Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice
Introduction
A number of recent studies re-evaluated the function of the antiviral Type I Interferon (IFN-I) and revealed its essential role as a regulator of both the innate and adaptive immune responses. Produced soon after an infection, IFN-I participates in the early cascade of inflammatory signals and is well known for its enhancing effect on the expression of MHC molecules. It also directly promotes the induction of dendritic cells [1], acts as a survival factor for activated and memory T cells [2], [3] and directly increases B cells sensitivity to BCR ligation [4], [5]. IFN-I is also constitutively produced in the bone marrow (BM) and thymus of normal mice [6], [7] and plays a key role in setting the stringency of BCR repertoire selection [8]. These immunoregulatory activities suggest that IFN-I, may control both the magnitude and the quality of an immune response, an assumption recently confirmed for responses of an antibody to a soluble protein [9].
It is now clearly established that autoimmune responses are regulated by infection and inflammation, even though the apparent paradoxical protective or causal effects according to the models considered are not clearly understood. Hence, while infectious agents have been shown to induce autoimmune disease (AID) through antigen mimicry or epitope spreading, in other systems, infections clearly protect from AID (discussed in Ref. [10]) Similarly, while IFN-I is often used in therapeutic protocols for multiple sclerosis and some forms of Lupus, a recurrent complication of IFN-I therapy in the management of viral infection andmalignant disease is the development of autoreactiveantibodies, associated with a large spectrum of tissue destruction (reviewed in Ref. [11]). In turn, several studies evidenced that elevated titers of IFN-I in the blood of systemic Lupus erythematosous patients correlate with disease severity [12], [13]. This increased IFN-I production has been proposed to be both consequence of the disease and cause of the aggravated pathology [1], [14], [15].
Mice homozygous for the lymphoproliferation (lpr) mutation develop spontaneously an autoimmune syndrome, the severity of which is dependent on the gender and genetic background [16]. MRL lpr female mice display severe accumulation of B and T lymphocytes (lymphadenopathy and splenomegaly), high levels of serum IgG (hypergammaglobulinemia) and developarthritis and immune complexes (IC) mediated renal damages (glomerulonephritis) leading to death at about 5 months of age (reviewed in Ref. [16]). In contrast, C57Bl/6 (B6) lpr mice have normal life span and develop an indolent AID with significant lymphadenopathy and hyperglobulinemia in 4- to 6-month-old females. Genetic approaches contributed to the identification of numerous modified genes affecting susceptibility to systemic autoimmunity [17]. Alternative strategies, based on physiological analyses may also significantly contribute to the discovery of genes involved in the emergence of complex diseases.
In this work, we investigated the role of IFN-I on the onset and severity of the autoimmune syndrome developed in the lpr mutant mice. We analyzed female animals that were either treated with polyinosinic:polycytidylic acid (poly I:C), a strong inducer of IFN-I,or deficient for the IFN-I-receptor. Evaluation of the kinetic and extent of the disorder indicate that IFN-I accelerates the emergence of the syndrome and amplifies the severity of the disease. These findings demonstrate the aggravating role of type I IFN in AID. Furthermore, they provide an alternative explanation for the effects attributed to infection on the onset of AID and may help defining therapeutic strategies.
Section snippets
Animals
All mice were bred under SPF conditions in our animal facilities. C57BL/6 (B6) and B6 lpr/lpr micewere initially purchased from Jackson Laboratory (Bar Harbord, ME, USA). 129Sv IFN-I receptor-deficient mice were a gift from Michel Aguet [18]. 129;B6 lpr IFN-IR−/−and +/−mice were generated by breeding B6 lpr/lpr and 129 Sv IFN-IR−/−mice. Animals with an lpr/lpr IFNR+/− genotype were selected from the F2 progeny. F3 were used to select lpr/lpr IFN-IR−/−animals. The analyses presented pertain to
Injection of poly I:C exacerbates glomerulonephritis and immune complex deposition in the kidney of B6 lpr mice
As an initial approach to evaluate the role of IFN-I during the course of murine lupus, we injected B6 lpr with poly I:C. This synthetic double-stranded RNA is a well-known inducer of IFN-I production in vivo [21]. Deposition of IC in the kidney is a characteristic of SLE-like diseases generally thought to trigger nephritis. One-month-old female mice were injected with PBS or poly I:C three times a week, for 12 weeks. At the end of this period, IC deposition in the kidney and glomerular
Discussion
Our conclusion that IFN-I exacerbates AID in lpr mice is based on the analyses of two experimental systems. We provide a first indirect evidence by showing that sustained injection of poly I:C, a strong inducer of IFN-I, dramatically increases IC deposition, Ig titer,and lymphoaccumulation. In a second approach we show that a deficiency of IFN-IR results in little renal features, reduced lymphocyte numbers and, albeit to a lesser extent, decreased IgG titer. This latter analysis formally proves
Acknowledgements
This work was conducted in the framework of the Laboratoire Associé ‘Génétique et développement de la tolérance naturelle’, Centre National de la Recherche Scientifique, France and Fundaçao para a Ciência e a Tecnologia, Portugal. D.B. received a fellowship from the Ministère de la Recherche et de l'Education, France. J.D. was supported by the Fundaçao para a Ciência e a Tecnologia PRAXIS XXI Portugal. We thank Saõ Alpiarça Santos for processing the tissue sections, Tatiana Vassilevskaia for
References (35)
- et al.
Resident bone-marrow macrophages produce type 1 interferons that can selectively inhibits interleukine-7-driven growth of B lineage
Immunity
(1995) - et al.
Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo
Immunity
(2001) Protective role of infections and vaccinations on autoimmune diseases
J Autoimmun
(2001)- et al.
The neglected role of type I interferon in the T-cell response: implications for its clinical use
Immunol Today
(1996) - et al.
An etiopathogenic role for the type I IFN system in SLE
Trends Immunol
(2001) - et al.
Delineating the genetic basis of systemic lupus erythematosus
Immunity
(2001) - et al.
Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease
Immunity
(2000) - et al.
Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus
Immunity
(2001) - et al.
Persisting viruses and autoimmunity
J Neuroimmunol
(2000) - et al.
Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus
Science
(2001)
Type I interferons keep activated T cells alive
J Exp Med
Induction of bystander T cell proliferation by viruses and type I interferon in vivo
Science
B lymphocyte sensitivity to IgM receptor ligationis independent of maturation stage and locally determined by macrophage-derived beta-interferon
Int Immunol
Interferon-alpha/beta enhances BCR-dependent B cell responses
Int Immunol
Interferons alpha/beta inhibit IL-7-induced proliferation of CD4- CD8- CD3- CD44+ CD25+ thymocytes, but do not inhibit that of CD4- CD8- CD3- CD44- CD25- thymocytes
Immunology
Type I interferon sets the stringency of B cell repertoire selection in the bone marrow
Int Immunol
Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies
Lupus
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Present address: Laboratoire d'Immunorégulation, Centre de Recherche du CHUM, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal, H2L4M1 Canada.