Current Immunology Reviews (Discontinued) - Volume 1, Issue 2, 2005

Leukocyte function-associated antigen (LFA)-1 (CD11a/CD18) is considered to play a pivotal role in a broad range of cellular events, ranging from firm adhesion of leukocytes to endothelial cells initiating leukocyte transmigration and extravasation to functional activation of various inflammatory cells promoting type 1-immune responses. Yet, recent studies argue against the role of LFA-1 in these inflammatory responses. Additionally, recent advances establish LFA-1 as a crucial molecule in regulation of pro-inflammatory and anti-inflammatory cytokine network and in control of granulopoiesis. Thus, it seems likely that LFA-1 plays more complicated/unique roles than originally thought.

Tuberculosis (TB) remains one of the most common potentially fatal infectious diseases worldwide. The need for more effective vaccines will benefit from a better understanding of the complex interactions between Mycobacterium tuberculosis and the human immune system. Among antigen-presenting cells, dendritic cells (DCs) are thought to play a central role in immunity against this bacillus, and numerous reports published since the early 1990s have focused on this topic. The culmination of the most appealing of these reports suggests the possible ability of M. tuberculosis to manipulate DCs to promote its own survival. These views, however, are rather difficult to reconcile with previous studies demonstrating the ability of mycobacteria-infected DCs to stimulate T lymphocytes in vitro and in vivo, and to confer significant protection against TB, as illustrated in murine models. The immune response elicited in the majority (>90%) of infected individuals, though not entirely perfect, is effective enough to allow the peaceful co-existence of the host and the microbe. A more vigorous response might prove sterilizing, but might also prove detrimental to the host tissues by inducing immunopathological injuries. Limiting DC functions to a certain extent may therefore be advantageous for the human host population as a whole, regardless of the 5-10% of infected individuals who will still develop the disease. The underlying question seems to be then: who's manipulating whom?

The innate immune system promotes and guides adaptive immune responses, particularly against intracellular pathogens, through the recognition of pathogen-associated molecular patterns. An improved understanding of the functional properties of this system, its key ligand-receptor systems and their signaling cascades is a pre-requisite for the development of new strategies for immune intervention. Toll-like receptors (TLRs) represent the best-characterized family of pattern-recognition receptors. Their engagement triggers overlapping, yet distinct patterns of gene expression. This review will be mainly focused on TLR2 and the signaling/effector events triggered by its activation. TLR2 ligands, such as lipoproteins from different bacterial species, were shown to promote the expression of pro-inflammatory genes, and to lead to the activation and maturation of dendritic cells. A synthetic analog of the Mycoplasma-derived macrophage activating lipopeptide MALP-2 is an agonist of the heterodimer TLR2/TLR6. MALP-2 is a potent mucosal adjuvant, as well as an efficient immune stimulator for tumor surveillance and wound healing. TLR signaling is regulated at multiple levels, to avoid immune pathological reactions. These aspects will be dissected in this review. The understanding of the interplay between activating and inhibiting cascades might facilitate the design of novel approaches based on TLR signaling to prevent and treat human disease.

In response to antigen stimulation, naïve T helper (Th) cells develop into highly polarized effector cells that mediate effective immune responses. Th1 cells promote cellular immunity and are characterized by the production of IFN-γ, whereas Th2 cells are important for humoral immunity and produce IL-4, IL-5, and IL- 13. Both Th1- and Th2-mediated immunities are important for the host's defense against infections. However, unbalanced Th1 and Th2 responses cause autoimmune and allergic diseases, respectively. Many factors, such as the type of antigen, antigen affinity or dose, costimulation signals and the cytokine milieu influence the Th1/Th2 balance. For example, IL-12 and IFN-γ are strong Th1-promoting cytokines, whereas IL-4 and IL-6 are cytokines that drive Th2 development. In addition, tissue-specific transcription factors exist that determine the commitment of Th1 and Th2 cells for the production of distinct profiles of cytokines. Recently, it has been shown that antigen presenting cells can instruct T-cell differentiation via a cytokine-independent Notch signaling pathway. Although much knowledge has been gained during the last decade about the molecular mechanisms that drive Th1/Th2 differentiation, many questions still remain open.

Interleukin-12 (IL-12) is a heterodimeric cytokine composed of the p35 and p40 subunits. It is produced by antigen-presenting cells and plays a critical role in host defense against intracellular microbial infection and control of malignancy via its ability to stimulate both innate and adaptive immune effector cells. The potency of IL-12 renders itself to stringent regulation of the timing, locality and magnitude of its production during an immune response. Subversion of the delicate control and balance frequently leads to immunologic disorders. In this article, we provide an update, since our last review of the subject four years ago, on recent advances in: (1) uncovering of novel activities of IL-12 and related molecules in various immunological settings and models; and (2) dissection of the physiological pathways involved in the modulation of IL-12 production by pathogens and immune regulators. The increased understanding of IL-12 immunobiology and expression will likely benefit the development of therapeutic modalities to correct immune dysfunctions.

The primary component of senile plaques is the β-amyloid peptide (Aβ), and the amyloid cascade hypothesis proposes that this putative neuropathological peptide is a causal factor in the onset and progression of Alzheimer's disease (AD). Many of the strategies currently being investigated as therapies for AD are aimed at reducing the level of Aβ in the brain or blocking the assembly of the peptide into potentially pathological forms. Immunization of APP/Tg mice with fibrillar Aβ, induced anti-Aβ antibodies, which reduced Ab plaque deposition and neuritic dystrophy, astrogliosis in the brains of APP/Tg mice, and diminished learning deficits in these mice. The first clinical trial was halted, however, when 6% of the participants developed some degree of meningoencephalitis. Preliminary analysis of the first clinical trial has produced some encouraging results including a reduction in plaque load and attenuation of cognitive decline in some vaccinated patients. In this review, we discuss the current status of Aβ-immunotherapy and offer our analysis of the probable cause of the failure of the clinical trial. We believe that the development of safe and effective Aβ-immunotherapy requires selection of an antigen that will induce an adequate anti-Aβ antibody response in the absence of potentially adverse self T cell- mediated events.

