Transient immunological control during acute hepatitis C virus infection: ex vivo analysis of helper T-cell responses.

Hepatitis C virus (HCV) readily sets up persistence after acute infection. Cellular immune responses are thought to play a major role in control of the virus. Failure of CD4+ T-cell responses in acute disease is associated with viral persistence but the dynamics of this are poorly understood. We aimed to assess such responses using a novel set of Class II tetrameric complexes (tetramers) to study helper T-cells ex vivo in acute disease. We analysed the HCV-specific CD4+ T-cell response in a patient with acute hepatitis c infection. We were able to track the virus-specific CD4+ T-cells directly ex vivo with HLA DR4 tetramers. Proliferative responses were absent initially, recovered as viral load dropped and were lost again during relapse. Longitudinal tetramer analyses showed expanded populations of antiviral CD4+ T-cells throughout acute infection despite lack of proliferation. A pattern of transient CD4+ T-cell proliferative responses as HCV is partially controlled is observed. Failure to control virus is associated with emergence of 'dysfunctional' CD4+ T-cell populations. Failure to control HCV in acute disease may relate to the capacity to sustain efficient immune responses as virus attempts to 'bounce back' after partial control.

Inflammatory arthritis and dermatitis in thymectomized, CD25+ cell-depleted adult mice.

OBJECTIVE: To investigate the effect of CD25+ or CTLA-4(+) cell depletion on the natural history of collagen-induced and spontaneous arthritis in male DBA1/J mice. METHODS: Male DBA/1J mice were treated with anti-CD25 depleting antibody (PC61) or isotype control (GL113), or with anti-CTLA-4 depleting antibody (4F10) at various time-points peri- and post-immunization with bovine collagen type II, emulsified in adjuvant. In order to develop a model system in which long-term depletion of CD25+ regulatory T cells can be achieved prior to immunization, adult male DBA/1J mice were thymectomized prior to administration of either PC61 or GL113. An ELISA demonstrated that PC61 and GL113 antibodies were undetectable by 21 days after administration and FACS analysis confirmed the long-term depletion of CD25+ cells in peripheral blood. RESULTS: In the thymectomized mice treated with PC61, the CD25+ population was depleted and a spontaneous arthritis developed (P = 0.03). In the non-thymectomized mice, administration of CTLA-4-depleting antibody prior to immunization exacerbated arthritis in mice immunized with bovine collagen type II emulsified in incomplete Freund's adjuvant (P < 0.01). However, no significant difference in the natural history of arthritis was evident in mice treated with CD25-depleting antibody (PC61) compared with control antibody (GL113). CONCLUSIONS: Two separate models implicate CD25+ CTLA-4(+) constitutive cells in suppression of arthritis in susceptible DBA/1 males: exacerbation of collagen-induced arthritis following CTLA-4 depletion at the start of induction and spontaneous arthritis in the thymectomy/CD25+ depletion model.

Associations of Fc epsilon R1-beta polymorphisms with immunoglobin E antibody responses to common inhalant allergens in a rural population.

BACKGROUND: Polymorphisms within the beta subunit of the high-affinity receptor for IgE (Fc epsilon R1-beta ) on chromosome 11q13 have been related to atopy and asthma and the lymphotoxin alpha (LT alpha) gene on chromosome 6 is implicated in asthma. OBJECTIVE: To elucidate the association of polymorphisms in the Fc epsilon R1-beta and LT alpha genes to IgE responses and asthma in a family-orientated rural population. METHODS: A total of 461 adult farmers, who participated in an epidemiological follow-up study on respiratory symptoms among farmers on the Swedish island of Gotland, were examined. The traits assessed included serum total IgE, IgE antibody responses to 21 common inhalant allergens and asthma. RESULTS: The 237G mutation was only detected in seven persons. Atopy was found to be associated with the RsaI-ex7 AB-genotype (OR = 1.9; P = 0.04). The RsaI-ex7 B allele had a significant influence on IgE responses to pollens and dust mites (OR = 5.5; P = 0.03 and OR = 5.2; P = 0.049, respectively). The influence of this allele was stronger when the association towards single dust mite species (Lepidoglyphus destructor) was estimated (OR = 7.1, P = 0.03) and the association increased even more when the major allergen of L. destructor (rLep d 2) was analysed (OR = 11.2, P = 0.02). These associations were independent of sex, age and smoking, and the estimates of RsaI-in2 independent of RsaI-ex7. RsaI-in2, RsaI-ex7 and LT alpha genotypes were unassociated with total serum IgE. No significant difference in the distribution of RsaI-in2, RsaI-ex7 and LT alpha genotypes was found among subjects with atopy or asthma compared to healthy controls. CONCLUSION: This study supports the notion that polymorphisms in the Fc epsilon R1-beta gene have significant effects on IgE responsiveness. Secondly, dust mites in rural populations influence the expression of genes on chromosome 11q13.