Carta Acesso aberto Revisado por pares

A hitchhiker’s guide to the galaxy-an H. pylori travel guide

2003; Elsevier BV; Volume: 124; Issue: 7 Linguagem: Inglês

10.1016/s0016-5085(03)00551-1

ISSN

1528-0012

Autores

Robert I. Handin,

Tópico(s)

Blood groups and transfusion

Resumo

Given the skepticism that accompanied early observations linking Helicobacter pylori infection to peptic ulceration, the protean manifestations of this bacterial infection are ironic. H. pylori is now thought to cause gastric carcinoma, MALT lymphomas, atrophic gastritis, and pernicious anemia, in addition to peptic ulcers. There is also evidence that H. pylori may have effects that extend beyond the GI tract. For example, infection with this pathogen has been reported to increase the risk of atherosclerotic vascular disease, myocardial infarction, and stroke. Recent studies also report that some patients with immunologic thrombocytopenic purpura (ITP) are infected with H. pylori and that their thrombocytopenia remits after the infections are eradicated.1Michel M. et al.Autoimmune thrombocytopenic purpura and Helicobacter pylori infection.Arch Intern Med. 2002; 162: 1033-1036Crossref PubMed Scopus (97) Google Scholar, 2Hashino S. et al.Platelet recovery in patients with idiopathic thrombocytopenic purpura after eradication of Helicobacter pylori.Int J Hematol. 2003; 77: 188-191Crossref PubMed Scopus (71) Google Scholar, 3Hino M. et al.Platelet recovery after eradication of Helicobacter pylori in patients with idiopathic thrombocytopenic purpura.Ann Hematol. 2003; 82: 30-32PubMed Google Scholar It has been difficult to explain how an infection that is apparently localized to the upper GI tract could have such powerful distant effects. The article by Byrne et al.4Byrne M.F. Kerrigan S.W. Corcoran P.A. Atherton J.C. Murray F.E. Fitzgerald D.J. Cox D.M. Helicobacter pylori binds von Willebrand Factor and interacts with GPIb to induce platelet aggregation.Gastroenterology. 2003; 124: 1846-1854Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar in this issue of Gastroenterology presents interesting data on the interaction of H. pylori with platelets and suggests at least one mechanism by which H. pylori or H. pylori constituents might extend their reach beyond the gastric mucosa. They report that the bacterium can interact with the platelet Glycoprotein Ib/IX complex, as well as with its principal ligand, the von Willebrand factor (vWF), and that they might interact within the gastric microcirculation. The authors also present evidence that these interactions are strain-specific and may require the simultaneous interaction of anti-H. pylori antibodies with the platelet Fcγ receptor (FcγRIIa). This may explain why systemic pathology has only been detected in a subset of infected patients. The vWF normally acts as a bridge between platelets and vascular subendothelium thereby stabilizing adherent platelets and allowing them to remain attached to the vessel wall despite the high shear forces extant in flowing blood that would likely detach them. Platelet adhesion is the pivotal first step in the process of hemostasis and this firm anchoring system involving collagen, vWF and the platelet GpIb/IX receptor co-evolved with the development of the high-flow high-shear closed circulatory system that characterizes all vertebrates. What is remarkable about the GpIb-vWF interaction is its remarkable specificity and the exquisite degree of control. The GpIb/IX complex is constitutively expressed only on blood platelets and its only physiologically relevant ligand is vWF. Although each milliliter of blood plasma contains 2.5 × 108 platelets and 10 μg or more of vWF, the 2 do not interact until the vWF molecule becomes “activated” by exposure to high shear forces or binding to collagen fibrils in vascular subendothelium. Atomic force micrographs show a dramatic unfolding of vWF when it is immobilized. It converts from a loosely coiled globular molecule to an extended linear structure.5Siedlecki C.A. et al.Shear-dependent changes in the three-dimensional structure of human von Willebrand factor.Blood. 1996; 88: 2939-2950Crossref PubMed Google Scholar vWF is synthesized by endothelial cells and megakaryocytes and circulates in plasma as a heterogeneous collection of multimers, which are derived from an extremely large precursor. A recently identified metalloproteinase, ADAMTS 13, trims the ultrahigh MW multimers secreted from endothelial cells into the array of smaller multimers seen in normal plasma.6Zheng X. et al.Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura.J Biol Chem. 2001; 276: 41059-41063Crossref PubMed Scopus (709) Google Scholar, 7Zheng X. Majerus E.M. Sadler J.E. ADAMTS13 and TTP.Curr Opin Hematol. 2002; 9: 389-394Crossref PubMed Scopus (71) Google Scholar Each multimer is made up of varying numbers of a 240,000 Mr subunit, which contains homologous repeated sequences that fold into independent functional domains. Of most relevance for hemostasis, the central third of each subunit contains a trio of A domain repeats, which represent “the business end” of the molecule.8Sadler J.E. Biochemistry and genetics of von Willebrand factor.Annu Rev Biochem. 