Dendritic cells (DCs) are essential to the induction of pathogen-specific immune responses. The initial interaction between DC and pathogen and the activation of different pattern recognition receptors, such as C-type lectins and Toll-like receptors, dictates the immune response. A prototypic C-type lectin DC-SIGN interacts with a variety of pathogens, including HIV-1, Hepatitis C virus, Mycobacterium tuberculosis and Helicobacter pylori. Although many pathogens interact with this receptor, it is becoming evident that the immunological outcome of this interaction is specific for the pathogen. Recent results suggest that DC-SIGN might cooperate with other innate immune receptors, such as Toll-like receptors to fine-tune the immune responses. Here we will discuss the function of DC-SIGN in the interaction with the myriad of pathogens and its possible cooperation with Toll-like receptors.

The high affinity IgE Fc receptor (FcεRI) on mast cells and basophils has a central role in allergy and asthma. The β subunit of this multimeric receptor is a membrane tetra-spanning protein that encodes a nonconventional immunoreceptor tyrosine-based activation motif (ITAM) that imparts it signaling competence. This subunit was shown to amplify FcεRI signaling causing increased cellular responses such as degranulation. Polymorphisms of the β subunit have been linked to atopy, asthma, and allergy. Although considerable effort has been made to understand the functional consequence(s) of expressing these polymorphisms, the outcome has not been revealing. Recent studies show a link between β subunit polymorphisms, β gene transcription, and increased FcεRI expression. Additionally, a newly described function for the β subunit suggests an important role in downregulating cytokine production. Among the molecules whose response is dampened by FcεRIb is NFkB, a central regulator of inflammation. Collectively, these studies suggest that the β subunit is important in controlling the sensitivity and extent of an elicited response upon mast cell or basophil activation. Thus the findings, described herein, provide new insights on the mechanistic link between the FcεRIb and allergic disease.

An interesting puzzle in the field of T cell costimulation is the apparent redundancy of costimulatory molecules for T cell activation. Our analysis over the last decade of CD24 may shed some light on the issue. CD24 was first identified as a costimulatory molecule for T cell activation over 12 years ago when we used activated B cells as antigen-presenting cells. Subsequent studies using mice with a targeted mutation of CD24 revealed that CD24 has an overlapping function with CD28 although it is dispensable for T cell activation in the lymphoid organs. Surprisingly, mice with a targeted mutation of CD24 are completely resistant to experimental autoimmune encephalomyelitis (EAE). Both T cells and non-T host cells must express CD24 in order to develop EAE. CD24 expression on non-T cells controls the local expansion of the pathogenic T cells in the central nervous system (CNS), while T cell expression of the CD24 gene is essential for homeostatic proliferation of T cells in a lymphopenic environment. The significance of CD24 in human autoimmune diseases is highlighted by the discovery that CD24 polymorphism is a genetic modifier for the risk and progression of multiple sclerosis. Thus, a costimulatory molecule redundant in the lymphoid organ can be essential for immune response in target organs. This type of costimulatory molecules is an ideal target for immunotherapy of the autoimmune diseases.

The near pandemic caused by the severe acute respiratory syndrome (SARS) emphasized that new and emerging infectious diseases not only continue to plague the world but also how the scientific community can unite to rapidly identify the causative agent and develop strategies such as vaccines to control its spread. The availability of the SARS coronavirus (SARS-CoV) genome sequence paved the way for the identification of recombinant vaccine candidates for SARS. Based on previous successful animal CoV vaccines, vaccinologists focused on the major CoV structural proteins such as the spike (S) and nucleocapsid (N) proteins as vaccine candidates. We will review the vaccine strategies SARS researchers have used and discuss current SARS animal models used for vaccine evaluation. The small number of SARS cases in 2004 has raised questions about whether SARS will return as a pandemic and the cost-effectiveness of testing a SARS vaccine in human clinical trials. Finally, the SARS outbreaks identified several gaps in the response to emerging infectious diseases. The SARS Accelerated Vaccine Initiative (SAVI) was established to provide rapid solutions to a public health emergency and to develop a new research paradigm for vaccine development for newly emerging and reemerging infectious diseases.

In order to respond adequately to pathogens without damaging the host, a balance between activating and inhibitory signals is required in the immune system. Over the past years a large number of inhibitory immune receptors has been identified. Most of these receptors contain one or several Immuno receptor Tyrosine-based Inhibitory Motif (ITIM)s in the intracellular part. These ITIMs recruit SH2 domaincontaining phosphatases, which can inhibit cellular activation. Studies using knock out mice have shown that ITIM-bearing receptors have crucial and non-redundant roles in the regulation of the immune system. However, the question remains why so many different ITIM-bearing receptors are required. ITIM-bearing receptors differ in their expression patterns and recognize different ligands, thus allowing for negative regulation at different levels and stages of an immune response. In addition, ITIM-bearing receptors may deliver different signals to the cell. Apart from the SH2 domain-containing phosphatases several ITIM-bearing receptors recruit other molecules that contribute to their function. In this review we will give an overview of the current model of ITIM-mediated signaling and discuss that alternative pathways may be used by ITIM-bearing receptors.