The protective roles of integrin α4ß7 and Amphiregulin-expressing innate lymphoid cells in lupus nephritis.

Type 2 innate lymphoid cells (ILC2s) have emerged as key regulators of the immune response in renal inflammatory diseases such as lupus nephritis. However, the mechanisms underlying ILC2 adhesion and migration in the kidney remain poorly understood. Here, we revealed the critical role of integrin α4ß7 in mediating renal ILC2 adhesion and function. We found that integrin α4ß7 enables the retention of ILC2s in the kidney by binding to VCAM-1, E-cadherin, or fibronectin on structural cells. Moreover, integrin α4ß7 knockdown reduced the production of the reparative cytokine amphiregulin (Areg) by ILC2s. In lupus nephritis, TLR7/9 signaling within the kidney microenvironment downregulates integrin α4ß7 expression, leading to decreased Areg production and promoting the egress of ILC2s. Notably, IL-33 treatment upregulated integrin α4ß7 and Areg expression in ILC2s, thereby enhancing survival and reducing inflammation in lupus nephritis. Together, these findings highlight the potential of targeting ILC2 adhesion as a therapeutic strategy for autoimmune kidney diseases.

Versatile roles of innate lymphoid cells at the mucosal barrier: from homeostasis to pathological inflammation.

Innate lymphoid cells (ILCs) are innate lymphocytes that do not express antigen-specific receptors and largely reside and self-renew in mucosal tissues. ILCs can be categorized into three groups (ILC1-3) based on the transcription factors that direct their functions and the cytokines they produce. Their signature transcription factors and cytokines closely mirror those of their Th1, Th2, and Th17 cell counterparts. Accumulating studies show that ILCs are involved in not only the pathogenesis of mucosal tissue diseases, especially respiratory diseases, and colitis, but also the resolution of such diseases. Here, we discuss recent advances regarding our understanding of the biology of ILCs in mucosal tissue health and disease. In addition, we describe the current research on the immune checkpoints by which other cells regulate ILC activities: for example, checkpoint molecules are potential new targets for therapies that aim to control ILCs in mucosal diseases. In addition, we review approved and clinically- trialed drugs and drugs in clinical trials that can target ILCs and therefore have therapeutic potential in ILC-mediated diseases. Finally, since ILCs also play important roles in mucosal tissue homeostasis, we explore the hitherto sparse research on cell therapy with regulatory ILCs. This review highlights various therapeutic approaches that could be used to treat ILC-mediated mucosal diseases and areas of research that could benefit from further investigation.

Bone Marrow Progenitors and IL-2 Signaling Contribute to the Strain Differences of Kidney Innate Lymphoid Cells.

Innate lymphoid cells (ILCs) are critical immune-response mediators. Although they largely reside in mucosal tissues, the kidney also bears substantial numbers. Nevertheless, kidney ILC biology is poorly understood. BALB/c and C57BL/6 mice are known to display type-2 and type-1 skewed immune responses, respectively, but it is unclear whether this extends to ILCs. We show here that indeed, BALB/c mice have higher total ILCs in the kidney than C57BL/6 mice. This difference was particularly pronounced for ILC2s. We then showed that three factors contributed to the higher ILC2s in the BALB/c kidney. First, BALB/c mice demonstrated higher numbers of ILC precursors in the bone marrow. Second, transcriptome analysis showed that compared to C57BL/6 kidneys, the BALB/c kidneys associated with significantly higher IL-2 responses. Quantitative RT-PCR also showed that compared to C57BL/6 kidneys, the BALB/c kidneys expressed higher levels of IL-2 and other cytokines known to promote ILC2 proliferation and/or survival (IL-7, IL-33, and thymic stromal lymphopoietin). Third, the BALB/c kidney ILC2s may be more sensitive to the environmental signals than C57BL/6 kidney ILC2s since they expressed their transcription factor GATA-3 and the IL-2, IL-7, and IL-25 receptors at higher levels. Indeed, they also demonstrated greater responsiveness to IL-2 than C57BL/6 kidney ILC2s, as shown by their greater STAT5 phosphorylation levels after culture with IL-2. Thus, this study demonstrates previously unknown properties of kidney ILC2s. It also shows the impact of mouse strain background on ILC2 behavior, which should be considered when conducting research on immune diseases with experimental mouse models.

Siglec-F-expressing neutrophils are essential for creating a profibrotic microenvironment in renal fibrosis.

