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  • Review Article
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New concepts in the generation and functions of IgA

Key Points

  • IgA accounts for more than two-thirds of the body's total immunoglobulin production. IgA serves as an important first-line barrier limiting the access of intestinal antigens to the gut mucosa, controls the intestinal microbiota and dampens pro-inflammatory immune responses.

  • IgA induction is supported by several anatomical and cellular pathways. Such alternative pathways might ensure robustness of the IgA response, but their actual contribution to overall IgA production is controversially discussed.

  • Some plasma cells can stay for prolonged time periods in the gut lamina propria. Plasma cell longevity might depend on dedicated survival niches and the local cytokine milieu.

  • IgA sequencing has revealed high numbers of normally distributed somatic mutations and a composite nature of the IgA repertoire, which comprises highly expanded clones along with less frequent clones. These results question the contribution of natural IgA and T cell-independent pathways of IgA induction to overall IgA production.

  • Control of the microbiota requires mutated IgA. I propose a tentative model to describe the generation of highly mutated IgA repertoires driven by pathogens and commensal microbiota.

  • The IgA system is tightly integrated with other innate and adaptive immune mechanisms, which act in concert to ensure homeostasis.

Abstract

The intestinal mucosa contains the largest population of antibody-secreting plasma cells in the body, and in humans several grams of secretory immunoglobulin A (SIgA) are released into the intestine each day. In the gut lumen, SIgA serves as a first-line barrier that protects the epithelium from pathogens and toxins. Recently, next-generation sequencing has revolutionized our understanding of the nature of the intestinal microbiota and has also shed new light on the important roles of SIgA in the regulation of host–commensal homeostasis. Here, I discuss pathways of IgA induction in the context of SIgA specificity and function.

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Figure 1: The cytokine micromilieu in the lamina propria may enable plasma cell survival.
Figure 2: Organization of IgA induction.
Figure 3: T cell-independent induction of IgA in isolated lymphoid follicles and in the lamina propria.
Figure 4: Alternative models to describe the quality of SIgA responses to pathogens and commensals.

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Acknowledgements

I thank N. Lycke, G. Bernhardt, A. Krueger, H. Herbrand, O. Schulz, I. Prinz and C. Lindner for discussion of the manuscript. This work was supported by Deutsche Forschungsgemeinschaft grant SFB621-TPA11 (to O.P.).

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Glossary

IgA

IgA is the major immuno- globulin isotype in humans, and its production exceeds that of all other immunoglobulin classes combined. In humans, IgA exists in two subclasses, IgA1 and IgA2, that differ in their heavy chains. IgA1 is the predominant subclass in serum, whereas IgA2 is produced along with IgA1 in the small intestine and dominates in the colon.

Secretory component

The secretory component exists in three forms: the membrane secretory component, which is identical to the polymeric immunoglobulin receptor; bound secretory component, which is part of secretory IgA and IgM; and free secretory component, which is the cleaved part of the polymeric immunoglobulin receptor when it is not bound to immunoglobulins.

Gnotobiotic mouse models

Germ-free mice are born and raised in sterile isolators and are devoid of colonization by any microorganisms. Following selective colonization by defined bacteria, these mice are said to be gnotobiotic and are kept in isolators to control their bacterial colonization status.

Germinal centres

Specialized microenvironments in lymph nodes and other peripheral lymphoid follicles that give rise to secondary B cell follicles. During an immune response, germinal centres develop dynamically following B cell activation by a T cell-dependent antigen. Germinal centres are the main site of mature B cell proliferation and differentiation, as well as of antibody class-switch recombination and somatic hypermutation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibodies.

Gut-associated lymphoid tissue

(GALT). Organized lymphoid tissue that functions in the induction of mucosal immune responses. The GALT comprises Peyers patches, the appendix and isolated lymphoid follicles. In mice, cryptopatches are the anlagen of isolated lymphoid follicles. The gut-draining mesenteric lymph nodes are not part of the GALT.

Plasmacytoid DCs

A subset of dendritic cells that were named plasmacytoid because their appearance under the microscope resembles that of plasmablasts. Plasmacytoid DCs produce large amounts of type I interferons following TLR7 or TLR9 stimulation.

Class-switch recombination

(CSR). A process that results in a molecular alteration in the constant (C) region genes of the immunoglobulin heavy chain locus, leading to a change in expression from one C region gene to another. This causes a switch in the class of the antibodies that are displayed on the cell surface of the B cell (and that the plasma cell will subsequently produce) from IgM to IgG, IgA or IgE without altering the specificity of the antibodies. This imparts flexibility to the humoral immune response and allows the different capacities of the antibody classes to be exploited to activate appropriate downstream effector mechanisms.

Specific pathogen free mice

(SPF mice). Laboratory mice that are known to be free from a list of specific pathogens defined by the Federation of European Laboratory Animal Science Associations (FELASA).

Peyer's patches

Groups of lymphoid nodules that are present in the small intestine and were named after the 17th century Swiss anatomist Johann Conrad Peyer. Peyers patches develop prenatally and are massed together on the intestinal wall opposite the line of attachment of the mesentery. Peyers patches are major induction sites of adaptive IgA responses.

Isolated lymphoid follicles

(ILFs). A heterogeneous array of small-sized lymphoid follicles in the gut. In mice, ILFs develop from another lymphoid structure known as a cryptopatch in a process that requires extrinsic stimulation by antigens and the intestinal microbiota. ILFs contribute to intestinal IgA responses and to homeostasis with the gut microbiota.

Follicular dendritic cells

(FDCs). Specialized non-haematopoietic stromal cells that reside in lymphoid follicles and germinal centres. These cells possess long dendrites and carry intact antigens on their surface. They are crucial for the optimal selection of B cells that produce antigen-binding antibodies.

Lymphoid tissue inducer cells

(LTi cells). Cells that are present in developing lymph nodes, Peyers patches, ILFs and nasopharynx-associated lymphoid tissue (NALT). LTi cells are required for the development of these lymphoid organs. The inductive capacity of LTi cells for the generation of Peyers patches and NALT has been shown by adoptive transfer experiments, and it is generally assumed that they have a similar function in the formation of lymph nodes.

B1 cells

An innate-like population of B cells that is mainly found in the peritoneal and pleural cavities of mice. B1 cell precursors develop in the fetal liver and omentum. B1 cells recognize self components as well as common bacterial antigens and secrete antibodies of low affinity and broad specificity.

Somatic hypermutation

A process that introduces mutations into the variable- region gene segments that encode part of the heavy and light chains of B cell immunoglobulins. These mutations can modify the sequence of the expressed proteins, and thus may alter the affinity or antigen-specificity of the respective immunoglobulin molecules.

Natural IgM

Antibodies circulating 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 IgM is derived from peritoneal B1 cells.

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Pabst, O. New concepts in the generation and functions of IgA. Nat Rev Immunol 12, 821–832 (2012). https://doi.org/10.1038/nri3322

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