Transcriptome network analysis implicates CX3CR1-positive type 3 dendritic cells in non-infectious uveitis.

Background: Type I interferons (IFNs) promote the expansion of subsets of CD1c+ conventional dendritic cells (CD1c+ DCs), but the molecular basis of CD1c+ DCs involvement in conditions not associated without elevated type I IFNs remains unclear. Methods: We analyzed CD1c+ DCs from two cohorts of non-infectious uveitis patients and healthy donors using RNA-sequencing followed by high-dimensional flow cytometry to characterize the CD1c+ DC populations. Results: We report that the CD1c+ DCs pool from patients with non-infectious uveitis is skewed toward a gene module with the chemokine receptor CX3CR1 as the key hub gene. We confirmed these results in an independent case-control cohort and show that the disease-associated gene module is not mediated by type I IFNs. An analysis of peripheral blood using flow cytometry revealed that CX3CR1+ DC3s were diminished, whereas CX3CR1- DC3s were not. Stimulated CX3CR1+ DC3s secrete high levels of inflammatory cytokines, including TNF-alpha, and CX3CR1+ DC3 like cells can be detected in inflamed eyes of patients. Conclusions: These results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology. Funding: The presented work is supported by UitZicht (project number #2014-4, #2019-10, and #2021-4). The funders had no role in the design, execution, interpretation, or writing of the study.

CD1a- and CD83-positive dendritic cells as prognostic markers of metastasis development in early breast cancer patients.

PURPOSE: Dendritic cells (DCs) are the most potent antigen-presenting cells that play a major role in initiating the antitumor immune response in different types of cancer. However, the prognostic significance of the accumulation of these cells in human early breast tumors is not totally clear. The aim of this study is to evaluate the prognostic relevance of CD1a( +) and CD83( +) dendritic cells in early breast cancer patients. METHODS: We conducted immunohistochemical assays to determine the number of stromal CD1a( +) and CD83( +) DCs in primary tumors from early invasive ductal breast cancer patients, and analyzed their association with clinico-pathological characteristics. RESULTS: Patients with high CD1a( +) DC number had lower risk of bone metastatic occurrence, as well as, longer disease-free survival (DFS), bone metastasis-free survival (BMFS) and overall survival (OS). Moreover, CD1a( +) DC number was an independent prognostic factor for BMFS and OS. In contrast, we found that patients with high number of CD83( +) DCs had lower risk of mix (bone and visceral)-metastatic occurrence. Likewise, these patients presented better prognosis with longer DFS, mix-MFS and OS. Furthermore, CD83( +) DC number was an independent prognostic factor for DFS and OS. CONCLUSION: The quantification of the stromal infiltration of DCs expressing CD1a or CD83 in early invasive breast cancer patients serves to indicate the prognostic risk of developing metastasis in a specific site.

Development of an Inflammatory CD14+ Dendritic Cell Subset in Humanized Mice.

Humanized mouse models are attractive experimental models for analyzing the development and functions of human dendritic cells (DCs) in vivo. Although various types of DC subsets, including DC type 3 (DC3s), have been identified in humans, it remains unclear whether humanized mice can reproduce heterogeneous DC subsets. CD14, classically known as a monocyte/macrophage marker, is reported as an indicator of DC3s. We previously observed that some CD14+ myeloid cells expressed CD1c, a pan marker for bona fide conventional DC2 (cDC2s), in humanized mouse models in which human FLT3L and GM-CSF genes were transiently expressed using in vivo transfection (IVT). Here, we aimed to elucidate the identity of CD14+CD1c+ DC-like cells in humanized mouse models. We found that CD14+CD1c+ cells were phenotypically different from cDC2s; CD14+CD1c+ cells expressed CD163 but not CD5, whereas cDC2s expressed CD5 but not CD163. Furthermore, CD14+CD1c+ cells primed and polarized naïve CD4+ T cells toward IFN-γ+ Th1 cells more profoundly than cDC2s. Transcriptional analysis revealed that CD14+CD1c+ cells expressed several DC3-specific transcripts, such as CD163, S100A8, and S100A9, and were clearly segregated from cDC2s and monocytes. When lipopolysaccharide was administered to the humanized mice, the frequency of CD14+CD1c+ cells producing IL-6 and TNF-α was elevated, indicating a pro-inflammatory signature. Thus, humanized mice are able to sustain development of functional CD14+CD1c+ DCs, which are equivalent to DC3 subset observed in humans, and they could be useful for analyzing the development and function of DC3s in vivo.

