Five cases of Candida peritonitis were diagnosed, representing the second most frequent cause of invasive fungal infection in the cohort. The incidence rate of Candida peritonitis during the first 30 days after transplantation was 6.5 cases/10 000 transplant days in pancreas recipients and 1.2 cases/10 000 transplant days in liver recipients (P = 0.035). Four of the five patients received an echinocandin in combination with other antifungal. All patients were alive and with good graft function at 1-year follow-up. In our series, Candida peritonitis

in liver and pancreas transplant recipients was not uncommon and had a good prognosis. “
“Vulvovaginal candidosis (VVC) is a common infection of the female genital tract affecting 75% women at least once in their selleck kinase inhibitor lifetime. The aim of this study was to determine the incidence and potential risk factors associated with VVC and recurrent vulvovaginal candidosis (RVVC). A prospective study of women with vaginitis symptoms was conducted over 2 years in the regional clinic of population and family education in Sfax. A discriminant analysis was used to evaluate the association between the incidence of Candida vaginitis and potential risk

factors. Sporadic and recurrent VVC were documented respectively in 48% and 6.1%. The most frequent factors associated with positive Candida culture were employed women, uncontrolled diabetes, history selleck compound of genital infection and intrauterine device contraception. Increased episode numbers of VVC and condom/spermicidal contraception

were positively associated with recurrences. Candida albicans was the predominantly isolated species (76.3%) followed by Candida glabrata (19.3%). Infection with C. glabrata occurred in 34% and 17.5% of patients MTMR9 with RVVC and VVC respectively. The discriminant investigation had provided further insights into the basis for prevention and control of RVVC. Increased prevalence of C. glabrata in patients with RVVC and observed risk factors should be taken into consideration to achieve success in the management of this infection. “
“Invasive fungal infections (IFIs) in patients with haematological malignancies are difficult to diagnose and outcome is often fatal. Over the 7-month study period, 117 cases with haematological malignancies receiving systemic antifungal treatment were included. Data regarding antifungal agents, dosage and reason for administration were recorded. Fungal infections in study patients were classified as possible, probable or proven according to recent European Organization for Research and Treatment of Cancer criteria. During the study period, 690 cases with haematological malignancies were admitted. A total of 117 cases received systemic antifungal therapy. Twenty-four of 117 patients (21%) had possible, six (5.1%) had probable and four (3.4%) had proven IFI. Seven of 10 probable and proven infections were caused by Candida spp., 2 by Aspergillus spp. and 1 by a fungus belonging to Zygomycetes.

Debelle et al. compiled a list of botanical Temozolomide price agents known to contain AA.65 Despite a ban in many countries, products containing AA continue to be widely available. Inappropriate nomenclature and imprecise labelling are other confounding issues. Cheung et al.35 found AA in a number of Chinese raw herbs and manufactured herbal products, many of which were due to the complexity of nomenclature leading to mistaken identification. It is

also possible that more nephrotoxic plants still remain unidentified. The possibility of plants being responsible for CKD in other parts of the world has been suggested. A large proportion of CKD patients in the Indian subcontinent present with a relatively short history, advanced renal failure, little or no oedema, mild hypertension and small

smooth kidneys. The primary disease in most of these cases Erlotinib remains a mystery.86 Out of over 3000 consecutive patients seen at our Institute, the aetiology could not be determined in over one-third. Clusters of CKD have also been reported from Sri Lanka, affected individuals being male farmers of poor socioeconomic status in the north-central provinces.87,88 Similar presentation has been described amongst South Asians living in the UK.89 The role of environmental toxins, such as herbs, pesticides or other chemicals in the genesis of CKD either directly or through contamination of drinking water, rice or edible fish65,87,88,90 has been proposed but remains unproven as yet. A recent Thai study91 showed an inverse relationship between the prevalence of CKD and the developmental status of the society. The prevalence increased progressively from urban areas to urban slums to the villages, suggesting the presence of unique risk factors in a less developed population. Lack of regulation is a major factor behind the widespread use of potentially toxic herbs. Classification as ‘dietary supplements’ keeps them out of the ambit of efficacy and safety requirements in the

Chorioepithelioma USA.17 The European Community introduced a list of unacceptable herbs and made adverse event reporting mandatory in 2004.57 However, locally prepared medicines using crude herbal ingredients and non-medicinal herbal products continue to be exempt from such rules. In conclusion, the use of herbal remedies is common in large parts of the developing world, especially amongst the rural population. The true incidence of CKD due to nephrotoxic herbs remains uncertain. The structural and functional abnormalities are non-specific and may be overlooked. AA, present in a number of commonly used plants has been proved to cause chronic interstitial nephritis and urothelial malignancy. Clinical inquiry should be extended to include the possibility of use of herbal medicine when investigating a case of unexplained kidney disease or urothelial carcinoma. Regulatory control is essential to prevent toxicity due to misuse of herbs.

