Antibody-secreting Plasma Cells Research Articles

A new perspective on therapies involving B-cell depletion in autoimmune diseases.

It has been rediscovered in the last fifteen years that B-cells play an active role in autoimmune etiology rather than just being spectators. The clinical success of B-cell depletion therapies (BCDTs) has contributed to this. BCDTs, including those that target CD20, CD19, and BAFF, were first developed to eradicate malignant B-cells. These days, they treat autoimmune conditions like multiple sclerosis and systemic lupus erythematosus. Particular surprises have resulted from the use of BCDTs in autoimmune diseases. For example, even in cases where BCDT is used to treat the condition, its effects on antibody-secreting plasma cells and antibody levels are restricted, even though these cells are regarded to play a detrimental pathogenic role in autoimmune diseases. In this Review, we provide an update on our knowledge of the biology of B-cells, examine the outcomes of clinical studies employing BCDT for autoimmune reasons, talk about potential explanations for the drug's mode of action, and make predictions about future approaches to targeting B-cells other than depletion.

Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice.

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned hIL-6 transgenic NSG mice (NSG+hIL6) reliably support the engraftment of malignant and pre-malignant human plasma cells including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and post-relapse myeloma, plasma cell leukemia, and AL amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells, developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single cell RNA sequencing showed non-malignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma engrafted mice given CAR T-cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results established NSG+hIL6 mice as an effective patient derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.

Hormones and B-cell development in health and autoimmunity.

The development of B cells into antibody-secreting plasma cells is central to the adaptive immune system as they induce protective and specific antibody responses against invading pathogens. Various studies have shown that, during this process, hormones can play important roles in the lymphopoiesis, activation, proliferation, and differentiation of B cells, and depending on the signal given by the receptor of each hormone, they can have a positive or negative effect. In autoimmune diseases, hormonal deregulation has been reported to be related to the survival, activation and/or differentiation of autoreactive clones of B cells, thus promoting the development of autoimmunity. Clinical manifestations of autoimmune diseases have been associated with estrogens, prolactin (PRL), and growth hormone (GH) levels. However, androgens, such as testosterone and progesterone (P4), could have a protective effect. The objective of this review is to highlight the links between different hormones and the immune response mediated by B cells in the etiopathogenesis of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). The data collected provide insights into the role of hormones in the cellular, molecular and/or epigenetic mechanisms that modulate the B-cell response in health and disease.

450 Developing Methods for High-Resolution Characterization of Plasma Cells

OBJECTIVES/GOALS: Antibodies play an important role in the pathogenesis of a wide range of diseases, including cancer, autoimmune diseases, and infections. There are currently no reliable methods to isolate and study specific plasma cell subpopulations as antibody production sources. We aim to develop methods to study plasma cells in high resolution. METHODS/STUDY POPULATION: We will use molecular cloning to engineer fusion proteins that would bind plasma cell proteins to study these cells based on their surface features. The first phase of our study consists of assessing the efficacy of this plasma cell isolation method in established cell lines (e.g., RPMI 8226) and also antibody-secreting cell lines that we are establishing as a part of this study. In the second phase of the study, we will assess the efficacy of this method by studying antigen-specific plasma cell populations in the bone marrow aspiration samples of 20 healthy volunteers using various assays, including ELISPOT, flow cytometry, and fluorescent microscopy. RESULTS/ANTICIPATED RESULTS: We have designed the constructs and have completed the cloning. The final plasmids have been verified using various restriction enzymes and Sanger sequencing. Following the transfection of Freestyle HEK 293F cells and isolation of respective proteins, we expect to be able to utilize these engineered proteins to differentiate various antibody-secreting plasma cells. We will use cell lines for proof-of-concept experiments and will subsequently move this method to human bone marrow samples. We expect to be able to visualize multiple specific antibody-secreting plasma cell populations using fluorescent microscopy and utilize this method to isolate them by cell sorting via flow cytometry. DISCUSSION/SIGNIFICANCE: We expect to be able to use this method to target specific plasma cell clones in the advancement of precision medicine regarding the treatment of plasma cell disorders (e.g., multiple myeloma) and also expand its use in other areas, such as antibody discovery and the assessment of the humoral immune responses in infectious diseases.

Development and Validation of an Individualized and Weighted Prognostic Model in Patients with Newly Diagnosed Multiple Myeloma

Introduction Multiple myeloma (MM) is a malignancy of terminally differentiated antibody-secreting plasma cells in the bone marrow with highly variable survival outcomes. Precise risk stratification not only plays a vital role in predicting patient prognoses, but critically can be used to develop risk-adapted treatment regimens. However, current risk stratification models do not adequately account for the heterogeneity of patients with new-diagnosed multiple myeloma (NDMM). Methods In this retrospective, multicohort study, we collected clinical data from 1792 NDMM patients and formulated a weighted Myeloma Prognostic Score System (MPSS) risk model to predict overall survival (OS). Construction of the MPSS model was carried out based on the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199) cohort, external validation cohort was created using TT2, TT3a, and TT3b cohorts from a series of randomized prospective studies from the University of Arkansas for Medical Sciences (UAMS). Results Each risk factor was defined as its weighted value respectively according to their hazard ratio for OS (thrombocytopenia 2, elevated LDH 1, ISS III 2, one high-risk cytogenetic aberration [HRA] 1, and ≥2 HRA 2 points). In the training cohort, patients were furtherly stratified into four risk groups: MPSS I (22.5%, 0 points), II (17.6%, 1 points), III (38.6%, 2-3 points), and IV (21.3%, 4-7 points). MPSS risk stratification showed optimal discrimination, as well as calibration, of four risk groups with median OS of 91.0, 69.8, 45.0, and 28.0 months, for patients in MPSS I to IV groups (P< 0.001), respectively. Importantly, the MPSS model retained its prognostic value in the internal validation cohort and an independent external validation cohort, and exhibited significant risk distribution compared with conventional prognostic models (R-ISS, R2-ISS, and MASS). Conclusions In conclusion, we formulated and validated the MPSS risk model to predict the prognosis of patients with MM using readily available standard clinical and genetic test data. The established MPSS profile shows a better performance in risk discrimination than the current R-ISS, R2-ISS, and MASS. A score-based risk stratification is derived, and identifies patients with high and ultra-high risk of death after diagnosis and may therefore aid the development of more personalized treatment strategies, especially for patients for whom current therapies are likely to fail.

Role of affinity in plasma cell development in the germinal center light zone.

Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic models suggest that there is a stringent affinity-based barrier to PC development. Whether a similar high-affinity barrier regulates PC development under physiologic circumstances and the nature of the PC fate decision has not been defined precisely. Here, we use a fate-mapping approach to examine the relationship between GC B cells selected to undergo additional rounds of affinity maturation, GC pre-PC, and PC. The data show that initial PC selection overlaps with GC B cell selection, but that the PC compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-PC selection sieves the GC to enable the accumulation of a more restricted group of high-affinity antibody-secreting PC.

Nasal polyp antibody-secreting cells display proliferation signature in aspirin-exacerbated respiratory disease

BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) causes nasal obstruction and olfactory dysfunction. Aspirin-exacerbated respiratory disease (AERD) is the triad of CRSwNP, asthma and respiratory reactions to cyclooxygenase-1 inhibitors. Patients with AERD have elevated nasal IL-5 levels and high numbers of antibody secreting cells (ASCs), plasma cells (PCs) and plasmablasts, in their polyp tissue, and nasal polyp IgE levels correlate with disease severity and recurrence of nasal polyposis. ObjectiveWe sought to explore differences in the transcriptomic profile, activation markers, and IL-5Rα expression and function of nasal polyp ASCs from patients with AERD and CRSwNP. MethodsNasal polyp tissue was collected from patients with AERD and CRSwNP and digested into single-cell suspensions. Nasal polyp cells were analyzed for protein expression by mass cytometry. For IL-5Rα functional studies, plasma cells were purified and cultured in vitro with/without IL-5 and analyzed by bulk RNA-sequencing. ResultsAERD polyp tissue contained significantly more ASCs and had increased ASC expression of IL-5Rα compared to CRSwNP. AERD ASCs expressed higher protein levels of B cell activation and regulatory markers (CD40, CD19, CD32, and CD38) and the proliferation marker Ki-67. AERD ASCs also expressed more IL5RA, IGHE, and cell cycle and proliferation-related transcripts (CCND2, MKI67, CDC25A and CDC25B) compared to CRSwNP. Stimulation of AERD PCs with IL-5 induced key cell cycle genes (CCND2 and PTP4A3), whereas IL-5 stimulation of ASCs from CRSwNP induced few transcriptomic changes. ConclusionNasal polyp tissue ASCs from patients with AERD express higher levels of functional IL-5Rα and markers associated with cell cycling and proliferation compared to those from aspirin-tolerant CRSwNP patients.

