Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17

Peter I. Lobo, Amandeep Bajwa, Kailo H. Schlegel, John Vengal, Sang J. Lee, Liping Huang, Hong Ye, Umesh Deshmukh, Tong Wang, Hong Pei, Mark D. Okusa

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Little is known about the function of natural IgM autoantibodies, especially that of IgM anti-leukocyte autoantibodies (IgM-ALA). Natural IgM-ALA are present at birth and characteristically increase during inflammatory and infective conditions. Our prior clinical observations and those of other investigators showing fewer rejections in renal and cardiac allografts transplanted into recipients with high levels of IgM-ALA led us to investigate whether IgM-ALA regulate the inflammatory response. In this article, we show that IgM, in physiologic doses, inhibit proinflammatory cells from proliferating and producing IFN-γ and IL-17 in response to alloantigens (MLR), anti-CD3, and the glycolipid a-galactosyl ceramide. We showed in an IgM knockout murine model, with intact B cells and regulatory T cells, that there was more severe inflammation and loss of function in the absence of IgM after renal ischemia reperfusion injury and cardiac allograft rejection. Replenishing IgM in IgM knockout mice or increasing the levels of IgM-ALA in wild-type B6 mice significantly attenuated the inflammation in both of these inflammatory models that involve IFN-γ and IL-17. The protective effect on renal ischemia reperfusion injury was not observed using IgM preadsorbed with leukocytes to remove IgM-ALA. We provide data to show that the anti-inflammatory effect of IgM is mediated, in part, by inhibiting TLR-4-induced NF-κB translocation into the nucleus and inhibiting differentiation of activated T cells into Th-1 and Th-17 cells. These observations highlight the importance of IgM-ALA in regulating excess inflammation mediated by both innate and adaptive immune mechanisms and where the inflammatory response involves Th-17 cells that are not effectively regulated by regulatory T cells. Copyright

Original languageEnglish (US)
Pages (from-to)1675-1685
Number of pages11
JournalJournal of Immunology
Volume188
Issue number4
DOIs
StatePublished - Feb 15 2012

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Autoantibodies
Immunoglobulin M
Leukocytes
Inflammation
Interleukin-17
Regulatory T-Lymphocytes
Reperfusion Injury
Kidney
Allografts
Galactosylceramides
Isoantigens
anti-IgM
Glycolipids
Knockout Mice
B-Lymphocytes
Anti-Inflammatory Agents
Research Personnel
Parturition
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17. / Lobo, Peter I.; Bajwa, Amandeep; Schlegel, Kailo H.; Vengal, John; Lee, Sang J.; Huang, Liping; Ye, Hong; Deshmukh, Umesh; Wang, Tong; Pei, Hong; Okusa, Mark D.

In: Journal of Immunology, Vol. 188, No. 4, 15.02.2012, p. 1675-1685.

Research output: Contribution to journalArticle

Lobo, PI, Bajwa, A, Schlegel, KH, Vengal, J, Lee, SJ, Huang, L, Ye, H, Deshmukh, U, Wang, T, Pei, H & Okusa, MD 2012, 'Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17', Journal of Immunology, vol. 188, no. 4, pp. 1675-1685. https://doi.org/10.4049/jimmunol.1101762
Lobo, Peter I. ; Bajwa, Amandeep ; Schlegel, Kailo H. ; Vengal, John ; Lee, Sang J. ; Huang, Liping ; Ye, Hong ; Deshmukh, Umesh ; Wang, Tong ; Pei, Hong ; Okusa, Mark D. / Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17. In: Journal of Immunology. 2012 ; Vol. 188, No. 4. pp. 1675-1685.
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AU - Vengal, John

AU - Lee, Sang J.

AU - Huang, Liping

AU - Ye, Hong

AU - Deshmukh, Umesh

AU - Wang, Tong

AU - Pei, Hong

AU - Okusa, Mark D.

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AB - Little is known about the function of natural IgM autoantibodies, especially that of IgM anti-leukocyte autoantibodies (IgM-ALA). Natural IgM-ALA are present at birth and characteristically increase during inflammatory and infective conditions. Our prior clinical observations and those of other investigators showing fewer rejections in renal and cardiac allografts transplanted into recipients with high levels of IgM-ALA led us to investigate whether IgM-ALA regulate the inflammatory response. In this article, we show that IgM, in physiologic doses, inhibit proinflammatory cells from proliferating and producing IFN-γ and IL-17 in response to alloantigens (MLR), anti-CD3, and the glycolipid a-galactosyl ceramide. We showed in an IgM knockout murine model, with intact B cells and regulatory T cells, that there was more severe inflammation and loss of function in the absence of IgM after renal ischemia reperfusion injury and cardiac allograft rejection. Replenishing IgM in IgM knockout mice or increasing the levels of IgM-ALA in wild-type B6 mice significantly attenuated the inflammation in both of these inflammatory models that involve IFN-γ and IL-17. The protective effect on renal ischemia reperfusion injury was not observed using IgM preadsorbed with leukocytes to remove IgM-ALA. We provide data to show that the anti-inflammatory effect of IgM is mediated, in part, by inhibiting TLR-4-induced NF-κB translocation into the nucleus and inhibiting differentiation of activated T cells into Th-1 and Th-17 cells. These observations highlight the importance of IgM-ALA in regulating excess inflammation mediated by both innate and adaptive immune mechanisms and where the inflammatory response involves Th-17 cells that are not effectively regulated by regulatory T cells. Copyright

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