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The air we breathe is filled with thousands of fungal spores (conidia) per cubic metre, which in certain composting environments can easily exceed 10(9) per cubic metre. They originate from more than a hundred fungal species belonging mainly to the genera Cladosporium, Penicillium, Alternaria and Aspergillus. Although these conidia contain many antigens and allergens, it is not known why airborne fungal microflora do not activate the host innate immune cells continuously and do not induce detrimental inflammatory responses following their inhalation. Here we show that the surface layer on the dormant conidia masks their recognition by the immune system and hence prevents immune response. To explore this, we used several fungal members of the airborne microflora, including the human opportunistic fungal pathogen Aspergillus fumigatus, in in vitro assays with dendritic cells and alveolar macrophages and in in vivo murine experiments. In A. fumigatus, this surface 'rodlet layer' is composed of hydrophobic RodA protein covalently bound to the conidial cell wall through glycosylphosphatidylinositol-remnants. RodA extracted from conidia of A. fumigatus was immunologically inert and did not induce dendritic cell or alveolar macrophage maturation and activation, and failed to activate helper T-cell immune responses in vivo. The removal of this surface 'rodlet/hydrophobin layer' either chemically (using hydrofluoric acid), genetically (DeltarodA mutant) or biologically (germination) resulted in conidial morphotypes inducing immune activation. All these observations show that the hydrophobic rodlet layer on the conidial cell surface immunologically silences airborne moulds.

The characteristics and functions of CD4+CD25+ regulatory cells have been well defined in murine and human systems. However, the interaction between CD4+CD25+ T cells and dendritic cells (DC) remains unclear. In this study, we examined the effect of human CD4+CD25+ T cells on maturation and function of monocyte-derived DC. We show that regulatory T cells render the DC inefficient as APCs despite prestimulation with CD40 ligand. This effect was marginally reverted by neutralizing Abs to TGF-β. There was an increased IL-10 secretion and reduced expression of costimulatory molecules in DC. Thus, in addition to direct suppressor effect on CD4+ T cells, regulatory T cells may modulate the immune response through DC.

The clinical use of intravenous immunoglobulin (IVIg) based on its immunomodulatory and anti-inflammatory potential remains an ongoing challenge. Fc␥ receptor-mediated effects of IVIg, although well elucidated in certain pathologies, cannot entirely account for its proven benefit in several autoimmune disorders mediated by autoreactive T cells. In this study, we show that prophylactic infusion of IVIg prevents the devel- IntroductionNatural CD4 ϩ CD25 ϩ regulatory T cells (nTreg) expressing the lineage marker Foxp3 are the key players in controlling immune responses and in maintenance of T-cell homeostasis. 1,2 Therapeutic induction of the Treg represents a novel approach in the treatment of autoimmune pathology. 3,4 CD4 ϩ CD25 ϩ Foxp3 ϩ nTreg develop in thymus, in contrast to "adaptive" or "induced" Treg that develop in peripheral lymphoid tissues from CD4 ϩ conventional T cells (Tconv) and are frequently Foxp3 Ϫ . Although studies have highlighted the role of cytokines interleukin-2 (IL-2), transforming growth factor-␤ (TGF-␤), and IL-10 in Treg development, other factors or mechanisms crucial to Treg homeostasis are not elucidated. 5 Intravenous immunoglobulin (IVIg) is an established therapy for several immune disorders. [6][7][8][9] Several mutually nonexclusive mechanisms have been proposed to explain the beneficial effect of IVIg 7,8 ; however, the issue remains debated and an ongoing challenge. For instance, the Fc␥R-mediated effects of IVIg 10-12 cannot entirely account for its proven benefit in several peripheral and central demyelinating diseases such as GuillainBarré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and relapsing-remitting multiple sclerosis (MS), which are primarily mediated by autoreactive T cells. 6,7,13,14 Because the T cells do not express Fc␥R, 15 the observed effects raise certain speculations, that is, if these effects could be attributed to a direct interaction of the variable region of the immunoglobulin (Ig) G molecules with the T cell or an indirect influence via other cell types such as dendritic cells (DC).During the induction phase of experimental autoimmune encephalomyelitis (EAE), myelin reactive proinflammatory CD4 ϩ T cells proliferate in the periphery, infiltrate the central nervous system (CNS) during the effector phase and, in concert with other inflammatory mediators, lead to demyelination characterized by a progressive paralysis. 16 Natural remission and recovery from relapse in EAE is associated with the recruitment or generation of Treg in the CNS. 17,18 We and others have shown that IVIg protects against EAE development only when administered prophylactically. 14,19 We reasoned that IVIg manifests its protective effect in EAE through an early modulation of autoreactive T cells, and therefore we investigated the regulatory mechanisms, particularly the effect of IVIg on regulatory T cells. Methods Animals, antigen, and tissue culture mediumWe purchased C57BL/6J mice (females, 6-8 weeks of age) from Charles River Laboratories (L'Arbresle, F...

