Insights into defective serological memory after acute lymphoblastic leukaemia treatment: The role of the plasma cell survival niche,memory B-cells and gut microbiota in vaccine responses

Acute lymphoblastic leukaemia (ALL) is the most common type of cancer in children, accounting for approximately 25% of childhood cancer cases. As a result of effective treatments over the past decades, paediatric ALL mortality has been greatly reduced. Chemotherapy, however, has a range of harmful side effects including the loss of protective antibodies against vaccine-preventable diseases. Since ALL survivors have an increased risk of health problems including organ insufficiencies, acquired vaccine-preventable infections subsequent to clinical remission could become life threatening to these individuals. This review will summarize clinical findings regarding defective humoral immunity in ALL survivors, identify current knowledge gaps and highlight mechanisms related to deficiencies in the B-cell compartment important for serological memory. Further, we illuminate the emerging evidence for a relationship between chemotherapy and gut microbiota, which could play an important role in vaccine responses and the shaping of a young immune system subjected to maturation and recovery.     

Cord blood monocyte subsets are similar to adult and show potent peptidoglycan-stimulated cytokine responses

Human monocytes can be divided into two major subpopulations, CD14(++) CD16(-) and CD14(+) CD16(+) cells, which are suggested to play different roles in antimicrobial responses. In neonates, characteristics and functional responses of monocyte subsets have not previously been explored, and might contribute to the qualitative difference between neonatal and adult cytokine profiles. We report that at baseline, monocyte subsets in cord blood and adult peripheral blood are present in similar frequencies, and show similar expression of CD11c, CD80/CD86, CD163 and HLA-DR. In response to the bacterial ligand peptidoglycan, cord blood monocytes had high inherent capacity for production of the early-response cytokines with levels of tumour necrosis factor and interleukin-12p70 exceeding adult levels, and also a higher phosphorylation of p38-mitogen-activated protein kinase. The CD14(+) CD16(+) cells expressed more interleukin-12p70 than CD14(++) CD16(-) cells and were present in a higher frequency in peptidoglycan-stimulated cord blood mononuclear cell cultures. Together, the behaviour of cord blood CD14(+) CD16(+) cells following peptidoglycan stimulation might indicate a qualitative difference between the neonatal antimicrobial response and that of the adult. In addition we found that serum factors in cord blood and adult sera affected cytokine production similarly, with the exception of tumour necrosis factor, regardless of the source of serum or cells. Overall, our data provide new insights into monocyte heterogeneity in cord blood and monocyte subset responses to a bacterial ligand at birth.     

Maternal allergy influences p38-mitogen-activated protein kinase activity upon microbial challenge in CD14+ monocytes from 2-year-old children

Background The development of allergic diseases is dependent on genetic and environmental factors. It has been shown previously that cord blood mononuclear cells (CBMCs) from infants with parental allergy have altered cytokine profiles upon bacterial encounter; it might be possible that such impairment persists during the early years of childhood. Objective The aim of this study was to investigate anti‐microbial responses with regard to p38‐mitogen‐activated protein kinase (MAPK) activity in CD14⁺ monocytes and IL‐6 release from mononuclear cells in the same group of children at birth and at 2 years of age. Methods Paired samples of CBMCs and peripheral blood mononuclear cells (PBMCs) were stimulated with either lipopolysaccharide (LPS) or peptidoglycan in vitro. CD14⁺ monocytes were analysed for p38‐MAPK activity by flow cytometry, and soluble IL‐6 receptor, soluble glycoprotein130 and IL‐6 release from PBMC cultures were quantified by ELISA. Results CBMCs from newborns with allergic mothers tended to have a lower IL‐6 response following an LPS (P=0.09) challenge compared with the group without maternal allergy while p38‐MAPK activation levels did not differ between the groups. PBMCs from 2‐year‐olds with allergic mothers released significantly less (P<0.05) IL‐6 upon peptidoglycan stimuli compared with age‐matched infants with non‐allergic mothers. Infants with allergic mothers displayed markedly reduced CD14⁺ monocyte p38‐MAPK phosphorylation after LPS (P<0.05) and peptidoglycan (P<0.01) challenge. This altered anti‐microbial response was attributed to maternal allergy rather than to being IgE‐sensitized at 2 years of age. Conclusion Monocytes from children with allergic mothers are less responsive to bacterial challenge than monocytes from children with non‐allergic mothers, and this impairment persists during the first 2 years of infancy.     

ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice

Glioblastoma multiforme is the most common and lethal form of primary brain cancer. Diagnosis of this advanced glioma has a poor prognosis due to the ineffectiveness of current therapies. Aberrant expression of receptor tyrosine kinases (RTK) in glioblastoma multiformes is suggestive of their role in initiation and maintenance of these tumors of the central nervous system. In fact, ectopic expression of the orphan RTK ROS is a frequent event in human brain cancers, yet the pathologic significance of this expression remains undetermined. Here, we show that a glioblastoma-associated, ligand-independent rearrangement product of ROS (FIG-ROS) cooperates with loss of the tumor suppressor gene locus Ink4a;Arf to produce glioblastomas in the mouse. We show that this FIG-ROS-mediated tumor formation in vivo parallels the activation of the tyrosine phosphatase SH2 domain-containing phosphatase-2 (SHP-2) and a phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling axis in tumors and tumor-derived cell lines. We have established a fully penetrant preclinical model for adult onset of glioblastoma multiforme in keeping with major genetic events observed in the human disease. These findings provide novel and important insights into the role of ROS and SHP-2 function in solid tumor biology and set the stage for preclinical testing of targeted therapeutic approaches.