Infection trains the host for microbiota-enhanced resistance to pathogens.

The microbiota shields the host against infections in a process known as colonization resistance. How infections themselves shape this fundamental process remains largely unknown. Here, we show that gut microbiota from previously infected hosts display enhanced resistance to infection. This long-term functional remodeling is associated with altered bile acid metabolism leading to the expansion of taxa that utilize the sulfonic acid taurine. Notably, supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Mechanistically, taurine potentiates the microbiota's production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens. As such, pharmaceutical sequestration of sulfide perturbs the microbiota's composition and promotes pathogen invasion. Together, this work reveals a process by which the host, triggered by infection, can deploy taurine as a nutrient to nourish and train the microbiota, promoting its resistance to subsequent infection.

Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota.

The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratinocyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the microbiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for heightened ERV- expression in response to commensal colonization, leading to increased immune responses and tissue inflammation. Together, our results support the idea that the host may have co-opted its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-kingdom dialog that controls both tissue homeostasis and inflammation.

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification.

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation.

Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration. Human ILCPs robustly generate all ILC subsets in vitro and in vivo. While human ILCPs express low levels of retinoic acid receptor (RAR)-related orphan receptor C (RORC) transcripts, these cells are found in RORC-deficient patients and retain potential for EOMES+ natural killer (NK) cells, interferon gamma-positive (IFN-γ+) ILC1s, interleukin (IL)-13+ ILC2s, and for IL-22+, but not for IL-17A+ ILC3s. Our results support a model of tissue ILC differentiation ("ILC-poiesis"), whereby diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.

Maternal-driven immune education in offspring.

Maternal environmental exposures, particularly during gestation and lactation, significantly influence the immunological development and long-term immunity of offspring. Mammalian immune systems develop through crucial inputs from the environment, beginning in utero and continuing after birth. These critical developmental windows are essential for proper immune system development and, once closed, may not be reopened. This review focuses on the mechanisms by which maternal exposures, particularly to pathogens, diet, and microbiota, impact offspring immunity. Mechanisms driving maternal-offspring immune crosstalk include transfer of maternal antibodies, changes in the maternal microbiome and microbiota-derived metabolites, and transfer of immune cells and cytokines via the placenta and breastfeeding. We further discuss the role of transient maternal infections, which are common during pregnancy, in providing tissue-specific immune education to offspring. We propose a "maternal-driven immune education" hypothesis, which suggests that offspring can use maternal encounters that occur during a critical developmental window to develop optimal immune fitness against infection and inflammation.

The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota.

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. The neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.

Microbiota configuration determines nutritional immune optimization.

Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. However, the factors and mechanisms involved remain to be elucidated. Here, we propose that DR-induced optimization of immunological memory requires a complex cascade of events involving memory T cells, the intestinal microbiota, and myeloid cells. Our findings suggest that DR enhances the ability of memory T cells to recruit and activate myeloid cells in the context of a secondary infection. Concomitantly, DR promotes the expansion of commensal Bifidobacteria within the large intestine, which produce the short-chain fatty acid acetate. Acetate conditioning of the myeloid compartment during DR enhances the capacity of these cells to kill pathogens. Enhanced host protection during DR is compromised when Bifidobacteria expansion is prevented, indicating that microbiota configuration and function play an important role in determining immune responsiveness to this dietary intervention. Altogether, our study supports the idea that DR induces both memory T cells and the gut microbiota to produce distinct factors that converge on myeloid cells to promote optimal pathogen control. These findings suggest that nutritional cues can promote adaptation and co-operation between multiple immune cells and the gut microbiota, which synergize to optimize immunity and protect the collective metaorganism.

A human immune system mouse model with robust lymph node development.

Lymph nodes (LNs) facilitate the cellular interactions that orchestrate immune responses. Human immune system (HIS) mice are powerful tools for interrogation of human immunity but lack secondary lymphoid tissue (SLT) as a result of a deficiency in Il2rg-dependent lymphoid tissue inducer cells. To restore LN development, we induced expression of thymic-stromal-cell-derived lymphopoietin (TSLP) in a Balb/c Rag2-/-Il2rg-/-SirpaNOD (BRGS) HIS mouse model. The resulting BRGST HIS mice developed a full array of LNs with compartmentalized human B and T cells. Compared with BRGS HIS mice, BRGST HIS mice have a larger thymus, more mature B cells, and abundant IL-21-producing follicular helper T (TFH) cells, and show enhanced antigen-specific responses. Using BRGST HIS mice, we demonstrated that LN TFH cells are targets of acute HIV infection and represent a reservoir for latent HIV. In summary, BRGST HIS mice reflect the effects of SLT development on human immune responses and provide a model for visualization and interrogation of regulators of immunity.