Impact of PFAS exposure on immune-mediated diseases and immune transcriptome in Czech adults

Abstract Background Per- and polyfluoroalkyl substances (PFASs) are emerging environmental contaminants with multiple hazardous properties including immunomodulation potency. We aimed to investigate 1) the association between PFAS exposure and immune-mediated diseases (IMDs) and 2) the expression of genes associated with PFAS exposure in a population of Czech adults. Methods This study involved 309 adults from the Czech CELSPAC:YA cohort. The associations of serum concentrations of 9 PFAS with 9 IMDs were assessed by logistic regression. Furthermore, Bayesian kernel machine regression (BKMR) was used to estimate the effect of the PFAS mixture on IMDs. In cases of a statistically significant interaction of PFASs and sex, sex-stratified analyses were performed. To identify transcriptomic profiles, isolated RNA from peripheral mononuclear blood cells was sequenced (QuantSeq) and analysed. Significantly expressed genes associated with multiple PFASs (at least with 4 PFASs) were employed for enrichment analysis by Pathway Studio. All analyses were adjusted for relevant confounders (i.e., sex, age, BMI, smoking, education, and family history of IMDs). Results PFOA, PFOS, and PFUnDA were negatively associated with allergies. Similarly, BKMR modeling showed a negative tendency in the overall effect of PFAS mixture on IMDs. Results of the stratified analysis suggest sex to be an effect modifier in the association of PFOS and atopic eczema. Regarding transcriptomic analysis, 166 statistically significant genes were associated with multiple PFAS exposure. Enrichment analysis of these genes showed involvement of B cell signaling, specifically mechanisms involved in the production of antibody-secreting plasma cells. Conclusions Our results contribute to the body of literature that observes the immunomodulatory effect of PFAS exposure on the level of disease prevalence and further brought new information about underlying deregulatory mechanisms. Key messages • Our study showed an immunosuppressive effect of PFAS exposure on the level of prevalence of immune-mediated diseases, both for PFASs individually and as a mixture. • Genome-wide transcriptomic analysis revealed the involvement of plasma cells as a potential key event of PFAS-induced immunomodulation.

Targeting TFH cells is a novel approach for donor-specific antibody desensitization of allograft candidates: an in vitro and in vivo study.

The presence of donor-specific antibodies (DSA) are associated with graft failure either following human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation or after organ transplantation. Although targeting B cells and plasma cells have been used for desensitization, there have been reports of failure. T-follicular helper (Tfh) cells assist B cells in differentiating into antibody-secreting plasma cells. We used haploidentical allograft as a platform to investigate the possibility of targeting Tfh cells to desensitize DSA. The quantities of circulating Tfh (cTfh) cell subsets in allograft candidates were abnormal, and these cells, including the cTfh2 and cTfhem cell subsets, were positively related to the production of anti-HLA antibodies. Ex vivo experiments showed that the cTfh cells of anti-HLA antibody-positive allograft candidates could induce B cells to differentiate into DSA-producing plasmablasts. The immune synapse could be involved in the assistance of cTfh cells to B cells in antibody production. In vitro experiments and in vivo clinical pilot studies indicated that targeting cTfh cells with sirolimus can inhibit their auxiliary function in assisting B cells. Ex vivo and in vivo studies demonstrated the effect of sirolimus and rituximab on DSA desensitization compared with either sirolimus or rituximab alone (60%, 43.75%, and 30%, respectively). Our findings provide new insight into the role of Tfh cells in the pathogenesis of DSA production in HLA-mismatched transplant candidates. Our data also indicate that targeting Tfh cells is a novel strategy for DSA desensitization and combination of sirolimus and rituximab might be a potential therapy. The prospective cohort of this study is registered at http://www.chictr.org.cn as #ChiCTR-OPC-15006672.

Exploring the dual role of B cells in solid tumors: implications for head and neck squamous cell carcinoma.

In the tumor milieu of head and neck squamous cell carcinoma (HNSCC), distinct B cell subpopulations are present, which exert either pro- or anti-tumor activities. Multiple factors, including hypoxia, cytokines, interactions with tumor cells, and other immune infiltrating lymphocytes (TILs), alter the equilibrium between the dual roles of B cells leading to cancerogenesis. Certain B cell subsets in the tumor microenvironment (TME) exhibit immunosuppressive function. These cells are known as regulatory B (Breg) cells. Breg cells suppress immune responses by secreting a series of immunosuppressive cytokines, including IL-10, IL-35, TGF-β, granzyme B, and adenosine or dampen effector TILs by intercellular contacts. Multiple Breg phenotypes have been discovered in human and mouse cancer models. However, when compartmentalized within a tertiary lymphoid structure (TLS), B cells predominantly play anti-tumor effects. A mature TLS contains a CD20+ B cell zone with several important types of B cells, including germinal-center like B cells, antibody-secreting plasma cells, and memory B cells. They kill tumor cells via antibody-dependent cytotoxicity and phagocytosis, and local complement activation effects. TLSs are also privileged sites for local T and B cell coordination and activation. Nonetheless, in some cases, TLSs may serve as a niche for hidden tumor cells and indicate a bad prognosis. Thus, TIL-B cells exhibit bidirectional immune-modulatory activity and are responsive to a variety of immunotherapies. In this review, we discuss the functional distinctions between immunosuppressive Breg cells and immunogenic effector B cells that mature within TLSs with the focus on tumors of HNSCC patients. Additionally, we review contemporary immunotherapies that aim to target TIL-B cells. For the development of innovative therapeutic approaches to complement T-cell-based immunotherapy, a full understanding of either effector B cells or Breg cells is necessary.

Rituximab treatment in myasthenia gravis.

Myasthenia gravis (MG) is a chronic autoimmune disease mediated by antibodies against post-synaptic proteins of the neuromuscular junction. Up to 10%-30% of patients are refractory to conventional treatments. For these patients, rituximab has been used off-label in the recent decades. Rituximab is a monoclonal antibody against the CD20 protein that leads to B cell depletion and to the synthesis of new antibody-secreting plasma cells. Although rituximab was created to treat B-cell lymphoma, its use has widely increased to treat autoimmune diseases. In MG, the benefit of rituximab treatment in MuSK-positive patients seems clear, but a high variability in the results of observational studies and even clinical trials has been reported for AChR-positive patients. Moreover, few evidence has been reported in seronegative MG and juvenile MG and some questions about regimen of administration or monitoring strategies, remains open. In this review, we intend to revise the available literature on this topic and resume the current evidence of effectiveness of Rituximab in MG, with special attention to results on every MG subtype, as well as the administration protocols, monitoring strategies and safety profile of the drug.

Chronic or recurrent Campylobacter enteritis in primary immunodeficiency: a UK national case-series and review of the literature.

