset of the appropriate therapy delay the evolution of the disease and improve the general conditions. Therefore, it is necessary to develop a sensible diagnostic method for early detection and treatment of the disease. CLINICAL CASE AND METHODS: The leukocyte cystine content was determined by HPLC in a 42 years old female patient after renal transplantation, and with the clinical characteristic complications of the intermediate cystinosis. Equally, the molecular characterization of the structural defects of the cystinosin (CTNS) gene was made in the patient and in all family members. RESULTS: By measuring of the leukocyte cystine content in the patient and family members, we have determined 5 family members as heterozygous. This result was confirmed by molecular analysis that showed the approximately 65 kb deletion in the 5 family members. The patient was heterozygous for the approximately 65 kb deletion, and the second alteration was not determined. CONCLUSIONS: We presented a useful diagnostic method, based in the determination of cystine content of polymorphonuclear leukocytes, which permits to detect the heterozygous individuals.