Dscam and pancrustacean immune memory – A review of the evidence

Evidence is accumulating for a memory-like phenomenon in the immune defence of invertebrates. Down syndrome cell adhesion molecule (Dscam) has been proposed as a key candidate for a somatically diversified receptor system in the crustaceans and insects (Pancrustacea) that could enable challenge-specific protection. However, what is the evidence for an involvement of Dscam in pancrustacean immune memory, and in particular specificity? Here we review the current state of the art, and discuss hypotheses of how Dscam could be involved in immunity. We conclude that while there is increasing evidence for the involvement of Dscam in pancrustacean immunity, crucial experiments to address whether it plays a role in specificity upon secondary encounter with a pathogen still remain to be done.     

Interferon-γ-secreting NK cells promote induction of dry eye disease

NK cells have been increasingly reported to be an important effector in autoimmune diseases. However, nothing is known in this regard in DED, the most common eye pathology, which is characterized by sustained inflammation on the ocular surface. In the present study, we have examined the profile of NK cells on the ocular surface as well as in the draining lymphoid tissues during the development of this disease. Our data demonstrate activated NK cells during the disease-induction phase. Moreover, in vivo depletion of NK cells in mice results in reduced disease severity and diminished proinflammatory cytokines. Furthermore, we show that NK cells are also able to modulate the maturation of APCs, which is correlated with IFN-γ from NK cells. Together, our findings provide new in vivo evidence that IFN-γ-secreting NK cells can promote induction of DED via direct target tissue damage and indirect influence on the priming phase of an adaptive immune response in secondary lymphoid tissue.     

Influence of a mutation in IFN-γ receptor 2 (IFNGR2) in human cells on the generation of Th17 cells in memory T cells

The T cell subsets involved in inflammatory reactions are mainly the IFN-γ secreting Th1 cells and IL17-producing Th17 cells. Although Th17 cells are primed in the thymus, there is evidence that Th17 cells can be generated from effector memory CD4⁺ T cells. Cytokines as IL-6, TGF-β, IL-21 and IL-23 involved in development of Th17 cells are well described. Here we analyzed the impact of a mutation in the IFN-γ receptor 2 (IFN-γR2) on the induction of Th17 cells. By isolation of T cells and monocytes of a patient with this mutation we could demonstrate an inhibitory role of IFN-γ signaling as IFN-γR2-deficient monocytes induce a higher percentage of IL-17⁺ cells from both healthy and IFN-γR2-deficient CD4⁺ T cells. This data confirm the interference of these two T helper subsets and points to a balance of Th1 and Th17 cells obtained by their own cytokine production and their interplay with APCs.     

Homeostasis of naïve, effector and memory CD8 T cells

Homeostatic control of CD8 T cell populations is essential for defense against infectious pathogens. Our understanding of the mechanisms that control na?ve, effector and memory T cell populations in the intact animal has increased significantly over the last several years. There have been some surprises. For example, peripheral tissues have been found to harbor unexpectedly large numbers of effector memory T cells. Also unexpected was the finding of programmed T cell proliferation following very brief exposure to antigen. These and other recent advances are summarized in the following review.     

Cytokine-driven proliferation and differentiation of human naïve,central memory and effector memory CD4+ T cells

Memory T lymphocytes divide in vivo in the absence of antigen maintaining a pool of central memory (T(CM)) and effector memory cells (T(EM)) with distinct effector function and homing capacity. We compared human CD4+ na?ve T, T(CM) and T(EM) cells for their capacity to proliferate in response to cytokines, which have been implicated in T cell homeostasis. Interleukin (IL)-7 and IL-15 expanded with very high efficiency T(EM), while T(CM) were less responsive and na?ve T cells did not respond at all. Dendritic cell (DC)-derived cytokines allowed na?ve T cells to respond selectively to IL-4 and potently boosted the response of T(CM) to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15Rss and the common gamma chain (gamma(c)). The ERK and the p38 MAP kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures T(CM) proliferated and some of the proliferating cells acquired effector function and non-lymphoid tissue homing capacity. Ex vivo BrdU incorporation experiments showed that both T(CM) and T(EM) proliferated under steady state conditions in vivo. Altogether these results provide a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4+ memory T cells and for a sustained antigen-independent generation of T(EM) from a pool of T(CM) cells.     

Age-associated changes in the frequency of naïve, memory and effector CD8+ T cells

We investigated age-associated changes in the frequency of CD8+ T cell subsets with different functions. Based on expression of CD45RA and CCR7, na?ve (CD45RA+ CCR7+), central memory (CM, CD45RA- CCR7+), effector memory (EM, CD45RA- CCR7-) and effector (CD45RA+ CCR7-) CD8+ T cells were identified in peripheral blood from healthy young (n = 17) and elderly (n = 17) people using flow cytometry. The elderly had a decreased frequency of na?ve and an increased frequency of EM and effector CD8+ T cells compared to the young. However, both groups had a similar frequency of CM cells. These findings suggest that age-associated changes in CD8+ T cell subsets occur, which could be a potential explanation for altered CD8+ T cell function in the elderly.     