Sera.  The sera from patients with acute Chagas’ disease, all from the states of Minas Gerais, Bahia, and Goiás, Brazil, were described in a previous study [14] except for serum samples collected during 1.9 month, 7.9 months and 15.15 years from an individual accidentally infected with T. cruzi, which were kindly made available to us for this study. In all patients,

T. cruzi was detected by microscopic examination of blood. The sera from chronic indeterminate disease and non-chagasic sera were also from previous studies [14]. Prior to use, the sera, stored in 50% glycerol at 4 °C, were centrifuged at 1,200 g for 10 min and diluted in appropriate buffers, as described later.

Ethical approval was obtained from the Human click here Investigation Review Committee of Tufts Medical Center. ELISA assay.  Microtitre wells were coated overnight at 4 °C with recombinant extracellular domain (ECD) of human TrkA, TrkB and TrkC receptors fused to the Fc region of human IgG (400 ng/ml) (R&D Systems, Minneapolis, MN, USA) as described earlier [7], blocked with 5% goat serum (2 h, 37 °C), followed by chagasic sera diluted at 1:200 (unless otherwise indicated) in 5% bovine serum albumin/phosphate-buffered saline pH 7.2 containing 0.1% Tween-20, washed and developed with alkaline phosphatase Smoothened antagonist (AP)-labelled secondary relevant antibody. To determine the antibody titres against T. cruzi, trypomastigotes were obtained from cellular cultures, lysed by repeated cycles Methane monooxygenase of

freeze/thaw, cleared of debris by centrifugation (12,000 g, 10 min), layered on microtitre wells (500 ng/ml, 4 °C) and probed with chagasic sera, as described earlier. ATA isotyping was performed by ELISA with commercially available kits (Sigma-Aldrich, St Louis, MO, USA) based on mouse mAb to human IgG isotypes and goat antibodies specific to IgA and IgM. Antibody avidity.  This was determined as previously described [11, 15] except that we used ELISA instead of ligand blotting to obtain avidity measurements. In brief, microtitre wells were coated overnight with Fc chimera of Trk receptors-ECD (TrkA, TrkB, and TrkC) or control receptor (p75NTR), blocked with 5% goat serum (2 h, 37 °C), washed and incubated with sera (1:200, 2 h) without pre-incubation or after pre-incubation (4 °C, overnight) with various concentrations of soluble receptor-ECD and developed with AP-labelled secondary relevant antibody, as described earlier. Avidity to TrkA was also determined in an affinity-purified rabbit TrkA antibody (Abcam, Cambridge, MA, USA). Avidity measurements and plots were obtained with the prism 4.0 program (GraphPad Software, La Jolla, CA, USA).

In addition, the microvasculature and its endothelium are a large metabolic tissue in their own right required to adapt its structure and function to both maintain microcirculatory integrity and meet its own metabolic needs throughout the life course [5]. There is accumulating evidence that deficits in microvascular structure and function may be a prodromal indicator and independent risk determinant in metabolic syndrome, hypertension, and diabetes [1,7]. Changes in small vessel

structure and function can be detected, often before the onset of Decitabine research buy macro-vascular disease and the development of end organ damage common to hypertension and obesity-associated clinical disorders. Thus, the clinical assessment of the microcirculation offers an important tool in disease risk stratification [8] and of the evaluation of the impact of both non modifiable (age) [5] and modifiable (lifestyle and environmental) [7] risk factors. However, given the lack of heterogeneity across microvascular beds and the lack of standardized tools to investigate microvascular function in humans routinely, the quantitative clinical evaluation of microvascular deficits remains a challenge [6]. David Strain and colleagues [8] review the microcirculation in epidemiology and how large AZD6244 datasheet scale epidemiological studies have identified the

associations between disordered microvascular control and subsequent target organ damage. They provide examples of how measuring microvascular status in large cohorts and epidemiological modeling have helped to establish the nature of the complex bidirectional interaction between microcirculatory STK38 outcome measures and end organ damage