The roles of neutrophils in renal inflammation are currently unclear. On examining these cells in the unilateral ureteral obstruction murine model of chronic kidney disease, we found that the injured kidney bore a large and rapidly expanding population of neutrophils that expressed the eosinophil marker Siglec-F. We first verified that these cells were neutrophils. Siglec-F+ neutrophils were recently detected in several studies in other disease contexts. We then showed that a) these cells were derived from conventional neutrophils in the renal vasculature by TGF-ß1 and GM-CSF; b) they differed from their parent cells by more frequent hypersegmentation, higher expression of profibrotic inflammatory cytokines, and notably, expression of collagen 1; and c) their depletion reduced collagen deposition and disease progression, but adoptive transfer increased renal fibrosis. These findings have thus unveiled a subtype of neutrophils that participate in renal fibrosis and a potentially new therapeutic target in chronic kidney disease.

Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells.

Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma. Here, we examined the effect of human umbilical cord blood-derived MSCs (hUC-MSC) on two mouse models of severe asthma, namely, Alternaria alternata-induced and house dust mite (HDM)/diesel exhaust particle (DEP)-induced asthma. hUC-MSC treatment attenuated lung type 2 (Th2 and type 2 innate lymphoid cell) inflammation in both models. However, these effects were only observed with particular treatment routes and timings. In vitro co-culture showed that hUC-MSC directly downregulated the interleukin (IL)-5 and IL-13 production of differentiated mouse Th2 cells and peripheral blood mononuclear cells from asthma patients. Thus, these results showed that hUC-MSC treatment can ameliorate asthma by suppressing the asthmogenic cytokine production of effector cells. However, the successful clinical application of MSCs in the future is likely to require careful optimization of the route, dosage, and timing.

Innate Lymphoid Cells in Tissue Homeostasis and Disease Pathogenesis.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells. ILCs can be categorized into three groups on the basis of the transcription factors that direct their functions and the cytokines they produce. Notably, these functions parallel the effector functions of T lymphocytes. ILCs play a frontline role in host defense and tissue homeostasis by responding rapidly to environmental factors, conducting effector responses in a tissue-specific manner, and interacting with hematopoietic and non-hematopoietic cells throughout the body. Moreover, recent studies reveal that ILCs are involved in development of various inflammatory diseases, such as respiratory diseases, autoimmune diseases, or cancer. In this review, we discuss the recent findings regarding the biology of ILCs in health and inflammatory diseases.

NK1.1- natural killer T cells upregulate interleukin-17 expression in experimental lupus nephritis.

Interleukin (IL)-17-secreting invariant natural killer T (NKT) cells are involved in several inflammatory diseases. However, their role in lupus nephritis (LN) has not been fully characterized. Samples from patients with LN or glomerulonephritis and healthy controls were obtained, and elevated IL-17+ NKT cell numbers and IL-17 expression were observed in blood cells and kidneys, respectively, in patients with LN. Comparison of a mouse model of experimental autoimmune LN with the parental strain (NKT-deficient B6.CD1d-/- mice) revealed improved proteinuria, disease severity, and histopathology and decreased levels of chemokine (C-X-C motif) ligand 16 and T cell receptor-α variable 14 expression. Spleens and kidneys of B6.CD1d-/- mice also showed downregulation of inflammatory markers and IL-17. In coculture with renal mesangial and NKT cells, inflammatory markers and IL-17 were upregulated following α-galactosylceramide treatment and downregulated after treatment with IL-17-blocking antibodies. This was most prominent with killer cell lectin-like receptor subfamily B member 1 C (NK1.1)- NKT cells. Thus, IL-17 is upregulated in LN. Activation of NKT cells regulates IL-17-related immune responses systemically and in the kidneys, primarily via NK1.1- NKT cells. IL-17-secreting NK1.1- NKT cells could serve as diagnostic and therapeutic targets for LN.NEW & NOTEWORTHY This study makes a significant contribution to the literature because our results indicate that IL-17 is upregulated in lupus nephritis and that natural killer T (NKT) cells are involved in its pathogenesis. Activation of NKT cells regulates IL-17-related immune responses, both systemically and in the kidney, and this mainly involves NK1.1- NKT cells. Furthermore, IL-17-secreting NK1.1- NKT cells could serve as a diagnostic and therapeutic target for lupus nephritis.

Reduction of circulating innate lymphoid cell progenitors results in impaired cytokine production by innate lymphoid cells in patients with lupus nephritis.

