Scientific Papers

Three-dimensional human germinal centers of different sizes in patients diagnosed with lymphadenitis show comparative constant relative volumes of B cells, T cells, follicular dendritic cells, and macrophages

There are about 600 lymph nodes in the human body that filter antigens carried by the lymph. Lymph nodes concentrate immune cells in strategic areas to generate immune responses to tumors or pathogens, including bacteria and viruses. These lymph nodes are divided into various compartments. One such compartment is the medulla, comprising sinuses and medullary cords, which house plasma cells and macrophages. Near the cortex, the T cell-rich paracortex is characterized by high endothelial venules (HEVs), which enable lymphocytes to enter the lymph node. The cortex is subcapsular and represents the B cell zone, where germinal centers are found.

Germinal centers (GCs) are ball-like structures that form a response to antigens in lymph nodes and extranodal tissue. These structures, which are essential to humoral immunity, comprise both dark and light zones (Nieuwenhuis and Opstelten, 1984). The dark zone (DZ) contains B cells that perform polyclonal expansion and somatic hypermutation of their variable immunoglobulin genes, resulting in clones and subclones of the B cells (Nieuwenhuis and Opstelten, 1984, Jacob et al., 1991, Küppers et al., 1993, MacLennan, 1994). In the light zone (LZ), B cells undergo selection for antigens according to the amounts and concentrations of immune complex-bound antigens on follicular dendritic cells (FDCs) during affinity maturation (Tew et al., 1980, Berek et al., 1991, MacLennan, 1994). T cells, macrophages, and a small number of bone marrow-derived dendritic cells (cDCs) are found in GCs (Grouard et al., 1996). CXCL12-expressing reticular cells (CRCs) have been found in mice’s GC DZs’ lymphoid tissue, including lymph nodes (Bannard et al., 2013, Rodda et al., 2015).

In addition to FDCs and B cells, T cells play an important role in affinity-based B cell selection and GC maintenance (Victora and Nussenzweig, 2012). During somatic hypermutation and affinity maturation, B cells are selected based on the affinity of their B cell receptors to antigens (Mesin et al., 2016). Positively selected B cells differentiate into memory B cells and plasma cells for antibody production (MacLennan, 1994). Negatively selected B cells are eliminated by tingible body macrophages (TBMs) (Fliedner, 1967).

In recent decades, researchers have achieved far greater knowledge about GCs. However, cellular proportions of cell types and the evolution of these proportions during immune reactions in human GCs have yet to be properly investigated. Identifying potential changes in both quantitative and qualitative composition may aid researchers in achieving a comprehensive understanding of the proliferation of GCs and, in turn, GC dynamics. Such an understanding could lead to a new approach to analyzing GC malignancies, such as follicular lymphoma (FL). Our 3D investigation entails a qualitative evaluation of immunostaining; it visualizes volumes of 3D cell composition to discern morphology rules and stainability differences, which may be realized more effectively than in a 2D investigation.

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