and how this in turn may inform prospective studies, intervention trials, and drive change in clinical practice. One such example is the interplay between diabetic nephropathy, metabolic syndrome and atherosclerosis. Strain and colleagues highlight this complexity in a series of reports on inter-ethnic comparisons between those of European and African Caribbean descent. While it might be anticipated that African Caribbeans have better microvascular function given that they are known to be relatively protected from atherosclerotic disease, paradoxically, the opposite is observed with the general African Caribbean population having attenuated microvascular function compared with Europeans. Findings from other large epidemiology studies, while supporting the role of microcirculatory dysfunction in the etiopathogenesis of cardiovascular disease, challenge the axiom that there is a “gold standard” endothelial assessment tool and that the same mechanisms underlie endothelial dysfunction across all vascular beds.

[28] The most straightforward mechanism of viral evasion of the IFN response is to avoid buy Dabrafenib detection in the first place. Several viruses conceal or degrade dsRNA, a by-product of viral replication. For example, tick-borne encephalitis virus delays antiviral signalling by sequestering RNA molecules into cytoplasmic membrane-defined compartments, where they are inaccessible to PRR recognition.[29] Similarly, Japanese encephalitis virus (JEV) conceals its dsRNA among intracellular membranes.[30] Amazingly, species-specific differences in the timing of the release of viral dsRNA into the cytosol account for the drastically different pathogenesis of JEV in humans compared with pigs.[30]

Rather than hide it, Lassa fever virus uses the 3′–5′ exonuclease activity of its NP protein to degrade its dsRNA,[31]

whereas the C protein from human parainfluenza virus type 1 is thought to regulate viral RNA production in such a way as to prevent dsRNA from accumulating at all.[32] Viral sensing phosphatase inhibitor library by PRRs activates three main transcription factor complexes involved in IFN-β production: NF-κB, IRF3/IRF7 and ATF2/c-jun (Fig. 2).[33] In resting cells, NF-κB is held as an inactive complex in the cytoplasm by its inhibitor, IκBα.[34] PRR activation stimulates IκBα phosphorylation and degradation, releasing NF-κB to translocate to the nucleus and induce target genes. A recent example of viral disruption of NF-κB activation involves the V protein from measles virus, which binds to the nuclear location signal of the NF-κB subunit p65, impairing its nuclear translocation.[35] The NF-κB essential modulator (NEMO), a regulatory component involved in the phosphorylation of IκBα,[36] is also targeted, as it is cleaved into inactive fragments by the FMDV protease 3Cpro.[37] Less is understood about ATF2/c-Jun. This complex is constitutively nuclear, even in its inactive form, and is stimulated by phosphorylation of its activation domains.[38] Virus infection triggers the stress-activated members of the mitogen-activated

protein (MAP) kinase superfamily, acetylcholine which phosphorylate and activate ATF2/cJun. For the first time, a viral protein blocking this complex has been described; the Zaire ebola virus protein VP24 prevents the phosphorylation of p38 MAP kinase and the downstream activation of ATF2.[39] Critical factors involved in IFN expression include IRF3 and IRF7.[40] IRF3, which is constitutively expressed in resting cells, is phosphorylated upon PRR signalling by the IκB kinase (IKK)-related kinases IKKε and TBK-1, causing IRF3 to homodimerize and translocate to the nucleus. There, IRF3 interacts with the histone acetyl transferases CBP and p300, and associates with the IFN-β promoter. IRF3 can also directly activate a subset of ISGs in the absence of IFN.[41, 42] Accordingly, IRF3 is a popular target for viral inhibition. The V protein of Sendai virus directly binds IRF3, impairing its function.

Pra1 is an important multifunctional fungal immune evasion protein [[15]]. The pro-inflammatory cytokine response to Candida

is complement- and cell-mediated and is distinct from the previously defined TLR-induced cytokine response to fungi defined by Netea et al. [[16]]. Cheng et al. [[1]] confirm the importance of complement in this process by using heat-inactivated serum, which lacks an active complement system, and also by blocking specific complement activation pathways, that is, the alternative, the classical, or the lectin pathways. In each scenario, release of pro-inflammatory cytokines, that is, IL-1β, TNF-α and IL-6 by PBMCs was significantly reduced. In addition, in the study by Netea et al. [16], the complement-induced inflammatory cytokine response via C5a–C5a receptor signaling was shown to cooperate and interact Selleckchem Saracatinib selleck inhibitor synergistically with TLR2 and TLR4 signaling induced by the ligands Pam3Cys and lipopolysaccharide (LPS), respectively. In order to confirm that the inflammatory response is indeed complement mediated and induced by the inflammatory activation fragment C5a, Cheng et al. [[1]] use recombinant C5a in competition assays to block C5a