ILC-poiesis: Ensuring tissue ILC differentiation at the right place and time.

Innate lymphoid cells (ILCs) represent a family of innate effector cells including NK cells, lymphoid tissue inducer (LTi) cells, and distinct ILC1, ILC2, and ILC3 subsets that produce IFN-γ, IL-5/IL-13, and IL-17A/IL-22, respectively. ILCs accumulate at mucosal sites and can promote the first-line defense against infection. ILCs are also implicated in tissue repair and can either pre-empt, or alternatively, exacerbate inflammation. Studies in mice have identified ILC precursors in fetal liver and adult BM that have diverse lineage potential. As such, these sites have been considered as the 'factories' to generate mature ILC. Here, we summarize knowledge concerning murine and human ILC development and discuss the recent identification of circulating multipotent and unipotent ILC precursors. We propose an alternative model of "ILC-poiesis", whereby blood ILC precursors migrate into tissues to complete their differentiation into mature ILC subsets under the influence of local environmental factors. Within this framework, ILC-poiesis guarantees appropriate ILC generation at the right place and the right time. We further discusss the potential applications of circulating ILC precursors for cell therapy of human disease.

Epigenome analysis links gene regulatory elements in group 2 innate lymphocytes to asthma susceptibility.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are major producers of the cytokines driving allergic asthma, and increased ILC2 numbers have been detected in blood and sputum of asthmatic patients. Asthma susceptibility has a strong genetic component, but the underlying mechanisms and whether asthma genetics affect ILC2 biology remain unclear. OBJECTIVE: We sought to study the ILC2 transcriptome and epigenome during airway inflammation (AI) to couple these to genes and genetic variants associated with asthma pathogenesis. METHODS: Mice harboring a reporter for the key ILC2 transcription factor GATA-3 were subjected to IL-33-driven AI, and ILC2s were isolated from bronchoalveolar lavage fluid and mediastinal lymph nodes. Human ILC2s were purified from peripheral blood and activated in vitro. We used RNA sequencing, genome-wide identification of histone-3 lysine-4 dimethylation-marked chromatin, and computational approaches to study the ILC2 transcriptome and epigenome. RESULTS: Activated ILC2s in mice displayed a tissue-specific gene expression signature that emerged from remarkably similar epigenomes. We identified superenhancers implicated in controlling ILC2 identity and asthma-associated genes. More than 300 asthma-associated genetic polymorphisms identified in genome-wide association studies localized to H3K4Me2+ gene regulatory elements in ILC2s. A refined set of candidate causal asthma-associated variants was uniquely enriched in ILC2, but not TH2 cell, regulatory regions. CONCLUSIONS: ILC2s in AI use a flexible epigenome that couples adaptation to new microenvironments with functional plasticity. Importantly, we reveal strong correlations between gene regulatory mechanisms in ILC2s and the genetic basis of asthma, supporting a pathogenic role for ILC2s in patients with allergic asthma.

BMP-7 represses albumin-induced chemokine synthesis in kidney tubular epithelial cells through destabilization of NF-κB-inducing kinase.

Protein overload activates proximal tubule epithelial cells (PTECs) to release chemokines. Bone morphogenetic protein-7 (BMP-7) reduces infiltrating cells and tissue damage in acute and chronic renal injuries. The present study examines the inhibitory effect and related molecular mechanism of BMP-7 on chemokine and adhesion molecule synthesis by PTECs activated with human serum albumin (HSA). The expression profiles of chemokines and adhesion molecules in cultured human PTECs were screened by PCR array. Expression of CXCL1, CXCL2 and vascular cell adhesion protein 1 (VCAM-1) by PTECs was significantly upregulated by HSA and reduced by BMP-7. HSA activated both the canonical and noncanonical nuclear factor (NF)-κB pathways in PTECs, as indicated by the increased nuclear translocation of NF-κB p50 and p52 subunits. The nuclear translocation of NF-κB p52 was completely abrogated by BMP-7, whereas NF-κB p50 activation was only partially repressed. BMP-7 increased the expression of cellular inhibitor of apoptosis 1 (cIAP1), tumor necrosis factor receptor-associated factor (TRAF)2 and TRAF3, but not of NF-κB-inducing kinase (NIK) that was significantly upregulated by HSA. Silencing NIK recapitulated the partial inhibitory effect on HSA-induced chemokine synthesis by BMP-7. Complete abolishment of the chemokine synthesis was only achieved by including additional blockade of the NF-κB p65 translocation on top of NIK silencing. Our data suggest that BMP-7 represses the NIK-dependent chemokine synthesis in PTECs activated with HSA through blocking the noncanonical NF-κB pathway and partially interfering with the canonical NF-κB pathway.