Clinical ImplicationsCampylobacter infection is an important diagnosis to consider in primary immunodeficiency patients with chronic or recurrent diarrhea, particularly in those with very low diagnostic immunoglobulin levels. Macrolides, aminoglycosides, and/or carbapenems are promising treatment options for this potentially debilitating condition. Campylobacter infection is an important diagnosis to consider in primary immunodeficiency patients with chronic or recurrent diarrhea, particularly in those with very low diagnostic immunoglobulin levels. Macrolides, aminoglycosides, and/or carbapenems are promising treatment options for this potentially debilitating condition. Campylobacter infection, usually by Campylobacter jejuni, is the most common cause of bacterial enteritis in the world. In healthy individuals, the infection is self-limiting, but in patients with immunodeficiency, recurrent or persistent symptomatic infection may occur. In this case series, we present a cohort of primary immunodeficiency patients with chronic or recurrent Campylobacter enteritis from the United Kingdom and review the previously published literature. To identify relevant cases, a request was circulated via the UK Clinical Immunology mailing list, which includes 41 centers. Primary immunodeficiency (PID) cases with confirmed Campylobacter in stool or colonic tissue, by culture or PCR, and symptoms of longer than 3-month duration or 3 or more symptomatic flares, were included. Successful clearance of the infection was defined as resolution of symptoms and no recurrence for at least 3 months. In parallel, a literature review was performed to identify previously published cases in PubMed, using the terms “chronic,” “recurrent,” “Campylobacter,” “enteritis,” “diarrhoea,” “immune deficiency,” “immunodeficiency,” and “hypogammaglobulinemia.” Six centers replied, reporting 13 cases of chronic or recurrent Campylobacter enteritis in total: 4 from Queen Elizabeth Hospital (Glasgow), 3 from Southmead Hospital (Bristol), 2 from Royal London Hospital (London), 1 from Frimley Park Hospital (Surrey), 1 from Derriford Hospital (Plymouth), 1 from Northern Care National Health Service Foundation Trust (Greater Manchester), and 1 from Gloucester Royal Hospital (Gloucester). Patients were all adults, aged 21 to 71 years, with the vast majority (n = 12) having common variable immunodeficiency (CVID, Table I). Laboratory investigations at diagnosis revealed undetectable (<0.1 g/L) serum IgA in 85% (11 of 13) of cases and IgM in 62% (8 of 13). Where data were available, very low (<1 g/L) pretreatment serum IgG was seen in 67% (6 of 9) of cases. Low circulating B cells (<0.1 × 109 cells/L), natural killer cells (<0.1 × 109 cells/L), and T cells (<0.67 × 109 cells/L) were seen in 58% (7 of 12), 33% (4 of 12), and 17% (2 of 12) of cases, respectively. In patients with normal B cells and where B-cell immunophenotyping was performed, 67% (2 of 3) had low (<2%) class-switched memory B cells (Table I).Table IUK cohort with PID and recurrent or persistent Campylobacter enteritis: Immunologic profileCaseImmune deficiencyComorbiditiesDiagnostic serum immunoglobulin levels (g/L) & postvaccination responses (where data are available)Diagnostic lymphocyte subsets (×109 cells/L)Immunoglobulin replacement (at Campylobacter diagnosis)Trough immunoglobulin level (at Campylobacter diagnosis)1CVIDBronchiectasis, proliferative bronchiolitis, asthma, obesity, raised alcohol intakeUndetectable IgA & IgMB cells 0.05, normal T & NK cellsIVIg 25 g every 3 wk8 g/L2CVIDExcised brain tumor with residual learning difficulties, previous B-cell lymphoma, pulmonary nodules, splenomegalyIgG 0.8, undetectable IgA & IgMB cells <0.01, T cells 0.15, NK cells <0.01IVIg 70 g every 2 wk13.1 g/L3CVIDIntermittent low-level CMV and EBV viremiaIgG 19 (units /mL), undetectable IgA, IgM 0.11B cells 0.02 T cells 0.14, NK cells 0.01 (class- switch memory B cells 0.9%, CD21 low B cells 6%)IVIg 30 g every 3 wk6.2 g/L4CVIDNoneUndetectable IgG, IgA, & IgM with poor response to Pneumococcal polysaccharide vaccineB cells <0.01, normal T cells, NK cells 0.03SCIg 20 g every week12.1 g/L5CVID (NFKB2 mutation)Asthma, chronic rhinosinusitisIgG 3.6, undetectable IgA, IgM 0.16 with poor response to Pneumococcal polysaccharide vaccineB cells 0.01, normal T & NK cellsIVIg 40 g every 3 wk10.9 g/L6CVIDBronchiectasis, hypersplenism, ulcerative colitisUndetectable IgA & IgMNASCIg 14 g every week11 g/L7XLA (btk mutation confirmed)BronchiectasisIgG 0.73, undetectable IgA, IgM 0.29B cells <0.01, normal T & NK cellsIVIg 40 g every 3 wk10.4 g/L8CVIDNoneIgG 0.7, undetectable IgA & IgM with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cells (class- switch memory B cells 1%)IVIg 35 g every 3 wk7.5 g/L9CVIDBronchiectasisIgG 3.8, IgA 0.53, IgM 0.61 with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cellsNo (patient declined)3.8 g/L10CVIDNoneUndetectable IgA & IgMB cells 0.03, normal T cells, NK cells 0.05IVIG 30 g every 3 wkNA11CVIDInterstitial lung disease, ischemic heart diseaseUndetectable IgG, IgM, & IgA with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cells (class- switch memory B cells 0.6%)No (began after Campylobacter diagnosis)<1.1 g/L12CVIDBronchiectasis, chronic sinusitisIgG 0.69, undetectable IgA & IgM with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cellsSCIg 12 g every week11.7 g/L13CVIDLiver nodular regenerative hyperplasia, monoclonal gammopathy of undetermined significanceIgG 3.37, IgA 0.38, IgM 0.25 with poor response to Pneumococcal polysaccharide vaccineNormal B, T, & NK cells (class-switch memory B cells 6.3%)No (patient declined)3.4 g/LCMV, Cytomegalovirus; EBV, Epstein Barr virus; IVIg, intravenous immunoglobulin; NA, not available; NK, natural killer; SCIg, subcutaneous immunoglobulin.Undetectable = <0.1 g/L for IgA & IgM, <1 g/L for IgG. Open table in a new tab CMV, Cytomegalovirus; EBV, Epstein Barr virus; IVIg, intravenous immunoglobulin; NA, not available; NK, natural killer; SCIg, subcutaneous immunoglobulin. Undetectable = <0.1 g/L for IgA & IgM, <1 g/L for IgG. The total duration of gastrointestinal symptoms varied from 10 months to 17 years, and symptoms were intermittent in 6 patients (Table II). Three patients also exhibited malabsorption and/or weight loss, and 4 had systemic symptoms and/or bacteremia. In all cases, Campylobacter jejuni was isolated, with 3 patients harboring strains that were resistant to multiple antibiotics. Detection was by stool culture in most (n = 11), but 2 patients were positive only by colonic tissue culture or PCR analysis. In certain patients, other potential causes of chronic diarrhea were detected, for example, colon inflammation, duodenal villous atrophy, and chronic norovirus infection (Table II). Clinically however, Campylobacter remained the most likely cause for their symptoms, with onset and resolution of the diarrhea coinciding with Campylobacter detection (Table II).Table IIUK cohort with PID and recurrent or persistent Campylobacter enteritis: Clinical features, microbiology, and antimicrobial therapyCaseAge at symptoms onset (y), sexGastrointestinal symptoms/ malabsorption, and durationNo. of Campylobacter- positive samplesOther GI investigationsSystemic symptomsUnsuccessful antibiotic courses (temporary or no clinical improvement)Successful antibiotic course (symptoms resolution & no recurrence for >3 mo)142, MChronic diarrhea for 10 mo10× Campylobacter jejuni (MCS stool, multiresistant)Stool: calprotectin normal; negative for other bacteria, parasites, Norovirus, Enterovirus;GI endoscopy: chronic active pancolitisNoneMultiple PO clarithromycin,IV ertapenem,IV meropenemIV 1 g once a day ertapenem for 4 wk with PO neomycin for 7 d255, MIntermittent diarrhea with malabsorption and weight loss for 8 y13× C jejuni (MCS stool, multiresistant)Stool: calprotectin >600 μg/g; Norovirus+, negative for other bacteria, parasites, Enterovirus;GI endoscopies: chronic villous atrophy in duodenum, widespread focal active colitisEpisodes of arthralgia, headache and fever but negative blood MCS for Clostridium difficilePO doxycycline, clarithromycin, azithromycin, ciprofloxacin,cotrimoxazoleIV 1 g once a day ertapenem for 4 wk with PO neomycin for 7 d353, MIntermittent diarrhea for 17 y3× C jejuni (MCS stool)Stool: Norovirus+ negative for other bacteria, parasites;GI endoscopies: antral gastritis, increased intraepithelial lymphocytes and substantial villous atrophy in duodenum, mild active chronic inflammation without granulomata in colonNone (blood MCS not tested)PO coamoxiclav, neomycin, rifaximin, immunoglobulin; IV meropenem, ertapenem(spontaneous resolution)460, MChronic diarrhea with malabsorption and weight /protein loss3× C jejuni (PCR & MCS stool, multiresistant)Stool: negative for other bacteria, parasites, Norovirus, Enterovirus, Adenovirus, Astrovirus, Rotavirus, Sapovirus;GI endoscopies: nil significantSeveral episodes of bacteremia (MCS confirmed)PO azithromycin; IV carbapenem, aminoglycoside, chloramphenicolIV meropenem & aminoglycoside, PO ciprofloxacin532, FChronic diarrhea for 2 y4× C jejuni (PCR & MCS stool)Stool: calprotectin 116 μg/g; Norovirus+, Helicobacter pylori+Negative for other bacteria, parasites, Enterovirus, Adenovirus, Astrovirus, Rotavirus, SapovirusNone (blood MCS not tested)NonePO azithromycin 500 mg once a day with ciprofloxacin 500 mg twice a day for 3 wk654, MChronic diarrhea for 10 mo3× C jejuni (2× MCS & 1× PCR stool)Stool: negative for other bacteria, parasitesNonePO erythromycin, azithromycin, coamoxiclav(ongoing infection)724, MIntermittent diarrhea for 3 y>10× C jejuni (MCS stool)Stool: H pylori+, calprotectin 500 μg/g; negative for other bacteria, parasites, Norovirus, Adenovirus, Astrovirus, Rotavirus, Sapovirus;GI endoscopy: colon cryptitis with crypt abscessesEpisode of suspected bacteremia (blood MCS not tested)PO ciprofloxacin, azithromycinIV meropenem for 10 d829, MIntermittent diarrhea for 12 y2× C jejuni (MCS stool)NoneNone (blood MCS not tested)NonePO clarithromycin926, FChronic diarrhea for 6 mo with weight loss1× C jejuni (MCS colonic tissue)Stool: calprotectin 907 μg/g; negative for other bacteria, parasites;GI endoscopy: severe inflammation in lamina propria with cryptitis, crypt abscess formation and prominent lymphoid follicles in right & transverse colon, mild chronic inflammatory infiltrate in left colon, negative CMV stainsFevers but negative blood MCS for C difficilePO ciprofloxacinPO azithromycin 500 mg once a day for 2 wk1060, MIntermittent diarrhea for 15 y with weight loss5× C jejuni (MCS stool)NoneNone (blood MCS not tested)NonePO erythromycin 500 mg 4 times a day for 2 wk1171, MIntermittent diarrhea for 8 y3× C jejuni (MCS stool)Stool: negative for other bacteria, parasites, Norovirus, Adenovirus, Astrovirus, Rotavirus, Sapovirus;GI endoscopy: normal colonNone (blood MCS not tested)PO clarithromycin 500 mg twice a day for 2 wk(patient passed away)1248, FIntermittent diarrhea for 4 y4× C jejuni (MCS stool)Stool: calprotectin >600 μg/g; negative for other bacteria, parasites, Norovirus, Adenovirus, Astrovirus, Rotavirus, SapovirusNone (blood MCS not tested)PO ciprofloxacin 500 mg twice a day for 2 wk, clarithromycin 3 d (not tolerated)PO ciprofloxacin 500 mg twice a day for 2 wk1355, FIntermittent diarrhea for 8 y2× C jejuni (MCS stool)Stool: negative for other