receptors on human PBMCs. Recombinant C5a alone has no effect on the inflammatory response, but C5a added together with Candida augments IL-6 and IL-1β production, but does not affect TNF-α release. Furthermore blocking experiments with antibodies against complement components clearly defines that C5a and C5a-receptor functions mediate this cytokine response. Cheng et al. [[1]] also identify host genetic susceptibility factors by analyzing the immune response of serum Pembrolizumab mouse derived from patients with defined genetic deficiencies. Previously, two authors (Schejbel and Garred) of Cheng et al. [1], were also involved in the identification of patients with inherited complement defects, that is, patients with C5-, C6-, and C7 deficiencies

[[17]]. C5-deficient serum, when activated, forms a C3 convertase and generates C3a and C3b; however complement progression is blocked at the C5 stage. When cultivated in C5-deficient serum, the cytokine response to Candida is abrogated, thus underlining the relevance of C5 for cytokine production. This C5-deficient serum forms neither C5a nor C5b. In order to conclude whether the block in the complement-mediated cytokine response is mediated by C5a or C5b-triggered TCCs, Cheng et al. [[1]] also used serum from patients who were deficient for single components of the terminal pathway, that is, C6 or C7. Both sera, when activated by Candida, form C3- as well as C5-activation products, that is, C5a and C5b. However, progression of the terminal pathway and TCC pore formation does not occur.

In another study, a discrete subset of myeloid (CD11b+) DCs was the only cell type in spleen that transcribed IFN-β1 genes after systemic DNP AZD3965 concentration treatment, though other cell types ingested DNPs and contained cargo DNA [33]. Thus it may not be a coincidence

that, in a recent study to examine antigen uptake in living lymphoid tissues using intra-vital techniques, CD11b+ DCs were shown to ingest particulate antigens rapidly [35]. Other spleen cells have also been shown to ingest DNPs rapidly. Marginal zone macrophages (MZMs; CD169+, F4/80neg) in mouse spleen ingested DNPs rapidly and avidly, but unlike CD11b+ DCs, no DNP cargo DNA was detected in MZMs [33], suggesting that MZMs ingest and degrade particulate material containing DNA such as chromatin, which resembles DNPs before DNA accesses the cytosol; this scenario is consistent with the ability of MZMs to remove blood-borne particulate

materials this website in a way that does not incite autoimmunity [36]. Unlike MZMs, some splenic CD8α+ DCs and myeloid non-DCs (CD11b+CD11cneg) also ingested DNPs and retained cargo DNA but did not transcribe IFN-β1 genes [33], suggesting that cytosolic DNA sensing to activate the STING/IFN-β pathway may be defective in these cell types. Treating mice with cdiGMP elicited responses in the spleen that were remarkably similar to those induced by DNPs [33], reinforcing the conclusions that myeloid DCs are “first-responder cells” and are specialized to sense cytosolic DNA and CDNs, and that the DNA sensing STING/IFN-β pathway may be functionally defective in other “nonresponder” cells. DNP and cdiGMP treatments were also shown to induce comparable patterns of IL-1β transcription via a STING-independent pathway [33]; however, myeloid non-DCs (not myeloid DCs)

expressed the highest levels of IL-1β transcripts. Another recent report revealed that bacterial CDNs stimulate mucosal immunity in mice via a pathway dependent on STING and NFκB signaling but not IRF3 and IFN-αβ signaling to induce TNF-α [37]. In summary, responses to DNA by innate immune cells are surprisingly complex and functionally PtdIns(3,4)P2 dichotomous, revealing tissue-, cell-type-, and pathway-specific differences in how innate immune cells respond to DNA. The molecular basis of such complex physiologic responses to DNA are poorly understood but are critically important for elucidating pivotal pathways that control downstream immune responses to DNA. Cytosolic DNA sensing to induce regulation via STING may be biologically significant for several reasons. Regulatory responses to DNA may help maintain self-tolerance during homeostasis and inflammation, thereby reducing the risk of inciting autoimmunity.