Albumin and glycated albumin activate KIM-1 release in tubular epithelial cells through distinct kinetics and mechanisms.

OBJECTIVE: Kidney injury molecule-1 (KIM-1) serves as a useful marker for monitoring tubular injury, and sustained KIM-1 expression may be implicated in chronic kidney fibrosis. In this study, we examine the kinetics and mechanisms of KIM-1 release in human proximal tubular epithelial cells (PTEC) under the activation by major pathologic players in diabetic nephropathy, including human serum albumin (HSA), glycated albumin (AGE-BSA) and high glucose. MATERIALS AND METHODS: The kinetics of KIM-1 release by PTEC under activation with HSA, AGE-BSA and high glucose, were determined by RT-PCR and ELISA. The activation profiles of major signaling pathways in PTEC were identified by PCR array. Based on the array data, blockade experiments were designed to assess their regulatory roles in KIM-1 release. RESULTS: Prompt shedding of KIM-1 was observed in PTEC cultured for 4 h with HSA and AGE-BSA, but not with high glucose. Culturing PTEC for 3 days with AGE-BSA exhibited sustained up-regulation of KIM-1 release, but not with HSA. In all culture experiments, high glucose did not induce KIM-1 release in PTEC. HSA and AGE-BSA activated multiple signaling pathways in PTEC including NFκB, ERK1/2 and the oxidative stress pathways. Long-term culturing PTEC with AGE-BSA but not HSA activated the Jak-Stat pathway. While incubation of PTEC with diphenylene iodonium blocked the short-term release of KIM-1 mediated by HSA or AGE-BSA, Jak-Stat inhibitors diminished the long-term KIM-1 release by PTEC induced by AGE-BSA. CONCLUSION: KIM-1 release in PTEC was differentially up-regulated by HSA and AGE-BSA. The short-term KIM-1 shedding was mediated by the reactive oxygen species, whereas Jak-Stat pathway regulates the long-term KIM-1 release.

Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis.

Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncovered a dominant role for type 2 innate lymphoid cells (ILC2s) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2s by androgens leads to a reduction in dendritic cell accumulation and activation in males, along with reduced tissue immunity. Collectively, our results reveal a role for the androgen-ILC2-dendritic cell axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.

Kidney injury molecule-1: more than just an injury marker of tubular epithelial cells?

Regardless of the original causes and etiology, the progression to renal function declines follows a final common pathway associated with tubulointerstitial injury, in which the proximal tubular epithelial cells (PTEC) are instrumental. Kidney injury molecule-1 (KIM-1) is an emerging biomarker, and its expression and release are induced in PTEC upon injury. KIM-1 plays the role as a double-edged sword and implicates in the process of kidney injury and healing. Expression of KIM-1 is also associated with tubulointerstitial inflammation and fibrosis. More importantly, KIM-1 expressing PTEC play the role as the residential phagocytes, contribute to the removal of apoptotic cells and facilitate the regeneration of injured tubules. The precise mechanism of KIM-1 and its sheded ectodomain on restoration of tubular integrity after injury is not fully understood. Other than PTEC, macrophages (Mø) also implicate in tubular repair. Understanding the crosstalk between Mø and the injured PTEC is essential for designing appropriate methods for controlling the sophisticated machinery in tubular regeneration and healing. This article will review the current findings of KIM-1, beginning with its basic structure, utility as a biomarker, and possible functions, with focus on the role of KIM-1 in regeneration and healing of injured PTEC.

The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota.

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide Calcitonin Gene-Related Peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo . Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8 + T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology. Significance statement: Multisystem coordination at barrier surfaces is critical for optimal tissue functions and integrity, in response to microbial and environmental cues. In this study, we identified a novel neuroimmune crosstalk mechanism between the sensory nervous system and the adaptive immune response to the microbiota, mediated by the neuropeptide CGRP and its receptor RAMP1 on skin microbiota-induced T lymphocytes. The neuroimmune CGPR-RAMP1 axis constrains adaptive immunity to the microbiota and overall limits the activation status of the skin epithelium, impacting tissue responses to wounding. Our study opens the door to a new avenue to modulate adaptive immunity to the microbiota utilizing neuromodulators, allowing for a more integrative and tailored approach to harnessing microbiota-induced T cells to promote barrier tissue protection and repair.

