Current Immunology Reviews (Discontinued) - Volume 4, Issue 3, 2008

With a relative failing of linkage and candidate gene association studies, there has been much sceptism about the ability of geneticists to identify genes for common, complex disorders. In the field of the genetics of type 1 diabetes (T1D), more than twenty years of labor-intensive and cost-expensive effort has resulted in the identification of only four T1D- predisposing loci, which are as follows: Human Leucocyte Antigens (HLA) class II, insulin gene region, cytotoxic T-lymphocyte associated 4 (CTLA-4), and protein tyrosine phosphatase, non-receptor member 22 (PTPN22). Recent technological advances and a better understanding of the genetic architecture of complex diseases has led to the development of the genome-wide association (GWA) study, which is a powerful new approach to identifying genes influencing predisposition to common, complex disease. For T1D, the implication of the GWA approach in 2005 resulted in rapid progress in the discovery of new etiological variants. To date, the involvement in T1D pathogenesis is proven for several new genes such as interleukin 2 receptor alpha (IL2RA/CD25), interferon-induced helicase domain 1 (IFIH1), and small ubiquitin-related modifier 4 (SUMO4). An extended list of likely candidates for T1D susceptibility identified through the GWA approach includes PTPN2, CD226, PPARG2, IL2/IL21, ADAM33, and some other genes. A great benefit to clinical medicine is expected in the years to come, and whilst prediction of disease and pharmacogenetics may eventually prove valuable, the greatest clinical benefit of GWA studies is likely to come from etiological insights into disease processes.

With research continuing apace, significant bidirectional interdependence between the immune system and the central nervous system (CNS) has been demonstrated, with the intervention of common messengers, cofactors and biological response modifiers. Cytokines, or biologic response modifiers, peptide hormones and neurotransmitters, as well as their receptors/ligands, are endogenous to the brain, endocrine and immune systems. These shared ligands and receptors are used as a common chemical language for communication within and between the immune and neuroendocrine systems. Such communication suggests an immunoregulatory role for the brain, on one hand, and a sensory function for the immune system, on the other hand. Furthermore, interplay between the immune, nervous and endocrine systems, so commonly known as the ‘trio’ complex, is most commonly associated with the pronounced effects of stress and stress-related conditions on immunity. The cytokines and related cofactors of the immune system are thus capable of modulating responses and certain processes in the CNS, while neuropeptides and neurotransmitters can exert their effects over cellular groups in the immune system. One way in the neuroimmunological system is controlled by the hypothalamic-pituitary-adrenals (HPA)-axis, a major coordinator and regulator of interaction among the immune, CNS and endocrine systems. The HPA axis is, therefore, the key player in stress responses; it is well established that both external and internal stressors activate the HPA axis. Cytokines, or immunotransmitters, are those chemical messengers that stimulate the HPA axis when the body is under stress or experiencing an infection. Neuroimmune interactions are essential to unravel vital communications between the immune and nervous systems in such a manner this crosstalk remains a cornerstone in maintaining and perpetuating a stance of homeostasis. It is the subject of this synopsis to tackle the issue of neuroimmune interactions, their pathways and mechanisms of action, and their relevance to physiologic and pathophysiologic arenas.

The progression of synovial inflammation and joint destruction in rheumatoid arthritis (RA) is characterized by a pronounced tumor-like expansion of the synovium. Neovascularization, which may play a pivotal role in the physiological and pathological condition, is a complex process involving endothelial cell division, selective degradation of vascular basement membranes and the surrounding extracellular matrix, and endothelial cell migration. The involvement of several endogenous molecules has been purported based on the ability of these molecules to regulate the proliferation of endothelial cells. Moreover, a number of factors which regulate both angiogenic and angiostatic functions may be crucial in promoting neovascularisation. These include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietins and chemokine family such as CXCL8 and CXCL10. This review will discuss the expression and regulation of these angiogenic and angiostatic cytokines in the context of chronic inflammatory arthritis such as RA and experimental arthritis.

The mucosal surface of the uterine cavity is a complex biosystem, which provides a barrier against the outside world and participates in both innate and acquired immune defense systems. This mucosal compartment has adapted to a dynamic, non-sterile environment challenged by a variety of antigenic/inflammatory stimuli associated with sexual intercourse and endogenous vaginal microbiota. Thus, the epithelial cells, fibroblasts, lymphocytes, macrophages, and dendritic cells associated with the human endometrium possess unique features that enable them to adapt to this dynamic milieu. Rapid innate immune defenses against microbial infection usually involve the recognition of invading pathogens by specific pattern-recognition receptors recently attributed to the family of Tolllike receptors (TLRs). TLRs recognize conserved pathogen-associated molecular patterns (PAMPs) synthesized by microorganisms, but not by the host. Members of the TLR family, which includes 10 human TLRs identified to date, recognize distinct PAMPs produced by various bacterial, fungal, and viral pathogens. The available literature regarding the innate immune system of the endometrium during human reproductive processes was reviewed in order to identify studies specifically related to the expression and function of TLRs under normal as well as pathological conditions. Increased understanding of these molecules in the endometrium may provide insight into site-specific immunoregulatory mechanisms in the female reproductive tract.

In developed countries, cancer has replaced infectious diseases as a major cause of death. Currently, efforts in the immunoprevention of cancer are beginning to resemble that presented by the prevention of infectious diseases by immunization a century ago. Breast cancer is the most frequent type of tumor in women and is the first cause of death by this illness, among them. Moreover, cancer incidence will grow during next years. Some findings in autoimmunity related to breast cancer in animal models have been important to clarify mechanisms that potentiate tumor growth. Clinical and experimental data now clearly indicate that chronic inflammation significantly contributes to cancer development. Emerging out of these studies is an appreciation that persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in neoplastic microenvironment where they regulate tissue remodeling, pro-angiogenic and pro-survival pathways that together potentiate cancer development. Generally, antigens involved in autoimmune response in breast cancer are modified self-proteins or over-expressed normal proteins that induce autoantibodies (autoAbs) formation which exhibit tumor promoting actions. This article will review recent results concerning to the ability of muscarinic acetylcholine receptors (mAChR) expressed in transformed cells, to trigger auto- Abs formation either in experimental models or in breast cancer patients. We will also discuss the action of these antibodies as agonists in mAChR functions.