Current Immunology Reviews (Discontinued) - Volume 9, Issue 2, 2013

Inflammation of the middle ear, otitis media, is a significant cause of pain and reduced auditory acuity in children. Recurrent episodes may delay development of speech, learning and social behaviour. Streptococcus pneumoniae, non-typeable Haemophilus influenzae and Moraxella catarrhalis are most often implicated. These bacteria colonise the nasopharynx asymptomatically but host tolerance of high nasopharyngeal load contributes to onset of inflammation. Immunosuppression is evident in susceptible children which may contribute to tolerance and therefore to progression to chronic disease. While the causative factors involved in the immunosuppressive response are not known, evidence from other mucosal sites suggests that T regulatory (Treg) lymphocytes, a subset of T helper (TH) lymphocytes, contribute to regulation of immunosuppression to commensal bacteria and promote advancement of infection. The major function of Treg lymphocytes is induction of immune tolerance via immunosuppression in the periphery to foreign and self antigen. They have been identified in adenoids and tonsils and are known to have a positive association with pneumococcus nasopharyngeal colonisation. Interestingly, the pro-inflammatory TH lymphocyte response to S. pneumoniae is reduced in pneumococcal-positive children. Furthermore, inadequate T lymphocyte proliferation to non-typeable H. influenzae is evident in otitis media-prone children. A weak T lymphocyte repertoire in young children may explain high nasopharyngeal bacterial carriage observed in this population. However, TH and TH lymphocyte responses may be subdued due to Treg lymphocyte suppression. The immune factors that regulate nasopharyngeal colonisation are not well understood and further research is required to elucidate the immunological mechanism that underlies development of otitis media.

The enzyme Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin (Ig) genes, which are critically important for an effective immune response. In addition, AID seems to contribute to B cell tolerance in mice and humans by, in some still undefined way, eliminating developing autoreactive B cells. As a trade-off for the benefits brought about by its physiological roles, AID can also contribute to cellular transformation and tumor progression through its mutagenic activity. AID deaminates deoxycytidines at the Ig genes thereby generating deoxyuridine, which as part of the normal mechanism of SHM and CSR is processed by DNA repair enzymes into a larger spectrum of point mutations and also DNA doublestrand breaks. Multiple mechanisms regulate AID function to minimize deleterious or pathogenic DNA damage during antibody gene diversification. Despite this, off-target AID activity still makes point mutations and initiates chromosomal translocations that affect tumor suppressor and proto-oncogenes associated with B-cell lymphoid neoplasms. Through this collateral damage, AID is etiological for the development of lymphoma in several mouse models and is expressed in many human malignancies of mature B-cell origin where it may contribute to tumor clonal evolution. Mounting evidences indicate a role for AID also in disease progression and worsening of the prognosis of Chronic Lymphocytic Leukemia (CLL) and Chronic Myelogenous Leukemia (CML). Since these leukemia are not immediately derived from germinal center B cells, normal AID regulation might not be fully functional in those cases. This review discusses recent findings on the role of AID in lymphomagenesis. We describe the multilevel regulation of AID expression and function in normal compared to tumor B cells, specially focusing on the emerging role of AID in CLL and CML.

The Inflammatory Bowel Disease (IBD) comprises two forms namely, Ulcerative Colitis (UC) and Crohn's Disease (CD). The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Evidence indicates that a dysregulation of these mechanisms in the mucosal immunity of the gut in IBD patients causes an overproduction of cytokines leading to an uncontrolled intestinal inflammation. The discovery of novel cytokines in the IBD is important in order to understand the mechanisms that are involved in the gut mucosal immunity, as well as for the design of new therapeutic targets focused on the production of specific cytokine inhibitors.