1998; 67: 395-424Crossref PubMed Scopus (1179) Google Scholar The vWF-A1 domain binds to a specific region on the GpIbα polypeptide. The vWF-A3 domain, in turn, binds to collagen fibrils in subendothelial matrix, thereby linking platelets to the vessel wall. The details of these interactions are very well understood as the crystal structure of the vWF-A1 and A3 domains and the vWF binding region of the GpIbα polypeptide have been solved and the amino acids that mediate binding have been precisely determined.9Bienkowska J. Cruz M. Atiemo A. Handin R. Liddington R. The von willebrand factor A3 domain does not contain a metal ion-dependent adhesion site motif.J Biol Chem. 1997; 272: 25162-25167Crossref PubMed Scopus (107) Google Scholar, 10Cruz M.A. Diacovo T.G. Emsley J. Liddington R. Handin R.I. Mapping the glycoprotein Ib-binding site in the von Willebrand factor A1 domain.J Biol Chem. 2000; 275: 19098-19105Crossref PubMed Scopus (99) Google Scholar, 11Emsley J. Cruz M. Handin R. Liddington R. Crystal structure of the von Willebrand Factor A1 domain and implications for the binding of platelet glycoprotein Ib.J Biol Chem. 1998; 273: 10396-10401Crossref PubMed Scopus (241) Google Scholar, 12Huizinga E.G. Martijn van der Plas R. Kroon J. Sixma J.J. Gros P. Crystal structure of the A3 domain of human von Willebrand factor implications for collagen binding.Structure. 1997; 5: 1147-1156Abstract Full Text Full Text PDF PubMed Google Scholar What then is the significance of the interaction between H. pylori, which is not a blood-borne pathogen, circulating platelets and vWF? Is this reported interaction only a laboratory curiosity or does it provide us with further insights into the fascinating role of H. pylori as a human pathogen? Is the proposed systemic pathology a direct or indirect consequence of a localized infection? The answers to these questions will help us understand the importance of this intriguing paper, as well as help us to determine how extensively to screen for the presence of H. pylori in patients without GI symptoms and how extensively physicians should work to eliminate this potential pathogen from the general population. It is already clear that the organism can cause serious disease in the GI tract. However, if it also contributes to atherosclerosis, stroke, and myocardial infarction, infection with this organism becomes an enormous international health issue that extends far beyond a single discipline like gastroenterology. Microorganisms may interact with platelets or other blood cells by several independent mechanisms. The most well understood interaction, of course, is the phagocytosis of opsonized microorganisms by macrophages, monocytes, and polymorphonuclear leukocytes. These reactions, which take place in the blood as well as in tissues, involve the coating of bacteria with specific antibody and complement and interactions with cellular receptors for C3 and IgG. The ingested organisms are then digested within the phagocytic cell. In addition, microorganisms that are complexed with antibodies may under certain circumstances bind to the Fc receptors of nonphagocytic cells including platelets. This may explain the thrombocytopenia seen in some patients with viral infections, as well as some cases of disseminated intravascular coagulation triggered by bacterial, viral, and fungal infections. Some microorganisms have evolved clever ways to interact with and even enter blood cells. One clear example is the relationship between the Duffy blood group system and malaria infection.13Cavasini C.E. Tarelho Pereira F.J. Ribeiro W.L. Wunderlich G. Ferreira M.U. Duffy blood group genotypes among malaria patients in Rondonia, Western Brazilian Amazon.Rev Soc Bras Med Trop. 2001; 34: 591-595Crossref PubMed Scopus (12) Google Scholar, 14Daniels G. Functional aspects of red cell antigens.Blood Rev. 1999; 13: 14-35Abstract Full Text PDF PubMed Scopus (62) Google Scholar, 15Rios M. Bianco C. The role of blood group antigens in infectious diseases.Semin Hematol. 2000; 37: 177-185Abstract Full Text PDF PubMed Scopus (28) Google Scholar, 16Suh I.B. et al.The analysis of Plasmodium vivax Duffy receptor binding domain gene sequence from resurgent Korea isolates.Parasitol Res. 2001; 87: 1007-1010PubMed Google Scholar Plasmodium vivax requires the presence of the Duffy blood group in order to penetrate the red blood cell. It is an absolute requirement, so that Duffy negative individuals are resistant to P. vivax. Retro and lenti viruses have co-opted cell surface proteins, which were designed for other uses to assist them as they penetrate host cells. For example, the Moloney murine ectotropic retroviruses bind to a cellular transporter for cationic amino acids,17Albritton L.M. Kim J.W. Tseng L. Cunningham J.M. Envelope-binding domain in the cationic amino acid transporter determines the host range of ecotropic murine retroviruses.J Virol. 1993; 67: 2091-2706Crossref PubMed Google Scholar, 18Closs E.I. Rinkes I.H. Bader A. Yarmush M.L. Cunningham J.M. Retroviral infection and expression of cationic amino acid transporters in rodent hepatocytes.J Virol. 1993; 67: 2097-2102Crossref PubMed Google Scholar, 19Yang Y.L. et al.Receptors for polytropic and xenotropic mouse leukaemia viruses encoded by a single gene at Rmc1.Nat Genet. 