bacteria, parasites, Norovirus, Adenovirus, Astrovirus, Rotavirus, Sapovirus;GI endoscopy: focal mild acute inflammation in cecumNone (blood MCS not tested)NonePO clarithromycin 500 mg twice a day for 1 wkF, female; GI, gastrointestinal; IV, intravenous; M, male; MCS, microscopy, culture & sensitivities, includes screen for Salmonella, Shigella, Giardia, Escherichia coli O157, Cryptosporidium, Giardia; PO, per os (by mouth); PCR, polymerase chain reaction. Open table in a new tab F, female; GI, gastrointestinal; IV, intravenous; M, male; MCS, microscopy, culture & sensitivities, includes screen for Salmonella, Shigella, Giardia, Escherichia coli O157, Cryptosporidium, Giardia; PO, per os (by mouth); PCR, polymerase chain reaction. Fifty-eight percent (7 of 12) of patients were on adequate immunoglobulin replacement (serum IgG trough ≥ 8 g/L) when they developed enteritis (Table I). In patients who successfully cleared the infection and had no relapse, oral macrolides (n = 5, azithromycin, clarithromycin, or erythromycin) and intravenous carbapenems (n = 4, meropenem or ertapenem) were most commonly used, followed by aminoglycosides (n = 3, eg, neomycin), oral ciprofloxacin (n = 3), and coamoxiclav (n = 1), either alone or in combination. A literature review identified 32 published cases of recurrent or persistent Campylobacter enteritis or multiple Campylobacter spp. stool isolation in PID (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org). Most were in X-linked agammaglobulinemia (XLA, n = 17), whereas 5 were in CVID and 3 in Good syndrome. Based on their diagnosis, very low or absent circulating B cells were expected to be present in at least 69% (22 of 32) of these cases, 18 with agammaglobulinemia and 3 with Good syndrome. The total duration of symptoms varied from 3 months to 15 years and resulted in weight loss in 7 of 32 (22%) cases. Sixty-six percent (21 of 32) also developed Campylobacter bacteremia, in some cases recurrent. Most stool cultures revealed C jejuni (n = 25), with Campylobacter coli being isolated in 6 cases and 1 patient harboring both. At least 20 of 32 (63%) patients were on immunoglobulin replacement when they developed enteritis, and these cases were more likely to clear the infection (80% vs 58% those who were not). The institution of immunoglobulin therapy alone led to resolution of the infection in 3 of 32 (9%) patients.1Schønheyder H.C. Søgaard P. Frederiksen W. A survey of Campylobacter bacteremia in three Danish counties, 1989 to 1994.Scand J Infect Dis. 1995; 27: 145-148Crossref PubMed Scopus (0) Google Scholar,2Borleffs J.C.C. Schellekens J.F. Brouwer E. Rozenberg-Arska M. Use of an immunoglobulin M containing preparation for treatment of two hypogammaglobulinemic patients with persistent Campylobacter jejuni infection.Eur J Clin Microbiol Infect Dis. 1993; 12: 772-775Crossref PubMed Scopus (0) Google Scholar In those patients who successfully cleared the infection, oral macrolides were most commonly used (n = 10; erythromycin, clarithromycin, or azithromycin), followed by aminoglycosides (n = 5; neomycin, gentamicin, netilmicin, or kanamycin), carbapenems (n = 5; meropenem, biapenem, or imipenem), tetracyclines (n = 4; doxycycline or minocycline), metronidazole (n = 3), fosfomycin (n = 2), ciprofloxacin (n = 1), and piperacillin (n = 1). Antibiotics were administered for a duration of 4 or more weeks in 7 of 32 (22%) cases. Overall, recurrent or persistent Campylobacter enteritis may contribute to significant morbidity in patients with PID, including debilitating diarrhea, malabsorption, weight loss, electrolyte disturbances, and bacteremia. A high index of suspicion for Campylobacter infection should be kept in these patients, particularly in those who have previously tested positive. Campylobacter can persist in the intestinal tract only giving intermittent symptoms and reinfection is commonly by the same microorganism.3Okada H. Kitazawa T. Harada S. Itoyama S. Hatakeyama S. Ota Y. et al.Combined treatment with oral kanamycin and parenteral antibiotics for a case of persistent bacteremia and intestinal carriage with Campylobacter coli.Intern Med. 2008; 47: 1363-1366Crossref Scopus (16) Google Scholar Furthermore, Campylobacter is difficult to grow even in specific culture media, and there are no validated consensus mechanisms to measure the bioburden in the gut flora, let alone eradication.4Buss J.E. Cresse M. Doyle S. Buchan B.W. Craft D.W. Young S. Campylobacter culture fails to correctly detect Campylobacter in 30% of positive patient stool specimens compared to non-cultural methods.Eur J Clin Microbiol Infect Dis. 2019; 38: 1087Crossref Scopus (25) Google Scholar Colonic tissue culture or stool PCR may thus be necessary in patients with ongoing symptoms.4Buss J.E. Cresse M. Doyle S. Buchan B.W. Craft D.W. Young S. Campylobacter culture fails to correctly detect Campylobacter in 30% of positive patient stool specimens compared to non-cultural methods.Eur J Clin Microbiol Infect Dis. 2019; 38: 1087Crossref Scopus (25) Google Scholar Other causes of chronic diarrhea should also be considered in these patients, particularly in those who remain symptomatic despite Campylobacter eradication. Most cases in our series were patients with CVID (12 of 13), in contrast to previously published cases where XLA was the most frequent diagnosis (17 of 32). This may echo improvements in patient management, with more patients being treated with adequate immunoglobulin replacement in recent years. The fact that fewer patients were suspected to be bacteremic in our cohort compared with previously published literature (31% vs 66%) also suggests the latter. The cases described above highlight the importance of humoral immunity in the prevention of chronicity or reinfection from Campylobacter spp. Previously published case reports suggest that patients who are on immunoglobulin therapy are more likely to clear the infection and immunoglobulin therapy alone led to eradication in a few cases. Most patients in our case series also had undetectable or very low diagnostic immunoglobulin levels. It is well established that most patients with CVID and XLA lack plasma cells in the lamina propria of their small and/or large intestine and this is important because the intestinal mucosa normally harbors the largest population of antibody-secreting plasma cells in the body.5Khan F. Person H. Dekio F. Ogawa M. Ho Hen Dunkin D. et al.Crohn’s-like enteritis in X-linked agammaglobulinemia: a case series and systematic review.J Allergy Clin Immunol Pract. 2021; 9: 3466-3478Abstract Full Text Full Text PDF Scopus (0) Google Scholar Interestingly, 58% of patients in our case series also had low or absent circulating B cells. This contrasts with what is known for CVID, where only 10% to 20% are expected to have low B cells.6Selenius J.S. Martelius T. Pikkarainen S. Siitonen S. Mattila E. Pietikäinen R. et al.Unexpectedly high prevalence of common variable immunodeficiency in Finland.Front Immunol. 2017; 8: 1190Crossref PubMed Scopus (39) Google Scholar This finding was echoed by the literature review, where 69% of patients were expected to have very low or absent circulating B cells based on their diagnosis. Low circulating B cells also seem to play an important role in the predisposition to other chronic gastrointestinal infections, like norovirus.7Grammatikos A. Moghaddas F. Reeve H. Johnston S. Gompels M. Albur M. Low circulating B cells in immunocompromised individuals are linked to poorer antibody responses to vaccines and a predisposition to viral infections.J Allergy Clin Immunol Global. 2023; 2: 111-113Abstract Full Text Full Text PDF Google Scholar Finally, 42% of patients in our case series had inadequate serum immunoglobulin trough levels when diagnosed with Campylobacter enteritis. These observations suggest that patients with CVID who are not maintained on adequate immunoglobulin replacement are at a higher risk of infection. In patients with CVID and low B cells in particular, higher IgG therapeutic targets may need to be considered. HIV-infected patients can also develop chronic or recurrent Campylobacter enteritis,8Molina J.M. Casin I. Hausfater P. Giretti E. Welker Y. Decazes J.M. et al.Campylobacter infections in HIV-infected patients: clinical and bacteriological features.AIDS. 1995; 9: 881-885Crossref PubMed Google Scholar but even in these patients, humoral immunity seems to play a key role: HIV patients who fail to clear the infection have poor Campylobacter-specific antibody responses while low CD4 T-cell levels do not seem to correlate with a worse outcome.9Perlman D.M. Ampel N.M. Schifman R.B. Cohn D.L. Patton C.M. Aguirre M.L. et al.Persistent Campylobacter jejuni infections in patients infected with the human immunodeficiency virus (HIV).Ann Intern Med. 1988; 108: 540-546Crossref PubMed Google Scholar In conclusion, Campylobacter enteritis is an important diagnosis to consider in patients with PID with chronic or recurrent diarrhea, particularly in those with very low diagnostic immunoglobulin levels. Diarrhea in CVID can be highly multifaceted and other potential causes should always be considered. We thank the patients for their collaboration and participation and the respective departments of the authors for supporting this study. Table E1Previously published cases of chronic/recurrent Campylobacter enteritis or Campylobacter spp. stool isolation in PIDLead author, year of publicationAge of onset (y), sexImmune deficiencyImmunoglobulin replacementSymptomsNo. of Campylobacter+ stool samplesFailed treatments (temporary or no clinical improvement)Definitive treatment (resulting in symptom resolution)Aguilar-Company et al,E1Aguilar-Company J. Los-Arcos I. Pigrau C. Rodríguez-Pardo D. Larrosa M.N. Rodríguez-Garrido V. et al.Potential use of fosfomycin-tromethamine for treatment of recurrent campylobacter species enteritis.Antimicrob Agents Chemother. 2016; 60: 4398-4400Crossref PubMed Scopus (9) Google Scholar 201664, FCVIDIVIg every 3 wkDiarrhea and hypovolemic shock1× Campylobacter jejuni, 1× Campylobacter coliNRPO fosfomycin 3 g every 48 h for 6 wkBarker et al,E2Barker C.R. Painset A. Swift C. Jenkins C. Godbole G. Maiden M.C.J. et al.Microevolution of Campylobacter jejuni during long-term infection in an immunocompromised host.Sci Rep. 2020; 1010109Crossref Scopus (11) Google Scholar 2020NRCVIDNRIntermittent diarrhea for 15 y25× C jejuniNRNRMerrick et al,E3Merrick B. Tamilarasan A.G. Luber R. Yong P.F.K. Cheent K. Irving P.M. et al.Recurrent Campylobacter jejuni infection in an immunodeficient patient treated with repeated faecal microbiota transplant (FMT)-A case report.Infect Dis Rep. 2022; 14: 56-62Crossref Scopus (0) Google Scholar 202270, FCVIDIVIg 20 g every 2 wkIntermittent diarrhea for 6 y, episode of bacteremia6× C jejuniPO clarithromycin, erythromycin, fosfomycin;IV meropenem; fecal microbiota transplantNRWard et al,E4Ward T.T. Klein K. Borthistle B.K. Jejunal infection with Campylobacter.Arch Intern Med. 1984; 144: 1072-1074Crossref PubMed Google Scholar 198442, MCVIDNRIntermittent diarrhea, malabsorption, weight loss for 7 mo3× C jejuniPO chloramphenicol, erythromycinIV metronidazole 2 g/d and neomycin 1 g/dLebar et al,E5Le Bar W.D. Menard R.R. Check F.E. Hypogammaglobulinemia and recurrent Campylobacter jejuni infection.J Infect Dis. 1985; 152: 1099-1100Crossref Scopus (18) Google Scholar 198539, FCVIDNoneIntermittent diarrhea, vomiting, and 2 episodes of bacteremia for 8 mo2× C jejuniNRIV gentamicin 70 mg for a week;PO erythromycin 500 mg 4 times a day for 2 wkLebar et al,E5Le Bar W.D. Menard R.R. Check F.E. Hypogammaglobulinemia and recurrent Campylobacter jejuni infection.J Infect Dis. 1985; 152: 1099-1100Crossref Scopus (18) Google Scholar 198524, MXLANoneIntermittent diarrhea, vomiting, and 4 episodes of bacteremia for 8 mo4× C jejuniIV tobramycinNRVan de Bruele et al,E6Van den Bruele T. Mourad-Baars P.E.C. Claas E.C.J. van der Plas R.N. Kuijper E.J. Bredius R.G.M. Campylobacter jejuni bacteremia and Helicobacter pylori in a patient with X-linked agammaglobulinemia.Eur J Clin Microbiol Infect Dis. 2010; 29: 1315-1319Crossref PubMed Scopus (0) Google Scholar 201015, MXLAIVIg every 4 wkDiarrhea, weight loss, and 2 episodes of bacteremia for 18 mo2× C jejuniPO erythromycin;IV meropenemPO doxycycline for 4 wk and azithromycin for 2 wkVan der Meer et al,E7Van der Meer J.W.M. Mouton R.P. Daha M.R. Schuurman R.K.B. Campylobacter jejuni bacteraemia as a cause of recurrent fever in a patient with hypogammaglobulinaemia.J Infect. 