Detection of metastatic lymph node and sentinel lymph node mapping ​using mannose receptor targeting in in vivo mouse footpad tumor models and rabbit uterine cancer models.

BACKGROUND: This study aimed to evaluate the effectiveness of neo-mannosyl human serum albumin-indocyanine green (MSA-ICG) for detecting metastatic lymph node (LN) and mapping sentinel lymph node (SLN) using mouse footpad uterine tumor models. Additionally, the authors assessed the feasibility of MSA-ICG in SLN mapping in rabbit uterine cancer models. MATERIALS AND METHODS: The authors compared the LN targeting ability of MSA-ICG with ICG. Six mouse footpad tumor models and two normal mice were each assigned to MSA-ICG and ICG, respectively. After the assigned tracers were injected, fluorescence images were taken, and the authors compared the signal-to-background ratio (SBR) of the tracers. A SLN biopsy was performed to confirm LN metastasis status and CD206 expression level. Finally, an intraoperative SLN biopsy was performed in rabbit uterine cancer models using MSA-ICG. RESULTS: The authors detected 14 groin LNs out of 16 in the MSA-ICG and ICG groups. The SBR of the MSA-ICG group was significantly higher than that of the ICG group. The metastatic LN subgroup of MSA-ICG showed a significantly higher SBR than that of ICG. CD206 was expressed at a high level in metastatic LN, and the signal intensity difference increased as the CD206 expression level increased. SLN mapping was successfully performed in two of the three rabbit uterine cancer models. CONCLUSIONS: MSA-ICG was able to distinguish metastatic LN for an extended period due to its specific tumor-associated macrophage-targeting property. Therefore, it may be a more distinguishable tracer for identifying metastatic LNs and SLNs during uterine cancer surgery. Further research is needed to confirm these results.

Exploring the Ion Channel TRPV2 and Testicular Macrophages in Mouse Testis.

The cation channel TRPV2 is known to be expressed by murine macrophages and is crucially involved in their functionality. Macrophages are frequent cells of the mouse testis, an immune-privileged and steroid-producing organ. TRPV2 expression by testicular macrophages and possible changes associated with age or inflammation have not been investigated yet. Therefore, we studied testes of young adult and old wild-type (WT) and AROM+ mice, i.e., transgenic mice overexpressing aromatase. In these animals, inflammatory changes are described in the testis, involving active macrophages, which increase with age. This is associated with impaired spermatogenesis and therefore AROM+ mice are a model for male infertility associated with sterile inflammation. In WT animals, testicular TRPV2 expression was mapped to interstitial CD206+ and peritubular MHC II+ macrophages, with higher levels in CD206+ cells. Expression levels of TRPV2 and most macrophage markers did not increase significantly in old mice, with the exception of CD206. As the number of TRPV2+ testicular macrophages was relatively small, their possible involvement in testicular functions and in aging in WT mice remains to be further studied. In AROM+ testis, TRPV2 was readily detected and levels increased significantly with age, together with macrophage markers and TNF-α. TRPV2 co-localized with F4/80 in macrophages and further studies showed that TRPV2 is mainly expressed by unusual CD206+MHC II+ macrophages, arising in the testis of these animals. Rescue experiments (aromatase inhibitor treatment and crossing with ERαKO mice) restored the testicular phenotype and also abolished the elevated expression of TRPV2, macrophage and inflammation markers. This suggests that TRPV2+ macrophages of the testis are part of an inflammatory cascade initiated by an altered sex hormone balance in AROM+ mice. The changes in testis are distinct from the described alterations in other organs of AROM+, such as prostate and spleen. When we monitored TRPV2 levels in another immune-privileged organ, namely the brain, we found that levels of TRPV2 were not elevated in AROM+ and remained stable during aging. In the adrenal, which similar to the testis produces steroids, we found slight, albeit not significant increases in TRPV2 in both AROM+ and WT mice, which were associated with age. Thus, the changes in the testis are specific for this organ.

Upper Gastrointestinal Langerhans Cell Histiocytosis: A Report of 2 Adult Cases and a Literature Review.

