LN tissues in the Ugandan participants in Group 1 have a similar amount of collagen as LN tissues from HIVC people from the U

LN tissues in the Ugandan participants in Group 1 have a similar amount of collagen as LN tissues from HIVC people from the U.S. impact on vaccine development, especially for infectious diseases prevalent in the developing world. Keywords: Immunology, Vaccines Keywords: Adaptive immunity, Bacterial vaccines, Fibrosis Introduction Vaccine responses are known to vary geographically. Bacillus Calmette-Guerin (BCG) for tuberculosis (TB) is perhaps the best known example of a vaccine for which efficacy rates vary according to geography, with better responses occurring in northern latitudes (1). Rotavirus vaccine is usually another example where sustained, neutralizing antibody titers are achieved after a single dose in the U.S. and Europe, but in developing countries protection is usually absent or short-lived even after multiple doses (2C4). Polio and cholera are also associated with poor antibody responses in developing countries (5C11) and it was recently shown that yellow fever vaccine (YFV) was associated with low levels of neutralizing antibodies in Uganda compared with Switzerland, and that heightened immune activation (IA) in Ugandans was an important factor limiting vaccine responses (12). This is important, as chronic IA may lead to T cell anergy (13), which would limit adaptive immune responses. Reasons for chronic IA and geographic differences in vaccine response are unknown but one possible explanation is usually that local environmental conditions or endemic infections somehow affect immune function. There are several studies documenting poor induction of adaptive immunity in the setting of a chronic infection, especially with helminthic infections (14C17). The mechanism is unknown but it is likely related to altered cytokine responses to contamination that impact T cell proliferation and antibody formation (15). HIV is RG7112 an infection that is associated with decreased immune function because of loss of CD4+ T cells and chronic IA (even during fully suppressive antiretroviral therapy) (18C20). You will find multiple mechanisms that contribute to CD4+ T cell loss in HIV contamination. Lymphatic tissue (LT) fibrosis from HIV replication is usually a significant mechanism caused by an inflammatory reaction that leads to collagen formation in the parafollicular T cell zone (TZ) (21). This fibrosis replaces the fibroblastic reticular cell network (FRCn), a structure that is vital to normal immune RG7112 function. The FRCn is usually a scaffold-like structure with several functions important to the development of mature immune responses. T cells and antigen presenting cells (APCs) migrate across these fibers so that antigen-specific T cells can interact with their cognate antigen on APCs (22, 23). The FRCn fibers are also hollow conduits through which soluble antigen may circulation to gain access to the TZ (24, 25) and, importantly, the fibers also produce the T cell homeostatic cytokine IL-7. Loss of the FRCn significantly reduces IL-7 levels in the TZ (21, 26, 27), which leads to depletion of T cells, making this an important mechanism HsT17436 for CD4+ T cell loss in HIV contamination (28, 29). It is unknown if this process of LN fibrosis leading to lower CD4+ T cell counts occurs with other infections; however, in large population-based studies of HIVC people in East Africa, the average CD4+ T cell count is significantly lower than in Northern European populations (30). For example, in Uganda, the mean CD4+ T cell count is usually 754 cells/mm3 for males and 894 cells/mm3 for females (30), and in Ethiopia the mean CD4+ T cell count, overall, is usually 667 cells/mm3 but in Denmark it is 1,067 cells/mm3 (31). You will find similar studies from other parts of the world that show the same pattern of higher CD4+ RG7112 T cell counts in countries further north than Uganda or in more developed countries (32C34). We reasoned that small CD4+ T cell populations in equatorial locales may be caused by a process similar to the one we explained above for HIV. Constant exposure to endemic infections may lead to chronic IA that could cause TZ fibrosis and damage to the FRCn. This, in turn, would lead to smaller populations of CD4+ and CD8+ T cells and all of their subpopulations. This could have an impact on B cell function for several reasons. T follicular helper (Tfh) cells may become depleted as part of the general loss of CD4+ T cells from LN fibrosis. Also, structural damage to the FRCn could directly impact a humoral response, as it has recently been shown that this FRCn is critical to follicle formation and normal B cell function (35) in that loss of the FRCn prospects to decreased production of B cell activating factor.