1986; 12: 235-239Abstract Full Text PDF PubMed Google Scholar 198624, MXLANRDiarrhea, fever4× C jejuniPO cotrimoxazole, neomycin, doxycycline;IV gentamicinNRSchonheyder et al,E8Schønheyder H.C. Søgaard P. Frederiksen W. A survey of Campylobacter bacteremia in three Danish counties, 1989 to 1994.Scand J Infect Dis. 1995; 27: 145-148Crossref PubMed Scopus (0) Google Scholar 199523, MXLANRWeight loss and 2 episodes of bacteremia for 4 wk1× C coliPenicillinIV netilmicin for 10 d and IVIgTokuda et al,E9Tokuda K. Nishi J. Miyanohara H. Sarantuya J. Iwashita M. Kamenosono A. et al.Relapsing cellulitis associated with Campylobacter coli bacteremia in an agammaglobulinemic patient.Pediatr Infect Dis J. 2004; 23: 577-579Crossref PubMed Scopus (23) Google Scholar 200422, MXLAIVIg every 3 wk2 episodes of bacteremia in 5 mo2× C coliPO clarithromycin;IV ceftazidime, cefazolin, amikacin, panipenem/ betamipronPO kanamycin 750 mg 4 times a dayChusid et al,E10Chusid M.J. Coleman C.M. Dunne W.M. Chronic asymptomatic Campylobacter bacteremia in a boy with X-linked hypogammaglobulinemia.Pediatr Infect Dis J. 1987; 6: 943-944Crossref PubMed Google Scholar 198711, MXLAIVIg every 4 wkBacteremia for 6 wk>3× C coliNRPO erythromycin; IV erythromycin, gentamicin, piperacillinHagiya et al,E11Hagiya H. Kimura K. Nishi I. Yoshida H. Yamamoto N. Akeda Y. et al.Emergence of carbapenem non-susceptible campylobacter coli after long-term treatment against recurrent bacteremia in a patient with X-linked agammaglobulinemia.Intern Med. 2018; 57: 2077-2080Crossref Scopus (12) Google Scholar 201837, MXLAIVIg every 3 wk3 episodes of bacteremia in 12 mo1× C coliPO tebipenem;IV cefazolin, meropenemIV biapenem 600 mg twice a day;PO minocycline 100 mg twice a day for 2 wk, metronidazole 250 mg 4 times a day for 4 wkAriganello et al,E12Ariganello P. Angelino G. Scarselli A. Salfa I. della Corte M. de Matteis A. et al.Relapsing Campylobacter jejuni systemic infections in a child with X-Linked agammaglobulinemia.Case Rep Pediatr. 2013; 2013: 1-3Crossref Google Scholar 201311, MXLAIVIg every 4 wkIntermittent diarrhea, and 2 episodes of bacteremia for 12 mo1× C jejuniPO ciprofloxacin;IV ceftriaxone, vancomycinIV meropenem, clarithromycinRafi et al,E13Rafi A. Matz J. An unusual case of Campylobacter jejuni pericarditis in a patient with X-linked agammaglobulinemia.Ann Allergy Asthma Immunol. 2002; 89: 362-367Abstract Full Text PDF PubMed Google Scholar2002NRXLAIVIg every 4 wk2 episodes of bacteremia in 2 y1× C jejuniIV erythromycin, ceftazidimeNRBorleffs et al,E14Borleffs J.C.C. Schellekens J.F. Brouwer E. Rozenberg-Arska M. Use of an immunoglobulin M containing preparation for treatment of two hypogammaglobulinemic patients with persistent Campylobacter jejuni infection.Eur J Clin Microbiol Infect Dis. 1993; 12: 772-775Crossref PubMed Scopus (0) Google Scholar 199323, MXLAIVIg every 3 wk2 episodes of bacteremia in 6 mo2× C jejuniPO ciprofloxacin;IV imipenemIV pentaglobin 500 mL every 3 wkBorleffs et al,E14Borleffs J.C.C. Schellekens J.F. Brouwer E. Rozenberg-Arska M. Use of an immunoglobulin M containing preparation for treatment of two hypogammaglobulinemic patients with persistent Campylobacter jejuni infection.Eur J Clin Microbiol Infect Dis. 1993; 12: 772-775Crossref PubMed Scopus (0) Google Scholar 199325, MXLAIVIg every 3 wk3 episodes of bacteremia in 6 mo3× C jejuniPO ciprofloxacin;IV imipenem, erythromycinIV pentaglobin 500 mL every 3 wkKim et al,E15Kim Y. Shin J.A. Han S.B. Cho B. Jeong D.C. Kang J.H. et al.Recurrent Campylobacter jejuni bacteremia in a patient with hypogammaglobulinemia: A case report.Medicine. 2017; 96e7238Google Scholar 201718, MXLA (suspected)IVIg every 3 wkIntermittent diarrhea, and 4 episodes of bacteremia for 18 mo2× C jejuniPO amoxicillin/ clavulanate, roxithromycin, clarithromycin, doxycycline;IV cefazolin, meropenem, amikacinNRAutenrieth et al,E16Autenrieth I.B. Schuster V. Ewald J. Harmsen D. Kreth H.W. An unusual case of refractory Campylobacter jejuni infection in a patient with X-linked agammaglobulinemia: successful combined therapy with maternal plasma and ciprofloxacin.Clin Infect Dis. 1996; 23: 526-531Crossref PubMed Google Scholar 19967, MXLAIVIg every 4 wkIntermittent diarrhea, and 4 episodes of bacteremia for 18 moSeveral C jejuniIV amoxicillin, doxycycline, imipenem, pentaglobin;PO bovine colostrumPO ciprofloxacin 250 mg twice a day for 3 wk;IV maternal plasma for 5 wkArai et al,E17Arai A. Kitano A. Sawabe E. Kanegane H. Miyawaki T. Miura O. Relapsing Campylobacter coli bacteremia with reactive arthritis in a patient with X-linked agammaglobulinemia.Intern Med. 2007; 46: 605-609Crossref Scopus (22) Google Scholar 200735, MXLAIVIg every 4 wk4 episodes of bacteremia in 18 mo2× C coliIV cefepimeIV meropenem;PO minocyclineVan der Meer et al,E7Van der Meer J.W.M. Mouton R.P. Daha M.R. Schuurman R.K.B. Campylobacter jejuni bacteraemia as a cause of recurrent fever in a patient with hypogammaglobulinaemia.J Infect. 1986; 12: 235-239Abstract Full Text PDF PubMed Google Scholar 198624, MXLAIVIgIntermittent diarrhea, and 5 episodes of bacteremia for >1 y2× C jejuniPO cotrimoxazole, neomycin, doxycycline;IM gentamicinNRKerstens et al,E18Kerstens P.J.S.M. Endtz H.P. Meis J.F.G.M. Oyen W.J.G. Koopman R.J.I. van den Broek P.J. et al.Erysipelas-like skin lesions associated with Campylobacter jejuni septicemia in patients with hypogammaglobulinemia.Eur J Clin Microbiol Infect Dis. 1992; 11: 842-847Crossref PubMed Scopus (0) Google Scholar 199224, MXLASCIgIntermittent diarrhea, and 3 episodes of bacteremia for 5 y3× C jejuniPO erythromycin, amoxicillin, flucloxacillinIV imipenem 500 mg 4 times a day for 6 wkKerstens et al,E18Kerstens P.J.S.M. Endtz H.P. Meis J.F.G.M. Oyen W.J.G. Koopman R.J.I. van den Broek P.J. et al.Erysipelas-like skin lesions associated with Campylobacter jejuni septicemia in patients with hypogammaglobulinemia.Eur J Clin Microbiol Infect Dis. 1992; 11: 842-847Crossref PubMed Scopus (0) Google Scholar 199226, MXLASCIg2 episodes of bacteremia in 2 wk2× C jejuniPO erythromycin;IV amoxicillin, flucloxacillin, gentamicinIV imipenem 500 mg 4 times a day for 2 wkPines et al,E19Pines A. Goldhammer E. Bregman J. Kaplinsky N. Frankl O. Campylobacter enteritis associated with recurrent abortions in agammaglobulinemia.Acta Obstet Gynecol Scand. 1983; 62: 279-280Crossref PubMed Google Scholar 198328, FAgammaglobulinemiaIVIgDiarrhea, weight loss, for 3 mo2× C jejuniPO cotrimoxazolePO erythromycin 1 g thrice a day and metronidazole 500 mg 4 times a dayAguilar-Company et al,E1Aguilar-Company J. Los-Arcos I. Pigrau C. Rodríguez-Pardo D. Larrosa M.N. Rodríguez-Garrido V. et al.Potential use of fosfomycin-tromethamine for treatment of recurrent campylobacter species enteritis.Antimicrob Agents Chemother. 2016; 60: 4398-4400Crossref PubMed Scopus (9) Google Scholar 201683, FGood syndromeIVIg every 2 wkIntermittent diarrhea for 6 mo1× C coliPO amoxicillin /clavulanatePO fosfomycin 3 g every 48 h for 4 wkTarr et al,E20Tarr P.E. Sneller M.C. Mechanic L.J. Economides A. Eger C.M. Strober W. et al.Infections in patients with immunodeficiency with thymoma (Good syndrome). Report of 5 cases and review of the literature.Medicine. 2001; 80: 123-133Crossref PubMed Scopus (0) Google Scholar 200157, MGood syndromeIVIg every 4 wkIntermittent diarrhea with episodes of bacteremia for 7 mo3× C jejuniNRAntibiotics (not specified)Green et al,E21Green E.S. Parker N.E. Gellert A.R. Beck E.R. Campylobacter infection mimicking Crohn’s disease in an immuno-deficient patient.Br Med J (Clin Res Ed). 1984; 289: 159Crossref PubMed Google Scholar 198451, MGood syndromeNRChronic diarrhea and weight loss for 4 mo1× C jejuniNRPO erythromycin 500 mg twice a day for a weekLever et al,E22Lever A.M.L. Dolby J.M. Webster A.D.B. Chronic campylobacter colitis and uveitis in patient with hypogammaglobulinaemia.Br Med J (Clin Res Ed). 1984; 288: 531Crossref PubMed Google Scholar 198436, FHypogammaglobulinemiaIVIg every 2 wkIntermittent diarrhea with weight loss for 6 y5× C jejuniPO erythromycin, tetracyclineIV erythromycin 600 mg thrice a day for 2 wk followed by PO 500 mg 4 times a day for 2 wkJohnson et al,E23Johnson R.J. Nolan C. Wang S.P. Shelton W.R. Blaser M.J. Persistent Campylobacter jejuni infection in an immunocompromised patient.Ann Intern Med. 1984; 100: 832-834Crossref PubMed Google Scholar 198426, FHypogammaglobulinemiaNoneIntermittent diarrhea and 4 episodes of bacteremia for 12 mo6× C jejuniPO amoxicillin, gentamicin, erythromycin;IV amoxicillin, gentamicin, tobramycin, amikacinPO doxycycline 100 mg once a day for monthsMoore et al,E24Moore J. Curran M. Wareing D. Fox A. Boyd N. Glynn G. et al.Investigation of infection with Campylobacter jejuni in a man with hypogammaglobulinaemia using PCR-single-strandedconformational polymorphism (PCR-SSCP) typing.Int J Med Microbiol. 2001; 291: 21-25Crossref Scopus (6) Google Scholar 2001NR, MHypogammaglobulinemiaNRIntermittent diarrhea and 4 episodes of bacteremia for 2 y2× C jejuniNRNRAhnen et al,E25Ahnen D.J. Brown W.R. Campylobacter enteritis in immune-deficient patients.Ann Intern Med. 1982; 96: 187-188Crossref PubMed Google Scholar 198263, MHypogammaglobulinemiaNRIntermittent diarrhea for 2 y4× C jejuniPO erythromycinPO erythromycinAhnen et al,E25Ahnen D.J. Brown W.R. Campylobacter enteritis in immune-deficient patients.Ann Intern Med. 1982; 96: 187-188Crossref PubMed Google Scholar 198239, FHypogammaglobulinemiaNRIntermittent diarrhea for 25 y2× C jejuniPO erythromycinNRPonka et al,E26Pönkä A. Tilvis R. Kosunen T.U. Prolonged campylobacter gastroenteritis in a patient with hypogammaglobulinaemia.Acta Med Scand. 1983; 213: 159-160Crossref PubMed Google Scholar 198367, FHypogammaglobulinemiaNRDiarrhea and weight loss for 4 mo2× C jejuniPO erythromycinPO erythromycin 250 mg 4 times a day for 3 wkF, female; IM, intramuscular; IV, intravenous; IVIg, intravenous immunoglobulin; M, male; NR, not reported; PO, per os (by mouth); SCIg, subcutaneous immunoglobulin. Open table in a new tab F, female; IM, intramuscular; IV, intravenous; IVIg, intravenous immunoglobulin; M, male; NR, not reported; PO, per os (by mouth); SCIg, subcutaneous immunoglobulin.

