Anti-CagA immunoglobulin G responses correlate with interleukin-8 induction in human gastric mucosal biopsy culture

Abstract

Helicobacter pylori persists in the human stomach despite eliciting both cellular and humoral immune responses and inducing proinflammatory cytokines. To determine whether local humoral and cytokine responses are related to each other and to histologic responses, we studied 66 Japanese patients who underwent gastroscopy. Using specific enzyme-linked immunosorbent assays, we examined gastric antral mucosal-organ biopsy culture supernatants to assess interleukin-6 (IL-6) and interleukin-8 (IL-8) levels and antibody responses to H. pylori whole-cell antigens CagA, HspA, and HspB. Of the patients studied, 11 were H. pylori negative and 55 were H. pylori positive; by PCR, all strains were cagA(+). As expected, compared to H. pylori-negative patients, H. pylori-positive patients had significantly higher humoral responses to all H. pylori antigens and had higher IL-8 (47.8+/-3.5 versus 10.1+/-4.3 ng/mg of biopsy protein; P<0.001) and IL-6 levels (2.8+/-0.3 versus 0.26+/-0.2 ng/mg of protein; P<0.001). Among the H. pylori-positive patients, supernatant anti-CagA immunoglobulin G (IgG) levels were significantly associated with H. pylori density (P<0.005) and neutrophil infiltration (P<0.005) scores. Anti-CagA immunoglobulin A levels were correlated with intestinal metaplasia (P<0.05). Mononuclear cell infiltration scores were significantly associated with supernatant IL-6 levels (P<0.005) and with IgG responses to whole-cell antigens (P<0.05). Supernatant IL-8 levels were significantly associated with anti-CagA IgG (r = 0.75, P<0.001). Anti-CagA responses correlated with neutrophil infiltration, intestinal metaplasia, H. pylori density, and IL-8 levels, suggesting that the absolute levels of these antibodies may be markers for gastric inflammation and premalignant changes in individual hosts.

FIG. 1

Cytokine levels (nanograms per milligram of protein in culture supernatants) in gastric antral mucosal-organ cultures from 66 study patients. Patients were classified based on H. pylori status and, if positive, on endoscopic findings. (A) IL-8. Values for H. pylori-positive persons in each group were significantly (P < 0.001) higher than for H. pylori-negative persons. Patients with DU had the highest values. (B) IL-6. Values for H. pylori-positive persons in each group were significantly (P < 0.001) higher than for H. pylori-negative persons.

FIG. 2

Correlation between organ culture IL-8 levels and concentrations of IgG to CagA in 55 persons colonized with cagA⁺ H. pylori strains (r = 0.75, P < 0.0001).