Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011;13(6):R209.
doi: 10.1186/ar3542. Epub 2011 Dec 16.

Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor

Affiliations

Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor

James J Kobie et al. Arthritis Res Ther. 2011.

Abstract

Introduction: As a group, rheumatoid arthritis (RA) patients exhibit increased risk of infection, and those treated with anti-tumor necrosis factor (TNF) therapy are at further risk. This increased susceptibility may result from a compromised humoral immune response. Therefore, we asked if short-term effector (d5-d10) and memory (1 month or later) B cell responses to antigen were compromised in RA patients treated with anti-TNF therapy.

Methods: Peripheral blood samples were obtained from RA patients, including a subset treated with anti-TNF, and from healthy controls to examine influenza-specific responses following seasonal influenza vaccination. Serum antibody was measured by hemagglutination inhibition assay. The frequency of influenza vaccine-specific antibody secreting cells and memory B cells was measured by EliSpot. Plasmablast (CD19+IgD-CD27hiCD38hi) induction was measured by flow cytometry.

Results: Compared with healthy controls, RA patients treated with anti-TNF exhibited significantly decreased influenza-specific serum antibody and memory B cell responses throughout multiple years of the study. The short-term influenza-specific effector B cell response was also significantly decreased in RA patients treated with anti-TNF as compared with healthy controls, and correlated with decreased influenza-specific memory B cells and serum antibody present at one month following vaccination.

Conclusions: RA patients treated with anti-TNF exhibit a compromised immune response to influenza vaccine, consisting of impaired effector and consequently memory B cell and antibody responses. The results suggest that the increased incidence and severity of infection observed in this patient population could be a consequence of diminished antigen-responsiveness. Therefore, this patient population would likely benefit from repeat vaccination and from vaccines with enhanced immunogenicity.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Serum hemagglutination-inhibition antibody titers. Peripheral blood was obtained prior to (baseline), and one and six months following vaccination with trivalent influenza vaccine (TIV) throughout multiple years. Influenza-specific serum antibody was measured by hemagglutination inhibition assay and geometric mean titer (GMT) determined for the indicated influenza subtype. GMT (upper 95% confidence interval (CI)/lower 95% CI) indicated. Relative difference in GMT among rheumatoid arthritis (RA) groups as compared with the healthy control (HC) group at same timepoint indicated by color. Cells with bold lines indicate significant difference (P < 0.05) compared with HC group at same timepoint. N, number of subjects measured per year. MTX, methotrexate.
Figure 2
Figure 2
Induction of serum antibodies and memory B cells. (a) The frequency of subjects within each group that had a four-fold or greater increase in serum hemagglutination inhibition assay (HAI) titer over baseline was determined in 2006/2007 through 2009/2010 influenza seasons, and combined results indicated. (b) Total B cells were isolated, cultured with CpG and IL-2 for four days, and trivalent influenza vaccine (TIV) and total IgG specific EliSpots performed to determine the frequency of TIV-specific memory B cells. The frequency of subjects that had a four-fold or greater increase in the frequency of TIV-specific IgG memory B cells over baseline is presented. The red star indicates significant difference (P < 0.05) compared with healthy control (HC) group, the blue star indicates significant difference as compared with rheumatoid arthritis (RA) group. An individual subject may have provided data from multiple study years. N, the cumulative number of paired subject events measured throughout the multiple years.
Figure 3
Figure 3
Plasmablast and antibody secreting cell response. The frequency of peripheral blood plasmablasts (IgD-CD24-CD27++CD38++) among total CD19+ B cells was determined by flow cytometry at baseline, day five to day seven, and day eight to day ten following vaccination with seasonal trivalent influenza vaccine (TIV). (a) Identification of plasmablasts from representative subjects at day five to day seven following 2010-2011 TIV. Plots are gated on live, CD3-CD19+IgD-CD24- cells. (b) Fold change in plasmablast frequency over baseline following 2009-2010 TIV is indicated. (c) TIV IgG-specific EliSpots were performed on total peripheral blood mononuclear cells (PBMC) following 2009-2010 TIV. The red star indicates significant difference (P < 0.05) as compared with healthy control (HC) group, the blue star indicates significant difference as compared with rheumatoid arthritis (RA) group. Each symbol represents an individual study subject, red line indicates group mean.
Figure 4
Figure 4
Influenza-specific serum antibodies following 2009-2010 TIV. Peripheral blood was obtained prior to (0) and at multiple time points within one month following vaccination with 2009 to 2010 seasonal trivalent influenza vaccine (TIV). Influenza-specific serum antibody was measured by hemagglutination inhibition assay (HAI) and geometric mean titer (GMT) determined. The red star indicates significant difference (P < 0.05) compared with healthy control (HC) group at same timepoint, the blue star indicates significant difference compared with the rheumatoid arthritis (RA) group at same timepoint. N, number of subjects measured for each group.
Figure 5
Figure 5
Comparison of effector and memory response following 2009-2010 TIV. (a) Trivalent influenza vaccine (TIV) IgG antibody-secreting cells (ASC) at day five to day seven vs. frequency of IgG TIV-specific memory B cells and (b) change in hemagglutination inhibition (HAI) titer as measured at one month. Fold change in IgD-CD27++CD38++ plasmablasts at (c) day five to day seven vs. frequency of IgG TIV-specific memory B cells and (d) change in HAI titer as measured at one month. Each symbol represents an individual study subject. Healthy controls (HC; n = 9 to 11), rheumatoid arthritis (RA; n = 3 to 5), RA+methotrexate (MTX; n = 3 to 4), RA+aTNF (n = 3 to 6). Spearman one-tailed correlation co-efficient (r) and significance (P) is indicated.

Comment in

References

    1. Furst DE. The risk of infections with biologic therapies for rheumatoid arthritis. Seminars in arthritis and rheumatism. 2010;39:327–346. doi: 10.1016/j.semarthrit.2008.10.002. - DOI - PubMed
    1. van Assen S, Elkayam O, Agmon-Levin N, Cervera R, Doran MF, Dougados M, Emery P, Geborek P, Ioannidis JP, Jayne DR, Kallenberg CG, Müller-Ladner U, Shoenfeld Y, Stojanovich L, Valesini G, Wulffraat NM, Bijl M. Vaccination in adult patients with auto-immune inflammatory rheumatic diseases: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases. Autoimmun Rev. 2011;10:341–352. doi: 10.1016/j.autrev.2010.12.003. - DOI - PubMed
    1. Kim SY, Solomon DH. Tumor necrosis factor blockade and the risk of viral infection. Nat Rev Rheumatol. 2010;6:165–174. doi: 10.1038/nrrheum.2009.279. - DOI - PMC - PubMed
    1. Gelinck LB, van der Bijl AE, Beyer WE, Visser LG, Huizinga TW, van Hogezand RA, Rimmelzwaan GF, Kroon FP. The effect of anti-tumour necrosis factor alpha treatment on the antibody response to influenza vaccination. Ann Rheum Dis. 2008;67:713–716. - PubMed
    1. Gelinck LB, van den Bemt BJ, Marijt WA, van der Bijl AE, Visser LG, Cats HA, Rimmelzwaan GF, Kroon FP. Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible. Vaccine. 2009;27:2469–2474. doi: 10.1016/j.vaccine.2009.02.053. - DOI - PubMed

Publication types

MeSH terms