Diagnostic usefulness of immunohistochemical evaluation of CD1a antigen and polyclonal anti-leishmania antibodies in cutaneous leishmaniasis.

BACKGROUND: Different immunohistochemical markers to detect amastigotes in cutaneous leishmaniasis have been proposed with variable diagnostic usefulness. OBJECTIVES: To evaluate the diagnostic usefulness of immunohistochemical amastigotes identification by specific polyclonal anti-Leishmania antibodies and CD1a expression (clone EP3622) in a series of PCR confirmed cutaneous leishmaniasis. MATERIALS AND METHODS: Thirty-three skin samples corresponding to PCR confirmed cutaneous leishmaniasis were included in the study. All samples were stained with Hematoxylin-eosin and Giemsa. Moreover, immunohistochemical studies with anti-CD1a and anti-Leishmania antibodies were performed. The patients clinical features and the observed histopathological features were also recorded. RESULTS: From the selected 33 biopsies, Leishmania spp. amastigotes were detected in 48.4% of cases with conventional Hematoxylin-eosin stain and in 57.5% of cases by Giemsa staining. In 31/33 cases, anti-CD1a allowed us to identify parasitic structures, and in 33/33 cases amastigotes were detected with anti-Leishmania antibodies. Concordance between both techniques, anti-CD1a and anti-Leishmania, was 94% [CI 95%: (79,8%-99,3%)] ; p value <0.05. The sensitivity of anti-CD1a in comparison with the PCR was 94%, with a positive predictive value of 100%. Two cases of low parasitic index were negative for CD1a immunostaining. In cases with high parasitic index, anti-CD1a stained amastigotes in superficial and deep dermis. Only a few cases were originally diagnosed with the available histological techniques, needing PCR for Leishmania spp. CONCLUSIONS: Anti-CD1a antibody seems to be a useful technique to identify amastigotes when PCR and anti-Leishmania antibodies are not available. The sensitivity to detect amastigotes is increased when the CD1a immunostaining is added to the classical Haematoxylin - eosin and Giemsa staining.

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.

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.

Placas similares a xantomas como forma de presentación de una histiocitosis de células de Langerhans en un paciente en edad adulta / Adult Onset Langerhans Cell Histiocytosis Diagnosed With Xanthomalike Plaque

No disponible

Role of inflammation and inflammasome activation in human bile cast nephropathy.

Bile cast nephropathy (BCN) is an underdiagnosed cause of acute kidney injury (AKI). The precise pathogenesis of bilirubin tubular toxicity remains unknown. The aim of this study is to explore the cellular and molecular pathophysiology of human BCN. Paraffin-embedded sections of renal biopsy tissue from a BCN patient were stained by immunohistochemistry (IHC) for oxidative stress (4-hydroxynonenal), immune cell subpopulations, including dendritic cells (CD1c), macrophages (CD68) and T cells (CD3), and inflammasome activation by staining for active-caspase-1 and the inflammasome adaptor protein, ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain). Quantitative analyses of IHC staining were compared to healthy renal cortical tissue. We identified yellow to brown granular casts within the BCN case, consistent with the presence of bile pigment. The presence of bile pigment was associated with strong tubular 4-hydroxynonenal staining intensity, a marker of oxidative stress. Diffuse tubulointerstitial inflammatory cell infiltrate was detected, with elevated CD1c, CD68 and CD3 staining. Foci of inflammasome activity were co-localized with this intense immune cell infiltration, with increased active-caspase-1 and ASC staining. Our findings are the first to suggest that bile casts may lead to oxidative stress and trigger the inflammasome signalling cascade, leading to interstitial inflammation and driving AKI pathobiology. SUMMARY AT A GLANCE The report suggests that bile casts may lead to oxidative stress and trigger the inflammasome signalling cascade, leading to interstitial inflammation and driving bile cast nephropathy pathobiology.

