Abstract
Human anti-IgG hinge (HAH) autoantibodies constitute a class of immunoglobulins that recognize cryptic epitopes in the hinge region of antibodies exposed after proteolytic cleavage, but do not bind to the intact IgG counterpart. Detailed molecular characterizations of HAH autoantibodies suggest that they are, in some cases, distinct from natural autoantibodies that arise independent of antigenic challenge. Multiple studies have attempted to define the specificity of HAH autoantibodies, which were originally detected as binding to fragments possessing C-terminal amino acid residues exposed in either the upper or lower hinge regions of IgGs. Numerous investigators have provided information on the isotype profiles of the HAH autoantibodies, as well as correlations among protease cleavage patterns and HAH autoantibody reactivity. Several biological functions have been attributed to HAH autoantibodies, ranging from house-cleaning functions to an immunosuppressive role to restoring function to cleaved IgGs. In this review, we discuss both the historic and current literature regarding HAH autoantibodies in terms of their origins, specificity, and proposed biological relevance.
Highlights
A long-standing question in immunology is how individuals are capable of generating a very broad range of diversity against foreign antigens, while at the same time eliminating reactivity against self-antigens
The mechanism that results in the production of Human anti-IgG hinge (HAH) autoantibodies is not entirely clear and any association with chronological age has not been studied to our knowledge
The existence of autoantibodies that bind to cryptic epitopes exposed by proteolysis of the IgG hinge region has been appreciated for some time, the origin and biological relevance of HAH autoantibodies remains unclear
Summary
A long-standing question in immunology is how individuals are capable of generating a very broad range of diversity against foreign antigens, while at the same time eliminating reactivity against self-antigens. Many of the selfreactive BCRs recognized antigens from the nucleus[18] Most of these self-reactive B cells were eliminated in the bone marrow by the first tolerance checkpoint. One process that contributes to humoral memory is class-switch recombination, whereby the immunoglobulin constant regions switch to other immunoglobulin isotypes, such as IgG Another process is somatic hypermutation, which entails introduction of random gene modifications within the IgHC and IgLC variable regions. A recent study has indicated that a significant increase in self-reactive IgG+ memory B cells emerge out of an immune response, suggesting that de novo autoreactive B cells can result from the process of somatic hypermutation[28]
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