SARS-CoV-2 specific plasma cells acquire long-lived phenotypes in human bone marrow

SARS-CoV-2 specific antibody-secreting plasma cells (PC) mediating specific humoral immunity have been identified in the human bone marrow (BM) after COVID-19 or vaccination against SARS-CoV-2. However, it remained unclear whether or not they acquire phenotypes of human memory plasma cells. SARS-CoV-2-specific human bone marrow plasma cells (BMPC) were characterised by tetramer-based, antigen-specific flow cytometry and FluoroSpot assay. SARS-CoV-2 spike-S1-specific PC were detectable in all tested BM samples of previously vaccinated individuals, representing 0.22% of total BMPC. The majority of SARS-CoV-2-specific BMPC expressed IgG and their specificity for the spike S1 protein indicated emergence from a systemic vaccination response. Of note, one-fifth of SARS-CoV-2-specific BMPC showed the phenotype of memory plasma cells, i.e., downregulated CD19 and present or absent CD45 expression. Our data indicate the establishment of phenotypically diverse SARS-CoV-2-specific PC in the human BM after basic mRNA immunization, including the formation of memory phenotypes. These results suggest the induction of durable humoral immunity after basic mRNA vaccination against SARS-CoV-2. The study was supported by funding by the DFG grants TRR130 TP24, ME 3644/8-1, and the Berlin Senate. SR received funding from DFGSFB-1444 C01 Central Service Project.

