Circulating Antibody and Memory B-Cell Responses to C. difficile Toxins A and B in Patients with C. difficile-Associated Diarrhoea, Inflammatory Bowel Disease and Cystic Fibrosis

Monaghan, Tanya; Robins, Adrian; Knox, Alan J.; Sewell, H. F.; Mahida, Yashwant R.

doi:10.1371/journal.pone.0074452

Cited by 40 publications

(44 citation statements)

References 30 publications

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“…CTD1-specific Bmem cells were also observed in 4/8 individuals with a previous C. difficile infection. The number of CTD1-specific spots detected ranged from 0.01 to 0.1% of total IgG-secreting cells (of all specificities) and is consistent with recent observations by another laboratory (43). Therefore, Bmem cells in some human subjects encoded CTD1-specific IgG.…”

Section: Fig 5 Ctd1 Induces Functional Bmem Ighsupporting

confidence: 90%

“…Furthermore, circulating TcdB-specific IgG is a correlate of protection against recurrent CDI (45). The mechanism by which serum IgG can protect against enteric CDI is not entirely clear, but mucosal TcdB-specific IgG can be detected in human intestines (43). The neonatal IgG Fc receptor (FcRn) mediates bidirectional transport of IgG across intestinal epithelia (46).…”

Section: Figmentioning

confidence: 99%

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Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B

et al. 2016

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T he role of immune cell memory in Clostridium difficile infection (CDI) remains poorly understood. CDI is complicated by a high frequency of recurrence, often after disease has apparently resolved, and can be associated with progressively worsening pathology and ultimately death (1). However, patients that develop antibodies (Ab) capable of neutralizing two toxins secreted by C. difficile (TcdA and TcdB) are less likely to experience recurrence (reviewed in reference 2). This suggests that memory B (Bmem) cells may contribute to resistance to reinfection by encoding toxin-neutralizing Ab. Bmem cells have typically undergone affinity maturation and Ab class switch in the germinal centers of secondary lymphoid organs (3). Bmem cells are therefore poised to respond rapidly to booster vaccinations or infection, by rapidly differentiating into plasma cells that secrete class-switched, highaffinity Ab (4). Such plasma cells may display a range of short-toextreme longevity, be associated with transient or sustained Ab titers, or secrete neutralizing or nonneutralizing Ab (5-7).In earlier studies, a correlation between bacterial load and advanced age was observed during CDI, with older individuals lacking toxin-neutralizing Ab (8). In more recent work, the probability of HIV-positive patients experiencing CDI increased as their CD4 ϩ T-cell counts declined (9), which could be partly attributable to altered CD4 ϩ T-cell-dependent B cell function (10). Indeed, there is growing concern about CDI in a variety of immunocompromised individuals, including organ transplant recipients (reviewed in reference 11). These observations highlight the wellrecognized importance of B cell responses and production of toxin-neutralizing antibodies in resisting CDI. However, the underlying characteristics of the Bmem cellular response and their contributions to production of toxin-neutralizing Ab have not been described.CDI is best known as a disease of the gastrointestinal tract, causing diarrhea, and this infection may progress to a severe pathological condition in which pseudomembranous colitis and toxic megacolon are evident (1, 2). However, CDI-associated mortality may be attributable to systemic sequelae of the disease (12). Although large-scale epidemiological studies are lacking, reported systemic complications include hepatic abscesses (13), ascites (14), pleural effusion with acute respiratory distress (15, 16), and severe sepsis and multiorgan dysfunction (17).TcdA and TcdB are large clostridial toxins that contribute sub-

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Section: Fig 5 Ctd1 Induces Functional Bmem Ighsupporting

confidence: 90%

Section: Figmentioning

confidence: 99%

Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B

et al. 2016

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“…All antigens were spotted in replicates of 5 on each array. (21). The Spearman correlation coefficient was used to assess the level of agreement between the two platforms, and results are visually represented in Fig.…”

Section: Quality Control Measuresmentioning

confidence: 99%

“…In this regard, all populations previously exposed to C. difficile bacterial antigens will produce seropositive responses. Nevertheless, it should be possible to enhance sensitivity for specific antibody detection through probing the microarrays with a larger bank of longitudinal (acute and convalescent) test sera and/or activated B lymphocyte supernatant samples, which secrete antigen-specific antibodies from patients with symptomatic CDI (21) and healthy controls who do not carry C. difficile in their stool. In addition, detection sensitivity may be improved by pooling several antigenic targets specific for C. difficile.…”

Section: Fig 4 Anti-toxin a (A) And Anti-toxin B (B)mentioning

confidence: 99%

“…Several reports have also assessed antibody responses following infection and have shown protection against recurrence associated with antibody responses to TcdA, TcdB, and several nontoxin antigens (Cwp66, Cwp84, FliC, FliD, and the surface layer proteins) (15)(16)(17)(18). In contrast, other studies have reported that humoral immune responses did not influence the clinical course of CDI (18)(19)(20)(21). These conflicting reports may be attributed to heterogeneity in study design and subject populations.…”

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confidence: 99%

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Profiling Humoral Immune Responses to Clostridium difficile-Specific Antigens by Protein Microarray Analysis