CD1a+ and CD207+ cells are reduced in oral submucous fibrosis and oral squamous cell carcinoma

BACKGROUND: The objective of this study investigated the distribution of immature dendritic cells (DCs), Langer-hans cells and plasmacytoid DCs in oral submucous fibrosis (OSMF), OSMF associated with oral squamous cell carcinoma (OSMF-OSCC), oral leukoplakia (OL), and oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: Fourteen cases of OSMF, 9 of OSMF-OSCC, 8 of OL ̧ 45 of OSCC and 8 of normal epi-thelium were retrospectively retrieved and their diagnoses confirmed. Immunoreactions against CD1a, CD207 e CD303 were performed and the number of positive cells quantified. RESULTS: A significant decrease of CD1a+ was found in OSMF (p≤0.05), OSMF-OSCC (p ≤ 0.01), and OSCC (p ≤ 0.001) when compared to normal epithelium. For CD207+ the significance decrease was observed in OSMF-OSCC (p ≤ 0.05), and OSCC (p ≤ 0.01) when compared with normal epithelium, and in OSMF when compared with OL (p ≤ 0.05). There was no significant difference for CD303, but increased in CD303+ was observed in OSCC when compared with normal epithelium. CONCLUSION: The decrease in the number of CD1a+ and CD207+ cells may be associate to the development of oral OSCC, and in OPMDs they might be indicators of malignant transformation

No disponible

Evaluation of the diagnostic potential of CD1a immunohistochemistry for visceral leishmaniasis.

Visceral Leishmaniasis is a public health problem caused by protozoans of the genus Leishmania. K39 serological test is commonly used in the initial investigation, with high specificity, but variable sensitivity. Amastigotes can be identified by optical microscopy, however, the differential diagnosis with cellular debris or other intracellular parasites is necessary. Recent studies have raised the possibility of using immunohistochemistry in the diagnosis of visceral leishmaniasis with labeling of amastigotes by the anti-CD1a antibody. This retrospective study was based on 38 samples from patients with visceral leishmaniasis whose diagnoses were confirmed by myelogram and/or k39 testing, aside from positive (N=13) and negative biopsies (N=25), 2 samples from patients with false positive biopsies for visceral leishmaniasis and 8 samples from patients with histoplasmosis diagnosis. The histological slides were evaluated for the presence of amastigotes and their Modified Ridley Parasitic Index. The samples were submitted to immunohistochemical reactions using the anti-CD1a antibody with MTB1 and O10 clones. Immunohistochemical reactions with MTB1 and O10 clones had low sensitivity in this study. However, all bone marrow samples were previously decalcified with nitric acid which is probably a deleterious treatment for immunohistochemical reactions in this site. Excluding these samples, we obtained 58.33% sensitivity and 100% specificity with the MTB1 clone. Despite the intermediate sensitivity, the immunohistochemistry for the CD1a marker with clone MTB1 can be useful in the differential diagnosis of visceral leishmaniasis, helping to discriminate leishmania amastigotes from other pathogens with similar morphology and cellular debris in different samples, except in bone marrow biopsies previously decalcified with nitric acid.

Atypical presentation of isolated orbital Langerhans cell histiocytosis.

BACKGROUND: A 9-year old female presented with one month of waxing and waning upper eyelid swelling. An excisional biopsy via anterior orbitotomy was performed. OBJECTIVE: To describe a patient presenting atypically with symptoms concerning for orbital cellulitis who was diagnosed with Langerhans cell histiocytosis (LCH). METHODS: Description of case report. RESULTS: We report a case of a 9-year old female with one month of periorbital edema and erythema suspected to be orbital cellulitis. A complete ophthalmological exam, subsequent imaging, and an excisional biopsy revealed the diagnosis of LCH. With a confirmed diagnosis, the patient started chemotherapy indicated by the Histiocyte Society Evaluation and Treatment Guidelines. CONCLUSION: Langerhans cell histiocytosis (LCH) embodies a spectrum of diseases with the primary pathologic process being the abnormal proliferation of polyclonal Langerhans cells. In children with isolated bony involvement, the most common presenting symptom is pain. Rarely is orbital involvement with associated periorbital edema and erythema the primary presentation.