Langerhans cell histiocytosis (LCH) with primary involvement of the upper gastrointestinal (GI) tract is rare. We report 2 adult cases of localized LCH in the upper-GI tract, including the second reported adult case of esophageal LCH and review 11 previously reported cases. Case 1 involved the esophagus of a 61-year-old man; histiocytosis was detected when endoscopy was performed for an examination of epigastric pain. Case 2 involved the stomach of a 56-year-old woman wherein the lesion was detected during a follow-up endoscopy after Helicobacter pylori infection. Both biopsy specimens exhibited diffuse proliferation of mononuclear cells with nuclear convolution and a background of eosinophilic infiltrate. The cells were immunohistochemically positive for CD1a and langerin, and BRAF V600E mutation was detected in Case 2. Follow-up endoscopy for both cases revealed that the lesions disappeared without any treatment. It is important to avoid misdiagnosing LCH of the upper-GI tract as a malignant neoplasm.

Adipose tissue macrophage burden, systemic inflammation, and insulin resistance.

Adipose tissue inflammation, as defined by macrophage accumulation, is proposed to cause insulin resistance and systemic inflammation. Because the strength of this relationship for humans is unclear, we tested whether adipose tissue macrophage (ATM) burden is correlated with these health indicators. Using immunohistochemistry, we measured abdominal subcutaneous CD68+ (total ATM), CD14+ (proinflammatory/M1), and CD206+ (anti-inflammatory/M2) ATM in 97 volunteers (BMI 20-38 kg/m2, in addition to body composition, adipocyte size, homeostasis model assessment of insulin resistance, ADIPO-IR, adipose tissue insulin resistance measured by palmitate, plasma lipids, TNF, and IL-6 concentrations. There were several significant univariate correlations between metabolic parameters to IL-6 and ATM per 100 adipocytes, but not ATM per gram tissue; adipocyte size was a confounding variable. We used matching strategies and multivariate regression analyses to investigate the relationships between ATM and inflammatory/metabolic parameters independent of adipocyte size. Matching approaches revealed that the groups discordant for CD206 but concordant for adipocyte size had significantly different fasting insulin and IL-6 concentrations. However, groups discordant for adipocyte size but concordent for ATM differeded in that visceral fat, plasma triglyceride, glucose, and TNF concentrations were greater in those with large adipocytes. Multivariate regression analysis indicated that indexes of insulin resistance and fasting triglycerides were predicted by body composition; the predictive value of ATM per 100 adipocytes or per gram tissue was variable between males and females. We conclude that the relationship between ATM burden and metabolic/inflammatory variables is confounded by adipocyte size/body composition and that ATM do not predict insulin resistance, systemic inflammation, or dyslipidemia. ATM may primarily play a role in tissue remodeling rather than in metabolic pathology.

Langerhans cell histiocytosis: A great imitator.

Langerhans cell histiocytosis (LCH) is an uncommon but serious inflammatory neoplasia that affects many organs, including the skin. Though uncommon, it should remain high on a clinician's differential diagnosis in treatment-resistant cases of conditions, such as seborrheic dermatitis, diaper dermatitis, arthropod bites, and many more. A thorough history nd physical examination for each patient can aid in the diagnosis; however, if clinically suspicious for LCH, a punch biopsy should be performed. Histologic evaluation of LCH is often enough to differentiate it from the many clinical mimickers. Characteristic findings include a histiocytic infiltrate with "coffee bean"-cleaved nuclei, rounded shape, and eosinophilic cytoplasm. Immunohistochemical stains, including CD1a, S100, and CD207 (langerin) are often needed for a definitive diagnosis. Electron microscopy also demonstrates the ultrastructural presence of Birbeck granules, but this is no longer needed due to immunohistochemical staining. Treatment is often necessary for LCH, if systemic involvement exists.

Molecular Recognition in C-Type Lectins: The Cases of DC-SIGN, Langerin, MGL, and L-Sectin.

Carbohydrates play a pivotal role in intercellular communication processes. In particular, glycan antigens are key for sustaining homeostasis, helping leukocytes to distinguish damaged tissues and invading pathogens from healthy tissues. From a structural perspective, this cross-talk is fairly complex, and multiple membrane proteins guide these recognition processes, including lectins and Toll-like receptors. Since the beginning of this century, lectins have become potential targets for therapeutics for controlling and/or avoiding the progression of pathologies derived from an incorrect immune outcome, including infectious processes, cancer, or autoimmune diseases. Therefore, a detailed knowledge of these receptors is mandatory for the development of specific treatments. In this review, we summarize the current knowledge about four key C-type lectins whose importance has been steadily growing in recent years, focusing in particular on how glycan recognition takes place at the molecular level, but also looking at recent progresses in the quest for therapeutics.