Therefore, we did not use IL-10 antisense ODNs in this study. Using SCIDbg mice depleted of Mϕs and PMNs (SCIDbgMN mice), we RXDX-106 in vitro have preliminarily examined whether orally infected pathogen causes infectious complications. After decontamination, these mice were infected orally with vancomycin-resistant Enterococcus faecium (VRE, ATCC 700221 strain), and the growth of VRE in the liver and MLNs was examined using EF agar containing vancomycin. In these experiments, we confirmed a source of

the pathogen for sepsis developed in burn mice orally infected with E. faecium. That is to say, the vancomycin-resistant property of enterococci was used as a biomarker of the pathogen, which was translocated from intestine. When 105 CFU/mouse of VRE was given to SCIDbgMN DNA Synthesis inhibitor mice, all of them died within 3–5 days of infection. VRE (105.7–106.2 CFU/g organ) was detected in tissue specimens taken from these mice 2 days after infection. No other bacteria were detected in these tissue samples. In addition, all SCIDbgMN mice exposed to the same dose of heat-killed VRE survived, and no bacteria were detected in tissue specimens from these mice. These results indicate that the development of infectious complications in these mice was caused by VRE given orally. Various cells such as neutrophils, monocytes/Mϕs, dendritic cells,

eosinophils and certain T-cell subpopulations are known to be producers of CCL2 33. So far, we do not know which cells are the major source of CCL2 in burned mice. Certain monocyte/Mϕ populations exposed to stress have been described as producer cells for CCL2 34. These monocytes/Mϕs may play a role on the CCL2 production in burned mice. In our previous studies utilizing severely burned mice 7, neutrophils with the functions to produce CCL2 and IL-10 have been demonstrated, and these neutrophils are designated as PMN-II. PMN-II may be the major cell to produce CCL2 in mice 1–3 days after burn injury. PMN-II were clearly distinguished from normal PMNs and immunopotentiating

PMNs (PMN-I) by the ability to express CD11b and CD49d surface antigens and cytokine/chemokine-producing profile 7. Thus, PMN-II (CD11b+CD49d− PMNs) are CCL2 and IL-10-producing cells, whereas PMN-I (CD11bCD49d+ PMNs) are IL-12 and IFN-γ-producing cells. However, neither ALOX15 CCL2 nor IL-10 was produced by neutrophils isolated from burn mice that were previously treated with CCL2 antisense ODNs (Supporting Information Fig. 1). These results indicate that CCL2 production by PMN-II is controllable by CCL2 antisense ODNs gene therapy. Further studies are needed. Eight to ten weeks-old male BALB/c mice (The Jackson Laboratory, Bar Harbor, ME, USA) were used in these experiments. Experimental protocols for animal studies were approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch at Galveston. As previously described 24, 25, E.

Isolated DAPT cost cells (2 × 106 cell per mL) were cultured in RPMI containing 1% HEPES (Sigma), 1%l-glutamine (Sigma), and 100 μg/mL gentamycin (Sigma) and 10% foetal calf serum (FCS) (GIBCO BRL, Karlsruhe, Germany) in 24-well culture plates

(Orange Scientific, Braine-l’Alleud, Belgium). Recombinant human GM-CSF (RELIATech GmbH, Wolfenbüttel, Germany) at specific concentrations including 5, 15, 25 and 50 ng/mL was added to the purified neutrophil cultures. In addition, neutrophils were stimulated with CpG-ODN class A (ggT GCA TCG ATG CAG ggg gg; TIB MolBIOL syntheselabor GmbH, Berlin, Germany), control ODN (ggT GCA TGC ATG CAG ggg gg; TIB MolBIOL syntheselabor GmbH) and class B (TCG TCG TTT TGT CGT TTT GTC GTT; Biospring, Frankfurt am Main, Germany) at the concentrations of 2, 15 and 40 μg/mL. The control medium was not stimulated with ODNs. Bases represented in capital letters were modified with phosphorodiester, and those in lower-case letters were modified with phosphorothioate. Female, 6–8 week old, BALB/c mice were obtained from the breeding stocks at the Pasteur Institute of Iran. Leishmania major (MHRO/IR/75/ER) promastigotes were grown at 26°C in M199 medium supplemented with 5% heat-inactivated FCS, 40 mm HEPES, 0·1 mm adenosine,