IFN-γ and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

Th1 and Th17 cells are distinct lineages of effector/memory cells, imprinted for re-expression of IFN-γ and IL-17, by upregulated expression of T-bet and retinoic acid-related orphan receptor γt (RORγt), respectively. Apparently, Th1 and Th17 cells share tasks in the control of inflammatory immune responses. Th cells coexpressing IFN-γ and IL-17 have been observed in vivo, but it remained elusive, how these cells had been generated and whether they represent a distinct lineage of Th differentiation. It has been shown that ex vivo isolated Th1 and Th17 cells are not interconvertable by TGF-β/IL-6 and IL-12, respectively. Here, we show that ex vivo isolated Th17 cells can be converted into Th1/Th17 cells by combined IFN-γ and IL-12 signaling. IFN-γ is required to upregulate expression of the IL-12Rβ2 chain, and IL-12 for Th1 polarization. These Th1/Th17 cells stably coexpress RORγt and T-bet at the single-cell level. Our results suggest a molecular pathway for the generation of Th1/Th17 cells in vivo, which combine the pro-inflammatory potential of Th1 and Th17 cells.     

Antigen-presenting effects of effector memory Vγ9Vδ2 T cells in rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. γδ T cells, a T-cell subpopulation, are characterized by multiple biological functions and associated with a variety of diseases. This study investigated the antigen-presenting effects of γδ T cells and their relationship with rheumatoid arthritis development. We found that Vγ9Vδ2 T cells (the predominant subtype of γδ T cells in peripheral blood) were activated by isopentenyl pyrophosphate to continuously proliferate and differentiate into effector memory cells. The effector memory Vγ9Vδ2 T cells exhibited phenotypic characteristics of specific antigen-presenting cells, including high HLA-DR and CD80/86 expression. These Vγ9Vδ2 T cells could present soluble antigens and synthetic peptides to CD4(+) T cells. Vγ9Vδ2 T cells with different phenotypes showed different cytokine secretion patterns. Effector memory Vγ9Vδ2 T cells simultaneously secreted not only interferon (IFN)-γ but also IL-17. The peripheral blood and joint synovial fluid from RA patients contained numerous heterogeneous γδ T cells that were predominantly effector memory Vγ9Vδ2 T cells with the ability to secrete inflammatory factors. We also found that γδ T cells had a similar antigen-presenting capability to B cells. These results suggest that during the development of rheumatoid arthritis, γδ T cells can aggravate immune dysfunction and produce abnormal immune damage by secreting cytokines and inducing inflammatory cells to participate in synergistic inflammatory responses. Furthermore, γδ T cells can behave similarly to B cells to present viral peptides and autoantigen peptides to CD4(+) T cells, thus sustaining CD4(+) T-cell activation.     

The diagnosis and classification of Henoch–Schönlein purpura: An updated review

Henoch–Schönlein purpura (HSP) is a common childhood systemic vasculitis with clinical characteristics of cutaneous palpable purpura, arthralgia/arthritis, bowel angina, and hematuria/proteinuria. HSP is identified mainly based on the above presentations. Combined with pathohistological findings of leukocytoclastic vasculitis (LCV) and IgA-immune deposits in vessel walls and/or glomeruli increase the diagnostic sensitivity and specificity. However, considering the accessibility of biopsy and some patients with atypical presentations, there are still medical unmet needs in HSP diagnosis. This article reviews the diagnosis of HSP including the aspects of classification criteria, differential diagnosis, and some laboratory findings as the biomarkers with diagnostic potential.     

NKG2A inhibits NKG2C effector functions of γδ T cells: implications in health and disease

The CD94/NKG2 complex is expressed on T and NK lymphocytes. CD94 molecules covalently associate to activating or inhibitory NKG2 molecules, and their expression finely tunes cell responses. Human γδ T cells express several NKRs. Expression of these receptors is confined to the cytolytic Vδ2 subset, which coexpresses the FcγRIII CD16 and CD45RA and has been defined as Vγ9Vδ2 T(EMRA) cells. We show that the CD94/NKG2C complex, associated with KARAP/DAP12, is fully functional in γδ T cells, as determined by measuring IFN-γ production, T cell proliferation, and cytolytic activity by γδ lymphocytes. In contrast, NKG2A expression was found on all γδ T cell memory subsets, suggesting a crucial role of the inhibitory signal provided by this receptor on γδ T cell responses. Moreover, we found Vγ9Vδ2 T(EMRA), NK, and CD8+ αβ T cells coexpressing NKG2A and NKG2C receptors. Functional experiments showed that the inhibitory signal mediated by the NKG2A receptor prevails when double-positive cells are activated. Finally, NKG2A expression on γδ LDGL correlates with asymptomatic pathology, even in the presence of NKG2C coexpression, whereas in symptomatic patients affected by severe disease, the inhibitory NKG2A receptor is absent, and a variety of activatory NKRs was found. We propose that the silent behavior of γδ cells in LDGL patients is a result of effective inhibitory HLA class I receptors.     