Antibody responses to dietary antigens are accompanied by specific plasma cells in the infant thymus

Human infants develop IgG responses to dietary antigens during the first 2 years of life. Yet, the source of these antibodies is unclear. In previous studies we reported on the thymus as a unique functional niche for plasma cells (PCs) specific to environmental antigens. We sought to examine whether PCs specific to dietary antigens are detected in the infant thymus. We tested IgG reactivity to 112 food antigens and allergens in the serum of 20 neonates and infants using microarrays. The presence of PC-secreting IgG specific to the most prominent antigens was then assessed among thymocytes in the same cohort. Using an LC-MS proteomics approach, we looked for traces of these antigens in the thymus. Our studies first confirmed that cow's milk proteins are prevalent targets of serum IgG in early life. Subjects with the highest serum IgG titers to cow's milk proteins also harbored IgG-producing PCs specific to the same antigens in the thymic niche. Furthermore, we detected multiple peptide fragments of cow's milk antigens in the thymus. Lastly, we verified that both serum IgG and IgG secreted by thymic PCs recognized the peptide epitopes found in the thymus. Our studies reveal the presence of antibody-secreting PCs specific to common dietary antigens in the infant thymus. The presence of these antigens in the thymus suggested that activation and differentiation of specific PCs occurred in this organ. Further studies are now warranted to evaluate the possible implication of these cells in tolerance to dietary antigens.

Elevated levels of enteric IgA in an unimmunised mouse model of Hyper IgM syndrome derived from gut-associated secondary lymph organs even in the absence of germinal centres.