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Normal immunoglobulin G for therapeutic use (intravenous immunoglobulin [IVIg]) is used in an increasing number of immune-mediated conditions, including acute and chronic/relapsing autoimmune diseases, transplantation, and systemic inflammatory disorders. Several mutually nonexclusive mechanisms of action account for the immunoregulatory effects of IVIg. Although IVIg inhibits T-cell proliferation and T-cell cytokine production, it is unclear whether these effects are directly dependent on the effects of IVIg on T cells or they are dependent through the inhibition of antigen-presenting cell activity. Here, we examined the effects of IVIg on differentiation, maturation, and function of dendritic cells (DCs). We show that IVIg inhibits the differentiation and maturation of DCs in vitro and abrogates the capacity of mature DC to secrete interleukin-12 (IL-12) on activation while enhancing IL-10 production. IVIg-induced down-regulation of costimulatory molecules associated with modulation of cytokine secretion resulted in the inhibition of autoreactive and alloreactive T-cell activation and proliferation. Modulation of DC maturation and function by IVIg is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions.

Atherosclerosis is associated with immune activation. T cells and macrophages infiltrate atherosclerotic plaques and disease progression is associated with formation of autoantibodies to oxidized lipoproteins. In the apo E knockout mouse, a genetic model of cholesterol-induced atherosclerosis, congenital deficiency of macrophages, lymphocytes, or interferon-␥ receptors result in reduced lesion formation. We have now evaluated whether immune modulation in the adult animal affects disease development. Injections of 7-wk-old male apo E knockout mice with polyclonal immunoglobulin preparations (ivIg) during a 5-d period reduced fatty streak formation over a 2-mo period on cholesterol diet by 35%. Fibrofatty lesions induced by diet treatment for 4 mo were reduced by 50% in mice receiving ivIg after 2 mo on the diet. ivIg treatment also reduced IgM antibodies to oxidized LDL and led to inactivation of spleen and lymph node T cells. These data indicate that ivIg inhibits atherosclerosis, that it is effective both during the fatty streak and plaque phases, and that it may act by modulating T cell activity and/or antibody production. Therefore, immunomodulation may be an effective way to prevent and/or treat atherosclerosis. ( J. Clin. Invest. 1998. 102:910-918.)

Intravenous immunoglobulin (IVIG) is a pooled preparation of normal IgG obtained from several thousand healthy donors. It is widely used in the immunotherapy of a large number of autoimmune and inflammatory diseases. The mechanisms of action of IVIG are complex and, as discussed in this review, experimental and clinical data provide an indicator that the therapeutic benefit of IVIG therapy is due to several mutually non-exclusive mechanisms affecting soluble mediators as well as cellular components of the immune system. These mechanisms depend on Fc and/or F(ab')2 fragments. A better understanding of the effector functions of IVIG should help in identification of biomarkers of responses to IVIG in autoimmune patients.