Pro- and Anti- Effects of Immunoglobulin A- Producing B Cell in Tumors and Its Triggers

B cells are well known as key mediators of humoral immune responses via the production of antibodies. Immunoglobulin A (IgA) is the most abundantly produced antibody isotype and provides the first line of immune protection at mucosal surfaces. However, IgA has long been a divisive molecule with respect to tumor progression. IgA exerts anti- or pro-tumor effect in different tumor types. In this review, we summarize emerging evidence regarding the production and effects of IgA and IgA+ cells in the tumor microenvironment (TME). Moreover, we discuss that the TME cytokines, host diet, microbiome, and metabolites play a pivotal role in controlling the class-switch recombination (CSR) of IgA. The analysis of intratumoral Ig repertoires and determination of metabolites that influence CSR may help establish novel therapeutic targets for the treatment of cancers.

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Blood-borne human plasma cells in steady state are derived from mucosal immune responses

Blood ◽

10.1182/blood-2008-04-153544 ◽

2009 ◽

Vol 113 (11) ◽

pp. 2461-2469 ◽

Cited By ~ 147

Author(s):

Henrik E. Mei ◽

Taketoshi Yoshida ◽

Wondossen Sime ◽

Falk Hiepe ◽

Kathi Thiele ◽

...

Keyword(s):

Bone Marrow ◽

Steady State ◽

Immune Responses ◽

Plasma Cells ◽

Immunoglobulin A ◽

Low Frequency ◽

Substantial Contribution ◽

Immune Reactions ◽

Humoral Immune ◽

Humoral Immune Responses

AbstractProviding humoral immunity, antibody-secreting plasma cells and their immediate precursors, the plasmablasts, are generated in systemic and mucosal immune reactions. Despite their key role in maintaining immunity and immunopathology, little is known about their homeostasis. Here we show that plasmablasts and plasma cells are always detectable in human blood at low frequency in any unimmunized donor. In this steady state, 80% of plasmablasts and plasma cells express immunoglobulin A (IgA). Expression of a functional mucosal chemokine receptor, C-C motif receptor 10 (CCR10) and the adhesion molecule β7 integrin suggests that these cells come from mucosal immune reactions and can return to mucosal tissue. These blood-borne, CCR10+ plasmablasts also are attracted by CXCL12. Approximately 40% of plasma cells in human bone marrow are IgA+, nonmigratory, and express β7 integrin and CCR10, suggesting a substantial contribution of mucosal plasma cells to bone marrow resident, long-lived plasma cells. Six to 8 days after parenteral tetanus/diphtheria vaccination, intracellular IgG+ cells appear in blood, both CD62L+, β7 integrin−, dividing, vaccine-specific, migratory plasmablasts and nondividing, nonmigratory, CD62L− plasma cells of different specificities. Systemic vaccination does not impact on peripheral IgA+ plasmablast numbers, indicating that mucosal and systemic humoral immune responses are regulated independent of each other.

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Protective Immunity against Canine Distemper Virus in Dogs Induced by Intranasal Immunization with a Recombinant Probiotic Expressing the Viral H Protein

Vaccines ◽

10.3390/vaccines7040213 ◽

2019 ◽

Vol 7 (4) ◽

pp. 213

Author(s):

Yanping Jiang ◽

Shuo Jia ◽

Dianzhong Zheng ◽

Fengsai Li ◽

Shengwen Wang ◽

...

Keyword(s):

Canine Distemper Virus ◽

Immunoglobulin A ◽

Canine Distemper ◽

Intranasal Route ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Protection Efficacy ◽

Specific Igg ◽

High Level ◽

H Protein

Canine distemper virus (CDV) elicits a severe contagious disease in a broad range of hosts. CDV mortality rates are 50% in domestic dogs and 100% in ferrets. Its primary infection sites are respiratory and intestinal mucosa. This study aimed to develop an effective mucosal CDV vaccine using a non-antibiotic marked probiotic pPGΔCm-T7g10-EGFP-H/L. casei 393 strain expressing the CDV H protein. Its immunogenicity in BALB/c mice was evaluated using intranasal and oral vaccinations, whereas in dogs the intranasal route was used for vaccination. Our results indicate that this probiotic vaccine can stimulate a high level of secretory immunoglobulin A (sIgA)-based mucosal and IgG-based humoral immune responses in mice. SIgA levels in the nasal lavage and lungs were significantly higher in intranasally vaccinated mice than those in orally vaccinated mice. Both antigen-specific IgG and sIgA antibodies were effectively elicited in dogs through the intranasal route and demonstrated superior immunogenicity. The immune protection efficacy of the probiotic vaccine was evaluated by challenging the immunized dogs with virulent CDV 42 days after primary immunization. Dogs of the pPGΔCm-T7g10-EGFP-H/L. casei 393 group were completely protected against CDV. The proposed probiotic vaccine could be promising for protection against CDV infection in dogs.

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Germline-activating mutations in PIK3CD compromise B cell development and function

Journal of Experimental Medicine ◽

10.1084/jem.20180010 ◽

2018 ◽

Vol 215 (8) ◽

pp. 2073-2095 ◽

Cited By ~ 33

Author(s):

Danielle T. Avery ◽

Alisa Kane ◽

Tina Nguyen ◽

Anthony Lau ◽

Akira Nguyen ◽

...

Keyword(s):

B Cell ◽

Cytidine Deaminase ◽

Pathogenic Mutation ◽

Gene Signature ◽

Cell Development ◽

B Cell Development ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Class Switch ◽

And Function

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.

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The in vivo function of a noncanonical TRAF2-binding domain in the C-terminus of CD40 in driving B-cell growth and differentiation

Blood ◽

10.1182/blood-2006-07-038414 ◽

2007 ◽

Vol 110 (1) ◽

pp. 193-200 ◽

Cited By ~ 18

Author(s):

Li-Fan Lu ◽

Cory L. Ahonen ◽

Evan F. Lind ◽

Vanitha S. Raman ◽

W. James Cook ◽

...

Keyword(s):

Immune Responses ◽

B Cell ◽

Cell Activation ◽

Affinity Maturation ◽

Functional Domain ◽

Antibody Isotype ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Cell Immunity

The recruitment of tumor necrosis factor receptor–associated factors (TRAFs) 1, 2, 3, 5, and 6 to the CD40 cytoplasmic tail upon CD40 trimerization results in downstream signaling events that ultimately lead to CD40-dependent, thymus-dependent (TD) humoral immune responses. Previously, we have shown signaling through the C-terminal tail of CD40 in the absence of canonical TRAF-binding sites is capable of signaling through an alternative TRAF2-binding site. Here, we demonstrate that B cells from mice harboring CD40 with only the C-terminal tail can activate both canonical and noncanonical NFκB signaling pathways. Moreover, while lacking germinal center formation, several hallmarks of humoral immune responses including clonal B-cell activation/expansion, antibody isotype switching, and affinity maturation remain normal. This study demonstrates a new functional domain in CD40 that controls critical aspects of B-cell immunity in an in vivo setting.

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Nano and Microparticles as Potential Oral Vaccine Carriers and Adjuvants Against Infectious Diseases

Frontiers in Pharmacology ◽

10.3389/fphar.2021.682286 ◽

2021 ◽

Vol 12 ◽

Author(s):

Seyed Davoud Jazayeri ◽

Hui Xuan Lim ◽

Kamyar Shameli ◽

Swee Keong Yeap ◽

Chit Laa Poh

Keyword(s):

Infectious Diseases ◽

Immune Responses ◽

Vaccine Development ◽

Proteolytic Enzymes ◽

Oral Vaccine ◽

Oral Immunization ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Mucosal Surfaces ◽

Successful Vaccine

Mucosal surfaces are the first site of infection for most infectious diseases and oral vaccination can provide protection as the first line of defense. Unlike systemic administration, oral immunization can stimulate cellular and humoral immune responses at both systemic and mucosal levels to induce broad-spectrum and long-lasting immunity. Therefore, to design a successful vaccine, it is essential to stimulate the mucosal as well as systemic immune responses. Successful oral vaccines need to overcome the harsh gastrointestinal environment such as the extremely low pH, proteolytic enzymes, bile salts as well as low permeability and the low immunogenicity of vaccines. In recent years, several delivery systems and adjuvants have been developed for improving oral vaccine delivery and immunogenicity. Formulation of vaccines with nanoparticles and microparticles have been shown to improve antigen stability, availability and adjuvanticity as well as immunostimulatory capacity, target delivery and specific release. This review discusses how nanoparticles (NPs) and microparticles (MPs) as oral carriers with adjuvant characteristics can be beneficial in oral vaccine development.

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Effects of a multispecies synbiotic on intestinal mucosa immune responses

Iranian Journal of Microbiology ◽

10.18502/ijm.v11i4.1467 ◽

2019 ◽

Cited By ~ 1

Author(s):

Alpha Fardah Athiyyah ◽

Nur Aisiyah Widjaja ◽

Pramira Fitri ◽

Ariani Setiowati ◽

Andy Darma ◽

...

