Alejo Chorny

B cell–helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen

Neutrophils utilize immunoglobulins (Igs) to clear antigen, but their role in Ig production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T-independent Ig responses to circulating antigen. Neutrophils colonized peri-MZ areas after post-natal mucosal colonization by microbes and enhanced their B-helper function upon receiving reprogramming signals from splenic sinusoidal endothelial cells, including interleukin 10 (IL-10). Splenic neutrophils induced Ig class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism involving the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and less preimmune Igs to T-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial Ig defense by interacting with MZ B cells.Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell–independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell–helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell–independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.

Immunoglobulin Responses at the Mucosal Interface

Mucosal surfaces are colonized by large communities of commensal bacteria and represent the primary site of entry for pathogenic agents. To prevent microbial intrusion, mucosal B cells release large amounts of immunoglobulin (Ig) molecules through multiple follicular and extrafollicular pathways. IgA is the most abundant antibody isotype in mucosal secretions and owes its success in frontline immunity to its ability to undergo transcytosis across epithelial cells. In addition to translocating IgA onto the mucosal surface, epithelial cells educate the mucosal immune system as to the composition of the local microbiota and instruct B cells to initiate IgA responses that generate immune protection while preserving immune homeostasis. Here we review recent advances in our understanding of the cellular interactions and signaling pathways governing IgA production at mucosal surfaces and discuss new findings on the regulation and function of mucosal IgD, the most enigmatic isotype of our mucosal antibody repertoire.

Innate signaling networks in mucosal IgA class switching.

The past 20 years have seen a growing interest over the control of adaptive immune responses by the innate immune system. In particular, considerable attention has been paid to the mechanisms by which antigen-primed dendritic cells orchestrate the differentiation of T cells. Additional studies have elucidated the pathways followed by T cells to initiate immunoglobulin responses in B cells. In this review, we discuss recent advances on the mechanisms by which intestinal bacteria, epithelial cells, dendritic cells, and macrophages cross talk with intestinal T cells and B cells to induce frontline immunoglobulin A class switching and production.

Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses.

Ruane et al. demonstrate a role for the microbiota in modulating protective immunity to intranasal vaccination via the ability of lung dendritic cells to induce B cell IgA class switching.

The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

Cerutti and collaborators show that the humoral arms of the innate and adaptive immune systems are functionally interconnected by pentraxin 3, a soluble pattern recognition receptor that couples innate immune recognition with antibody-inducing function.

SORT1 Mutation Resulting in Sortilin Deficiency and p75NTR Upregulation in a Family With Essential Tremor

*These authors contributed equally to this work. Essential tremor (ET) is the most prevalent movement disorder affecting millions of people in the United States. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In this study, whole exome sequencing and subsequent approaches were performed in a family with an autosomal dominant form of early-onset ET. Functional analyses including mutagenesis, cell culture, gene expression, enzyme-linked immunosorbent, and apoptosis assays were also performed. A disease-segregating mutation (p.Gly171Ala), absent in normal population, was identified in the SORT1 gene. The p.Gly171Ala mutation was shown not only to impair the expression of its encoding protein sortilin but also the mRNA levels of its binding partner p75 neurotrophin receptor that is known to be implicated in brain injury, neuronal apoptosis, and neurotransmission.

Regulation of frontline antibody responses by innate immune signals

Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions with T cells that express CD40 ligand. This T-cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus, it must be integrated with a faster, T-cell-independent pathway for B-cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here, we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly “frontline” B cells located in the marginal zone of the spleen and in the intestine.

A gut triumvirate rules homeostasis

IgA regulates intestinal homeostasis by maintaining appropriate communities of bacteria within the gut. A new study shows that intestinal bacteria regulate metabolism via IgA (pages 1585–1593 ).

CEACAM1-S: The Virtues of Alternative Splicing in Gut Immunity

Immunoglobulin A (IgA) is the main intestinal antibody. In this issue of Immunity, Chen et al. (2012) show that intestinal T cells enhance protective IgA responses by expressing a short isoform of the CEACAM1 protein.

Regulation and Function of Mucosal IgA and IgD

Abstract The gut contains diverse communities of commensal bacteria that process nutrients, provide protection against pathogens by competing for ecological niches, and stimulate the local immune system to mount homeostatic innate and adaptive responses without causing inflammation. These responses shape the composition and function of the commensal microbiota through a symbiotic regulatory loop. One striking feature of intestinal adaptive immunity consists in its ability to generate massive amounts of noninflammatory immunoglobulin A (IgA) through multiple follicular and extrafollicular pathways that operate in the presence or absence of cognate help to B cells by T cells. Here we review the function of IgA and the mechanisms governing its production by B cells in different areas of the gut. Furthermore, we discuss the regulation and function of IgD, an enigmatic antibody isotype produced by B cells in the upper respiratory mucosa.