Current Immunology Reviews (Discontinued) - Volume 1, Issue 3, 2005

The protozoan Toxoplasma gondii is an enormously successful parasite that asymptomatically infects 10-50 percent of the human population worldwide. During immunodeficiency, Toxoplasma emerges as a virulent pathogen causing lethal disease if untreated. The normally innocuous nature of infection is dependent upon the parasite's ability to trigger protective immunity enabling host survival, at the same time avoiding an excessively strong immune response that could cause excessive host pathology. Recent data from our laboratory and others are revealing this key principle in action within the innate immune system. Infection triggers early activation of mitogen-activated protein kinase (MAPK), nuclear factor (NF)κB and signal transducer and activator of transcription (STAT) pathways. Nevertheless, Toxoplasma suppresses other components of proinflammatory signaling, and this is likely to down-modulate effector functions of both macrophages and dendritic cells. The ability of T. gondii to simultaneously activate and suppress signal transduction in infected cells is a likely consequence of the parasite's need to manipulate cellular immunity to achieve a stable interaction at the host-parasite interface.

Hepatitis C virus (HCV) is a major problem in human health infecting 200 million chronic carriers worldwide. The HCV genome consists of a single strand of RNA and the most remarkable feature of HCV is its ability to persist in the majority (%) of infected individuals. Chronic HCV infection is associated with liver cirrhosis, the development of hepatocellular carcinoma, and extrahepatic autoimmune disease. This non-cytolytic virus has developed several mechanisms by which it can evade or subvert the host immune system. While the development of quasispecies allows the virus to escape the immune surveillance, direct interactions of HCV viral proteins with immune cells modulates host immune responses. Recently, T regulatory cells have been suggested to play a role in dampening HCV-specific T cell responses during chronic HCV infection. In addition to the virus-mediated modulation of immune response, the local environment (i.e. liver) for HCV replication influences the control of viral infection. Understanding the viral interaction with host immune system within the liver environment will prove useful to the design of new HCV therapeutics and vaccine strategies. virus.

Sepsis represents a perplexing challenge for the innate immune system. In response to microbial challenge, an immunocompetent host initiates an immediate robust response to contain and clear infection. However, if the infection is not controlled and spreads beyond the local site, this pervasive immune response, once systemic, often results in detrimental complications such as systemic inflammatory response syndrome, multiple organ failure, and immune paralysis, contributing to the high mortality observed in sepsis. Resident tissue macrophages, as sentinels of the host immune response to infection, are responsible for recognition of infection through several pattern recognition molecules and initiation of a complex cytokine/chemokine cascade. Chemokines are central mediators involved in recruitment of specific leukocyte populations to the site of infection, differentiation of classically- and alternatively-activated macrophages, and regulation of important processes such as pathogen phagocytosis and killing, release of reactive oxygen intermediates and proteases, and subsequent chemokine production. This review explores the role of the peritoneal macrophage and the importance of chemokines in macrophage activation during septic peritonitis. Continued investigation of chemokines and their mechanisms of action will provide valuable insight into the development of effective clinical therapeutics for the treatment of sepsis as well as other inflammatory disorders.

Atherosclerosis is a chronic inflammatory disease characterized by the progressive growth of lesions in the artery wall with activation of both innate and adaptive immunity. Recently, a unique group of immune cells, termed natural killer T (NKT) cells, has emerged as playing a critical role in the regulation of inflammation and immunity. NKT cells share characteristics of conventional T lymphocytes and natural killer cells and express an invariant T cell receptor, which recognizes glycolipid antigen associated with the major histocompatibility complex class I-like molecule CD1d. NKT cells play a role in protection against many autoimmune, inflammatory diseases such as type 1 diabetes, multiple sclerosis and systemic lupus erythematosus. Interestingly, new data is emerging that describes a role for NKT cells in atherosclerosis. Recent studies have shown that CD1d and NKT cells are present in the atherosclerotic lesions of both humans and mice. Furthermore, we and others have demonstrated that absence of CD1d in apolipoprotein E-deficient (apoE-/-) mice ameliorates atherosclerosis and that specific activation of NKT cells is proatherogenic. In addition, hyperlipidemic apoE-/- mice exhibit defective NKT cell numbers and functions. These findings and the well-established role of NKT cells in regulating immunity make these cells attractive targets for immunotherapy of atherosclerosis.