Antibody combinations for optimized staining of macrophages in human lung tumours.

The analysis of tumour-associated macrophages (TAMs) has a high potential to predict cancer recurrence and response to immunotherapy. However, the heterogeneity of TAMs poses a challenge for quantitative and qualitative measurements. Here, we critically evaluated by immunohistochemistry and flow cytometry two commonly used pan-macrophage markers (CD14 and CD68) as well as some suggested markers for tumour-promoting M2 macrophages (CD163, CD204, CD206 and CD209) in human non-small cell lung cancer (NSCLC). Tumour, non-cancerous lung tissue and blood were investigated. For immunohistochemistry, CD68 was confirmed to be a useful pan-macrophage marker although careful selection of antibody was found to be critical. The widely used anti-CD68 antibody clone KP-1 stains both macrophages and neutrophils, which is problematic for TAM quantification because lung tumours contain many neutrophils. For TAM counting in tumour sections, we recommend combined labelling of CD68 with a cell membrane marker such as CD14, CD163 or CD206. In flow cytometry, the commonly used combination of CD14 and HLA-DR was found to not be optimal because some TAMs do not express CD14. Instead, combined staining of CD68 and HLA-DR is preferable to gate all TAMs. Concerning macrophage phenotypic markers, the scavenger receptor CD163 was found to be expressed by a substantial fraction (50%-86%) of TAMs with a large patient-to-patient variation. Approximately 50% of TAMs were positive for CD206. Surprisingly, there was no clear overlap between CD163 and CD206 positivity, and three distinct TAM sub-populations were identified in NSCLC tumours: CD163+ CD206+ , CD163+ CD206- and CD163- CD206- . This work should help develop macrophage-based prognostic tools for cancer.

COMP in the Infrapatellar Fat Pad-Results of a Prospective Histological, Immunohistological, and Biochemical Case-Control Study.

Knee osteoarthritis (OA) involves several structures and molecules in the joint, which interact in a pathophysiological process. One of these molecules is the cartilage oligomeric matrix protein (COMP). Elevated COMP levels in the synovial fluid as well as in the serum have been described in OA patients. However, this has not been described in the infrapatellar fat pad (IPFP) tissue before. In this prospective trial, we collected 14 IPFPs from patients with high-grade OA (mean age 63.8 ± 17.6 years) who underwent total knee replacement (OA group) and from 11 healthy patients (mean age 33.7 ± 14.8 years) who underwent anterior cruciate ligament reconstruction (control group). The presence of macrophages (CD68 and CD206) and proinflammatory cytokines (interleukin 1ß [IL-1ß] and IL-6) was analyzed. Histological and immunohistological examinations as well as immunoblotting analysis for COMP, leptin, and matrix-metalloproteinase-3 were performed. The IPFPs of both the OA and control group consisted of adipose tissue and fibrous tissue, and the fibrous tissue showed higher score values than the adipose tissue for COMP staining (intensity as well as stained area) in both groups. Although COMP could be detected in most samples, leptin expression was found only in single specimens. COMP could be detected mostly in the fibrous tissue portion of the IPFP. We speculate that it is involved in a remodeling process taking place in the IPFP during OA. Presence of leptin was irregular in immunohistology, and the control group showed higher scores in case of presence. Interestingly, immunoblotting could detect leptin in all analyzed samples. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:747-758, 2020.

Mannan Enhances IL-12 Production by Increasing Bacterial Uptake and Endosomal Degradation in L. acidophilus and S. aureus Stimulated Dendritic Cells.

