Mounting evidence points to the germinal center (GC) reaction as a site where not only novel specificities are made to foreign pathogens through affinity maturation of B cells and antibodies, but potentially to self-antigen as well, particularly in autoimmune-prone hosts. This is not surprising considering that along with the generation of IgG antibodies, novel mutations, particularly base pair substitutions are made by the Activation-induced deaminase, AID, in GC's in a generally random fashion. While this somatic hypermutation mechanism (SHM) targets the genomic region encoding the variable portion of immunoglobulin receptors and antibodies, with some predilection for microsequences, it generally impacts most of the variable region. Evidence suggests that this randomness in SHM occasionally leads to incidental amino acid replacements that enhance autoreactivity.
This appears to be the case in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis , and other systemic autoimmune disorders. For example, mutations associated with SHM in GC’s are known to enhance autoreactivity of class switched antibodies in SLE, and deletion of AID is associated with a dramatic reduction in glomerulonephritis. In addition, new evidence is emerging that key residues or epitopes needed for neutralization of certain viruses, like HIV-1, may conflict with negative selection against autoreactivity creating a "tug of war" between affinity maturation and negative selection or tolerance in GC’s. This conflict may limit immune responses to some viruses. It is also possible that during acute infection or in immunocompromised individuals, a permissive environment may select for autoreactive or polyreactive lymphocytes to participate in the response. In this edition, we will explore the evidence for conflicted selection in GC's, the environments that alter tolerance thresholds in GC’s and the role this “tug of war” may play in limiting antibody responses to important pathogens.
The scope of the Research Topic is to summarize our understanding of the tolerance process and thresholds in Germinal Centers and how they may impact the development of immune responses to various pathogens. The processes that are relevant to this topic include tolerance mechanisms in GC’s, immune responses to HIV and other pathogens, the contribution of somatic hypermutation, and class-switch recombination to autoimmunity, and the role of inflammation and local factors in promoting autoimmune B and T cell responses during infection. This Research Topic welcomes the submission of manuscripts focusing on, but not limited to:
• Somatic Hypermutation and autoimmunity
• The mechanisms governing tolerance checkpoints in Germinal Centers both in recruitment to GC’s and selection into the memory compartment
• The role of autoreactive B and T cells in promoting or limiting immune responses to HIV-1 and other pathogens
• Ways to overcome conflicted selection in GC’s between tolerance and affinity maturation
Mounting evidence points to the germinal center (GC) reaction as a site where not only novel specificities are made to foreign pathogens through affinity maturation of B cells and antibodies, but potentially to self-antigen as well, particularly in autoimmune-prone hosts. This is not surprising considering that along with the generation of IgG antibodies, novel mutations, particularly base pair substitutions are made by the Activation-induced deaminase, AID, in GC's in a generally random fashion. While this somatic hypermutation mechanism (SHM) targets the genomic region encoding the variable portion of immunoglobulin receptors and antibodies, with some predilection for microsequences, it generally impacts most of the variable region. Evidence suggests that this randomness in SHM occasionally leads to incidental amino acid replacements that enhance autoreactivity.
This appears to be the case in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis , and other systemic autoimmune disorders. For example, mutations associated with SHM in GC’s are known to enhance autoreactivity of class switched antibodies in SLE, and deletion of AID is associated with a dramatic reduction in glomerulonephritis. In addition, new evidence is emerging that key residues or epitopes needed for neutralization of certain viruses, like HIV-1, may conflict with negative selection against autoreactivity creating a "tug of war" between affinity maturation and negative selection or tolerance in GC’s. This conflict may limit immune responses to some viruses. It is also possible that during acute infection or in immunocompromised individuals, a permissive environment may select for autoreactive or polyreactive lymphocytes to participate in the response. In this edition, we will explore the evidence for conflicted selection in GC's, the environments that alter tolerance thresholds in GC’s and the role this “tug of war” may play in limiting antibody responses to important pathogens.
The scope of the Research Topic is to summarize our understanding of the tolerance process and thresholds in Germinal Centers and how they may impact the development of immune responses to various pathogens. The processes that are relevant to this topic include tolerance mechanisms in GC’s, immune responses to HIV and other pathogens, the contribution of somatic hypermutation, and class-switch recombination to autoimmunity, and the role of inflammation and local factors in promoting autoimmune B and T cell responses during infection. This Research Topic welcomes the submission of manuscripts focusing on, but not limited to:
• Somatic Hypermutation and autoimmunity
• The mechanisms governing tolerance checkpoints in Germinal Centers both in recruitment to GC’s and selection into the memory compartment
• The role of autoreactive B and T cells in promoting or limiting immune responses to HIV-1 and other pathogens
• Ways to overcome conflicted selection in GC’s between tolerance and affinity maturation