The pleiotropic cytokine IFN-γ is a key component controlling and linking intrinsic, innate and adaptive immune responses yet, only recently has its expression been definitively demonstrated in macrophages. Unlike macrophages generated from monocyte with M-CSF, those generated with IL-12/IL-18 are a functionally distinct IFN-γ and chemokine secreting, macrophage population. We therefore, propose that the interaction of pathogen-exposed macrophages with IL-12 and IL-18 at the early inflammatory site constitutes a critical and decisive event, in the orchestration of the immune response through the secretion of IFN-γ, prior to the arrival of activated NK and T cells. The chemokine profile of IL-12/IL-18 generated macrophage is interesting, not only attracting of monocytes and neutrophils to the inflammation, but also contributing to the wound healing process. Also, the ICAM-1 mediated aggregation of IL-12/IL-18 generated macrophages, may have relevance for granuloma formation. Stimulation of IFN-γexpression through IL-12 and IL-18 maybe particularly relevant in the lungs, an environment rich in IL-12 and IL-18, where macrophages constitute the first line of defense against airborn pathogens, and must function without inducing a dangerous inflammation. Indeed, an uncontrolled inflammatory responses can be fatal, and so the requirement for signaling via two unrelated signaling systems ( IL-12 and IL-18), may have evolved to provide suitable and flexible control. Finally, and in contrast to M1 or M2 macrophages, which are infectable with HIV-1, the IL-12/IL-18 population is resistant in an IFN-γ independent, SAMHD1 restriction factor dependent manner.

The identification of the histamine H4 receptors has allowed new interest in the mechanism of action of an autacoid, which was originally identified in 1900s. Histamine is an important mediator of allergic disease, asthma and inflammation. The pharmacologic effects of histamine are mediated through four types of membrane histamine receptors, H1, H2, H3 and H4, which are all hepatohelical G-protein-coupled receptors. The H4 receptors, first considered to be present only on immunocompetent cells, are expressed on both the hematopoietic and non-hematopoietic cells. However, they are preferentially present on the cells, which are involved in the immune response, including eosinophils, basophils, mast cells, dendritic cells, helper T cells, cytolytic T cells and regulatory T cells. A number of other tissues including lung, heart, skin, small intestine and colon also express the H4 receptors. These receptors play a major role in the development of allergic diseases and asthma. The current understanding of allergic asthma is that it results from an abnormal TH2 production in response to environmental allergens, resulting in overproduction of IL-4, IL-5, and IL-13. The interaction of dendritic cells and allergen-specific T cells derives the polarization of naïve TH0 cells to the TH2 cells. Histamine along with other mediators plays a crucial role in this process. The H4 receptors have been identified as potential modulator for the activation of dendritic cells and polarization of T cells. In addition to their role in allergic asthma, these receptors are also involved in the inflammation of other tissues such as skin and the central nervous system. The vast body of evidence indicates a pro-inflammatory role for the H4 receptors, but there are reports where an antiinflammatory role for the H4 receptors, by their effects on regulatory T cells, has been reported. Agonist-biased signaling at the H4 receptors has added to the controversy regarding the role of these receptors. The histamine H1 receptor antagonists provide a limited relief in allergy and possess negligible to almost no efficacy in asthma. Consequently, the new histamine H4 receptor ligands may present an exciting opportunity to understand the etiology and pathogenesis of these disease states, along with new therapeutic opportunities.

Chronic hepatitis C virus (HCV) coinfects nearly 25% of HIV patients and it has been associated with more rapid progression of liver fibrosis, leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emerging data support multiple derangements attending HIV coinfection, including increases in profibrogenic cytokine expression and secretion, generation of enhanced oxidative stress, and increases in hepatocyte apoptosis. Furthermore, liver-related death is a major cause of morbidity and mortality in HCV/HIV coinfected patients on antiretroviral therapy therefore, anti-HCV treatment is advised to be considered for all HCV/HIV patients.Unfortunately, treatment with pegylated interferon (PegIFN) plus ribavirin (RBV) has shown a low efficacy in these patients, mainly among those coinfected with genotype 1. Triple therapy with PegIFN plus RBV and telaprevir or boceprevir, the first approved direct-acting antiviral agents (DAAs) will improve the likelihood of cure for genotype 1 infected patients. Nevertheless, a significant number of coinfected patients are ineligible for IFN-containing regimens and concerns remain in regard with drug-to-drug interactions and safety of triple therapy in cirrhotic patients. Furthermore, therapeutic decisions today need take into account the promise of new DAAs, some combined in IFN-free regimens, currently being investigated in multiple clinical trials to be in a near future, an easier, shorter and more effective HCV treatment in HIV coinfected patients.