Lymphoid follicle and germinal centre

Folliculus lymphoideus

Also known as: lymphoid nodule, lymphatic nodule, germinal centre, germinal center, primary follicle, secondary follicle

Spherical B-cell aggregates found in all secondary lymphoid tissues; after antigen stimulation they develop a pale germinal centre where B cells proliferate, mutate their antibody genes and are selected for high affinity.

Overview

A primary follicle is a dense ball of small, naive, recirculating B cells (IgM⁺ IgD⁺) held on a network of follicular dendritic cells (FDCs), which secrete the chemokine CXCL13. When a T-dependent antigen arrives, activated B cells that have received help from T cells at the follicle edge migrate into the follicle centre and proliferate explosively, forming a secondary follicle: a pale germinal centre surrounded by a dark mantle zone of displaced naive B cells (and, in the spleen and MALT, an outer marginal zone). Germinal centres appear about a week after immunisation.

The germinal centre is polarised. In the dark zone, large dividing centroblasts undergo somatic hypermutation of their immunoglobulin variable-region genes, driven by the enzyme activation-induced cytidine deaminase (AID). They then move to the light zone as centrocytes, where they compete to bind antigen held as immune complexes on FDCs and to present it to follicular helper T cells (Tfh). Cells whose mutated receptors bind best receive CD40L and IL-21 help and survive; the rest die by apoptosis and are cleared by tingible-body macrophages. Repeated cycles produce affinity maturation; AID also drives class-switch recombination (IgM → IgG, IgA or IgE).

The products are long-lived plasma cells, which home to the bone marrow and secrete high-affinity antibody for years, and memory B cells.

Location

Outer cortex of lymph nodes; splenic white pulp; tonsils, Peyer patches, appendix and other MALT; ectopic (tertiary) follicles in chronically inflamed tissues (e.g. Hashimoto thyroiditis, rheumatoid synovium, H. pylori gastritis).

Parts & subdivisions

Follicular dendritic cells

Stromal (non-haematopoietic) cells that retain intact antigen as immune complexes via complement receptors (CR1/CR2) and Fc receptors for B-cell selection. Unlike conventional dendritic cells, they do not present peptide on MHC.

Dark zone

Centroblasts: rapid proliferation and somatic hypermutation.

Light zone

Centrocytes, FDCs and Tfh cells: selection of high-affinity B cells.

Mantle zone

Rim of small naive B cells surrounding the germinal centre; origin of mantle cell lymphoma.

Marginal zone

Outer zone (prominent in spleen) of B cells responding rapidly to blood-borne polysaccharide antigens.

Follicular helper T cells

CXCR5⁺ Bcl-6⁺ CD4 T cells providing CD40L and IL-21.

Tingible-body macrophages

Macrophages containing apoptotic B-cell debris — a hallmark of reactive germinal centres.

Function

Concentrate naive B cells where they can encounter antigen.

Generate high-affinity, class-switched antibody through somatic hypermutation and selection (affinity maturation).

Produce long-lived plasma cells and memory B cells.

Physiology

Germinal centres form ≈ 1 week after T-dependent antigen exposure and persist for weeks. Somatic hypermutation occurs at a rate about a million times higher than the background mutation rate. T-independent antigens (e.g. bacterial polysaccharides) generate little germinal-centre activity, so they induce mainly low-affinity IgM and poor memory — the reason for conjugate vaccines.

Clinical significance

Follicular lymphoma vs reactive hyperplasia

Follicular lymphoma, driven by t(14;18) placing BCL2 next to the immunoglobulin heavy-chain gene, produces crowded back-to-back follicles that lack polarity and tingible-body macrophages and are BCL2-positive — reactive germinal-centre B cells are BCL2-negative because they depend on selection to survive.

Hyper-IgM syndrome

X-linked CD40-ligand deficiency (or AID deficiency) prevents germinal-centre formation and class switching: normal or high IgM but very low IgG, IgA and IgE, with recurrent pyogenic and opportunistic (Pneumocystis) infections.