1999; 21: 216-219Crossref PubMed Scopus (117) Google Scholar and it is well known that HIV binds to the lymphocyte cell surface protein CD4. It is possible that H. pylori has evolved a similar mechanism to latch onto blood platelets using a cell surface protein that either mimics the vWF-A1 domain itself or can activate vWF, i.e., mimics the effect of collagen. It is also possible that certain strains of H. pylori bind only when the host has also produced specific antimicrobial antibody, which form bacterial-antibody immune complexes that bind to the Fc receptors on platelets or other cells rather than promoting phagocytosis. Evidence is presented in the Byrne article for both possible mechanisms. Is any of this plausible? While there clearly is precedent, there is no evidence that any of these interactions actually occurs in vivo, nor is there a compelling case to be made for how interacting with platelets might aid the microorganism in what appears to be its primary job—setting up residence in the gastric mucosa. A second possibility is that proteins shed from the microbial surface find their way into the circulation and bind to platelets and/or vWF. If this does occur it has not caused a big enough change in platelet function to cause clinical bleeding. It might however explain why H. pylori proteins are found at sites that are quite distant from the GI tract. Although the findings are intriguing, the role of H. pylori in the pathogenesis of atherosclerosis remains unknown. Chlamydia, a GU pathogen, has also been detected in atherosclerotic blood vessels and has been considered as a cause of vascular pathology. Treatment with antibiotics designed to eliminate Chlamydia from the body have not halted or reversed atherosclerotic vascular disease.20Bloemenkamp D.G. Mali W.P. Vissere F.L. van der Graaf Y. Meta-analysis of sero-epidemiologic studies of the relation between Chlamydia pneumoniae and atherosclerosis does study design influence results?.Am Heart J. 2003; 145: 409-417Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 21Campbell L.A. Kuo C.C. Chlamydia pneumoniae and atherosclerosis.Semin Respir Infect. 2003; 18: 48-54Crossref PubMed Scopus (42) Google Scholar, 22Watt S. Aesch B. Lanotte P. Tranquart F. Quentin R. Viral and bacterial DNA in carotid atherosclerotic lesions.Eur J Clin Microbiol Infect Dis. 2003; 22: 99-105PubMed Google Scholar A final possibility is that chronic infection with H. pylori elicits a low-grade inflammatory response and that cytokines and other mediators that are generated locally may spill over and affect a distant site. There is increasing evidence that inflammation plays a role in atherosclerotic vascular disease. In fact, C-reactive protein (CRP), a nonspecific indicator of systemic inflammation, has been established as a valid marker for cardiovascular risk23Blake G.J. Ridker P.M. C-reactive protein and other inflammatory risk markers in acute coronary syndromes.J Am Coll Cardiol. 2003; 41: S37-S42Abstract Full Text Full Text PDF PubMed Google Scholar, 24Ridker P.M. Clinical application of C-reactive protein for cardiovascular disease detection and prevention.Circulation. 2003; 107: 363-369Crossref PubMed Scopus (2051) Google Scholar, 25Rifai N. Ridker P.M. Inflammatory markers and coronary heart disease.Curr Opin Lipidol. 2002; 13: 383-389Crossref PubMed Scopus (92) Google Scholar and studies are now underway to determine if treatment programs that lower CRP levels will halt or reverse vascular pathology. Thus, it is theoretically possible, but by no means proven, that low-grade chronic infection with H. pylori might, over many years, cause distant pathology. The article under discussion here provides a mechanism for the spread of a gastrointestinal infection-hitching a ride to distant sites on the platelet surface. However, in the absence of more definitive clinical and epidemiologic data or some compelling studies in experimental animals, it is hard to view this, at present, as more than a fascinating laboratory observation. Perhaps, the traditional watch and wait approach is most appropriate. We need only look at the fascinating story of how H. pylori became recognized as a human pathogen. Although it took some time and there was resistance in the medical community, it is now firmly established that it is an important pathogen. This observation has revolutionized the therapy of peptic ulcer disease, benefited our patients enormously and humbled more than a few medical experts and naysayers. The identification and eradication of H. pylori infection has changed our entire strategy for treating peptic ulcer disease. When was the last time you referred a patient for a vagotomy and pyloroplasty who had failed to respond to therapy with antibiotics, proton pump inhibitors, or H2 blockers? In fact, how many surgeons under the age of 50 have ever performed the operation? I think I can state with certainty that there is a lot more to learn about H. pylori and that the microorganism will continue to vex and fascinate the physicians and scientists who study it. Since it is estimated that two thirds of the world’s population is infected with H. pylori any work in this area has enormous implications. Stay tuned.

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