Plasmodium falciparum infection leads to the development of protective classical and atypical memory B cell antibody responses.

No abstract

The mortality of patients with hormone-resistant prostate cancer can be ascribed to a large degree to metastasis to distant organs, predominantly to the bones. In this review, we discuss the contribution of micro-RNAs (miRs) to the metastatic process of prostate cancer. The criteria for selection of miRs for this review were the availability of preclinical in vivo metastasis-related data in conjunction with prognostic clinical data. Depending on their function in the metastatic process, the corresponding miRs are up-or downregulated in prostate cancer tissues when compared to matching normal tissues. Up-regulated miRs preferentially target suppressors of cytokine signaling or tumor suppressorrelated genes and metastasis-inhibitory transcription factors. Down-regulated miRs promote epithelial-mesenchymal transition or mesenchymal-epithelial transition and diverse pro-metastatic signaling pathways. Some of the discussed miRs exert their function by simultaneously targeting epigenetic pathways as well as cell-cycle-related, antiapoptotic and signaling-promoting targets. Finally, we discuss potential therapeutic options for the treatment of prostate cancer-related metastases by substitution or inhibition of miRs. In 2017, 160,000 new cases of prostate cancer (PC) were diagnosed in the US and an equal number in the EU with 27,000 patients dying due to metastatic PC in the US and the EU (1). Localized disease can be potentially cured by therapies such as surgery and radiation, but in some patients, the disease progresses despite these therapies (2). Androgendeprivation therapy leads to long-lasting responses between 2 and 3 years, however the disease inevitably progresses to castration-resistant prostate cancer (CRPC) that is associated with metastatic disease and poor prognosis. Over the past 5 years, five drugs have been approved for treatment of CRPC (2). These are cabazitaxel, a taxane-based cytostatic; radium 223, an α-emitter; enzalutamide, a small-molecule androgen receptor (AR) antagonist; abiraterone, a blocker of de novo synthesis of androgens; and Sipuleucel, a dendritic cell-based immunotherapy (3). The recent genetic classification of PC has revealed seven subtypes and new molecular targets for molecular intervention such as vets erythroblastosis virus E26 homolog (ETS) family transcription factor-based fusion proteins as well as mutations in speckle-type POZ protein (SPOP), forkhead protein A1 (FOXA1) and isocitrate dehydrogenase 1 (IDH1) (4). The serine protease inhibitor Kazal-type 1 (SPINK), which is up-regulated in ETSrearrangement-negative tumors, is also being pursued as a new target for treatment of CRPC (5). Nucleic acid-based therapy is another approach for treatment of CRPC. Custirsen, a second-generation phosphorothioate antisense oligonucleotide targeting clusterin mRNA is presently undergoing phase III clinical studies in combination with chemotherapy in patients with CRPC (6, 7). Clusterin is upregulated in patients with CRPC and functions as an ATPindependent molecular chaperone with anti-a...

Both immunoglobulin (Ig) isotype and conserved Fc glycosylation sites often dictate the downstream activity of an Ab where complexity and degree of glycosylation contribute to its ability to bind Fc receptors (FcRs) and activate complement. Most information on the effects of glycosylation center on IgG in cancer therapy and autoimmunity. In cancer therapy, glycosylation modifications that enhance affinity for activating FcRs are utilized to facilitate immune-mediated tumor cell killing. In autoimmunity, disease severity has been linked to alterations in the presence, location, and composition of Fc glycans. Significantly less is understood about the role of glycosylation in the setting of allergy and asthma. However, recent data demonstrate that glycosylation of IgE at the asparagine-394 site of Cε3 is necessary for IgE interaction with the high affinity IgE receptor but, surprisingly, glycosylation has no effect on IgE interaction with its low-affinity lectin receptor, CD23. Variations in the specific glycoform may modulate the interaction of an Ig with its receptors. Significantly more is known about the functional effects of glycosylation of IgG than for other Ig isotypes. Thus, the role of glycosylation is much better understood in the areas of autoimmunity and cancer therapy, where IgG is the dominant isotype, than in the field of allergy, where IgE predominates. Further work is needed to fully understand the role of glycan variation in IgE and other Ig isotypes with regard to the inhibition or mediation of allergic disease.

Immediate hypersensitivity reactions are induced by the interaction of allergens with specific IgE antibodies bound via FcεRI to mast cells and basophils. While these specific IgE antibodies are needed to trigger such reactions, not all individuals harboring IgE exhibit symptoms of allergy. The lack of responsiveness seen in some subjects correlates with the presence of IgG antibodies of the same specificity. In cell culture studies and in vivo animal models of food allergy and anaphylaxis such IgG antibodies have been shown to exert suppression via FcγRIIb. However, the reported absence of this inhibitory receptor on primary mast cells derived from human skin has raised questions about the role of IgG-mediated inhibition of immediate hypersensitivity in human subjects. Here, we tested the hypothesis that mast cell FcγRIIb expression might be tissue specific. Utilizing a combination of flow cytometry, quantitative PCR, and immunofluorescence staining of mast cells derived from the tissues of humanized mice, human skin, or in fixed paraffin-embedded sections of human tissues, we confirm that FcγRIIb is absent from dermal mast cells but is expressed by mast cells throughout the gastrointestinal tract. IgE-induced systemic anaphylaxis in humanized mice is strongly inhibited by antigen-specific IgG. These findings support the concept that IgG, signaling via FcγRIIb, plays a physiological role in suppressing hypersensitivity reactions.