Mature B cells express immunoglobulin D, but its function is unknown. Cerutti and colleagues show that respiratory mucosal B cells secrete immunoglobulin D, which activates basophils and enhances antimicrobial function. Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells express together with IgM through alternative RNA splicing. Here we report active T cell–dependent and T cell–independent IgM-to-IgD class switching in B cells of the human upper respiratory mucosa. This process required activation-induced cytidine deaminase (AID) and generated local and circulating IgD-producing plasmablasts reactive to respiratory bacteria. Circulating IgD bound to basophils through a calcium-mobilizing receptor that induced antimicrobial, opsonizing, inflammatory and B cell–stimulating factors, including cathelicidin, interleukin 1 (IL-1), IL-4 and B cell–activating factor (BAFF), after IgD crosslinking. By showing dysregulation of IgD class–switched B cells and 'IgD-armed' basophils in autoinflammatory syndromes with periodic fever, our data indicate that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation.

IgD is considered to be a recently evolved Ig, being previously found only in primates and rodents. Here we describe, from a teleost fish (the channel catfish,Ictalurus punctatus), a novel complex chimeric Ig heavy chain, homologous, in part, to the heavy chain (δ) of IgD. In addition to alternative secretory or membrane-associated C termini, this chimeric molecule contains a rearranged variable domain, the first constant domain of μ, and seven constant domains encoded by a δ gene homolog. Identification of the catfish gene as δ is based on the following properties: sequence relatedness to mammalian δ; a location within the IgH locus that is immediately downstream of the μ gene; separate terminal exons for the secretory and membrane forms; coexpression with the complete μ chain in some but not all B cells. These results (i) suggest that IgD is an ancient immunoglobulin that was present in vertebrates ancestral to both the mammals and the ray-finned fishes, and (ii) raise the possibility that this Ig isotype may have served an as yet unidentified important function early in the evolution of the immune system.

Channel catfish Ictalurus punctatus express two Ig isotypes: IgM and IgD. Although catfish IgM has been extensively studied at the functional and structural levels, much less is known about IgD. In this study, IgM⁺/IgD⁺ and IgM⁻/IgD⁺ catfish B cell populations were identified through the use of anti-IgM and anti-IgD mAbs. Catfish IgM⁺/IgD⁺ B cells are small and agranular. In contrast, IgM⁻/IgD⁺ B cells are larger and exhibit a plasmablast morphology. The use of cell sorting, flow cytometry, and RT-PCR demonstrated that IgD⁺ B cell expression varies among individuals. For example, some catfish have <5% IgM⁻/IgD⁺ B cells in their PBLs, whereas in others the IgM⁻/IgD⁺ B cell population can represent as much as 72%. Furthermore, IgD expressed by IgM⁻/IgD⁺ B cells preferentially associates with IgL σ. Comparatively, IgM⁺/IgD⁺ B cells can express any of the four catfish IgL isotypes. Also, transfection studies show that IgD functions as a typical BCR, because Igδ-chains associate with CD79a and CD79b molecules, and all membrane IgD transcripts from sorted IgM⁻/IgD⁺ B cells contain viable VDJ rearrangements, with no bias in family member usage. Interestingly, all secreted IgD transcripts from IgM⁺/IgD⁺ and IgM⁻/IgD⁺ B cells were V-less and began with a leader spliced to Cδ1. Importantly, transfection of catfish clonal B cells demonstrated that this leader mediated IgD secretion. Together, these findings imply that catfish IgM⁻/IgD⁺ B cells likely expand in response to certain pathogens and that the catfish IgD Fc-region, as has been suggested for human IgD, may function as a pattern recognition molecule.

Host defense against opportunistic fungi requires coordination between innate and adaptive immunity for resolution of infection. Antibodies generated in mice vaccinated with the fungus Pneumocystis prevent growth of Pneumocystis organisms within the lungs, but the mechanisms whereby antibodies enhance antifungal host defense are poorly defined. Nearly all species of fungi contain the conserved carbohydrates β-glucan and chitin within their cell walls, which may be targets of innate and adaptive immunity. In this study, we show that natural IgM antibodies targeting these fungal cell wall carbohydrates are conserved across many species, including fish and mammals. Natural antibodies bind fungal organisms and enhance host defense against Pneumocystis in early stages of infection. IgM antibodies influence recognition of fungal antigen by dendritic cells, increasing their migration to draining pulmonary lymph nodes. IgM antibodies are required for adaptive T helper type 2 (Th2) and Th17 cell differentiation and guide B cell isotype class-switch recombination during host defense against Pneumocystis. These experiments suggest a novel role for the IgM isotype in shaping the earliest steps in recognition and clearance of this fungus. We outline a mechanism whereby serum IgM, containing ancient specificities against conserved fungal antigens, bridges innate and adaptive immunity against fungal organisms.

We have shown that hypertension in response to chronic placental ischemia is associated with elevated inflammatory cytokines and CD4 ⁺ T cells. However, it is unknown whether these cells play an important role in mediating hypertension in response to placental ischemia. Therefore, we hypothesize that reduced uterine perfusion pressure (RUPP)–induced CD4 ⁺ T cells increase blood pressure during pregnancy. To answer this question, CD4 ⁺ T cells were isolated from spleens at day 19 of gestation from control normal pregnant (NP) and pregnant RUPP rats, cultured, and adjusted to 10 ⁶ cells per 100 μL of saline for intraperitoneal injection into NP rats at day 13 of gestation. On day 18, in the experimental groups of rats, arterial catheters were inserted, and on day 19 mean arterial pressure was analyzed. Inflammatory cytokines and antiangiogenic factor soluble fms-like tyrosine kinase 1 were determined via ELISA. Mean arterial pressure increased from 104±2 mm Hg in NP rats to 124±2 mm Hg in RUPP rats ( P <0.001) and to 118±1 mm Hg in rats receiving RUPP CD4 ⁺ T cells ( P <0.001). Circulating tumor necrosis factor-α and soluble fms-like tyrosine kinase 1 were elevated in recipients of RUPP CD4 ⁺ T cells to levels similar to control RUPP rats. In contrast, virgin rats injected with NP or RUPP CD4 ⁺ T cells exhibited no blood pressure changes compared with control virgin rats. Importantly, mean arterial pressure did not change in recipients of NP CD4 ⁺ T cells (109±3 mm Hg). These data support the hypothesis that RUPP-induced CD4 ⁺ T cells play an important role in the pathophysiology of hypertension in response to placental ischemia.