December 4, 2022

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SEMIN IMMUNOPATHOL: IgA-induced immune landscape in the gut

SEMIN IMMUNOPATHOL: IgA-induced immune landscape in the gut



 

SEMIN IMMUNOPATHOL: IgA-induced immune landscape in the gut

Antibodies are a key element of protective immunity. Especially in the mucosal immune system, secretory immunoglobulin A (SIgA) is the most abundant antibody isotype, which can prevent infections and protect the mucosal surface from toxins and the environment.

The influence of factors, and can regulate immune homeostasis and coexist peacefully with the human microbiota.

 

It can regulate immune homeostasis and coexist peacefully with the human microbiota. However, the dark side of immunoglobulin A (IgA) biology can promote the formation of immune complexes and cause pathology, such as IgA nephropathy (IgAN) .

 

IgAN is characterized by mesangial deposits of IgA-containing immune complexes. IgA deposits continue to recur in IgAN patients undergoing kidney transplantation and are transplanted from IgAN donors (with renal IgA immune complexes) to non-IgAN recipients.

Later, these deposits usually subside, indicating that the main defect of IgAN may not be in the kidney itself but in the IgA system .

 

SEMIN IMMUNOPATHOL: IgA-induced immune landscape in the gut

Image source: https://doi.org/10.1007/s00281-021-00879-4

 

In the field of nephrology, since some scholars described IgAN in 1968, people have developed a special interest in IgA. However, the research centered on IgA has not been promoted together, but followed in mucosal immunology and nephrology. Mostly independent pathways.

Therefore, the researchers suggest that strengthening cooperation between the two fields will help to understand IgAN more comprehensively.

The research provides a comprehensive and consistent framework for IgA biology in mucosal tissues and peripheral organs (including kidneys).

 

SEMIN IMMUNOPATHOL: IgA-induced immune landscape in the gut

Picture source of the structure of human immunoglobulin (Ig): https://doi.org/10.1007/s00281-021-00879-4

 

IgA is secreted by class-switched plasma cells and displays the basic core structure shared by all human Igs. Two identical heavy chains are covalently linked to two identical light chains, and each heavy/light chain pair forms an antibody specific antigen binding Fragment (Fab) arm.

In humans (but not mice), there are two IgA isotypes, IgA1 and IgA2. IgA1 and IgA2 have different representations in different compartments and have different characteristics. The main structural differences between IgA1 and IgA2 It lies in their hinge region, which is a small stretch of loosely structured amino acids that connect the antibody Fab and the crystallizable fragment (Fc).

In IgA2, this hinge region is 16 amino acids shorter than IgA1 and lacks oxygen atom (O)-linked glycans.

The shorter length of the hinge region reduces the sensitivity of IgA2 to proteolytic cleavage, which may increase IgA2 in the colonic microbiota. Stability in dense and highly proteolytic environments.

The study found that IgA in patients with IgAN showed abnormal glycosylation, that is, the modification of IgA-linked glycans and galactose was reduced, and there was a lower proportion of β-1,3-galactosidic bonds and sialylation, while IgA More terminal N-acetylgalactosamine (GAlNac) in the hinge is exposed and can be detected by binding to GalNac-specific lectins .

 

SEMIN IMMUNOPATHOL: IgA-induced immune landscape in the gut

Image source of immunoanatomy of IgA response: https://doi.org/10.1007/s00281-021-00879-4

 

The intestinal immune system includes an effector site and an induction site. The effector site is the intestinal epithelium that mediates the barrier function and transepithelial IgA transport, and then the underlying lamina propria. In addition to other immune cell populations, it also includes IgA-secreting plasma.

Cells, and induction sites include intestinal associated lymphoid tissue (GALT) and intestinal draining mesenteric lymph nodes. Regarding the induction of IgA response, the main GALT compartments are Pyle’s node (PP), worm-like appendix and isolated lymphoid follicle (ILF), and mesenteric lymph nodes are thought to play a secondary role in IgA response.

The area between the PP follicle and the epithelium is called the subepithelial dome (SED), and the epithelium that separates PPSED from the intestinal lumen is called follicular-associated epithelium (FAE). FAE is a special kind of epithelial cells that can directly pass from the intestinal lumen.

Collect antigens, and PP relies on homologous interactions, leukocyte differentiation antigen 40 and its ligands (CD40-CD40L) interactions and the germinal center (GC) cytokine environment that is conducive to antibody production, making the typical T cell dependent ( TD) IgA reaction becomes possible.

In addition, T cells similar to follicular helper T cells are located in SED and promote B cell expansion in the pre-GC stage .

 

There are still many unknowns in the intestinal IgA system, as is the pathogenesis of IgAN. The basic defects of IgAN seem to be related to changes in the IgA system (rather than the kidney).

However, elevated IgA levels are not pathogenic in themselves, and the properties of serum IgA and IgA-containing immune complexes in patients with IgAN are different from those of ordinary intestines. Road IgA reaction.

In the field of IgAN research, abnormal glycosylation has long been recognized and may drive changes in the physical, chemical and immunological properties of IgA. Abnormal glycosylation may also support the formation of IgA-containing immune complexes and IgA deposits in the kidney.

In the future, mucosa Immunologists may contribute to the understanding of IgAN by helping to identify the anatomical, cellular, and molecular pathways that drive the abnormal IgA response in IgAN. 

 

References

Claudia Seikrit et al. The immune landscape of IgA induction in the gut. SEMINARS IN IMMUNOPATHOLOGY(2021 Aug 11) doi:https://doi.org/10.1007/s00281-021-00879-4

SEMIN IMMUNOPATHOL: IgA-induced immune landscape in the gut

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