Sialic acid binding immunoglobulin-like lectins may regulate innate immune responses by modulating the life span of granulocytes

The regulation of cell death is a key element in building up and maintaining both innate and adaptive immunity. A critical role in this process plays the tumor necrosis factor (TNF)/nerve growth factor (NGF) receptor family of death receptors. Recent work suggests that sialic acid binding immunoglobulin (Ig) -like lectins (Siglecs) are also empowered to transmit death signals, at least into myeloid cells. Strikingly, death induction by Siglecs is enhanced when cells are exposed to proinflammatory survival cytokines. Based on these recent insights, we hypothesize that at least some members of the Siglec family regulate immune responses via the activation of caspase-dependent and caspase-independent cell death pathways.

Comparison of innate immune responses towards rhinovirus infection of primary nasal and bronchial epithelial cells.

BACKGROUND AND OBJECTIVE Rhinoviruses (RV) replicate in both upper and lower airway epithelial cells. We evaluated the possibility of using nasal epithelial cells (NEC) as surrogate of bronchial epithelial cells (BEC) for RV pathogenesis cell culture studies. METHODS We used primary paired NEC and BEC cultures established from healthy subjects and compared the replication of RV belonging to the major (RV16) and minor (RV1B) group, and the cellular antiviral and proinflammatory cytokine responses towards these viruses. We related antiviral and pro-inflammatory responses of NEC isolated from CF and COPD patients with those of BEC. RESULTS RV16 replication and major group surface receptor (ICAM-1) expression were higher in healthy NEC compared with BEC (P < 0.05); RV1B replication and minor group surface receptor (LDLR) expression were similar. Healthy NEC and BEC produced similar levels of IFN-β and IFN-λ2/3 upon RV infection or after simulation with poly(IC). IL-8 production was similar between healthy NEC and BEC. IL-6 release at baseline (P < 0.01) and upon infection with RV16 (P < 0.05) and poly(IC) stimulation (P < 0.05) was higher in NEC. RV1B viral load in NEC was related to RV1B viral load in BEC (r = 0.49, P = 0.01). There was a good correlation of IFN levels between NEC and BEC (r = 0.66, P = 0.0004 after RV1B infection). IL-8 production in NEC was related to IL-8 production in BEC (r = 0.48, P = 0.02 after RV1B infection). CONCLUSION NEC are a suitable alternative cellular system to BEC to study the pathophysiology of RV infections and particularly to investigate IFN responses induced by RV infection.

Lack of Host Gut Microbiota Alters Immune Responses and Intestinal Granuloma Formation during Schistosomiasis

Fatalities from schistosome infections arise due to granulomatous, immune-mediated responses to eggs that become trapped in host tissues. Schistosome-specific immune responses are characterized by initial Th1 responses and our previous studies demonstrated that Myd88-deficient mice failed to initiate such responses in vivo. Paradoxically, schistosomal antigens fail to stimulate innate cells to release pro-inflammatory cytokines in vitro. Since S. mansoni infection is an intestinal disease, we hypothesized that commensal bacteria could act as bystander activators of the intestinal innate immune system to instigate Th1 responses. Using a broad spectrum of orally-administered antibiotics and antimycotics we analyzed schistosome-infected mice that were simultaneously depleted of gut bacteria. After depletion there was significantly less inflammation in the intestine which was accompanied by decreased intestinal granuloma development. In contrast, liver pathology remained unaltered. In addition, schistosome-specific immune responses were skewed and fecal egg excretion was diminished. This study demonstrates that host microbiota can act as a third partner in instigating helminth-specific immune responses.

Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection

BACKGROUND Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes. OBJECTIVE This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3. DESIGN We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound. RESULTS Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome. CONCLUSIONS This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.

Fish Immune Responses to Myxozoa

Myxozoans evoke important economic losses in aquaculture production, but there is almost a total lack of disease control methods as no vaccines or commercial treatments are currently available. Knowledge of the immune responses that lead to myxozoan elimination and subsequent disease resistance is vital for shaping the future development of disease control measures. Different fish immune factors triggered by myxozoan parasites are reviewed in this chapter. Detailed information on the phenotypic and underlying molecular aspects of innate and adaptive responses, at both cellular and humoral levels, is provided for some well-studied fishmyxozoan systems. The importance of the local immune response, mainly at mucosal sites, is also highlighted. Myxozoan tactics to disable or avoid immune responses, such as modulation of immune gene transcription and immune evasion, are also reviewed. The existence of innate and acquired resistance to some myxozoan species suggest promising possibilities for controlling myxozooses through immune-based strategies, such as genetic selection for host resistance, vaccination, immune therapies and administration of immunostimulants.