The mannose receptor (MR) is a C-type lectin involved in endocytosis and with a poorly defined ability to modulate cellular activation. We investigated the effect of mannan treatment prior to stimulation of murine bone marrow-derived dendritic cells with the Gram-positive bacteria Lactobacillus acidophilus NCFM (L. acidophilus) on the induction of Interleukin (IL)-12. Mannan enhanced the IL-12 production induced by L. acidophilus in a dose dependent manner (up to 230% enhancement). Additionally, mannan-enhanced IL-12 induction was also demonstrated with another Gram-positive bacteria, Staphylococcus aureus (S. aureus), while an IL-12 reducing effect was seen on Escherichia coli stimulated cells. Furthermore, the expression of Interferon ß (Ifnb) was increased in cells treated with mannan prior to stimulation with L. acidophilus. The addition of mannan but not of bacteria led to endocytosis of MR, while addition of mannan prior to L. acidophilus or S. aureus resulted in increased endocytosis of bacteria, a faster killing of endocytosed bacteria, and increased reactive oxygen species production. Expression of signaling lymphocytic activation molecule (SLAMF)1 shown previously to be involved in the facilitation of endosomal degradation was upregulated by mannan but not by L. acidophilus and S. aureus. The IL-12 enhancement by mannan but not the IL-12 induced by the bacteria was abrogated by addition of inhibitors of clathrin coated pits (chlorpromazine and monodansylcadaverine). Furthermore, the addition of acid sphingomyelinase, a facilitator of ceramide raft formation, prior to addition of L. acidophilus enhanced the IL-12 production and the endocytosis of bacteria. In summary, our results show that mannan increases the IL-12 production induced by some Gram-positive bacteria through MR-endocytosis, which increases bacterial endocytosis and endosomal killing. The differential effect of MR activation on the IL-12 production induced by Gram-positive and Gram-negative bacteria may influence the immune response toward allergens and other glycoproteins.

Geography and ethnicity related variation in the Chinese human milk serum proteome.

Human milk provides a range of nutrients and bioactive components, which can support the growth and development of infants. However, human milk composition may change due to geographic and ethnic variation. This study investigated the variation of the Chinese human milk serum proteome based on mothers with different ethnicities living in different parts of China, using TMT labeling combined with Nano-LC Q Exactive HF MS/MS proteomics. In total, 693 proteins were identified and quantified in human milk serum from Yunnan (Han and Bai ethnicity), Gansu (Han and Tibetan ethnicity), Xinjiang (Uygur ethnicity), and Inner Mongolia (Mongolian ethnicity). The biological function distribution of identified proteins and the summed intensity of proteins belonging to each biological function were similar among groups. The five relatively highly abundant milk serum proteins, lactoferrin, serum albumin, polymeric immunoglobulin receptor, macrophage mannose receptor 1, and bile salt-activated lipase were not significantly different among different geographies and ethnicities. On the other hand, we found 34 proteins that did significantly differ with geography and ethnicity. Those significantly different proteins have known strong interaction in inflammation response and regulation of multi-organism processes. Taken together, biological function distribution was similar on both the qualitative and quantitative levels, and proteins with similar abundance are important in providing basic nutrition and protection for infants, whereas the significantly different proteins may be important for the healthy development of infants from different locations and ethnicities.

Mild Hypobaric Hypoxia Effects on Murine Skeletal Muscle Morphology and Macrophages and Well-Being.

BACKGROUND: In the last 10 yr, the number of ultra-haul flights-defined as flights greater than 12 h of flying time-has increased. While the medical complications of these flights are well-known, the underlying cellular effects are less clear. The primary objective of this study was to test the effects of extended mild hypobaric hypoxia on overall well-being and skeletal muscle morphology and macrophage populations.METHODS: A total of 22 male C57BL/6 mice were assigned to a normobaric (NB) or hypobaric (HB) chamber for 14-17 h. Overall mouse well-being and the general morphology and resident macrophage number in hindlimb muscles were compared between the two pressure conditions.RESULTS: During mild hypobaric hypoxia, the mice behaved normally and no changes were observed in general muscle morphology. Regarding resident macrophages, the mean antigen area of CD206 in the hindlimb muscles, lateral gastrocnemius (LG, 33.8 ± 2.0 vs. 35.3 ± 1.6), medial gastrocnemius (MG, 32.4 ± 1.6 vs. 32.6 ± 1.5), and quadriceps femoris (QF, 36.3 ± 1.2 vs. 34.3 ± 1.1) were similar between NB and HB conditions, and the number of CD68-positive cells in the LG and QF were similar between the two conditions. Significantly fewer CD206-positive cells were counted in the LG muscle under the HB condition.CONCLUSION: Our findings indicate that extended exposure to mild hypobaric hypoxia, similar to that of an ultra-long-haul flight, does not adversely affect healthy skeletal muscle.Zhang L, Soulakova J, St. Pierre Schneider B. Mild hypobaric hypoxia effects on murine skeletal muscle morphology and macrophages and well-being. Aerosp Med Hum Perform. 2019; 90(12):1050-1054.