Crawling of effector T cells on extracellular matrix： role of integrins in interstitial migration in inflamed tissues

Tcells are one of the most migratory cells in the body. The development and function of T cells depend on their interaction with other cells, which is, in turn, dependent on optimal cell migra- tion. T cells migrate largely in three dif- ferent ways： rapid distribution via blood vessels through hemodynamic move- ment, transendothelial migration and interstitial movement. Transendothelial migration involves sequential activation of selectins, chemokine receptors and integrin molecules expressed by migrat- ing T cells, leading to extravasation from blood vessel into local tissue environ- ments.     

Influence and implications of the renin–angiotensin–aldosterone system in obstructive sleep apnea: An updated systematic review and meta-analysis

Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin–angiotensin–aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin–angiotensin–aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04–0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05–60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11–7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42–10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86–5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57–6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub-group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin–angiotensin–aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension.     

Th17-Inducing Conditions Lead to in vitro Activation of Both Th17 and Th1 Responses in Behcet’s Disease

Objectives: Interleukin-17 (IL-17) has been associated with the pathogenesis of various autoimmune/inflammatory diseases. The aim of this study was to investigate the expression of Th17-related immunity in an innate immunity-dominated vasculitis, namely Behcet’s disease (BD).

Methods: Peripheral blood mononuclear cells from 37 patients (age: 38.5 ± 9.8 years) with BD, and 25 healthy controls (HC) (age: 39.1 ± 9.3 years), were cultured in Th17-inducing conditions (IL-6, Phytohemagglutinin (PHA), IL-1β, and IL-23) for 6 days. Cultured cells were stained with CD4, CD8, CD3, TCR gamma/delta, CD19, interferon-γ (IFN-γ), and IL-17 antibodies to determine the intracellular cytokine secretion by flow cytometry.

Results: IL-17 expression by CD8+ and γδ+ T cells was higher in BD compared to HC (p = 0.004, p = 0.003, respectively). No differences were observed between the groups in the IL-17 production by B cells. Under Th17-inducing conditions, production of IFN-γ by CD4+, CD8+, and γδ+ T cells was also higher in BD compared to HC (p < 0.05 in all).

Conclusion: Our results suggest that under Th17-stimulating conditions, T cells express both IL-17 and IFN-γ in BD. More prominent IL-17 and IFN-γ production by all lymphocyte subsets in BD might be associated with the increased innate responses, early tissue neutrophil infiltrations and late adaptive immunity in BD.     

Does mitochondrial DNA play a role in Parkinson's disease? A review of cybrid and other supportive evidence

SIGNIFICANCE: Mitochondria are currently believed to play an important role in the neurodysfunction and neurodegeneration that underlie Parkinson's disease (PD). RECENT ADVANCES: While it increasingly appears that mitochondrial dysfunction in PD can have different causes, it has been proposed that mitochondrial DNA (mtDNA) may account for or drive mitochondrial dysfunction in the majority of the cases. If correct, the responsible mtDNA signatures could represent acquired mutations, inherited mutations, or population-distributed polymorphisms. CRITICAL ISSUES AND FUTURE DIRECTIONS: This review discusses the case for mtDNA as a key mediator of PD, and especially focuses on data from studies of PD cytoplasmic hybrid (cybrid) cell lines.     

The role of Th17 cells: explanation of relationship between periodontitis and COPD?

Periodontitis and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases with common risk factors, such as long-term smoking, age, and social deprivation. Many observational studies have shown that periodontitis and COPD are correlated. Moreover, they share a common pathophysiological process involving local accumulation of inflammatory cells and cytokines and damage of soft tissues. The T helper 17 (Th17) cells and the related cytokines, interleukin (IL)-17, IL-22, IL-1β, IL-6, IL-23, and transforming growth factor (TGF)-β, play a crucial regulatory role during the pathophysiological process. This paper reviewed the essential roles of Th17 lineage in the occurrence of periodontitis and COPD. The gaps in the study of their common pathological mechanism were also evaluated to explore future research directions. Therefore, this review can provide study direction for the association between periodontitis and COPD and new ideas for the clinical diagnosis and treatment of the two diseases.

     

Translational Mini-Review Series on Th17 Cells: Are T helper 17 cells really pathogenic in autoimmunity?

OTHER ARTICLES PUBLISHED IN THIS MINI‐REVIEW SERIES ON Th17 CELLS
Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365‐2249.2009.04037.x
Induction of interleukin‐17 production by regulatory T cells. Clin Exp Immunol 2009; doi:10.1111/j.1365‐2249.2009.04038.x
CD4⁺ T helper cells: functional plasticity and differential sensitivity to regulatory T cell‐mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365‐2249.2009.04040.x
Development of mouse and human T helper 17 cells. Clin Exp Immunol 2009; doi:10.1111/j.1365‐2249.2009.04041.x

Summary

In this review the authors discuss the evidence for T helper type 17 (Th17) cells as pathogenic T cells in autoimmunity. Studies with cytokine‐deficient mice or blocking of interleukin (IL)‐17, IL‐21 and IL‐22 have resulted in a conflicting data set. Although in the experimental autoimmune encephalomyelitis model the role of Th17 cells remains a point of debate, this IL‐17‐producing T cell in experimental arthritis is clearly contributing to inflammation and destruction.