IntroductionTo effectively fight invading pathogens, mammals have developed a repertoire of adaptive immune mechanisms that include the production of high-affinity antibodies. A critical event in the initiation of the humoral immune response reflects the timely interaction of B and T cells specific for the same antigen. The border between T-cell zone and B cell-rich follicles in lymph nodes (LNs) and the white pulp of the spleen are commonly considered as the place where the initial interaction between antigen-specific T and B cells occurs. 1 After receiving signals from activated CD4 T cells via the interaction of CD40/CD40L and further costimulatory molecules, some B cells differentiate into plasmablasts, which migrate to the red pulp of the spleen to become short-lived plasma cells secreting low-affinity antibodies. Following the interaction with T cells, other B cells migrate into the B follicle, start to proliferate, and form germinal centers (GCs). 2 It is widely accepted that isotype switching and affinity maturation of B cells depend on CD4 T helper cells. Some of these might also migrate into the follicle and GC. Thus, the coordinated migration of B and T cells appears to represent a decisive event that allows lymphocytes to make contact with each other.Ample evidence indicates that the migration of lymphocytes into secondary lymphoid organs is controlled by a chemokinedriven process. During the last decade several chemokines have been identified that are expressed in lymphoid organs, which guide resting or activated cells to their point of destination. Naive T cells express the chemokine receptor CCR7, which allows recruitment of these cells into T-cell areas of LNs or to the splenic white pulp through interaction with its ligands CCL19 and CCL21. These chemokines are expressed at specialized high endothelial venules (HEVs) in LNs and by lymphoid and nonlymphoid cells in the T-cell area of LNs and spleen. 3,4 In addition to CXCR4, CCR6, and CXCR5, B cells also express CCR7 to be able to enter lymphoid organs efficiently. Once entered these cells require CXCR5 to follow a chemokine gradient build up by CXL13 that is constitutively expressed on stromal cells in the follicles. 5 The differential localization of B cells during the different phases of an antigenspecific immune response is facilitated by the balanced responsiveness of these cells toward the chemokines CXCL13 and CCL19/CCL21. 6 In contrast to the situation described for B cells, less is known about molecular mechanisms that guide the small subpopulation of CD4 ϩ helper T cells into the B-cell follicle. These cells lack a distinct T H 1 or T H 2 cytokine expression profile but express costimulatory molecules such as inducible costimulator (ICOS) and CD40L and induce B cells to produce IgG and IgA in vitro. 7,8 Based on this ability and due to the fact that these cells express CXCR5, a chemokine receptor known to be essential for the localization of B cells to the follicle, we and others termed these T cells "follicular B helper T cells" (T FH ...

Allergic airway diseases such as asthma are caused by a failure of the immune system to induce tolerance against environmental Ags. The underlying molecular and cellular mechanisms that initiate tolerance are only partly understood. In this study, we demonstrated that a CCR7-dependent migration of both CD103+ and CD103− lung dendritic cells (DC) to the bronchial lymph node (brLN) is indispensable for this process. Although inhaled Ag is amply present in the brLN of CCR7-deficient mice, T cells cannot be tolerized because of the impaired migration of Ag-carrying DC and subsequent transport of Ag from the lung to the draining lymph node. Consequently, the repeated inhalation of Ag protects wild-type but not CCR7-deficient mice from developing allergic airway diseases. Thus, the continuous DC-mediated transport of inhaled Ag to the brLN is critical for the induction of tolerance to innocuous Ags.

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Homeostatic chemokines participate in the development of secondary lymphoid organs and later on in the functional organization of these tissues. The development of lymph nodes (LNs) and Peyer's patches depends on the recruitment of CD3− CD4+ interleukin (IL)-7Rαhi cells to sites of future organ development. CD3− CD4+ IL-7Rαhi cells express the chemokine receptor CXCR5 and might be attracted by its ligand CXCL13, which is secreted by mesenchymal cells. Mesenchymal cells also secrete CCL19, a ligand for CCR7, yet it is not clear whether CCR7 and CCL19 are important for secondary lymphoid organ development. Analyzing CXCR5−/− CCR7−/− double deficient mice we now show that these mice lack all examined peripheral LNs suggesting a profound role for both receptors in secondary lymphoid organ development. We demonstrate that CD3− CD4+ IL-7Rαhi cells express CXCR5 as well as CCR7 indicating that both receptors cooperate during an early step of secondary lymphoid organ development. Furthermore, CXCR5−/− CCR7−/− mice display a severely disturbed architecture of mesenteric LN and spleen. Due to an impaired migration of B cells into the white pulp, CXCR5−/− CCR7−/− mice fail to develop B cell follicles but show small clusters of unorganized lymphocytes in the spleen. These data demonstrate a cooperative function of CXCR5 and CCR7 in lymphoid organ organogenesis and organization.

Ribavirin is a safe treatment option for HEV infections. However, the optimal dose of ribavirin for the treatment of chronic hepatitis E remains to be determined as treatment failure may occur.

IFNα-based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2017;65:414-425).

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible ''trial endpoints") that could be used across different clinical trials.

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