Langerhans cells in hypospadias: an analysis of Langerin (CD207) and HLA-DR on epidermal sheets and full thickness skin sections.

BACKGROUND: Hypospadias are among the most common genital malformations. Langerhans Cells (LCs) play a pivotal role in HIV and HPV infection. The migration of LC precursors to skin coincides with the embryonic period of hypospadias development and genetic alterations leading to the formation of hypospadias impact the development of ectodermally derived tissues. We hypothesized that this might be associated with a difference in frequency or morphology of epidermal and dermal LCs in hypospadias patients. METHODS: A total of 43 patients from two centers were prospectively included into this study after parental consent and ethics approval. Epidermal and dermal sheets were prepared from skin samples of 26 patients with hypospadias, 13 patients without penile malformations and 4 patients with penile malformations other than hypospadias. Immunofluorescence staining of sheets was performed with anti-HLA-DR-FITC and anti-CD207/Langerin-A594 antibodies. Skin sections from 11 patients without penile malformation and 11 patients with hypospadias were stained for Langerin. Frequencies as well as morphology and distribution of epidermal and dermal LCs on sheets and sections were microscopically evaluated. Cell counts were compared by unpaired t-tests. RESULTS: There was no difference in frequency of epidermal LCs, Neither on sheets (873 ± 61 vs. 940 ± 84LCs/mm2, p = 0.522) nor on sections (32 ± 3 vs. 30 ± 2LCs/mm2, p = 0.697). Likewise, the frequency of dermal LCs (5,9 ± 0,9 vs. 7.5 ± 1.3LCs/mm2, p = 0.329) was comparable between patients with hypospadias and without penile malformation. No differences became apparent in subgroup analyses, comparing distal to proximal hypospadias (p = 0.949), younger and older boys (p = 0.818) or considering topical dihydrotestosterone treatment prior to surgery (p = 0.08). The morphology of the LCs was not different comparing hypospadias patients with boys without penile malformations. CONCLUSIONS: LCs are present in similar frequencies and with a comparable morphology and distribution in patients with hypospadias as compared to children without penile malformations. This suggests that patients with hypospadias are not different from patients with normal penile development considering this particular compartment of their skin immunity.

A Case of Orbital Langerhans Cell Histiocytosis in an Adult.

Langerhans cell histiocytosis remains an enigmatic disease with a very heterogeneous presentation. We describe a rare case of orbital Langerhans cell histiocytosis in a 39-year-old female patient who presented right orbital pain and edema of the upper right eyelid. Surgery showed a friable lesion and underlying bone irregularity. Morphological aspects and immunohistochemical profile favored the diagnosis of Langerhans cell histiocytosis, which was confirmed with evidence of Langerin expression. The staging tests did not reveal any organ involvement, so we decided to follow the algorithm proposed by Euro Histio Net: in case of unifocal disease and in a single organ, clinical surveillance was preferred. This case aims to raise awareness of a manifestation of Langerhans cell histiocytosis, which should always be considered as a differential diagnosis in adults with osteolytic orbital lesions.

A histiocitose de células de Langerhans permanece uma doença enigmática com apresentação muito heterogénea. Descrevemos um caso raro de histiocitose de células de Langerhans orbitária numa doente do sexo feminino, 39 anos, com dor orbitária e edema da pálpebra superior direita. A tomografia computorizada das órbitas revelou uma lesão lítica próxima da glândula lacrimal. Na cirurgia observou-se uma lesão friável e irregularidade óssea subjacente. Os aspetos morfológicos e perfil imunohistoquímico favoreciam o diagnóstico de histiocitose de células de Langerhans, confirmando-se com a evidência da expressão da Langerina. Uma vez que os exames de estadiamento não revelaram envolvimento de outro órgão, decidimos seguir o algoritmo proposto pelo Euro Histio Net: tratando-se de doença unifocal e uni-órgão, optamos pela vigilância. Este relato de caso visa alertar para uma manifestação rara da histiocitose de células de Langerhans, a qual deve ser sempre considerada como um diagnóstico diferencial em adultos com lesões orbitárias osteolíticas.

