Is defective lymphatic drainage a trigger for lymphoid neogenesis?

The progressive organization of cellular infiltrates into functional ectopic germinal centers (i.e. lymphoid neogenesis) has been recently evidenced in various chronic inflammatory diseases. Failure of the immune system to eradicate the targeted antigen(s) is a shared feature of all of the pathological situations associated with lymphoid neogenesis. Although necessary, inability of the immune system to eradicate the antigen(s) seems insufficient to trigger lymphoid neogenesis by itself. We propose that both defective lymphatic drainage of the inflamed tissue and enduring local antigenic stimulation are the crucial triggers of the cascade of events leading to lymphoid neogenesis. In turn, ectopic germinal centers prevent the restoration of lymph outflow by diverting inflammation-dependent lymphangiogenesis. Antigens and immune effectors are rerouted towards the neoformed ectopic lymphoid structures. A self-perpetuating feedback loop, which further sustains the development of the local immune response, is now imposed.

Introduction

The task of the immune system is to protect the host from a wide range of invading pathogens and from malignancies. To meet this challenge, an adaptive immune system has emerged through evolution, based on an array of T cells and B cells, each expressing a unique receptor for a particular antigen. Because these receptors have to display a gigantic diversity to confront the wide spectrum of potential antigens, and because the size of the lymphocyte population is limited by immune homeostasis, only a small number of lymphocytes share the same antigen specificity. Meanwhile, the expanse of environmental interfaces makes the continual representation of all clones, at all potential sites of antigen display impossible. Instead, the generation of protective immune responses relies on specialized tissues – that is, secondary lymphoid organs – where the antigen and the rare lymphocytes bearing appropriate receptors are gathered in three-dimensional structures, providing appropriate conditions for the antigen-driven clonal expansion and the differentiation of the responding clones. The architecture of these secondary organs is characterized by an elaborate system of circulation for antigens and cells 1, 2, 3. On the one hand, the afferent lymphatics that drain lymph and collect antigens and antigen-loaded antigen-presenting cells from most tissues of the body end in lymph nodes, the prototypic secondary lymphoid organ (Figure 1a,b). On the other hand, the naive T and B cells enter lymph nodes via high endothelial venules 4, 5, 6, a unique vascular adaptation of secondary lymphoid organs designed to recruit lymphocytes from the blood with high efficiency. Inside the secondary lymphoid organs, naive T and B cells home to distinct compartments: the T-cell areas and the B-cell follicles. They remain in their compartments for several hours and then leave the lymph nodes via efferent lymphatics, unless they are held back by their specific antigens. The antigen-specific interaction that occurs at the interface of the T- and B-cell zones initiates germinal center (GC) reactions (Figure 1b). After migrating into the network of follicular dendritic cells, B cells proliferate 7, 8, 9 and revise their antigen receptors through somatic hypermutation of IgV region genes. This process generates antibodies with a higher or lower affinity to the corresponding antigen. Newly generated antibody mutants are then selected 10, 11 on the basis of their ability to bind their cognate antigen with the help of follicular dendritic cells and T cells. A large fraction of B cells undergoes apoptosis as a result of having acquired deleterious somatic mutations in their IgV regions that abolish antigen binding, whereas B cells expressing high-affinity antibody mutants eventually differentiate into plasma cells or memory B cells. Some B cells also switch from expression of IgM and IgD to that of other Ig classes by somatic DNA recombination to generate antibodies with different effector functions [12]. The GC reaction of antigen-activated B cells is thought to be the hallmark of antibody-mediated immune responses to T-cell-dependent antigens, and individuals with genetic defects impairing GC formation suffer from immune incompetence.

Surprisingly, growing evidence suggests that GC reactions can take place outside specialized secondary lymphoid organs. Indeed, chronic inflammatory infiltrates within nonlymphoid organs can organize themselves into local functional ectopic GCs. This process, known as lymphoid neogenesis [13], has been evidenced in various experimental and clinical situations, such as chronic infectious diseases, autoimmune diseases and neoplasia 14, 15.