Keyword(s):

Immune Responses ◽

Intestinal Mucosa ◽

Immunoglobulin A ◽

Streptococcus Thermophilus ◽

Orogastric Tube ◽

Humoral Immune ◽

Cellular Immune Responses ◽

Humoral Immune Responses ◽

Colony Forming Units ◽

Cellular Immune

Background and Objectives: Probiotics and prebiotics are known to regulate immune responses. A synbiotic is a product that combines probiotics and prebiotics in a single dosage form. In this study, we attempt to present the effects of a multispe- cies synbiotic on intestinal mucosa immune responses after exposure to Escherichia coli O55:B5 lipopolysaccharide (LPS). Materials and Methods: Totally 21 male Balb/c mice were randomly classified into two groups. The K-I group received LPS and a synbiotic, and the K-II group received LPS alone. The synbiotic was administered for 21 consecutive days, where- as LPS was administered once on the 15th day. Specifically, a synbiotic containing 1 × 109 colony forming units (CFUs) of the probiotic combination of Lactobacillus acidophilus PXN 35, L. casei subsp. casei PXN 37, L. rhamnosus PXN 54, L. bul- garicus PXN 39, Bifidobacterium breve PXN 25, B. infantis PXN 27 and Streptococcus thermophilus PXN 66 and the prebi- otic fructo-oligosaccharide was administered through an orogastric tube. Immunohistochemistry was performed to measure immunoglobulin A (IgA) levels for humoral immune responses and CD4+ and CD8+ levels for cellular immune responses. Results: An independent-samples t-test revealed significant increases of the numbers of IgA- (p = 0.027) and CD4-express- ing cells (p = 0.009) but not the number of CD8-expressing cells in the K-I group compared with those in the K-II group. Conclusion: The multispecies synbiotic had immunoregulatory effects on IgA and CD4 expression in LPS-exposed mice.

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Role of Immunoglobulin A in Protection against Reovirus Entry into Murine Peyer's Patches

Journal of Virology ◽

10.1128/jvi.75.22.10870-10879.2001 ◽

2001 ◽

Vol 75 (22) ◽

pp. 10870-10879 ◽

Cited By ~ 52

Author(s):

Katherine J. Silvey ◽

Amy B. Hutchings ◽

Michael Vajdy ◽

Mary M. Petzke ◽

Marian R. Neutra

Keyword(s):

Viral Entry ◽

Immunoglobulin A ◽

Peyer's Patches ◽

Peyer’S Patches ◽

Wild Type ◽

M Cell ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Adult Mice ◽

Reovirus Type

ABSTRACT Reovirus type 1 Lang (T1L) infects the mouse intestinal mucosa by adhering specifically to epithelial M cells and exploiting M-cell transport to enter the Peyer's patches. Oral inoculation of adult mice has been shown to elicit cellular and humoral immune responses that clear the infection within 10 days. This study was designed to determine whether adult mice that have cleared a primary infection are protected against viral entry upon oral rechallenge and, if so, whether antireovirus secretory immunoglobulin A (S-IgA) is a necessary component of protection. Adult BALB/c mice that were orally inoculated on day 0 with reovirus T1L produced antiviral S-IgA in feces and IgG in serum directed primarily against the reovirus ς1 attachment protein. Eight hours after oral reovirus challenge on day 21, the Peyer's patches of previously exposed mice contained no detectable virus whereas Peyer's patches of naive controls contained up to 2,300 PFU of reovirus/mg of tissue. Orally inoculated IgA knockout (IgA−/−) mice cleared the initial infection as effectively as wild-type mice and produced higher levels of reovirus-specific serum IgG and secretory IgM than C57BL/6 wild-type mice. When IgA−/− mice were rechallenged on day 21, however, their Peyer's patches became infected. These results indicate that intestinal S-IgA is an essential component of immune protection against reovirus entry into Peyer's patch mucosa.

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Role of Humoral Mechanisms in Etiology of Lichen Planus

PRILOZI ◽

10.1515/prilozi-2015-0023 ◽

2014 ◽

Vol 35 (3) ◽

pp. 185-194

Author(s):

Mirjana Popovska ◽

Kristina Mitik ◽

Ladislava Grchevska ◽

Aneta Atanasovska-Stojanovska ◽

Biljana Kapushevska ◽

...

