Srini V. Kaveri

Surface hydrophobin prevents immune recognition of airborne fungal spores

The air we breathe is filled with thousands of fungal spores (conidia) per cubic metre, which in certain composting environments can easily exceed 109 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 (ΔrodA 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.

Cutting Edge: Human CD4 + CD25 + T Cells Restrain the Maturation and Antigen-Presenting Function of Dendritic Cells

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.

Th17 Cells: Biology, Pathogenesis of Autoimmune and Inflammatory Diseases, and Therapeutic Strategies

Th17 cells that secrete the cytokines IL-17A and IL-17F and express lineage-specific transcription factor RORC (RORγt in mice) represent a distinct lineage of CD4(+) T cells. Transforming growth factor-β and inflammatory cytokines, such as IL-6, IL-21, IL-1β, and IL-23, play central roles in the generation of Th17 cells. Th17 cells are critical for the clearance of extracellular pathogens, including Candida and Klebsiella. However, under certain conditions, these cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSF, and CCL20, are associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, and allergy and asthma. This review discusses these disease states and the various therapeutic strategies under investigation to target Th17 cells, which include blocking the differentiation and amplification of Th17 cells, inhibiting or neutralizing the cytokines of Th17 cells, and suppressing the transcription factors specific for Th17 cells.

Self-reactive antibodies (natural autoantibodies) in healthy individuals

Antibodies that are present in the serum of healthy individuals in the absence of deliberate immunization with any antigen, are refered to as natural antibodies. A vast majority of natural antibodies react with one or more self antigens and are termed as natural autoantibodies. The importance of natural autoantibodies in immune regulation has long been neglected, since tolerance to self was thought to be primarily dependent on the deletion of autoreactive clones, rather than on peripheral suppressive mechanisms. Clonal deletion and energy cannot account, however, for the prevalence of natural autoreactivity among healthy individuals. It is now well established that autoreactive antibodies and B cells, and autoreactive T cells, are present in healthy individuals, and in virtually all vertebrate species. Autoreactive repertoires are predominantly selected early in ontogeny. Questions pertaining to the role of natural antibodies in the regulation of the immune response and maintenance of immune homeostasis and to the distinction between natural autoreactivity and pathological autoimmunity have not been adequately addressed. Here, we focus on the current knowledge on the physicochemical and functional properties of NAA in man, and the use of NAA for therapeutic intervention. reserved.

Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice.

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-gamma 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.

Intravenous Immunoglobulin: An Update on the Clinical Use and Mechanisms of Action

Initially used as a replacement therapy for immunodeficiency diseases, intravenous immunoglobulin (IVIg) is now widely used for a number of autoimmune and inflammatory diseases. Considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory effects in autoimmune and inflammatory disorders. The mechanisms of action of IVIg are complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network and of idiotype network, regulation of cell growth, and effects on the activation, differentiation, and effector functions of dendritic cells, and T and B cells.

Modulation of the cellular immune system by intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) is therapeutically used in a variety of immune-mediated diseases. The beneficial effects of IVIg in auto-antibody-mediated diseases can be explained by neutralization, accelerated clearance and prevention of Fcgamma-receptor binding of auto-antibodies. However, the means by which IVIg exerts therapeutic effects in disorders mediated by cellular immunity have remained enigmatic. Clinical improvements, followed by IVIg treatment, often extend beyond the half-life of infused IgG, thereby indicating that IVIg modifies the cellular immune compartment for a prolonged period. Here, we discuss recent advances in the understanding of different, mutually non-exclusive mechanisms of action of IVIg on cells of the innate and adaptive immune system. These mechanisms might explain the beneficial effects of IVIg in certain autoimmune and inflammatory diseases.

Intravenous immunoglobulins - understanding properties and mechanisms

High‐dose intravenous immunoglobulin (IVIg) preparations are used currently for the treatment of autoimmune or inflammatory diseases. Despite numerous studies demonstrating efficacy, the precise mode of action of IVIg remains unclear. Paradoxically, IgG can exert both pro‐ and anti‐inflammatory activities, depending on its concentration. The proinflammatory activity of low‐dose IVIg requires complement activation or binding of the Fc fragment of IgG to IgG‐specific receptors (FcγR) on innate immune effector cells. In contrast, when administered in high concentrations, IVIg has anti‐inflammatory properties. How this anti‐inflammatory effect is mediated has not yet been elucidated fully, and several mutually non‐exclusive mechanisms have been proposed. This paper represents the proceedings of a session entitled ‘IVIg – Understanding properties and mechanisms’ at the 6th International Immunoglobulin Symposium that was held in Interlaken on 26–28 March 2009. The presentations addressed how IgG may affect the cellular compartment, evidence for IVIg‐mediated scavenging of complement fragments, the role of the dimeric fraction of IVIg, the anti‐inflammatory properties of the minor fraction of sialylated IgG molecules, and the genetic organization and variation in FcγRs. These findings demonstrate the considerable progress that has been made in understanding the mechanisms of action of IVIgs, and may influence future perspectives in the field of Ig therapy.

Surveillance of Antigen-Presenting Cells by CD4+CD25+ Regulatory T Cells in Autoimmunity : Immunopathogenesis and Therapeutic Implications

CD4+CD25+ regulatory T cells (Tregs) play a critical role in preventing immune aggression. One way in which Tregs exert immune surveillance activities is by modifying the function of antigen presenting cells (APCs) such as dendritic cells, macrophages, and B cells. Tregs can induce apoptosis of APCs or inhibit their activation and function, thereby regulating subsequent innate and adaptive immune responses. These actions of Tregs are mediated by both soluble factors (interleukin [IL]-10, transforming growth factor-beta, perforins, granzymes) and cell-associated molecules (cytotoxic T lymphocyte antigen 4, lymphocyte activation gene-3, CD18, neuropilin-1, LFA-1/CD11a, CD39), of which cytotoxic T lymphocyte antigen 4 has a key role. However, in autoimmunity, chronically activated APCs under the influence of intracellular signaling pathways, such as phosphatidyl inositol 3 kinase, JAK-STAT, MAPK, and nuclear factor-kappaB pathways, can escape surveillance by Tregs, leading to the activation of T cells that are refractory to suppression by Tregs. Moreover, APCs and APC-derived inflammatory cytokines such as tumor necrosis factor, IL-6, IL-1beta, and IL-23 can render Tregs defective and can also reciprocally enhance the activity of the IL-17-producing pathogenic Th17 T cell subset. Emerging knowledge of the importance of APC-Treg interactions in maintaining immune tolerance and aberrations in this cross talk in autoimmune diseases provides a rationale for therapeutic approaches specifically targeting this axis of the immune system.

In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4+CD25+ regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4+ T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4+ T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design.