0·5 μg/mL hemin and 50 μg/mL gentamycin. The stationary-phase promastigotes of L. major were used to infect the animals. After 6–8 weeks, the dissected lymph nodes were used to isolate parasite. Afterwards, L. major Histamine H2 receptor was cultured in vitro in M199 medium containing 5% of heat-inactivated FCS, 40 mm HEPES, 0·1 mm Panobinostat purchase adenosine, 0·5 μg/mL hemin and 50 μg/mL gentamicin, incubated at 26°C for 7 days until reached the stationary growth phase. Three hours after incubation, GM-CSF-treated neutrophils stimulated with CpG-ODN were infected with stationary-phase L. major promastigotes (MHRO/IR/75/ER) at a parasite-to-cell ratio of 5 : 1. Extracellular parasites were removed 2 h after co-incubation by centrifugation

at 200 × g. Culture supernatants were collected 18 h after co-incubation of treated cells with L. major. The levels of TNF-α, IL-8 and TGF-β in culture supernatants were measured in duplicate using commercially available ELISA kits (R&D systems, Wiesbaden, Germany) according to the manufacturer’s instructions. The kit of TNF-α is designed for analysis of cell culture supernatants containing the lowest level of TNF-α up to 15·625 pg/mL, whereas the lowest specificity of TGF-β and IL-8 kits is 31·25 pg/mL. In the case of TGF-β measurement, all samples were activated by acidification using 1 m HCl with an incubation of 10 min at room temperature as recommended by manufacturer’s instructions. The performed method separated the TGF-β from its binding proteins. The activated samples were neutralized using 1·2 m NaOH/0·5 m HEPES. Immediately after this process, the samples were loaded in duplicate on the ELISA plate.

Analysis was performed with the Living Image software (v2.50, Xenogen). Lethally irradiated (9 Gy) C57BL/6 WT recipients received adoptive transfer of a total number of 1×107 BM cells that were either a 1:1 or a 1:20 mixture of

Thy1.2−Foxp3-eGFP WT to Thy1.2+Foxp3-eGFP OT-II, respectively. Chimeric mice were analyzed at 8–10 wk BMS-354825 mouse after transfer. The C57BL/6 (H-2b) into BALB/c (H-2d) acute GvHD model was performed as described elsewhere 35. In addition, some groups received 0.5×106 sorted Treg cells from WT or OT-II mice with a purity of >95%. Thy1.1+ Treg cells from either WT or OT-II donors were co-cultivated in round-bottom 96-well plates with MACS-enriched CFSE-labeled Thy1.2+ T cells at the indicated ratios under stimulatory conditions applying RPMI 1640 supplemented with 10% FCS, 2 mM glutamine and antibiotics, 100 IU/mL rh-IL2, and 1.5 μL T-cell expander beads (anti-CD3/anti-CD28, Dynal). After 4 days of co-culture, proliferation was assessed by flow cytometry determining CFSE dilution

on live Thy1.2+ T cells. Dead cells were identified by counterstaining with 4′,6-diamidino-2-phenylindol. Averages and SD or SEM were calculated with Graphpad Prism®. Group data were compared with the two-tailed unpaired t-test. Similarity between two sequenced TCR repertoires was statistically measured by the Morisita-Horn index 58. This index ranges between 0 (complete dissimilar) and 1 (identical) and is comparatively resistant to sample size. Proportional Euler diagrams were generated using the program VennMaster, which is Rebamipide available at http://www.informatik.uni-ulm.de/ni/staff/HKestler/vennm/doc.html. INK 128 mouse The authors thank Andreas Krueger and Oliver Pabst for discussions and carefully reading the MS. The authors thank Mathias Herberg, Georgios-Leandros Moschovakis, Sebastian Seth, Henrike Fleige, Sabrina

Woltemate, Kerstin Püllmann, Monika Bischoff, Anna Smoczek, Frano Malinarich, Manuel Winter, and Vijaykumar Chennupati for help. They also acknowledge the assistance of the Cell Sorting Core Facility of the Hannover Medical School. The authors are grateful to Véronique Guidicelli and the IMGT® team for their helpful collaboration and the analysis of nucleotide sequences on the IMGT/HighV-QUEST web portal, prior to its public availability. This work was supported by grants from the Deutsche Forschungsgemeinschaft SFB621-A14 (IP), and Deutsch-Französische Hochschule/Université franco-allemande DFH-UFA G2RFA 104-07-II. L. F. is supported by Hannover Biomedical Research School. Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors.