IL-4, IL-10, IL-13, and TGF-β from an Altered Peptide Ligand-Specific Th2 Cell Clone Down-Regulate Adoptive Transfer of Experimental Autoimmune Encephalomyelitis

Females tend to have stronger Th1-mediated immune responses and are more prone to develop autoimmune diseases, including multiple sclerosis. Macrophages are major effector cells capable of mediating or modulating immune responses in experimental autoimmune encephalomyelitis (EAE). IL-13 and estrogen have opposing roles on macrophages (the former enhancing and the latter inhibiting) in terms of MHC class II (MHC II) up-regulation and, thus, these factors might influence susceptibility to EAE differently in females vs males. In accordance with this hypothesis, females lacking IL-13 displayed lower incidence and milder EAE disease severity than males after immunization with myelin oligodendrocyte glycoprotein (MOG)-35–55 peptide/CFA/pertussis toxin. Female IL-13 knockout (KO) mice with EAE consistently had reduced infiltration of CD11b+ macrophages in the CNS along with significantly reduced expression of MHC II on these cells. Impaired MHC II expression was further corroborated upon LPS stimulation of female but not male bone marrow-derived CD11b+ macrophages from IL-13KO mice, with restored expression after IL-13 pretreatment of female but not male macrophages. APCs from IL-13KO females induced less proliferation by MOG-35–55-reactive T cells, and splenocytes from MOG peptide-immunized females had lower expression of IL-12, IFN-γ, MIP-2, and IFN-γ-inducible protein 10 than males. In contrast, these splenocytes had higher expression of anti-inflammatory factors, IL-10, TGF-β1, and FoxP3, a cytokine pattern typical of regulatory type II monocytes. These data suggest that the difference in EAE susceptibility in females is strongly influenced by gender-specific proinflammatory effects of IL-13, mediated in part through up-regulation of Th1-inducing cytokines and MHC II on CD11b+ macrophages.

Section: Discussionmentioning

confidence: 86%

IL-13-Mediated Gender Difference in Susceptibility to Autoimmune Encephalomyelitis

Sinha

Kaler

Proctor³

et al. 2008

“…It should be noted that although NKT cells have been frequently associated with Th2 responses (61,62), depletion of only NK cells can affect IgE (63) as well as IgG1 responses under specific conditions of immunization (2). In addition, although IL-13 has generally been associated with allergic inflammation (45), the cytokine may also play a role in other diseases as well (64). It remains to be shown whether the B cell induction of IL-13 expression by NK cells plays a significant role in these responses.…”

Section: Discussionmentioning

confidence: 99%

B Cell Induction of IL-13 Expression in NK Cells: Role of CD244 and SLAM-Associated Protein

Gao

Schwartzberg

Wilder

et al. 2006

NK cells are an important component of the innate immune system that can also interact with B cells in a mutually productive manner. We have previously shown that activated B cells can induce NK cells to up-regulate their secretion of IFN-γ. In this study, we show that B cells, and, particularly, marginal zone B cells, can, in addition, induce NK cells via direct cell-cell interactions to express mRNA encoding the Th2 cytokine IL-13. The induction of NK cell IL-13 mRNA expression requires the ligation of the CD244 receptor by the CD48 ligand on B cells via signaling pathways that depend upon expression of the X-linked lymphoproliferative disease gene product, SH2D1A/DSHP/SAP (SLAM-associated protein, or SAP) in NK cells. Thus, the positive signals attributed to the B cell activation of CD244 on murine NK cells appears to be more similar to the activity of CD244 on human cells. The induction of IL-13 mRNA by B cells may account for the effect of NK cells on the generation of Th2-type responses in the presence of some adjuvants.

“…Autoantigen-reactive Th2 cells have mostly been associated with protection from autoimmune disease (32)(33)(34). However, it has recently been shown that Th2 cells can mediate autoimmune pathology in some models (35,36).…”

Section: Ifa-induced Plpp139 -151-specific Th2 Cells Are Not Renderedmentioning

confidence: 99%

Pertussis Toxin Modulates the Immune Response to Neuroantigens Injected in Incomplete Freund’s Adjuvant: Induction of Th1 Cells and Experimental Autoimmune Encephalomyelitis in the Presence of High Frequencies of Th2 Cells

Hofstetter

Shive

Forsthuber

2002

143

110

Pertussis toxin (PT) has been widely used to facilitate the induction of experimental autoimmune encephalomyelitis (EAE) in rodents. It has been suggested that this microbial product promotes EAE by opening up the blood-brain barrier and thereby facilitates the migration of pathogenic T cells to the CNS. However, PT has other biological effects that could contribute to its activity in EAE, such as enhancing the cytokine production by T cells and induction of lymphocytosis. In this work, we investigated the effects of PT on the pathogenicity, cytokine differentiation, and clonal sizes of neuroantigen-reactive T cells in EAE in mice. Our results show that PT prevented the protection from EAE conferred by injection of PLPp139–151 in IFA and induced high frequencies of peptide-specific Th1 cells and disease. Interestingly, the mice developed EAE despite the simultaneous vigorous clonal expansion of PLPp139–151-specific Th2 cells. The data indicate that the Th2 cells in this model neither were protective against EAE nor promoted the disease. Furthermore, the results suggested that the effects of the toxin on neuroantigen-reactive T cells were promoted by the PT-induced activation of APCs in lymphoid tissues and the CNS. Together, the results suggest that microbial products, such as PT, could contribute to the initiation of autoimmune disease by modulating the interaction between the innate and adaptive immune system in the response to self Ags.