Human herpesvirus 8: Biology and role in the pathogenesis of Kaposi’s sarcoma and other AIDS-related malignancies

Human herpesvirus type 8, or Kaposi's sarcoma-associated herpesvirus (KSHV), is the only known human g(2) herpesvirus (rhadinovirus) and the most recently discovered tumor virus. KSHV is associated with Kaposi's sarcoma and two other lymphoproliferative disorders in the AIDS setting: primary effusion lymphoma and the plasma cell variant of multicentric Castleman's disease. This review offers an update on the epidemiology and the role of KSHV genes in the development of disease.     

Atopy and the gastrointestinal tract – a review of a common association in unexplained gastrointestinal disease

In addition to diseases conventionally associated with atopy there is increasing recognition that atopy is also linked to a spectrum of gastrointestinal (GI) manifestations, including food allergy, primary eosinophilic GI disease, functional gastrointestinal disorders, gluten interactions, gastroesophageal reflux disease and inflammatory bowel disease. These associations may be underpinned by shared genetic susceptibilities, initiation of related immune pathways and common patterns of exposure to environmental cues, including allergen/pathogen encounters and variations in the composition of the intestinal microbiota. Further scrutiny of GI diseases with prominent allergic-type immune responses may yet redefine treatment paradigms for these common and important atopy-associated diseases. Looking forward, interventions by manipulation of the microbiota or host immune responses hold promise, but there is still room for further exploration of this novel field of host susceptibility, host-microbe interactions and atopy-associated GI diseases.     

Dendritic cells in the pathogenesis and treatment of human diseases: a Janus Bifrons?

Dendritic cells (DCs) represent the bridging cell compartment between a variety of nonself antigens (i.e., microbial, cancer and vaccine antigens) and adaptive immunity, orchestrating the quality and potency of downstream immune responses. Because of the central role of DCs in the generation and regulation of immunity, the modulation of DC function in order to shape immune responses is gaining momentum. In this respect, recent advances in understanding DC biology, as well as the required molecular signals for induction of T-cell immunity, have spurred many experimental strategies to use DCs for therapeutic immunological approaches for infections and cancer. However, when DCs lose control over such 'protective' responses - by alterations in their number, phenotype and/or function - undesired effects leading to allergy and autoimmune clinical manifestations may occur. Novel therapeutic approaches have been designed and currently evaluated in order to address DCs and silence these immunopathological processes. In this article we present recent concepts of DC biology and some medical implications in view of therapeutic opportunities.     

COVID-19 and the gastrointestinal tract: Source of infection or merely a target of the inflammatory process following SARS-CoV-2 infection?

Gastrointestinal (GI) symptoms have been described in a conspicuous percentage of coronavirus disease 2019 (COVID-19) patients. This clinical evidence is supported by the detection of viral RNA in stool, which also supports the hypothesis of a possible fecal-oral transmission route. The involvement of GI tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is corroborated by the theoretical assumption that angiotensin converting enzyme 2, which is a SARS-CoV-2 target receptor, is present along the GI tract. Studies have pointed out that gut dysbiosis may occur in COVID-19 patients, with a possible correlation with disease severity and with complications such as multisystem inflammatory syndrome in children. However, the question to be addressed is whether dysbiosis is a consequence or a contributing cause of SARS-CoV-2 infection. In such a scenario, pharmacological therapies aimed at decreasing GI permeability may be beneficial for COVID-19 patients. Considering the possibility of a fecal-oral transmission route, water and environmental sanitation play a crucial role for COVID-19 containment, especially in developing countries.     

Olfactomedin 4, a novel marker for the differentiation and progression of gastrointestinal cancers

Olfactomedin 4 (OLFM4) is a member of olfactomedin domain-containing protein family. Human OLFM4 is preferentially expressed in the gastrointestinal tract (stomach, small intestine and colon), prostate, and bone marrow. Recent studies demonstrate that OLFM4 is involved in the establishment and/or development of some types of malignancies, especially in gastrointestinal cancers. Induction of OLFM4 in cancer cells has a novel antiapoptotic action and promotes proliferation of cancer cells. OLFM4 regulates cell cycle and promotes S phase transition in proliferation of cancer cells. In addition, OLFM4 is associated with cancer adhesion and metastasis. In this minireview, we mainly focus on the OLFM4 expression and its biological significances in tumor differentiation and progression as well as the contributions of OLFM4 to tumorigenesis.     

Endothelial apoptosis: could it have a role in the pathogenesis and treatment of disease?