Keyword(s):

Immune Response ◽

Lichen Planus ◽

Oral Mucosa ◽

Humoral Immune Response ◽

Immunoglobulin A ◽

Control Group ◽

Direct Immunofluorescence ◽

Humoral Immune

AbstractAim: To examine the role of IgA, CIC and component C3 as indicators of humoral immune response in the etiopathogenesis of oral erosive lichen planus (OELP).Material and method: The study comprised 19 patients with OELP whose samples of blood, saliva and tissue were obtained after carefully taken medical history and clinical examination. Samples of oral mucosa were taken from the site of lesion, i.e. exclusively from buccal mucosa (1 cm in width and length), and from the deep epithelium as well as a segment from the lamina propria. Determination of immunoglobulins in serum and saliva, and determination of component C3, was done using the micro-elisa technique by Rook & Cameron, Engvall and Ulman. Determination of CIC in serum and mixed saliva was done with the PEG (polyethylene glycol) method. Determination of immunoglobulin A and component C3 in biopsy material was done with direct immunofluorescence.Results: Levels of immunoglobulin A in serum in OELP during exacerbation were decreased (1.04 ± 0.49 gr/l) and during remission increased (5.92 ± 0.62) in comparison with the control group (p < 0.001). Levels of CIC during exacerbation and remission were increased (p < 0.001), and component C3 levels were increased in both examined phases in the examined group compared with the control group (p < 0.05). Deposits of IgA were registered in one (5.88%) patient with OELP and component C3 was registered in 3 (17.64%) patients.Conclusion: Changes in IgA values, as well as CIC and component C3, may correlate with changes in oral mucosa emphasizing the role of humoral immune response in the pathogenesis of oral lichen planus.

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Secretor status and humoral immune responses to Neisseria lactamica and Neisseria meningitidis

Epidemiology and Infection ◽

10.1017/s0950268800050433 ◽

1992 ◽

Vol 109 (3) ◽

pp. 445-452 ◽

Cited By ~ 9

Author(s):

A. A. Zorgani ◽

J. Stewart ◽

C. C. Blackwell ◽

R. A. Elton ◽

D. M. Weir

Keyword(s):

Secretory Iga ◽

Total Serum ◽

Blood Group Antigens ◽

Humoral Immune ◽

Neisseria Lactamica ◽

Secretor Status ◽

Humoral Immune Responses ◽

Mucosal Surfaces ◽

Secretory Igm

SUMMARYNon-secretors of ABO blood group antigens are over-represented among patients with meningococcal diseases. Lower levels of secretory IgA reported for non-secretors have been suggested to compromise mucosal defences. Total serum and salivary IgG, IgA and IgM and levels of these isotypes specific for Neisseria lactamica and five isolates of meningococci were determined by ELISA for 357 pupils and staff of a secondary school in which an outbreak of meningitis occurred. There were no differences in total or specific levels of serum IgG, IgA or IgM or salivary IgG or IgA of secretors compared with non-secretors. Non-secretors had significantly lower levels of salivary IgM (P=0·022) A similar pattern was observed for levels of IgM specific for N. lactamica and five meningococcal isolates. The significance of these results is discussed with reference to the role of secretory IgM in protection of mucosal surfaces in infants.

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Enhanced Humoral Immune Responses against Toxin A and B of Clostridium difficile is Associated with a Milder Disease Manifestation

Journal of Clinical Medicine ◽

10.3390/jcm9103241 ◽

2020 ◽

Vol 9 (10) ◽

pp. 3241

Author(s):

Wasef Na’amnih ◽

Yehuda Carmeli ◽

Valeria Asato ◽

Sophy Goren ◽

Amos Adler ◽

...

Keyword(s):

Clostridium Difficile ◽

Immune Responses ◽

Large Scale ◽

Immunoglobulin A ◽

Toxin A ◽

Disease Manifestation ◽

Humoral Immune ◽

Humoral Immune Responses ◽

And Control

The role of the humoral immune response to Clostridium difficile in modulating the severity of C. difficile infection (CDI) is unclear. We compared the levels of serum immunoglobulin G (IgG) and immunoglobulin A (IgA) against toxin A (TcdA) and toxin B (TcdB) of C. difficile between CDI and control patients and according to disease severity. The levels of IgG and IgA antibodies against TcdA and TcdB were measured in sera from patients with CDI (n = 50; 19 had severe CDI) and control patients (n = 52), using ELISA. Patients with CDI had higher levels of IgG antibodies against TcdA and TcdB than controls (p = 0.001 and p = 0.04, respectively). Higher IgG levels against TcdA and TcdB were found in patients with mild vs. severe CDI 7–14 days after the diagnosis (p = 0.004 and 0.036, respectively). A factor analysis included both IgA and IgG levels against both toxins into one composite variable, which was of higher values in patients with mild vs. severe CDI (p = 0.026). In conclusion, the systemic humoral immune responses against TcdA and TcdB might modulate the severity of CDI. These preliminary findings provide a basis for future large-scale studies and support the development and evaluation of active and passive immunotherapies for CDI management.

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