The Role of Interleukin-6 in Mucosal IgA Antibody Responses in Vivo

Ramsay, Alistair J.; Husband, Alan J.; Ramshaw, Ian A.; Bao, Shisan; Matthaei, Klaus I.; Koehler, Georges; Köpf, Manfred

doi:10.1126/science.8160012

Cited by 430 publications

(241 citation statements)

References 39 publications

Supporting

Mentioning

221

Contrasting

Unclassified

Order By: Relevance

“…Culturing B cells in vitro with anti-IL-6 antibodies inhibited immunoglobulin production even when added on the fourth day of an 8-day culture, indicating that IL-6 acts on the late phase of the B cell response (5). Interestingly, a marked reduction of mucosal IgA-producing cells has been observed, along with deficient local antibody responses in IL-6-deficient mice (40). In vivo data from an open-label study of tocilizumab in SLE indicate a reduction in anti-DNA antibody and serum IgG levels (37).…”

Section: Discussionmentioning

confidence: 99%

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

Roll¹,

Muhammad²,

M³

et al. 2011

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. Interleukin-6 (IL-6) receptor inhibition by tocilizumab was recently licensed for the treatment of rheumatoid arthritis (RA). IL-6 induces in vitro differentiation of B cells into antibody-forming cells; however, the in vivo effects of IL-6 inhibition on the B cell compartment are currently not known. The purpose of this study was to examine this feature.Methods. Sixteen patients with active RA were treated in an open-label study with tocilizumab (8 mg/kg every 4 weeks). Immunophenotyping was performed at baseline, week 12, and week 24.Results. Memory B cell subsets declined significantly during tocilizumab therapy. Preswitch memory B cells decreased from a median of 19.6% to 12.3% at week 24 and postswitch memory B cells declined from a median of 18.6% to 15.0% at week 24 (P ‫؍‬ 0.04). In parallel, CD19؉IgA؉ and CD19؉IgG؉ B cells decreased significantly. The proportion of IgA-expressing B cells fell from a median of 9.2% at baseline to 4.3% at week 12 and to 3.6% at week 24 (P ‫؍‬ 0.01). IgG؉ B cells declined from a median of 6.7% at baseline to 4.9% at week 12 (P ‫؍‬ 0.007) and 2.8% at week 24 (P ‫؍‬ 0.01). In parallel, serum levels of IgA and IgG were significantly diminished at week 24 (P < 0.05). There was a good correlation between relative and absolute numbers of IgA؉ B cells with serum IgA at week 24.Conclusion. Tocilizumab induced a significant reduction in the frequency of peripheral preswitch and postswitch memory B cells. In addition, the number of IgG؉ and IgA؉ B cells declined and correlated well with reduced serum immunoglobulin levels. The data indicate that IL-6 blockade affects the B cell hyperreactivity in RA patients.

show abstract

Section: Discussionmentioning

confidence: 99%

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

Roll¹,

Muhammad²,

M³

et al. 2011

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…It functions in the terminal differentiation of B cells into plasma cells, the proliferation of lymphocytes and the regulation of IL-2 receptor expression [22][23][24]34] . Furthermore, IL-6 plays a critical role in the development of local IgA antibody responses and vector-directed cytokine gene therapy in vivo [29] .…”

Section: Discussionmentioning

confidence: 99%

“…However, the presence of IL-6 as a vaccine adjuvant can significantly elicit both the mucosal and systemic immune responses, which provides a method of stimulating mucosal immunity with the combined DNA plasmid and il-6 gene [20,28] . In vivo studies have shown that IL-6 plays a critical role in the development of mucosal IgA antibody responses, which acts as the first line of the host immune defense and is critical for the protection of mucosal tissues [29] . In this study, we determined whether co-immunization of the il-6 gene with pCIA-P induced higher levels of IgA in the saliva and IgG in the serum against PAc in intranasally immunized mice and provided better protection against dental caries in rats.…”

Section: Introductionmentioning

confidence: 99%

Intranasal co-delivery of IL-6 gene enhances the immunogenicity of anti-caries DNA vaccine

et al. 2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To investigate the effects of co-delivering IL-6 expressing plasmid pCI-IL-6 on the immunogenicity of the anti-caries DNA vaccine pCIA-P, which encodes the surface protein antigen PAc of Streptococcus mutans. Methods: Plasmid pCI-IL-6 was constructed by inserting the murine IL-6 gene into the pCI vector. Expression of IL-6 in vitro was assessed using Western blot analysis. BALB/c mice were intranasally co-immunized with pCIA-P plus pCI-IL-6 on d 0 and 14. Anti-PAc IgG and secretory IgA (sIgA) were assessed by ELISA. Splenocytes from the mice were re-stimulated with the PAc protein, and IFN-γ and IL-4 production was measured using ELISA. Splenocyte proliferation was analyzed with flow cytometry. Rats were similarly immunized, and dental caries scores were determined using the Keyes method. Results: Marked expression of IL-6 was found in COS-7 cells transfected with pCI-IL-6. In the pCI-IL-6 co-immunized mice, the specific IgG antibodies in serum and sIgA antibodies in saliva were significantly higher than those in the control mice at weeks 4 and 8. Moreover, the secretion of IFN-γ from splenocytes in response to re-stimulation with PAc protein was significantly higher in the pCI-IL-6 co-immunized mice than that in the control mice, whereas the secretion of IL-4 had no significant difference. The proliferation of splenocytes from the pCI-IL-6 co-immunized mice was significantly higher than that from the mice immunized with pCIA-P and pCI vector. In the rat caries model, the pCI-IL-6 co-immunization rats displayed lower caries scores than the control rats. Conclusion: Intranasal co-delivery of IL-6 gene significantly enhances the immunogenicity of the anti-caries DNA vaccine.

show abstract

“…While IL-6 appears to have little to do with the day-to-day "housekeeping" functions of the body, along with other cytokines it represents an important frontline component of the body's armory against infection or tissue damage (Akira et al, 1993;Nicola, 1994). In vivo studies using IL-6 knockout mice demonstrate that, while IL-6-deficient mice develop normally, they have impaired immune and acute-phase responses (Fattori et al, 1994;Kopf et al, 1994;Poli et al, 1994;Ramsay et al, 1994).…”

mentioning

confidence: 99%

Interleukin‐6: Structure‐function relationships

et al. 1997

View full text Add to dashboard Cite

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-1 1, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affhity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.

show abstract

The Role of Interleukin-6 in Mucosal IgA Antibody Responses in Vivo

Cited by 430 publications

References 39 publications

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

Intranasal co-delivery of IL-6 gene enhances the immunogenicity of anti-caries DNA vaccine

Interleukin‐6: Structure‐function relationships

Contact Info

Product

Resources

About