Human Vγ2Vδ2T cells recognize nonpeptide antigens derived from microbial pathogens in a TCR-dependent manner, such as isopentenyl pyrophosphate-related metabolites and alkyl amines. Recent crystallographic analysis of the γ2VδTCR along with the site-directed mutagenesis studies has strongly suggested that theγ2VδTCR directly interacts with nonpeptide antigens via a positively-charged pocket formed by CDR2 and CDR3 regions. Full activation ofγ2VδT cells by nonpeptide antigens leading to proliferation and cytokine production was suggested to require cognate cellular interaction with the cells displaying the antigens via specific adhesion molecules. Synthetic nitrogen-containing bisphosphonate compounds such as pamidronate were also shown to activate the same subset ofγ2VδT cells in a TCR-dependent manner. Most notably, these compounds can efficiently sensitize a wide spectrum of human tumor cells to the lysis byγ2VδT cells. These characteristics ofγ2VδT cells confer them a unique role in cross-immunity in infection and malignancy, and may provide a novel strategy for immunotherapy of human cancer.

Antigen receptors on B and T lymphocytes utilize specific adapter and scaffolding proteins to relay antigen recognition at the cell surface to the activation of downstream signaling pathways. One central pathway that is induced upon TCR and BCR ligation cumulates in the activation of NF-κB. This cascade is essential for the elicitation of proper immune responses but when aberrantly activated can also promote diseases including malignancy. Recent work identified the CARD protein BCL10 and the paracaspase MALT1 as key regulators of antigen receptor mediated NF-κB induction. The genes encoding these proteins were originally identified from recurrent chromosomal translocations in mucosa associated lymphoid tissue (MALT) lymphoma associated with advanced disease. In physiological adaptive immune responses antigen receptor proximal signaling and PKC activation induces recruitment of BCL10 and MALT1 to the scaffold protein CARMA1 at the immunoreceptor. Here BCL10 and MALT1 cooperate directly to assemble a multi protein complex that mediates lysine-63-linked ubiquitination of NEMO, the regulatory subunit of the I B kinase (IKK). This mechanism induces signal specific IKK activation, leading to phosphorylation and degradation of the NF-κB inhibitor IκB-α and finally results in controlled activation of NF-κB. However chromosomal translocations in MALT lymphoma uncouple BCL10 or MALT1 from upstream stimuli and promote antigen independent lymphoma growth with tumor progression. This review discusses the mechanisms of BCL10 and MALT1 signal transduction and their critical role in lymphocyte physiology and neoplasia.

Eosinophilic esophagitis (EE), first recognized as a unique entity some 12 years ago, is a chronic, TH2-type inflammatory disorder of the esophagus. The diagnostic criterion is a peak infiltration of the esophageal epithelium with >24 eosinophils/HPF. Though originally believed extremely rare, EE is increasingly recognized and its prevalence may soon equal chronic inflammatory bowel diseases. The main symptom of EE is dysphagia for solid foods with imminent risk of food impaction. Endoscopic abnormalities are varied but discreet, with white exudates being the most prominent sign. Though EE likely remains restricted to the esophagus, chronic inflammatory processes may induce esophageal fibrosis. Therapeutic recommendations include systemic or topical corticosteroids, leukotriene antagonists, protein elimination diet and dilation. In EE, the inflammatory pattern consists of eosinophils, T-cells and mast cells, together with increased expression of IL-5 and TNF-α . Interestingly, clinical data as well as animal studies show a striking association of EE with allergic airway disorders. Immunologic interactions between the airways and the esophagus might be transmitted, at least in part, by IL-13. Adult EE patients are most frequently sensitized to aeroallergens, whereas in children, sensitization to food allergens is predominant. Despite enormous research effort, many crucial questions remain unsolved requiring further investigation.