Endothelial apoptosis can be found in a number of diseases. This review summarizes the current knowledge about the causes and consequences of endothelial apoptosis, and analyzes its possible role in the pathogenesis and treatment of several diseases. Novel forms of therapy based on the proposed pathophysiologic mechanisms are discussed.     

Perception of stimuli in the gastrointestinal physiology and new methods:From the editor

This special issue of World Journal of Gastroenterology contains a number of reviews on physiology and perception of stimuli in the gastrointestinal tract. Pain is probably the most prevalent symptom in medicine and characterization of pain is of major importance in the diagnosis and choice of treatment. Consequently, understanding and characterization of the physiology behind gut pain is one of the most important issues in the diagnosis and assessment of organ dysfunction. Research leading to a better insight into pain mechanisms in the gastrointestinal tract will     

B cells: a fundamental role in the pathogenesis of rheumatoid arthritis?

The role of T cells in the pathogenesis of RA is well established, whereas to date the precise contribution of B cells is less well defined. B cells have many potential key roles: they can act as antigen-presenting cells, secrete pro-inflammatory cytokines (including tumour necrosis factor-alpha), produce rheumatoid factor (RF) and other autoantibodies and activate T cells. B cells act as antigen-presenting cells by processing and presenting antigenic peptides to T cells, which become activated, proliferate and exert pro-inflammatory activities. RF may also play a role in perpetuating B-cell activation and antigen presentation to T cells, thus leading to sustained production of RF. This, combined with RF immune-complex-mediated complement activation, may contribute to the sustained inflammatory response. Studies have shown that the use of an anti-CD20 monoclonal antibody in RA depletes circulating B cells, resulting in improvement in disease activity for up to 1 yr. It is thus evident that B cells play a central role in the pathophysiology of RA and therefore merit further investigation as a therapeutic target.     

Relative maturity and the development of immunity to gastrointestinal nematodes in sheep: an overlooked paradigm?

Sheep display considerable variation in both the timing and magnitude of development of immunity to gastrointestinal nematodes (GIN). Onset of immunity is dependent on a number of factors, including antigenic stimulus, nutrition supply, age and size of the animals, the latter of which are confounded. Here, we review the factors associated with the development of immunity to GIN in sheep, particularly in the context of the role that relative maturity may have through applying the rules of genetic size scaling based on examples from published literature. Comparing animals based on their metabolic age, rather than chronological age, may provide an explanation for the timing of immune development and may reduce the variation in immune development that frequently is observed both between and within breeds. Further, this approach may help explain the phenotypic differences in animal performance between animals of varying immunological capacity to GIN through influences on mature body weight. As such, when considering factors influencing immune development to GIN, physiological age or relative maturity may be considered an overlooked paradigm. We propose it may be worthwhile to consider metabolic age when comparing the immune competence of animals to ensure the subjects are at an analogous stage of physiological development.     

Estimation of the difference in HbF expression due to loss of the 5' δ-globin BCL11A binding region

BCL11A was the focus of recent studies on its inhibiting effect when bound onto the β-globin cluster in the mechanism of hemoglobin switching and HbF downregulation. We examined a cohort of 10 patients displaying different HbF levels and short deletions within the γβ-δ intergenic region to find a possible correlation with the BCL11A binding site located 5'' to the δ-globin gene. Precise characterization of deletions was achieved using a custom DNA-array chip and breakpoint sequencing. The α-globin cluster and major SNP associated with HbF expression were genotyped. Our results show that the loss of the BCL11A binding domain located 5'' to the δ-globin gene is correlated with a strong HbF difference (mean+2.7 g/dL, ratio 2.81). This result provides evidence for the use of BCL11A level down-regulation or this domain blockage for new therapies in sickle cell disease and β-thalassemia major patients.     

Targeting of the Hedgehog pathway in myeloid malignancies: still a worthy chase?

Deregulated Hedgehog (Hh) signalling activity may be associated with a broad range of cancer types and hence has become an attractive target for therapeutic intervention. Although initial haematological interest focused on the therapeutic targeting of this pathway in chronic myeloid leukaemia), small molecule inhibitors targeting the Hh pathway are now being tested in a range of other myeloid disorders, including myelofibrosis, myelodysplasia and acute myeloid leukaemia. In this review we will evaluate the rationale for targeting of the Hh pathway in myeloid diseases and discuss the novel agents that have entered the clinical arena. We will discuss pre‐clinical models, emerging clinical trial data, and suggest how these targeted therapies may address current unmet medical needs. Finally, we will explore potential limitations of these therapies due to the emergence of secondary resistance mechanisms and speculate on future developments within this arena.