THelper Cells

A Th-cell immune response has been demonstrated in HDV-infected patients who eliminated HDV after acute hepatitis due to superinfection. Immunization studies (protein and DNA, see Sects. 4.1 and 4.3) in mice and woodchucks also revealed a multispecific Th response.

Nisini et al. analyzed the proliferative response to recombinant HDAg and synthetic peptides in HDV-infected patients (Nisini et al. 1997). Eight of 30 patients specifically responded to HDAg. Interestingly, all responders had an inactive HDV infection (HDV PCR negative), while none of the patients with active disease showed any significant proliferation. The use of the synthetic peptides revealed that the T-cell recognition was directed against different epitopes, with patient-to-patient variation. The response to peptides was generally oligospecific: all together 15 different peptides induced proliferation. T-cell clones generated from the cells of three patients produced large amounts of IFN-y belonging to either Th1 or Th0 subsets, and some of them exerted cytotoxic activity in an antigen specific manner. The authors speculate that these T cells could play a pivotal role either in the defense against HDV infection or for the immunopathogenesis of liver disease. A further characterization of the clones using the overlapping synthetic peptides allowed the identification of four Th epitopes [amino acids (aa) 26-41,50-65,66-81, and 106-121;

B-cell epitopes on HDAg aa 2-17 (Wang et al. 1990, Poisson et al. 1993)

aa 52-93 (Bergmann et al. 1989) aa 1-83 (Srizer et al. 2005)_

1 7 13 19 25 31 37 43 49 55 61 67 73 79 85 91 97 193 199 115 121 127 133 139 145 151 157 163 169 175 181 187 193 199 295 211

Th-cell epitopes on HDAg aa 26-34 aa 43-51 (Huang et al. 2004)

CTL epitopes on HDAg

Fig. 2 Localization of CTL, Th, and B-cell epitopes on HDAg (aa 1-214). The corresponding studies are indicated see Fig. 2]. HDAg and these four peptides were recognized in the context of different class II gene products (either DR, DP, or DQ alleles). In particular, peptide amino acids 50-65 and 106-121 were presented in association with two or more different HLA-DR molecules (promiscuous peptides). The authors discuss the possibility that these regions could be relevant for further vaccine development.

One of the identified HDV epitopes (aa 106-121) may be generated by extracellular processing for presentation to specific CD4+ T cells, a rare form of processing (Accapezzato et al. 1998). The authors discuss that this 106-121 peptide could enhance the presentation to specific CD4+ T cells for mounting of a protective immune response against HDV after extracellular processing. Alternatively, this peptide may play a crucial role in the pathogenesis of HDV-mediated liver disease: the 106-121 peptide could bind to MHC class II molecules that are expressed on hepatocytes activated by inflammatory cytokines and cause extensive lysis of bystander class II hepatocytes by liver-infiltrating HDV-specific cytotoxic CD4+ T cells. Either of these proposed mechanisms could be relevant in a large cohort of patients, because the 106-121 peptide is recognized by T cells in the context of multiple HLA-DR molecules (Nisini et al. 1997).

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