Helicobacter pylori Eradication in Patients with Immune Thrombocytopenic Purpura: A Review and the Role of Biogeography

Abstract

Idiopathic thrombocytopenic purpura (ITP) is typically a diagnosis of exclusion, assigned by clinicians after ruling out other identifiable etiologies. Since a report by Gasbarrini et al. in 1998, an accumulating body of evidence has proposed a pathophysiological link between ITP and chronic Helicobacter pylori (H. pylori) infection. Clinical reports have described a spontaneous resolution of ITP symptoms in about 50% of chronic ITP patients following empirical treatment of H. pylori infection, but response appears to be geography dependent. Studies have also documented that ITP patients in East Asian countries are more likely to express positive antibody titers against H. pylori-specific cytotoxic-associated gene A (CagA), a virulence factor that is associated with an increased risk for gastric diseases including carcinoma. While a definitive mechanism by which H. pylori may induce thrombocytopenia remains elusive, proposed pathways include molecular mimicry of CagA by host autoantibodies against platelet surface glycoproteins, as well as perturbations in the phagocytic activity of monocytes. Traditional treatments of ITP have been largely empirical, involving the use of immunosuppressive agents and immunoglobulin therapy. However, based on the findings of clinical reports emerging over the past 20 years, health organizations around the world increasingly suggest the detection and eradication of H. pylori as a treatment for ITP. Elucidating the exact molecular mechanisms of platelet activation in H. pylori-positive ITP patients, while considering biogeographical differences in response rates, could offer insight into how best to use clinical H. pylori eradication to treat ITP, but will require well-designed studies to confirm the suggested causative relationship between bacterial infection and an autoimmune disease state.

Keywords: CagA; Helicobacter; biogeography; immune-mediated; infectious; thrombocytopenia.

Figure 1

Effects of Helicobacter pylori CagA virulence factor on host cell. Helicobacter pylori injects CagA (red) into a host gastric epithelial cell via a type IV secretion system (T4SS, tan). Dimerizatiom of primary receptors activated by T4SS core complex: α₅β₁ integrin and receptor tyrosine kinases (purple). Within ECs, CagA EPIYA motif is recognized by major host kinases, Src, and Abl, resulting in tyrosine phosphorylation (yellow). Phosphorylated CagA (red and yellow) induces host cell pathology. Both, intracellular CagA and phosphorylated CagA, induce major effects on host cell signaling, resulting in changes in cell morphology, cell cycle regulation, and pro-inflammatory cytokine transcription. Intercellular junctions (gray): AJ, adherens junctions; TJ, tight junctions. This figure is an adaptation of Figures 2, 3, and 4 from [103].

Figure 2

Host production of anti-CagA Abs, resulting in ITP. (1) Helicobacter pylori injects CagA (red) into host gastric ECs via T4SS (tan). (2) CagA undergoes intracellular phosphorylation (red and yellow). (3) Two Ags are produced and presented on the cell surface of the infected host cell: one specific for CagA (light blue) and one that shows molecular mimicry to platelet surface glycoproteins (purple). (4) Host Abs recognizing either Ag undergo replication within the host lymph nodes. (5) These Abs are then released into the circulatory system, resulting in a secondary immune-mediated thrombocytopenia. (6) Increased platelet clearance is a result of Ab-Ag recognition in the reticuloendothelial system (R.E.S.), increased immune complex formation, and decreased platelet production in the bone marrow. (pink: platelet; orange: megakaryocyte; blue: mononuclear phagocyte; green: R.E.S.)

Figure 3

Distribution of cag PAI in a collection of Helicobacter pylori strains from different world populations. Geographic sources of strains whose cag PAI sequences are now available. Each dot indicates the source of isolation of one of the 38 cag PAI sequences that were analyzed. The dots are color-coded by population or subpopulation as in (A). Representation of geographical distribution of platelet response after eradication treatment in H. pylori-positive adult patients (B). Data extrapolated from Table 1. Gray (0–25% response), yellow (25–50% response), green (50–75% response), and red (75–100% response) (modified with permission from [63]).

Figure 4

Diversity in CagA tyrosine phosphorylation (pY) sites. Tyrosine phosphorylation of cytotoxin-associated antigen A (CagA) by SRC kinase occurs at the EPIYA motif. There are four different EPIYA sites, called EPIYA-A, -B, -C, and -D, based on the sequence surrounding the EPIYA motif. Western strains of Helicobacter pylori express a form of CagA that contains the EPIYA-A and EPIYA-B sites, followed by 1–3 repeats of the 34-amino acid sequence that contains the EPIYA-C site (red boxes). East Asian strains of H. pylori express a form of CagA in which the EPIYA-C site is replaced with the EPIYA-D site (yellow box) (reprinted with permission from [41]).