The role of leptin and its short-form receptor in inflammation in db/db mice infused with peritoneal dialysis fluid.

BACKGROUND: In peritoneal dialysis (PD), the peritoneal membrane exhibits structural and functional changes following continuous exposure to the non-physiological peritoneal dialysis fluid (PDF). In this study, we examined the effect of PDF on peritoneal adipose tissue in a diabetic milieu. METHODS: Six-week-old db/db mice and their non-diabetic littermates (db/m) were subjected to uninephrectomy. All animals then received intra-abdominal infusion of lactated Ringer's solution (Ringer) or 1.5% glucose-containing PDF (Dianeal) twice daily. Mice were sacrificed 4 weeks later. Parietal and visceral adipose tissues were harvested for examining gene and protein expression of adiponectin, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, tumor necrosis factor alpha (TNF-α), transforming growth factor beta and interleukin 6 (IL-6). Expression of TNF-α and F4/80+ macrophage accumulation in adipose tissues was assessed by immunohistochemical staining. Modulation of leptin synthesis and leptin receptors expression and the relevant signaling pathways were also determined by quantitative reverse transcription-polymerase chain reaction, immunoblotting or enzyme-linked immunosorbent assay. RESULTS: Compared to Ringer infusion, Dianeal infusion significantly increased serum leptin but decreased adiponectin in db/db mice. Increased expression of leptin, TNF-α and IL-6 was observed in visceral but not in parietal adipose tissue. Dianeal infusion also increased F4/80+ macrophage accumulation and enhanced the expression of pro-inflammatory cytokines including IL-6 and TNF-α in the visceral adipose tissue. Compared to db/m mice, infusion with Dianeal exhibited a more deleterious effect on db/db mice, characterized by an upregulation of short-form leptin receptor ObRa and activation of the mitogen-activated protein kinase signaling pathway. CONCLUSION: In conclusion, PD-induced hyperleptinemia amplifies the inflammatory response of adipose tissue through short-form leptin receptor when the long-form isotype is defective.

Oxidative damages in tubular epithelial cells in IgA nephropathy: role of crosstalk between angiotensin II and aldosterone.

BACKGROUND: Inhibition of the renin-angiotensin-aldosterone system (RAAS) slows down the progression of chronic renal diseases (CKD) including IgA nephropathy (IgAN). Herein, we studied the pathogenetic roles of aldosterone (Aldo) in IgAN. METHODS: Human mesangial cells (HMC) was activated with polymeric IgA (pIgA) from IgAN patients and the effects on the expression of RAAS components and TGF-ß synthesis examined. To study the roles of RAAS in the glomerulotubular communication, proximal tubular epithelial cells (PTEC) was cultured with conditioned medium from pIgA-activated HMC with eplerenone or PD123319, the associated apoptotic event was measured by the generation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS). RESULTS: Polymeric IgA up-regulated the Aldo synthesis and aldosterone synthase expression by HMC. The release of TGF-ß by HMC was up-regulated synergistically by AngII and Aldo and this was inhibited by incubation of HMC with losartan plus eplerenone. Cultured PTEC express the mineralocorticoid receptor, but not synthesizing aldosterone. Apoptosis, demonstrated by cleaved PARP expression and caspase 3 activity, was induced in PTEC activated by conditioned medium prepared from HMC cultured with pIgA from IgAN patients. This apoptotic event was associated with increased generation of NADPH oxidase and ROS. Pre-incubation of PTEC with PD123319 and eplerenone achieved complete inhibition of PTEC apoptosis. CONCLUSIONS: Our data suggest that AngII and Aldo, released by pIgA activated HMC, served as mediators for inducing apoptosis of PTEC in glomerulo-tubular communications. Crosstalk between AngII and Aldo could participate in determining the tubular pathology of IgAN.

Prenatal maternal infection promotes tissue-specific immunity and inflammation in offspring.

The immune system has evolved in the face of microbial exposure. How maternal infection experienced at distinct developmental stages shapes the offspring immune system remains poorly understood. Here, we show that during pregnancy, maternally restricted infection can have permanent and tissue-specific impacts on offspring immunity. Mechanistically, maternal interleukin-6 produced in response to infection can directly impose epigenetic changes on fetal intestinal epithelial stem cells, leading to long-lasting impacts on intestinal immune homeostasis. As a result, offspring of previously infected dams develop enhanced protective immunity to gut infection and increased inflammation in the context of colitis. Thus, maternal infection can be coopted by the fetus to promote long-term, tissue-specific fitness, a phenomenon that may come at the cost of predisposition to inflammatory disorders.

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.