The soluble mannose receptor (sMR/sCD206) in critically ill patients with invasive fungal infections, bacterial infections or non-infectious inflammation: a secondary analysis of the EPaNIC RCT.

BACKGROUND: Invasive fungal infections (IFI) are difficult to diagnose, especially in critically ill patients. As the mannose receptor (MR) is shed from macrophage cell surfaces after exposure to fungi, we investigate whether its soluble serum form (sMR) can serve as a biomarker of IFI. METHODS: This is a secondary analysis of the multicentre randomised controlled trial (EPaNIC, n = 4640) that investigated the impact of initiating supplemental parenteral nutrition (PN) early during critical illness (Early-PN) as compared to withholding it in the first week of intensive care (Late-PN). Serum sMR concentrations were measured in three matched patient groups (proven/probable IFI, n = 82; bacterial infection, n = 80; non-infectious inflammation, n = 77) on the day of antimicrobial initiation or matched intensive care unit day and the five preceding days, as well as in matched healthy controls (n = 59). Independent determinants of sMR concentration were identified via multivariable linear regression. Serum sMR time profiles were analysed with repeated-measures ANOVA. Predictive properties were assessed via area under the receiver operating curve (aROC). RESULTS: Serum sMR was higher in IFI patients than in all other groups (all p < 0.02), aROC to differentiate IFI from no IFI being 0.65 (p < 0.001). The ability of serum sMR to discriminate infectious from non-infectious inflammation was better with an aROC of 0.68 (p < 0.001). The sMR concentrations were already elevated up to 5 days before antimicrobial initiation and remained stable over time. Multivariable linear regression analysis showed that an infection or an IFI, higher severity of illness and sepsis upon admission were associated with higher sMR levels; urgent admission and Late-PN were independently associated with lower sMR concentrations. CONCLUSION: Serum sMR concentrations were higher in critically ill patients with IFI than in those with a bacterial infection or with non-infectious inflammation. However, test properties were insufficient for diagnostic purposes.

Aqueous two phase based selective extraction of mannose/glucose specific lectin from Indian cultivar of Pisum sativum seed.

Pisum sativum lectin (Psl) being a high-value protein has marked its application in the biomedical and therapeutic field. Aqueous two phase extraction (ATPE) was implemented as a selective partitioning technique for the partial purification of Psl from its seeds. PEG/citrate based biodegradable aqueous two phase system (ATPS) was screened and the factors such as the type and concentration of citrate salts, molar mass and concentration of polyethylene glycol (PEG), tie line length (TLL) and additive (NaCl) concentration, pH, crude load and volume ratio were studied for the selective partition of Psl. The Psl was successfully extracted to the top phase in the ATPS formed with 18% PEG 6000/16% sodium citrate at 41.01% TLL, 2% NaCl and pH of 7.5. A volume ratio of 0.76 and a crude load of 20% showed maximum activity yield of 122.12% with the purification factor of 16.26. The subunits of Psl namely α and ß were identified with a molecular weight of 6 and 18 kDa respectively during the purity analysis using SDS PAGE and HPLC.

Langerin staining identifies most littoral cell angiomas but not most other splenic angiomatous lesions.

Although littoral cell angiomas (LCAs) are phenotypically well characterized, the antibodies used to support the diagnosis identify many other cells in the normal spleen, and some may be found in other angiomatous lesions. Based on a langerin/CD207+ LCA index case, langerin and other selected immunohistochemical staining was performed on 10 LCAs, 20 other splenic angiomatous lesions, and 7 reactive lymph nodes to further investigate the role of langerin as a diagnostic tool. Ninety percent (9/10) of LCAs were langerin positive, whereas only 1 (5%) of 20 other splenic vascular lesions was partially positive (P < .00001). All LCAs were CD1a-, CD68+, CD34-, and CD8-; 20% were S100+, 70% CD21+, and 90% cyclin D1+. Ultrastructural studies of one LCA did not show Birbeck-type granules in definite lining cells. Sinus lining cells in 7 of 7 reactive lymph nodes showed partial langerin positivity, and 4 of 4 showed partial cyclin D1 positivity. In conclusion, langerin staining is an easily interpreted and highly sensitive and specific (sensitivity [0.90], specificity [0.95]) ancillary study to help distinguish LCA from other vascular tumors of the spleen. Whether this represents cross-reactivity or true CD207 expression is uncertain, as other immunohistochemical and ultrastructural studies do not support a Langerhans cell origin. The cyclin D1 staining seen in most LCA would be consistent with their expression of other selected vascular and histiocytic markers. The similar staining pattern in some lymph node sinus lining cells suggests a possible similar cell of origin, although LCA of lymph nodes is not described.

