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Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction.

ABSTRACT: It is unclear why selective deficiency in secreted (s)IgM causes Ab-mediated autoimmunity. We demonstrate that sIgM is required for normal B cell development and selection. The CD5(+) B cells that were previously shown to accumulate in body cavities of sIgM(-/-) mice are not B-1a cells, but CD19(int), CD43(-), short-lived, BCR signaling-unresponsive anergic B-2 cells. Body cavity B-1 cells were >10-fold reduced, including VH11(+) and phosphotidylcholine-specific B-1a cells, whereas splenic B-1 cells were unaffected and marginal zone B cells increased. Follicular B cells had higher turnover rates, survived poorly after adoptive transfer, and were unresponsiveness to BCR stimulation in vitro. sIgM bound to B cell precursors and provided a positive signal to overcome a block at the pro/pre-B stage and during IgVH repertoire selection. Polyclonal IgM rescued B cell development and returned autoantibody levels to near normal. Thus, natural IgM deficiency causes primary autoimmune disease by altering B cell development, selection, and central tolerance induction.

SUBMITTER: Nguyen TT

PROVIDER: S-EPMC4324358 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction.

Nguyen Trang T T TT Elsner Rebecca A RA Baumgarth Nicole N

Journal of immunology (Baltimore, Md. : 1950) 20150116 4

It is unclear why selective deficiency in secreted (s)IgM causes Ab-mediated autoimmunity. We demonstrate that sIgM is required for normal B cell development and selection. The CD5(+) B cells that were previously shown to accumulate in body cavities of sIgM(-/-) mice are not B-1a cells, but CD19(int), CD43(-), short-lived, BCR signaling-unresponsive anergic B-2 cells. Body cavity B-1 cells were >10-fold reduced, including VH11(+) and phosphotidylcholine-specific B-1a cells, whereas splenic B-1 c ...[more]

PMID: 25595791

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Project description:UnlabelledThe initiating events in autoimmune disease remain to be completely understood, but it is thought that genetic predisposition synergizes with "environmental" factors, including viral infection, leading to disease. One elegant animal model used to study the pathogenesis of multiple sclerosis that perfectly blends genetics and environmental components in the context of virus-induced autoimmunity is Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD). TMEV-infected disease-susceptible SJL/J mice develop a persistent central nervous system (CNS) infection and later develop autoimmune demyelination, while disease-resistant C57BL/6 (B6) mice rapidly clear the infection and develop no autoimmune pathology. Mice of the (B6 × SJL/J)F1 cross between these two mouse strains are classified as intermediately susceptible. We employed this model to investigate if rapid virus clearance in B6 versus SJL/J mice was perhaps related to differences in the innate immune response in the CNS of the two strains in the first few days following intracerebral virus inoculation. Here we show that SJL/J mice lack, in addition to NK cells, a novel innate immune subset known as natural killer dendritic cells (NKDCs), which express phenotypic markers (CD11c(int) NK1.1(+)) and functional activity of both NK cells and DCs. These NKDCs are activated in the periphery and migrate into the infected CNS in a very late antigen 4 (VLA-4)-dependent fashion. Most significantly, NKDCs are critical for CNS clearance of TMEV, as transfer of NKDCs purified from B6 mice into TMEV-IDD-susceptible (B6 × SJL/J)F1 mice promotes viral clearance. Together the findings of this work show for the first time a link between NKDCs, viral infection, and CNS autoimmunity.ImportanceViral infection is an important cofactor, along with genetic susceptibility, in the initiation of a variety of organ-specific autoimmune diseases. Thus, in-depth understanding of how virus infections trigger autoimmunity may lead to novel ways to prevent or treat these diseases. Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD) serves as an important model for the human T cell-mediated autoimmune demyelinating disease multiple sclerosis. Induction of TMEV-IDD is genetically controlled as SJL/J mice develop persistent central nervous system (CNS) infection leading to chronic autoimmune demyelination, while C57BL/6 mice rapidly clear virus and are disease resistant. We determined that, as opposed to resistant B6 mice, disease-susceptible SJL/J mice lacked a unique innate immune population, the natural killer dendritic cell (NKDC), which was shown to play a critical role in early CNS virus clearance via its ability to both present virus antigen to T cells and to lyse target cells.

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Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction.

Publications

Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction.

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