Patients with Human Hyper IgM syndromes (HIGM) developed pulmonary and gastrointestinal infections since infancy and most patients have mutations in the CD40 ligand (CD40L) gene. Most HIGM patients compared to healthy subjects have higher/similar IgM and lower IgG, and IgA serum concentrations but gut antibody concentrations are unknown. CD40L on activated T-cells interacts with CD40 on B-cells, essential for the formation of germinal centres (GCs) inside secondary lymphoid organs (SLOs), where high-affinity antibodies, long-lived antibody-secreting plasma cells, and memory B-cells, are produced. C57BL6-CD40 ligand deficient mice (C57BL6-cd40l -/-), are a model of HIGM, because serum immunoglobulin concentrations parallel levels observed in HIGM patients and have higher faecal IgA concentrations. In mice, TGFβ and other cytokines induce IgA production. To compare and evaluate B-cell populations and IgA-producing plasma cells in peritoneal lavage, non-gut-associated SLOs, spleen/inguinal lymph nodes (ILN), and gut-associated SLOs, mesenteric lymph nodes (MLN)/Peyer´s patches (PP) of unimmunised C57BL6-cd40l -/- and C57BL6-wild-type (WT)mice. Peritoneal lavages, spleens, ILN, MLN, and PP from 8-10 weeks old C57BL6-cd40l -/- and WT mice, were obtained. Organ cryosections were analysed by immunofluorescence and B-cell populations and IgA-positive plasma cell suspensions by flow cytometry. In unimmunised WT mice, GCs were only observed in the gut-associated SLOs, but GCs were absent in all C57BL6-cd40l -/- SLOs. PP and MLN of C57BL6-cd40l -/- mice exhibited a significantly higher number of IgA-producing cells than WT mice. In the spleen and ILN of C57BL6-cd40l- /- mice IgA-producing cells significantly decreased, while IgM-positive plasma cells increased. C57BL6-cd40l -/- B-1 cells were more abundant in all analysed SLOs, whereas in WT mice most B-1 cells were contained within the peritoneal cavity. C57BL6-cd40l -/- B-cells in MLN expressed a higher TGFβ receptor-1 than WT mice. Mouse strains small intestine microvilli (MV), have a similar frequency of IgA-positive cells. Together our results confirm the role of PP and MLN as gut inductive sites, whose characteristic features are to initiate an IgA preferential immune response production in these anatomical sites even in the absence of GCs. IgA antibodies play a pivotal role in neutralising, eliminating, and regulating potential pathogens and microorganisms in the gut.

The histone H2B ubiquitination regulator Wac is essential for plasma cell differentiation.

Naïve B cells become activated and differentiate into antibody-secreting plasma cells (PCs) when encountering antigens. Here, we reveal that the WW domain-containing adapter protein with coiled-coil (Wac), which is important for histone H2B ubiquitination (ubH2B), is essential for PC differentiation. We demonstrate that B cell-specific Wac knockout mice have severely compromised T cell-dependent and -independent antibody responses. PC differentiation is drastically compromised despite undisturbed germinal center B cell response in the mutant mice. We also observe a significant reduction in global ubH2B in Wac-deficient B cells, which is correlated with downregulated expression of some genes critical for cell metabolism. Thus, our findings demonstrate an essential role of Wac-mediated ubH2B in PC differentiation and shed light on the epigenetic mechanisms underlying this process.

Final step of B-cell differentiation into plasmablasts; the right time to activate plasma cell PIM2 kinase

The differentiation of B cells into antibody-secreting plasma cells is a complex process that involves extensive changes in morphology, lifespan, and cellular metabolism to support the high rates of antibody production. During the final stage of differentiation, B cells undergo significant expansion of their endoplasmic reticulum and mitochondria, which induces cellular stress and may lead to cell death in absence of effective inhibition of the apoptotic pathway. These changes are tightly regulated at transcriptional and epigenetic levels, as well as at post-translational level, with protein modifications playing a critical role in the process of cellular modification and adaptation.Our recent research has highlighted the pivotal role of the serine/threonine kinase PIM2 in B cell differentiation, from commitment stage to plasmablast and maintenance of expression in mature plasma cells. PIM2 has been shown to promote cell cycle progression during the final stage of differentiation and to inhibit Caspase 3 activation, raising the threshold for apoptosis. In this review, we examine the key molecular mechanisms controlled by PIM2 that contribute to plasma cell development and maintenance.

Intrinsically determined turnover underlies broad heterogeneity in plasma-cell lifespan

Antibodies produced by antibody-secreting plasma cells (ASCs) underlie multiple forms of long-lasting immunity. Here we examined the mechanisms regulating ASC turnover and persistence using a genetic reporter to time-stamp ASCs. This approach revealed ASC lifespans as heterogeneous and falling on a continuum, with only a small fraction surviving for >60days. ASC longevity past 60days was independent of isotype but correlated with a phenotype that developed progressively and ultimately associated with an underlying "long-lived" ASC (LL ASC)-enriched transcriptional program. While some of the differences between LL ASCs and other ASCs appeared to be acquired with age, other features were shared with some younger ASCs, such as high CD138 and CD93. Turnover was unaffected by altered ASC production, arguing against competition for niches as a major driver of turnover. Thus, ASC turnover is set by intrinsic lifespan limits, with steady-state population dynamics governed by niche vacancy rather than displacement.

The Use of Novel Antibodies to Characterize B cells in Health and Disease

IntroductionCD38, a glycoprotein ectoenzyme found on the surface of majority of hematopoietic cells, can exist in monomeric or multimeric conformations and enzymatic activity correlates with multimerization. During human B cell differentiation, CD38 expression levels are low on naïve and memory B cells, intermediate on transitional cells, and high on antibody-secreting plasmablasts and plasma cells. Conventional anti-CD38 (C-CD38) antibodies, recognize all CD38 formations and are not selective for identification of plasmablasts, thus requiring the use of additional antibodies including CD27. In contrast, a novel sea lamprey derived monoclonal VLRB antibody, tetVLRB MM3 (V-CD38), recognizes an epitope likely located within the catalytic site of active multimeric CD38 and therefore might be more specific to plasmablasts, which express active CD38. ObjectivesCharacterize the B cells recognized by V-CD38 in the peripheral blood of individuals with or without inborn errors of immunity (IEI). MethodsB cell subsets were characterized as described in figure 1 using conventional antibodies to CD3, CD19, IgM, CD27, C-CD38, and by V-CD38 generated by a collaborator. Results were presented as means with standard deviations (SD). Correlations were calculated using the Pearson’s Correlation Coefficient formula. ResultsTo validate our identification of plasmablasts with V-CD38, samples from patients with X-linked agammaglobulinemia lacking B cells, and tonsils rich in plasmablasts were used as negative and positive controls, respectively. Analysis of samples from 16 individuals revealed nearly identical (r = 0.99, p <.00001) proportions of CD27hi plasmablasts recognized by V-CD38 (0.51%+/-0.74%) and C-CD38 (0.49%+/-0.70%), suggesting that all cells expressed multimeric CD38. In contrast, only 45.28% ±16.19% of transitional IgMhighCD27-C-CD38int B cells were also recognized by V-CD38, (2.52%+/–3.62% and 1.15%+/–1.75%, respectively), a finding that was consistent across samples (r = 0.98, p <.00001). Preliminary studies in three IEI patients demonstrated markedly reduced plasmablasts (0.035%+/–0.026%), class-switched memory B cells (1.25% +/–1.52%) and transitional cells (1.25%+/–1.06%) compared to healthy controls (0.59%+/–0.74%, 15.29%+/–8.95%, and 2.81%+/–3.96% respectively). [Display omitted] ConclusionsWhile C-CD38 and V-CD38 antibodies can identify plasmablasts in peripheral blood, V-CD38 allows more selective detection of CD38 on plasmablasts. Some circulating transitional cells also express multimeric CD38. Additional studies will determine whether V-CD38 can better identify patients suffering from abnormal plasmablast formation and impaired production of antibodies.

Laboratory and Clinical Settings of Heavy/Light Chain (HLC) Assays in the Management of Monoclonal Gammopathies and Multiple Myeloma.

The antibody-related immune response is mediated by immunoglobulins (Igs), soluble circulating glycoproteins produced by activated B cells that, upon the recognition of specific epitopes on pathogen surfaces, activate, proliferate, and differentiate into antibody-secreting plasma cells. Although the antibodies are effectors of the humoral immune adaptive response, their overproduction in response to a dysregulated proliferation of clonal plasma cell production in tumoral conditions (i.e., multiple myeloma), enriches the serum and urinary matrices, assuming the crucial role of biomarkers. Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the expansion and accumulation of clonally activated plasma cells in bone marrow, determining the release of high amounts of monoclonal component (MC) that can be detected as intact immunoglobulin (Ig), immunoglobulin fragments, or free light chains (FLCs). The importance of detecting biomarkers for the diagnosis, monitoring, and prognosis of diseases is highlighted by the international guidelines that recommend specific assays for the analysis of intact Igs and FLC. Moreover, a developed assay called Hevylite® allows for the quantification of immunoglobulins that are both involved (iHLC) and not involved (uHLC) in the tumor process; this is a fundamental aspect of following up the patient's workup and evaluating the progression of disease, together with the treatments response. We here summarize the major points of the complex scenario involving monoclonal gammopathies and MM clinical management in view of advantages derived for the use of Hevylite®.