BACKGROUND: Innate lymphoid cells (ILCs) play an essential role in maintaining homeostasis; however, they can also cause chronic inflammation and autoimmune disease. This study aimed to identify the role of ILCs in the pathogenesis of lupus nephritis (LN). METHODS: The percentage of ILCs within the peripheral blood mononuclear cell (PBMC) population and urine of patients with LN (n = 16), healthy controls (HC; n = 8), and disease controls (ANCA-associated vasculitis (AAV; n = 6), IgA nephropathy (IgAN; n = 9), and other glomerular diseases (n = 5)) was determined by flow cytometry analysis. In addition, ILCs were sorted and cultured with plasma from LN patients or HC to elucidate whether the reduced population of CD117+ ILCs observed in LN was due to changes in the ILC progenitor population. RESULTS: The percentage of total ILCs and CD117+ ILCs in LN was significantly lower than that in HC. The percentage of cytokine-secreting ILCs was also lower in LN; however, when the disease stabilized, cytokine production was restored to levels similar to those in HC. The increase in the number of exhausted ILCs (cells unable to secrete cytokines) correlated positively with disease activity. When CD117+ ILCs were cultured with LN plasma, the number of CD117+ ILCs fell, but that of other ILC subsets increased. CONCLUSIONS: The percentage of CD117+ ILCs and the capacity of ILCs to secrete cytokines fell as LN severity increased, suggesting that an inflammatory environment of LN induces persistent differentiation and exhaustion of ILCs.

Lipid-Reactive T Cells in Immunological Disorders of the Lung.

Regulation of T cell-mediated immunity in the lungs is critical for prevention of immune-related lung disorders and for host protection from pathogens. While the prevalent view of pulmonary T cell responses is based on peptide recognition by antigen receptors, called T cell receptors (TCR), on the T cell surface in the context of classical major histocompatibility complex (MHC) molecules, novel pathways involving the presentation of lipid antigens by cluster of differentiation 1 (CD1) molecules to lipid-reactive T cells are emerging as key players in pulmonary immune system. Whereas, genetic conservation of group II CD1 (CD1d) in mouse and human genomes facilitated numerous in vivo studies of CD1d-restricted invariant natural killer T (iNKT) cells in lung diseases, the recent development of human CD1-transgenic mice has made it possible to examine the physiological roles of group I CD1 (CD1a-c) molecules in lung immunity. Here, we discuss current understanding of the biology of CD1-reactive T cells with a specific focus on their roles in several pulmonary disorders.

Associates and predictors of pleurisy or pericarditis in SLE.

BACKGROUND/PURPOSE: Serositis is one of both ACR and SLICC classification criteria for systemic lupus erythematosus (SLE) and a common type of extra renal flare. However, little is known about clinical or immunological associations of pleurisy or pericarditis. The aim of this study is to analyze associates and predictors of pleurisy versus pericarditis in Caucasians and African Americans with SLE. METHODS: 2,390 SLE patients in the Hopkins Lupus Cohort were analyzed for demographic, clinical and serologic associates of pleurisy or pericarditis, defined using the SELENA revision of the SLE Disease Activity Index (SLEDAI). The cross-sectional and prospective study using either univariate or multivariate analysis were performed to evaluate the associates of serositis in SLE. We reported associates with a p-value of less than 0.05 for pleurisy or pericarditis. RESULTS: 43% had pleurisy and 22% had pericarditis. African-American ethnicity was a predictive factor for new pericarditis. Hemolytic anemia, proteinuria, lymphadenopathy and anti-Sm were predictive only of pericarditis, whereas pulmonary fibrosis and GI infarction were predictive only of pleurisy. Fever, Raynaud's syndrome, and anti-DNA were predictors for both pericarditis and pleurisy. CONCLUSION: Our study provides further insights into the associates of pleurisy and pericarditis in SLE. Predictors of pleurisy and pericarditis are shown for the first time. The long term consequences from the cross-sectional analysis gives a lesson that serositis in SLE should not be considered benign.

Line-defect calibration for line-scanning projection display.

A method of line-defect calibration for line-scanning projection display is developed to accomplish acceptable display uniformity. The line scanning display uses a line modulating imaging and scanning device to construct a two-dimensional image. The inherent line-defects in an imaging device and optical lenses are the most fatal performance-degrading factor that should be overcome to reach the basic display uniformity level. Since the human eye recognizes line defects very easily, a method that perfectly removes line defects is required. Most line imaging devices are diffractive optical devices that require a coherent light source. This particular requirement makes the calibration method of sequential single pixel measurement and correction insufficient to take out the line defects distributed on screen due to optical crosstalk. In this report, we present a calibration method using a recursively converging algorithm that successfully transforms the unacceptable line-defected images into a uniform display image.