Immune Responses Against Classical Swine Fever Virus: Between Ignorance and Lunacy.

Classical swine fever virus infection of pigs causes disease courses from life-threatening to asymptomatic, depending on the virulence of the virus strain and the immunocompetence of the host. The virus targets immune cells, which are central in orchestrating innate and adaptive immune responses such as macrophages and conventional and plasmacytoid dendritic cells. Here, we review current knowledge and concepts aiming to explain the immunopathogenesis of the disease at both the host and the cellular level. We propose that the interferon type I system and in particular the interaction of the virus with plasmacytoid dendritic cells and macrophages is crucial to understand elements governing the induction of protective rather than pathogenic immune responses. The review also concludes that despite the knowledge available many aspects of classical swine fever immunopathogenesis are still puzzling.

Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses

The lower intestine of adult mammals is densely colonized with nonpathogenic (commensal) microbes. Gut bacteria induce protective immune responses, which ensure host-microbial mutualism. The continuous presence of commensal intestinal bacteria has made it difficult to study mucosal immune dynamics. Here, we report a reversible germ-free colonization system in mice that is independent of diet or antibiotic manipulation. A slow (more than 14 days) onset of a long-lived (half-life over 16 weeks), highly specific anticommensal immunoglobulin A (IgA) response in germ-free mice was observed. Ongoing commensal exposure in colonized mice rapidly abrogated this response. Sequential doses lacked a classical prime-boost effect seen in systemic vaccination, but specific IgA induction occurred as a stepwise response to current bacterial exposure, such that the antibody repertoire matched the existing commensal content.

Cellular immune responses to HCV core increase and HCV RNA levels decrease during successful antiretroviral therapy

Background Hepatitis C virus (HCV) infection is a major cause of morbidity in HIV infected individuals. Coinfection with HIV is associated with diminished HCV-specific immune responses and higher HCV RNA levels. Aims To investigate whether long-term combination antiretroviral therapy (cART) restores HCV-specific T cell responses and improves the control of HCV replication. Methods T cell responses were evaluated longitudinally in 80 HIV/HCV coinfected individuals by ex vivo interferon-γ-ELISpot responses to HCV core peptides, that predominantly stimulate CD4+ T cells. HCV RNA levels were assessed by real-time PCR in 114 individuals. Results The proportion of individuals with detectable T cell responses to HCV core peptides was 19% before starting cART, 24% in the first year on cART and increased significantly to 45% and 49% after 33 and 70 months on cART (p=0.001). HCV-specific immune responses increased in individuals with chronic (+31%) and spontaneously cleared HCV infection (+30%). Median HCV RNA levels before starting cART were 6.5 log10 IU/ml. During long-term cART, median HCV-RNA levels slightly decreased compared to pre-cART levels (−0.3 log10 IU/ml, p=0.02). Conclusions Successful cART is associated with increasing cellular immune responses to HCV core peptides and with a slight long-term decrease in HCV RNA levels. These findings are in line with the favourable clinical effects of cART on the natural history of hepatitis C and with the current recommendation to start cART earlier in HCV/HIV coinfected individuals.

The function of secretory IgA in the context of the intestinal continuum of adaptive immune responses in host-microbial mutualism

The large production of immunoglobulin (Ig)A is energetically costly. The fact that evolution retained this apparent luxury of intestinal class switch recombination to IgA within the human population strongly indicates that there must be a critical specific function of IgA for survival of the species. The function of IgA has been investigated in a series of different models that will be discussed here. While IgA has clear protective functions against toxins or in the context of intestinal viral infections, the function of IgA specific for non-pathogenic commensal bacteria remains unclear. In the context of the current literature we present a hypothesis where secretory IgA integrates as an additional layer of immune function into the continuum of intestinal CD4 T cell responses, to achieve a mutualistic relationship between the intestinal commensal microbiota and the host.

