A central tenet of immunity is that primary immune responses are carried out in secondary lymphoid organs (SLOs) such as lymph nodes, spleen, and Peyer´s patches. However, in view of the recent characterization of tertiary lymphoid organs (TLOs) in clinically important diseases, this paradigm calls for re-examination. Unlike SLOs, TLOs arise in response to nonresolving diseases at undetermined locations of peripheral tissues. TLO-associated diseases include chronic infection by microbes, graft rejection in transplantation medicine, major types of cancer, and autoimmune and autoimmune-related diseases. One of the shared facets of these diseases is the long-lasting presence of (auto)antigens in territorialized niches of peripheral tissues. Evidence indicates that the immune system utilizes TLOs rather than SLOs to organize and control primary immune responses towards such disease-causing antigens within or close to the antigen-hosting tissue. The cellular constituents of TLOs is abnormal in the sense that it can be distinguished from the composition of immune cells in SLOs: The innate immune cell compartment including macrophages is rather pronounced yielding a chronic unyielding inflammatory environment. Moreover, adaptive immune cells including B and T cells at various stages of differentiation are in a chronic stage of hyperactivation. Cells that are not present in significant numbers in SLOs during a primary immune response such as B-1 cells and plasma cells locate in TLOs. Advanced stages of TLOs are separated into distinct T cell areas and B cell follicles with activated germinal centers and follicular dendritic cells. Newly formed blood vessels, high endothelial venules, lymph vessels, and conduits are major structural features of TLOs. The recent surge in the interest in TLOs follows observations suggesting either protective or detrimental impacts of TLOs in disease progression. Although similarities of SLOs and TLOs are apparent, major differences indicate that TLOs have distinct and controlling roles in disease progression. Identification of these roles may clearly open important hitherto unrecognized windows to understand disease immune pathogenesis and may lead to novel therapeutic approaches. However, major urgent issues of TLO research remain to be addressed. This Research Topic therefore aims at covering the most recent developments in the area of TLO neogenesis and function in an attempt to provide information where this rapidly expanding area is heading: Cellularity of TLOs; the role of mesenchymal immune cell interactions; functional impacts of TLOs in cancer progression; triggers of TLO neogenesis; lymph vessels in TLOs; TLO formation in the gastrointestinal tract; microbial determinants in gastrointestinal tract TLO formation; TLOs in autoimmune diseases; clinical association studies to evaluate impacts of TLOs in disease progression; autoimmune disease-related TLOs; characteristics of TLOs in primary cancers; structural features of TLOs; methodological hurdles to study TLOs; features of lung TLOs; lymphokines and cytokines in TLO neogenesis; distinct developmental cues of SLO and TLO ontogeny; lymphoid tissue organizers and lymphoid tissue inducer cells; TLOs in atherosclerosis; adventitial lymphocytes in human arterial disease; formation of artificial TLOs to impact the immune response.
A central tenet of immunity is that primary immune responses are carried out in secondary lymphoid organs (SLOs) such as lymph nodes, spleen, and Peyer´s patches. However, in view of the recent characterization of tertiary lymphoid organs (TLOs) in clinically important diseases, this paradigm calls for re-examination. Unlike SLOs, TLOs arise in response to nonresolving diseases at undetermined locations of peripheral tissues. TLO-associated diseases include chronic infection by microbes, graft rejection in transplantation medicine, major types of cancer, and autoimmune and autoimmune-related diseases. One of the shared facets of these diseases is the long-lasting presence of (auto)antigens in territorialized niches of peripheral tissues. Evidence indicates that the immune system utilizes TLOs rather than SLOs to organize and control primary immune responses towards such disease-causing antigens within or close to the antigen-hosting tissue. The cellular constituents of TLOs is abnormal in the sense that it can be distinguished from the composition of immune cells in SLOs: The innate immune cell compartment including macrophages is rather pronounced yielding a chronic unyielding inflammatory environment. Moreover, adaptive immune cells including B and T cells at various stages of differentiation are in a chronic stage of hyperactivation. Cells that are not present in significant numbers in SLOs during a primary immune response such as B-1 cells and plasma cells locate in TLOs. Advanced stages of TLOs are separated into distinct T cell areas and B cell follicles with activated germinal centers and follicular dendritic cells. Newly formed blood vessels, high endothelial venules, lymph vessels, and conduits are major structural features of TLOs. The recent surge in the interest in TLOs follows observations suggesting either protective or detrimental impacts of TLOs in disease progression. Although similarities of SLOs and TLOs are apparent, major differences indicate that TLOs have distinct and controlling roles in disease progression. Identification of these roles may clearly open important hitherto unrecognized windows to understand disease immune pathogenesis and may lead to novel therapeutic approaches. However, major urgent issues of TLO research remain to be addressed. This Research Topic therefore aims at covering the most recent developments in the area of TLO neogenesis and function in an attempt to provide information where this rapidly expanding area is heading: Cellularity of TLOs; the role of mesenchymal immune cell interactions; functional impacts of TLOs in cancer progression; triggers of TLO neogenesis; lymph vessels in TLOs; TLO formation in the gastrointestinal tract; microbial determinants in gastrointestinal tract TLO formation; TLOs in autoimmune diseases; clinical association studies to evaluate impacts of TLOs in disease progression; autoimmune disease-related TLOs; characteristics of TLOs in primary cancers; structural features of TLOs; methodological hurdles to study TLOs; features of lung TLOs; lymphokines and cytokines in TLO neogenesis; distinct developmental cues of SLO and TLO ontogeny; lymphoid tissue organizers and lymphoid tissue inducer cells; TLOs in atherosclerosis; adventitial lymphocytes in human arterial disease; formation of artificial TLOs to impact the immune response.