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Objective: To identify an MS-specific immune cell population by deep immune phenotyping and relate it to soluble signaling molecules in CSF., Methods: We analyzed surface expression of 22 markers in paired blood/CSF samples from 39 patients using mass cytometry (cytometry by time of flight). We also measured the concentrations of 296 signaling molecules in CSF using proximity extension assay. Results were analyzed using highly automated unsupervised algorithmic informatics., Results: Mass cytometry objectively identified a B-cell population characterized by the expression of CD49d, CD69, CD27, CXCR3, and human leukocyte antigen (HLA)-DR as clearly associated with MS. Concentrations of the B cell-related factors, notably FCRL2, were increased in MS CSF, especially in early stages of the disease. The B-cell trophic factor B cell activating factor (BAFF) was decreased in MS. Proteins involved in neural plasticity were also reduced in MS., Conclusion: When analyzed without a priori assumptions, both the soluble and the cellular compartments of the CSF in MS were characterized by markers related to B cells, and the strongest candidate for an MS-specific cell type has a B-cell phenotype., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases., (Copyright © 2020 Carballido, Regairaz, Rauld, Raad, Picard and Kammüller.)

Differentiation of B cells is a stringently controlled multi-step process, which is still incompletely understood. Here we identify and characterize a rare population of human B cells, which surprisingly carry CD8AB on their surface. Existence of such cells was demonstrated both in tonsils and in human apheresis material. Gene expression profiling and real time PCR detected however no CD8A or CD8B message in these cells. Instead, we found that surface CD8 was hijacked from activated CD8+ T cells by a transfer process that required direct cell-to-cell contact. A focused transcriptome analysis at single cell level allowed the dissection of the CD8 positive B cell population. We found that the affected cells are characteristically of the CD27+CD200- phenotype, and consist of two discrete late-stage subpopulations that carry signatures of activated memory B like cells, and early plasmablasts. Thus, there is only a restricted time window in the differentiation process during which B cells can intimately interact with CD8+ T cells. The findings point to a novel link between the T and B arms of the adaptive immune system, and suggest that CD8+ T cells have the capability to directly shape the global antibody repertoire., Competing Interests: The authors are employees of Novartis and declare no other competing interest. The commercial affiliation does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The low molecular weight compound VAF347, and its pro-drug version VAG539, interact with the transcription factor aryl hydrocarbon receptor (AhR) on monocytes to mediate its anti-inflammatory activity in vitro and in vivo. AhR is a crucial factor for IL-22 production, which regulates skin and gut homeostasis. Here we investigated whether VAF347 might control the differentiation of naïve T cells into IL-22-secreting cells and/or regulate IL-22 production by memory T cells. Human monocytes exposed to VAF347 differentiated into dendritic cells capable of instructing a naïve CD4(+) T cell differentiation program that promoted IL-22 secretion and concomitantly inhibited IL-17 production. Whilst AhR ligation by VAF347 on naïve CD4(+) T cells favored the development of single IL-22-secreting cells (Th22), it suppressed the generation of T cells secreting either IL-22 and IFN-γ or IL-17 and IFN-γ. In contrast, memory T cells were refractory to AhR regulation since VAF347, AhR antagonist or AhR gene silencing did not modulate the production of any of these cytokines. Interfering with AhR functions using VAF347 may provide an efficient way to intervene with autoimmune disease since it would enhance the host protective function mediated by IL-22 while preventing the development of Th cells secreting pro-inflammatory cytokines., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Having observed 4 personal cases, the authors review the distal complications of therapeutic arteriovenous fistulaes. Ischaemic complications are of arterial origin and may be severe: strong pain increasing during dialysis, soft tissue trophic disorders and ulcerations, and functional sequelae. Venous stasis disappear without permanent damage. The carpal tunnel syndrome is of uncertain and probably mixed aetiology and can easily be cured by surgical decompression. The use of small calibre, termino-terminal or latero-terminal distal anastomoses should help to prevent these complications.

A study of 10 cases of villous tumors treated by cryosurgery shows that this is a simple, benign, and conservative method which can be repeated if need be. It is possible to associate this method with other methods, in particular radiotherapy. The first results obtained suggest that cryosurgery can take its place amongst all the other non-invasive methods but requires, like them, a careful and continuous surveillance of the result which involves repeated endoscopy. The follow up time and the number of patients involved is not large enough to state definitely its long term efficacy but the results of this series are encouraging and optimistic for the future use of this method.

A retrospective study of 240 cases of haemorrhoids treated by cryosurgery with a 1 to 5 years' follow-up confirmed the immediate and long-term effectiveness of this method which resulted in lasting cure in more than 95% of the cases. The main advantages of the method are that it causes little pain and disablement, is relatively inexpensive and has virtually no complications. It main drawback is that the procedure must sometimes be repeated when the lesions are large. Although cryosurgery is in theory applicable to all forms of the haemorrhoidal disease, it is best indicated for stage I and stage II haemorrhoids.

The management of peptic oesophagitis after upper polar oesophagogastric resection is difficult, when this upper polar gastrectomy is carried out for prehepatic portal hypertension, the constant presence of newly formed oesophageal varices which often bleed, complicates the problem of the therapeutic indications. We adopted in one case an etiological solution by performing an end-to-side spleno-renal anastomosis after splenectomy which was symptomatic by interposition between the oesophagus and the stomach of part of the descending colon. Modern methods of mechanical suture facilitated this surgical operation.

Study of pulmonary arterial flow in the transplanted lung by means of an implanted ultrasonic flowmeter enables us: 1. To confirm results obtained by other methods (De Bono,8 Strider14 and Strandberg18): without specific treatment, rejection of graft causes increased peripheral resistances and the pulmonary arterial flow decreases progressively. 2. To prove by direct observation the existence in the treated animal of authentic precapillary shunts whose importance can cause the animal's death through functional disorder alone.