Germinal centers (GCs) are ephemeral, multicellular organized structures that form in the secondary lymphoid organs in response to invading pathogen. Activated B-cells that participate in the establishment of this dynamic microenvironment leverage it to generate specific and high-affinity antibodies necessary to establish an effective humoral immune response. Two mechanisms specific to the GC B lymphocyte that target the B cell receptor (BCR) genes are mobilized to achieve this (i) Somatic hypermutation that induce high numbers of random point mutations in the variable region of the BCR and (ii) class switch recombination (CSR) which is a DNA rearrangement reaction allowing replacement of the constant region of the IgM heavy chain with one of the alternative isotype (IgG, IgA or IgE) in order to enhance the capability of antigen specific antibodies to effectively dispose of the pathogens. Of course, the differentiation of B cells into antibody secreting cells needs highly organized genetic and epigenetic modifications that sustain this cell metamorphosis.
The success of the GC reaction involves several other cellular mechanisms including extensive cell proliferation, trafficking, and differentiation, all of which rely on cell contact and communication with the other cell types within the structure. All these events are orchestrated by a plethora of factors and tightly regulated in order to limit both genomic instability and to enforce self-tolerance by avoiding the emergence of autoreactive B-cell clones. The functional output of GCs results from the differentiation and exit of long-lived antibody secreting plasma cells and long-lasting memory B-cells that provide protection against reinfection. Besides these classical GC which appear in the secondary lymphoid organs following an immunization, two other GC-like structures can arise spontaneously in the absence of any obvious infection with different outcomes. First, in patients with autoimmune disease such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune lymphoproliferative syndrome or Type 1 Diabetes, these ectopic GC-like structures are thought to be involved in promoting or driving the disease through the development of mutated and class switched pathogenic autoantibodies. Second, several recent studies have shown the presence GC-like structures within tumor environments. The presence of these spontaneous GCs is now considered a key event in predicting response to immunotherapy. Indeed, the presence of activated B-cells in mature tertiary lymphoid structures that harbor GCs is associated with better outcomes and increased patient survival.
In this Research Topic, we aim to gather a series of articles that discuss the key events involved in the initiation of and the implementation of GC structure and function during the humoral immune response. We also wish to explore the establishment of multicellular structures, resembling GCs, that can either promote pathogenesis in the case of autoimmune disease or promote an efficient immune response during tumor treatment.
We seek Original Research, Review, Mini-Review, Hypothesis and Theory, Clinical Trial and Opinion articles that cover, but are not limited to, the following subjects:
- Temporal and spatial regulation of GC reactions
- Signals and factors that direct terminal B differentiation (Plasma cells and memory B-cells)
- B cell modifications sustaining antibody secreting capacities: ER stress, vesicles trafficking, energy/metabolism adaptation
- Immunoglobulin gene diversifications: physiology and B-cell neoplasia
- Role of the microenvironment: input of Non-B GC-cells
- B-cell tolerance mechanisms within GC
- Novel experimental approaches and modeling to study the GC reaction
- Emergence of ectopic GC structures during inflammation and its role in autoimmunity
- Appearance of tertiary lymphoid structures (GC like) within tumor microenvironments: role, similarities and differences with a classical GC structure
Germinal centers (GCs) are ephemeral, multicellular organized structures that form in the secondary lymphoid organs in response to invading pathogen. Activated B-cells that participate in the establishment of this dynamic microenvironment leverage it to generate specific and high-affinity antibodies necessary to establish an effective humoral immune response. Two mechanisms specific to the GC B lymphocyte that target the B cell receptor (BCR) genes are mobilized to achieve this (i) Somatic hypermutation that induce high numbers of random point mutations in the variable region of the BCR and (ii) class switch recombination (CSR) which is a DNA rearrangement reaction allowing replacement of the constant region of the IgM heavy chain with one of the alternative isotype (IgG, IgA or IgE) in order to enhance the capability of antigen specific antibodies to effectively dispose of the pathogens. Of course, the differentiation of B cells into antibody secreting cells needs highly organized genetic and epigenetic modifications that sustain this cell metamorphosis.
The success of the GC reaction involves several other cellular mechanisms including extensive cell proliferation, trafficking, and differentiation, all of which rely on cell contact and communication with the other cell types within the structure. All these events are orchestrated by a plethora of factors and tightly regulated in order to limit both genomic instability and to enforce self-tolerance by avoiding the emergence of autoreactive B-cell clones. The functional output of GCs results from the differentiation and exit of long-lived antibody secreting plasma cells and long-lasting memory B-cells that provide protection against reinfection. Besides these classical GC which appear in the secondary lymphoid organs following an immunization, two other GC-like structures can arise spontaneously in the absence of any obvious infection with different outcomes. First, in patients with autoimmune disease such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune lymphoproliferative syndrome or Type 1 Diabetes, these ectopic GC-like structures are thought to be involved in promoting or driving the disease through the development of mutated and class switched pathogenic autoantibodies. Second, several recent studies have shown the presence GC-like structures within tumor environments. The presence of these spontaneous GCs is now considered a key event in predicting response to immunotherapy. Indeed, the presence of activated B-cells in mature tertiary lymphoid structures that harbor GCs is associated with better outcomes and increased patient survival.
In this Research Topic, we aim to gather a series of articles that discuss the key events involved in the initiation of and the implementation of GC structure and function during the humoral immune response. We also wish to explore the establishment of multicellular structures, resembling GCs, that can either promote pathogenesis in the case of autoimmune disease or promote an efficient immune response during tumor treatment.
We seek Original Research, Review, Mini-Review, Hypothesis and Theory, Clinical Trial and Opinion articles that cover, but are not limited to, the following subjects:
- Temporal and spatial regulation of GC reactions
- Signals and factors that direct terminal B differentiation (Plasma cells and memory B-cells)
- B cell modifications sustaining antibody secreting capacities: ER stress, vesicles trafficking, energy/metabolism adaptation
- Immunoglobulin gene diversifications: physiology and B-cell neoplasia
- Role of the microenvironment: input of Non-B GC-cells
- B-cell tolerance mechanisms within GC
- Novel experimental approaches and modeling to study the GC reaction
- Emergence of ectopic GC structures during inflammation and its role in autoimmunity
- Appearance of tertiary lymphoid structures (GC like) within tumor microenvironments: role, similarities and differences with a classical GC structure