Negm

Hamed

Dilnot

et al. 2015

Clin Vaccine Immunol

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g Clostridium difficile is an anaerobic, Gram-positive, and spore-forming bacterium that is the leading worldwide infective cause of hospital-acquired and antibiotic-associated diarrhea. Several studies have reported associations between humoral immunity and the clinical course of C. difficile infection (CDI). Host humoral immune responses are determined using conventional enzyme-linked immunosorbent assay (ELISA) techniques. Herein, we report the first use of a novel protein microarray assay to determine systemic IgG antibody responses against a panel of highly purified C. difficile-specific antigens, including native toxins A and B (TcdA and TcdB, respectively), recombinant fragments of toxins A and B (TxA4 and TxB4, respectively), ribotypespecific surface layer proteins (SLPs; 001, 002, 027), and control proteins (tetanus toxoid and Candida albicans). Microarrays were probed with sera from a total of 327 individuals with CDI, cystic fibrosis without diarrhea, and healthy controls. For all antigens, precision profiles demonstrated <10% coefficient of variation (CV). Significant correlation was observed between microarray and ELISA in the quantification of antitoxin A and antitoxin B IgG. These results indicate that microarray is a suitable assay for defining humoral immune responses to C. difficile protein antigens and may have potential advantages in throughput, convenience, and cost. C lostridium difficile is the leading worldwide infective cause of hospital-acquired and antibiotic-associated diarrhea, imposing a considerable financial burden on health service providers in both Europe and the United States (1-3). Infection causes a spectrum of clinical presentations ranging from an asymptomatic carrier state to severe fulminant colitis and death (4). Following successful treatment, an estimated 20% to 30% of patients with primary C. difficile infection (CDI) develop recurrence of symptoms, caused by either relapse of the original infection or reinfection with a new strain (5).This anaerobic and spore-forming bacterium exerts its major pathological effects through two proinflammatory and cytotoxic protein exotoxins, TcdA (toxin A) and TcdB (toxin B) (6). Nontoxin virulence factors, such as surface layer proteins (SLPs) and cell wall proteins, have also been described and may play a role in disease expression (7-9).The majority of healthy adults have detectable antibodies to C. difficile TcdA and TcdB in their sera that are thought to arise from colonization in infancy or from repeated exposure to C. difficile in adulthood from the environment (10, 11). Several clinical studies suggest that adaptive humoral immune responses, in particular to TcdA and TcdB, may influence clinical outcomes of CDI (12). Most notably, a landmark study in 2000 reported that a low IgG titer to TcdA, but not TcdB, at the time of infection is associated with development of symptomatic disease (13). More recently, the same group demonstrated an association between median IgG titers to TcdA and 30-day all-cause mortality (14). Several r...

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Adaptive immune response to Clostridium difficile infection: A perspective for prevention and therapy

Rees

Steiner

2018

Eur J Immunol

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Clostridium difficile infection (CDI) is one of the most important nosocomial illnesses and a major cause of morbidity and mortality. While initial treatment of CDI is usually successful, unprovoked relapses remain an important and frustrating problem. This review examines the literature describing the natural immune response to CDI, and to what extent it can explain the propensity for relapses. In particular, we discuss studies on antibody and, to a lesser extent, B cell and T cell responses in CDI. Despite years of study, there remains incomplete understanding of the natural antibody response to the major pathogenic toxins, TcdA and TcdB, and other bacterial antigens, in CDI. Recent literature suggests that a specific subset of neutralizing antibodies that target the putative carbohydrate-binding domains of TcdB and possibly TcdA have the greatest protective ability. This is further supported by recent successful clinical trials of a humanized monoclonal antibody to the major toxin TcdB. A better understanding of how and why the most protective adaptive immune response develops may lead to improved vaccine and therapeutic targets for recurrent CDI. Keywords:Clostridium difficile r Immunotherapy r TcdA r TcdB r Vaccination IntroductionClostridium difficile is a gram positive, spore-forming anaerobic bacillus that colonizes the large intestine. While asymptomatic colonization is common, Clostridium difficile infection (CDI) typically develops after opportunistic growth that occurs when antibiotic treatment diminishes the host commensal microbiota [1,2]. CDI incidence and mortality have increased dramatically in the United States, Canada, and Europe in the last 20 years [3][4][5]. More than 450 000 cases of CDI occur every year in the United States, resulting in around 29 000 deaths and costs of up to $4.8 billion dollars [5].CDI is characterized by predominantly neutrophilic inflammation within the colonic mucosa and lumen [1,6]. In patients, this causes symptoms ranging from mild diarrhea to more severe or life threatening complications, such as pseudomembranous coliCorrespondence: Dr. Theodore S. Steiner e-mail: tsteiner@mail.ubc.ca tis, toxic megacolon and death [7]. These symptoms stem from two major C. difficile toxins, TcdA and TcdB, encoded by the genes tcdA and tcdB residing in the pathogenicity locus [8][9][10]. These two large glucosyltransferases, weighing 308 and 270 kDa respectively, are believed to bind most commonly via the C-terminal, carbohydrate-binding combined repetitive oligopeptide (CROP) domain to target gut epithelial cells. Once bound, the toxins enter the cell through receptor-mediated endocytosis and autodigest using a protease domain, liberating a glucosyltransferase domain that inactivates Rho GTPases within target cells, ultimately leading to rounding and apoptosis of the target cells [11,12].The most common treatment for CDI is antibiotic therapy. Typically, vancomycin, fidaxomicin, or metronidazole is effective for most patients. However, recurring CDI is an issue for approximatel...

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Circulating Antibody and Memory B-Cell Responses to C. difficile Toxins A and B in Patients with C. difficile-Associated Diarrhoea, Inflammatory Bowel Disease and Cystic Fibrosis

Cited by 40 publications

References 30 publications

Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B

Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B

Profiling Humoral Immune Responses to Clostridium difficile-Specific Antigens by Protein Microarray Analysis

Adaptive immune response to Clostridium difficile infection: A perspective for prevention and therapy

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