Renal transplant recipients receiving loop diuretic therapy have increased urinary tract infection rate and altered medullary macrophage polarization marker expression.

Loop diuretics deplete the renal cortico-medullary salt gradient that has recently been established as a major modulator of immune responses. Renal transplant recipients suffer from a markedly increased rate of urinary tract infections (UTIs). Whether diuretic therapy affects renal macrophage polarization in the human kidney graft and the incidence of UTI have not been reported. In a cohort of 112 adult renal allograft recipients, loop diuretic therapy significantly correlated with the rate of UTI during five years after transplantation in uni- and multivariable regression analysis. The M1 macrophage marker human leukocyte antigen-DR (HLA-DR) and the M2 macrophage marker CD206 co-localized with the pan-macrophage marker CD68 in the kidney graft. Both were more common in renal medulla than cortex. With increasing loop diuretic dose, the renal medullary M1/M2 macrophage marker ratio decreased in early surveillance biopsies of this cohort. In vitro, the sodium chloride concentration dose-dependently increased monocyte chemotactic cytokine CCL2 production in human myeloid and renal tubular epithelial cells. More CCL2 was detected in the renal medulla than cortex of the kidney grafts. However, in patients receiving loop diuretic therapy, the renal cortico-medullary CCL2 gradient was diminished and CCL2 serum levels decreased significantly. Thus, diuretic therapy associated with increased bacteriuria and leukocyturia after kidney transplantation and a decreased M1/M2 macrophage marker ratio in the renal medulla. Hence, adjustment of diuretic therapy should be investigated further as a possible approach in patients with frequent UTIs.

Partial depletion of CD206-positive M2-like macrophages induces proliferation of beige progenitors and enhances browning after cold stimulation.

Beige adipocytes are an inducible form of thermogenic adipocytes that become interspersed within white adipose tissue (WAT) depots in response to cold exposure. Previous studies have shown that type 2 cytokines and M2 macrophages induce cold-induced browning in inguinal WAT (ingWAT) by producing catecholamines. Exactly how the conditional and partial depletion of CD206+ M2-like macrophages regulates the cold-induced browning of ingWAT, however, remains unknown. We examined the role of CD206+ M2-like macrophages in the cold-induced browning of WAT using genetically engineered CD206DTR mice, in which CD206+ M2-like macrophages were conditionally depleted. The partial depletion of CD206+ M2-like enhanced UCP1 expression in ingWAT, as shown by immunostaining, and also upregulated the expression of Ucp1 and other browning-related marker genes in ingWAT after cold exposure. A flow cytometry analysis showed that the partial depletion of CD206+ M2-like macrophages caused an increase in the number of beige progenitors in ingWAT in response to cold. Thus, we concluded that CD206+ M2-like macrophages inhibit the proliferation of beige progenitors and that the partial depletion of CD206+ M2-like macrophages releases this inhibition, thereby enhancing browning and insulin sensitivity.

Langerin (CD207)-positive cells in leprosy: Possible implications for pathogenesis of the disease with special emphasis on dermal immunoreactivity.

Leprosy is a disease caused by Mycobacterium leprae, which is characterized by two distinct poles, the tuberculoid pole and the lepromatous pole, depending on the immune response to the bacillus. Langerin-positive cells are dendritic cells that appear to play an essential role in the development of the disease. These cells are specialized in the processing and presentation of antigens, exerting an important function in the activation of the immune system. To evaluate the expression of langerin-positive cells (CD207+) in skin lesion fragments of patients with a diagnosis of M. leprae infection and to associate the expression of these cells with the polar forms of the disease. Langerin-positive cells were detected in larger numbers in lesions of patients with the tuberculoid form compared to those with the lepromatous form. The presence of a larger number of these cells in patients with the tuberculoid form suggests an important participation of langerin-positive cells, capturing antigens and favoring an effective immune response to infection with M. leprae.