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Intestinal IgA synthesis: regulation of front-line body defences

Key Points

  • Intestinal immunoglobulin A (IgA)+ plasma cells are derived from conventional B2 cells located in the Peyer's patches or isolated lymphoid follicles of the gut, and from B1 cells, which reside in the body cavities, in particular the peritoneal cavity.

  • CCL25 is produced by the small intestine epithelium and specifically attracts IgA-committed B cells derived from conventional B2 cells.

  • The presence of IgM+ B cells and IgA+ plasma cells in the gut depends on interactions between lymphotoxin (LT) and LTβ receptor, which are present on lymphocytes and lamina-propria stromal cells, respectively.

  • IgM+ B cells switch to IgA+ B cells and differentiate to IgA+ plasma cells in situ in the lamina propria, with the help of local dendritic cells and stromal cells.

  • The presence of somatically mutated IgAs is essential for the maintenance of gut homeostasis. AID-deficient mice develop hyperplasia of isolated lymphoid follicles, which is triggered by a large increase in the number of anaerobic bacteria in the small intestine.

  • Dysregulation of the gut flora causes activation of all the immune systems of the body.

Abstract

Immunoglobulin A is the most abundant immunoglobulin isotype in mucosal secretions. In this review, we summarize recent advances in our understanding of the sites, mechanisms and functions of intestinal IgA synthesis in mice. On the basis of these recent findings, we propose an updated model for the induction and regulation of IgA responses in the gut. In addition, we discuss new insights into the role of IgA in the maintenance of gut homeostasis and into the reciprocal interactions between gut B cells and the bacterial flora.

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Figure 1: Gut-associated lymphoid tissue.
Figure 2: Lamina-propria lymphoid cells in normal and AID-deficient mice.
Figure 3: Possible pathways for the induction of IgA responses in the gut lamina propria.
Figure 4: AID deficiency leads to hyperplasia of isolated lymphoid follicles in the gut lamina propria.

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Acknowledgements

This study was supported in part by a Center of Excellence Grant from the Ministry of Education, Science, Sports and Culture of Japan. We thank Y. Doi, K. Kinoshita, M. Muramatsu, H. Nagaoka and K. Suzuki for their contributions to both the work cited and the writing of this manuscript. Because of the extent and complexity of the mucosal immunology field, we could not discuss many interesting studies, and we apologize to those excellent scientists whose work could not be cited.

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Correspondence to Tasuku Honjo.

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DATABASES

LocusLink

α4β7

AID

APRIL

BAFF

BAFFR

BCMA

CCL25

CCR9

CD40

claudin 1

CXCL13

IFN-α

IFN-γ

IL-2

IL-2R

IL-4

IL-5

IL-6

IL-10

LTα

LTβR

MADCAM1

Nik

occludin

pIgR

Rag2

TACI

TGF-β

TNF

zona occludens 1

OMIM

CVID

Gardner syndrome

FURTHER INFORMATION

Tasuku Honjo's lab

Glossary

J CHAIN

A polypeptide produced by immunocytes that is essential for the polymerization of immunoglobulin A and IgM, which is required for binding to the polymeric-immunoglobulin receptor and transport through epithelia.

B2 CELLS

IgMlowIgDhiMac1B220hiCD23+ cells that are produced continuously in adult bone marrow and secrete antibodies with high affinity and fine specificity.

CLASS-SWITCH RECOMBINATION

(CSR). Alters the immunoglobulin heavy-chain constant-region (CH) gene that will be expressed from the Cμ region to one of the other CH genes. This results in a switch of immunoglobulin isotype from IgM/IgD to IgG, IgA or IgE, without altering antigen specificity.

SOMATIC HYPERMUTATION

(SHM). Results in the accumulation of point mutations in the variable-region genes of immunoglobulin heavy and light chains. B cells that express high-affinity immunoglobulins on their surface are selected by limited amounts of the antigens, giving rise to high-affinity antibodies.

B1 CELLS

Self-renewing IgMhiIgDlowMac1+B220loCD23 cells that are dominant in the peritoneal and pleural cavities. B1 cells recognize self-components, as well as common bacterial antigens, and they secrete antibodies that tend to have low affinity and broad specificity.

NATURAL IgMS

These antibodies normally circulate in the blood of non-immunized mice. They are highly cross-reactive, and bind with low affinity to both microbial and self-antigens. A large proportion of natural IgMs is derived from peritoneal B1 cells.

OMENTUM

A bilayered sheet of mesothelial cells connecting the spleen, pancreas, stomach and transverse colon, terminating in an 'apron-like' structure that contains adipocytes.

M CELLS

(Microfold cells). Specialized epithelial cells that deliver antigens by transepithelial vesicular transport from the gut lumen directly to intraepithelial lymphocytes and to subepithelial lymphoid tissues.

COMMON VARIABLE IMMUNODEFICIENCY SYNDROME

(CVID). The most common symptomatic primary antibody deficiency, characterized by decreased levels of serum immunoglobulin. Most patients suffer from recurrent infections, predominantly of the respiratory and gastrointestinal tracts. The incidence of malignancies, such as gastric carcinoma or lymphoma, is increased in patients with CVID.

INTUSSUSCEPTION

The telescoping or prolapse of one portion of the intestine into an immediately adjacent segment.

μMT−/− MICE

These mice carry a stop codon in the first membrane exon of the μ-chain constant region. They lack IgM+ B cells, and B-cell development is arrested at the pre-B-cell stage.

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Fagarasan, S., Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nat Rev Immunol 3, 63–72 (2003). https://doi.org/10.1038/nri982

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