Lipopolysaccharide and lipoteichoic acid induce different immune responses in the bovine mammary gland

Different pathogens, such as Escherichia coli and Staphylococcus aureus, can be responsible for different outcomes of mastitis; that is, acute and severe or chronic and subclinical. These differences in the disease could be related to different mammary responses to the pathogens. The objective of this study was to determine if intramammary challenge with the endotoxins lipopolysaccharide (LPS), from E. coli, and lipoteichoic acid (LTA), from Staph. aureus, induce different immune responses in vivo in milk cells and mammary tissue. To provide a reference level for comparing the challenge and to show the different stimulation of the mammary immune system on a quantitatively similar level, dosages of LPS and LTA were chosen that induced an increase of somatic cells in milk to similar maxima. One udder quarter in each of 21 lactating dairy cows was challenged with 0.2 mug of LPS or 20 mug of LTA. From these quarters and from respective control quarters, milk cells or tissue biopsies were obtained at 0, 6, and 12h relative to the challenge to measure mRNA expression of tumor necrosis factor-alpha (TNFalpha), IL-1beta, IL-8, lactoferrin, and RANTES (regulated upon activation, normal T-cell expressed and secreted). Furthermore, if no biopsies were performed, hourly milk samples were taken for measurement of somatic cell count, lactate dehydrogenase (LDH), and TNFalpha. Somatic cell count increased in all treatments to similar maxima with LPS and LTA treatments. Concentrations of TNFalpha in milk increased with LPS but not with LTA. The activity of LDH in milk increased in both treatments and was more pronounced with LPS than with LTA. The mRNA expression of TNFalpha, IL-1beta, IL-8, and RANTES showed increases in milk cells, and LPS was a stronger inducer than LTA. Lactoferrin mRNA expression decreased in milk cells with LPS and LTA treatments. The measured factors did not change in either treatment in mammary tissue. Challenge of udder quarters with dosages of LPS and LTA that induce similar increases in SCC stimulate the appearance of different immune factor patterns. This dissimilar response to LPS and LTA may partly explain the different course and intensity of mastitis after infection with E. coli and Staph. aureus, respectively.

DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially.

Rapid downregulation of innate immune cells, interleukin-12 and interleukin-23 in generalized pustular psoriasis with infliximab in combination with acitretin

Generalized pustular psoriasis (GPP) is a severe inflammatory disease characterized by recurrent eruptions of sterile pustules on erythematous skin. Although tumor necrosis factor (TNF) antagonists may lead to a rapid resolution of GPP, the mechanism of action of these agents remains to be investigated. Here, we sought to evaluate markers of immune response in the skin of a patient who experienced a rapid amelioration of GPP after treatment with infliximab and acitretin.

Innate and adaptive immunity in host-microbiota mutualism

Healthy individuals live in peaceful co-existence with an immense load of intestinal bacteria. This symbiosis is advantageous for both the host and the bacteria. For the host it provides access to otherwise undigestible nutrients and colonization resistance against pathogens. In return the bacteria receive an excellent nutrient habitat. The mucosal immune adaptations to the presence of this commensal intestinal microflora are manifold. Although bacterial colonization has clear systemic consequences, such as maturation of the immune system, it is striking that the mutualistic adaptive (T and B cells) and innate immune responses are precisely compartmentalized to the mucosal immune system. Here we summarize the mechanisms of mucosal immune compartmentalization and its importance for a healthy host-microbiota mutualism.

The MHC-haplotype influences primary, but not memory, immune responses to an immunodominant peptide containing T- and B-cell epitopes of the caprine arthritis encephalitis virus Gag protein

In this report, we describe a short peptide, containing a T helper- and a B-cell epitope, located in the Gag protein of the caprine arthritis encephalitis virus (CAEV). This T-cell epitope is capable of inducing a robust T-cell proliferative response in vaccinated goats with different genetic backgrounds and to provide help for a strong antibody response to the B-cell epitope, indicating that it may function as a universal antigen-carrier for goat vaccines. The primary immune response of goats homozygous for MHC class I and II genes showed an MHC-dependent partitioning in rapid-high and slow-low responses, whereas the memory immune response was strong in both groups, demonstrating that a vaccine based on this immunodominant T helper epitope is capable to overcome genetic differences.