Inmunohistoquímica de las lesiones cutáneas en la lepra y las leprorreacciones / No disponible

Objetivos: 1. Evaluar la immunohistoquimica de los granulomas de la lepra en las muestras de biopsias cutáneas de pacientes con lepra tuberculoide y lepromatosa, con respecto a la presencia y distribución de células T CD4+, CD8+ y CD28+, células CD 68+ y células CD1a+. 2. Evaluar los hallazgos inmunohistoquimicos observados en leprorreacciones. Metodología: Estudio descriptivo. Se seleccionaron para el estudio biopsias cutaneas, en las que se había diagnosticado clínica e histopatologicamente lepra entre el 1.8.2016 al 31.5.2017 en el Instituto Medico Gubernamental, Kozhikode. Se estudió la immunohistoquimica de las lesiones cutáneas en lepra y leprorreacciones, observando específicamente la distribución de células CD4/ CD8/ CD28/ CD68/ CD1a en la lepra en distintos escenarios. Resultados: En el estudio se incluyeron veintiséis casos tuberculoides y 14 lepromatosos. Todos los granulomas independientemente del tipo de enfermedad presentaron tinción positiva por CD4 y CD68. Dos de los 14 casos lepromatosos (14・3%), y 15/26 (57・7%) de las muestras tuberculoides presentaron expresion CD4 de moderada a fuerte. Se detectó negatividad CD28 en cuatro casos tuberculoides (15・4%) y en 10 lepromatosos (71・4%). La expresion CD4 moderada a fuerte se detectó en más del 70% de los T1R incremento mientras que en los demás grupos solo fue de 20%-50%. Más del 80% de las T1R estáticas e incremento presentaban positividad CD28, mayor de que el 30%-50% registrado en otros grupos. Conclusiones: Los resultados revelan que la inmunohistoquimica tiene un papel en aclarar los complejos procesos inmunológicos empleados en la lepra y las leprorreacciones

Objectives: 1. To study the immunohistochemistry of leprosy granulomas in the skin biopsy specimens of patients with tuberculoid and lepromatous leprosy, with respect to the presence and arrangement of CD4+, CD8+ and CD28+ T cells, CD 68+ cells and CD1a+ cells. 2. To study the immunohistochemistry findings observed in leprosy reactions. Design: Descriptive study. Skin biopsies in which the clinical and histopathological diagnosis of leprosy was reported between 1.8.2016 to 31.5.2017 in the Government Medical College, Kozhikode, were selected for the study. Immunohistochemistry of the skin lesions in leprosy and leprosy reactions was studied, looking specifically for the distribution of CD4/ CD8/ CD28/ CD68/ CD1a positive cells in leprosy at different scenarios. Results: Twenty-six tuberculoid and 14 lepromatous cases were included in the study. All granulomas irrespective of disease type showed positive staining for CD4 and CD68. Two of the 14 lepromatous leprosy cases (14・3%), and 15/26 (57・7%) tuberculoid specimens manifested moderate to strong CD4 expression. CD28 negativity was documented in four tuberculoid (15・4%) and 10 lepromatous cases (71・4%). Moderate to strong CD4 expression was noted in more than 70% of upgrading T1R while a similar finding was documented in only 20%-50% of other groups. More than 80% of static and upgrading T1R showed CD28 positivity, which was higher than the 30%-50% positivity recorded in other groups. Conclusions: The observations of the current study indicate a role for immunohistochemistry analysis in delineating the complex immunological processes involved in leprosy and leprosy reactions

A case report of orbital Langerhans cell histiocytosis presenting as a orbital cellulitis. / Caso clínico de histiocitosis de células de Langerhans presentándose como una celulitis orbitaria.

CLINICAL CASE: A 10-year-old girl was seen with a 3-week history of right upper lid swelling and with no other symptoms or fever. There was no recent history of sinusitis, trauma, or previous infection involving the periorbital area, or response to oral antibiotic treatment. Orbital computed tomography showed a lesion involving the upper margin of the orbit, and bone destruction at the orbital roof. Biopsy performed revealed the presence of Langerhans cell Histiocytosis. The lesion was surgically debulked and corticosteroids were used intra-operatively. The lesion responded to treatment. DISCUSSION: The orbital involvement of Langerhans cell histiocytosis, despite its low incidence, should be considered in the examination of acute peri-orbital swelling. It usually presents as an osteolytic lesion, and it is confirmed with a histological examination and immunohistochemical techniques for CD1a and S100. An interdisciplinary approach is recommended to rule out multifocal or multisystemic diseases, as well as to develop an appropriate treatment strategy.

Analysis of dendritic cells and ischemia-reperfusion changes in postimplantation renal allograft biopsies may serve as predictors of subsequent rejection episodes.

Ischemia-reperfusion injury increases allograft immunogenicity and enhances myeloid dendritic cell maturation and trafficking to recipient's secondary lymphoid tissue. Here, we used postreperfusion biopsies from patients who received kidney allografts from deceased donors between 2006 and 2009 to assess the impact of ischemia-reperfusion damage and myeloid dendritic cell density on subsequent allograft rejection episodes. Histologic changes of severe ischemia-reperfusion damage in postreperfusion biopsies were found to be associated with subsequent rejection episodes and suboptimal allograft survival. Using BDCA-1 as a marker of myeloid dendritic cells, postreperfusion biopsies from deceased donors had lower dendritic cell density compared to postreperfusion biopsies from living donors or normal controls. This suggests a rapid emigration of donor dendritic cells out of the allograft. In our cohort, low dendritic cell density was associated with a subsequent increase in rejection episodes. However, it appears that the donor's cause of death also influenced dendritic cell density. Therefore, we assessed the additive impact of severe ischemia-reperfusion changes and low dendritic cell density on subsequent rejection. The aforementioned combination was a powerful and independent predictor of allograft rejection. Thus, our data highlight the prognostic value of histopathologic changes associated with ischemia-reperfusion in postreperfusion biopsies and suggest a rapid posttransplant emigration of myeloid dendritic cells out of the allograft to enhance alloimmunity. These findings may provide a rationale for minimizing ischemia-reperfusion injury and therapeutic targeting of donor-derived dendritic cells to promote rejection-free allograft survival.

Nueva clasificación de las histiocitosis / New classification of histiocytosis

No disponible

A decreased peritumoral CD1a+ cell number predicts a worse prognosis in oral squamous cell carcinoma.

AIMS: Dendritic cells (DCs) are known to play a central role in the regulation of both innate and adaptive immunological responses, including antitumour immunity. The aim of this study was to evaluate the prognostic impact of intratumoral and peritumoral DCs in oral squamous cell carcinoma (OSCC) affecting the tongue and floor of the mouth. METHODS AND RESULTS: Immunohistochemistry for CD1a and CD83 was performed in 53 patients with OSCC in the tongue and floor of the mouth. The markers were evaluated by automated examination in intratumoral and peritumoral compartments, and the results were expressed as density of cells/mm2 . Correlations between these data and clinicopathological and survival outcomes were investigated. Depletion of peritumoral CD1a+ cells was associated with lymph node metastasis (P = 0.05), whereas depletion of peritumoral CD83+ cells was correlated with smoking history (P = 0.04), lymph node metastasis (P = 0.015), and extracapsular spread of lymph nodes (P = 0.018). Peritumoral CD1a+ was correlated with recurrence (P = 0.007) and overall survival (P = 0.03). The results of the survival analysis with the Cox proportional hazard model showed that depletion of peritumoral CD1a+ cells is an independent factor associated with overall survival and disease-free survival. CONCLUSION: Our results suggest that depletion of peritumoral CD1a+ cells is a strong independent prognostic factor, predicting a higher recurrence rates and worse survival outcomes.

Enhanced dendritic cells and regulatory T cells in the dermis of porokeratosis.

Porokeratosis is characterized clinically by annular lesions and histologically by the presence of a cornoid lamella (CL) in the epidermis. The underlying mechanism of porokeratosis development remains unclear. We performed immunohistochemical staining of CD1a, langerin, Ki67, CD3, CD4, CD8, FOXP3, and RANKL (receptor activator of nuclear factor κB ligand) in samples from 17 porokeratosis lesions and analyzed the differences in staining patterns among the CL, the inner part of the annular ridge (IC), and the adjacent normal skin (ANS). Numbers of CD1a+ Langerhans cells in the epidermis were reduced and numbers of CD1a+ dermal dendritic cells were significantly increased in the CL and IC compared to those in the ANS. In addition, there was also an increase in FOXP3+ cells in the dermis below the CL and IC. Our findings suggest that Langerhans cells are downregulated in the epidermis in CL and that regulatory T cells and dendritic cells are upregulated in the dermis below the CL. This alteration in the distribution of immune cells, such as various lymphocyte subsets, Langerhans cells, and dermal dendritic cells, may play a key role in the pathomechanisms of porokeratosis.