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Vitiligo is an autoimmune skin disease characterized by melanocyte destruction. Regulatory T cells (Tregs) are greatly reduced in vitiligo skin, and replenishing peripheral skin Tregs can provide protection against depigmentation. Ganglioside D3 (GD3) is overexpressed by perilesional epidermal cells, including melanocytes, which prompted us to generate GD3-reactive chimeric antigen receptor (CAR) Tregs to treat vitiligo. Mice received either untransduced Tregs or GD3-specific Tregs to test the hypothesis that antigen specificity contributes to reduced autoimmune reactivity in vitro and in vivo. CAR Tregs displayed increased IL-10 secretion in response to antigen, provided superior control of cytotoxicity towards melanocytes, and supported a significant delay in depigmentation compared to untransduced Tregs and vehicle control recipients in a TCR transgenic mouse model of spontaneous vitiligo. The latter findings were associated with a greater abundance of Tregs and melanocytes in treated mice versus both control groups. Our data support the concept that antigen-specific Tregs can be prepared, used, and stored for long-term control of progressive depigmentation.

Recent data have demonstrated that chronic inflammation is a crucial component of tumor initiation and progression. We previously reported that immature myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity toward effector T cells were expanded in experimental chronic inflammation. We hypothesized that elevated levels of MDSCs, induced by chronic inflammation, may contribute to the progression of tumor growth. Using the Ehrlich carcinoma animal model, we found increased tumor growth in mice with chronic adjuvant arthritis, which was accompanied by a persistent increase in the proportion of splenic monocytic and granulocytic MDSCs expressing CD62L (l-selectin), when compared to tumor mice without adjuvant arthritis. Depletion of inflammation-induced MDSCs resulted in decreased tumor growth. In vitro studies demonstrated that increased expression of CD62L by MDSCs was mediated by TNFα, elevated concentrations of which were found in tumor mice subjected to chronic inflammation. Moreover, the addition of exogenous TNFα markedly enhanced the suppressive activity of bone marrow-derived MDSCs, as revealed by the ability to impair the proliferation of CD8+ T cells in vitro. This study provides evidence that chronic inflammation may promote tumor growth via induction of CD62L expression by MDSCs that can facilitate their migration to tumor and lymph nodes and modulation of their suppressor activity.

Highlights • Population screening has confirmed circulation of West Nile virus in the southern region of Kazakhstan (Almaty region). • We report two cases of meningoencephalitis of unknown etiology occurred in the rural area near Tekeli city, Kazakhstan, in August 2019. • Retrospective analysis showed high titers of anti-WNV IgG in both patients’ serum specimens obtained on day 9 after the onset of symptoms. • These are the first reports of West Nile virus infection in Kazakhstan., Background West Nile virus (WNV) is a member of the genus Flavivirus, which transmitted to humans mainly by mosquitoes. Recent pilot serosurveillance data from the Almaty region, Kazakhstan, suggest widespread WNV circulation in this area. This report includes two cases of neuroinvasive WNV infection in the same family living in a rural area near Tekeli city, Eskeldinsky district, Almaty region, Kazakhstan. Occurring concurrently and manifesting as WNV infection with febrile illness and symptoms of meningoencephalitis. Methods The study performed retrospective analysis of clinical histories and achieved serum samples obtained from patients with febrile and meningoencephalitic syndromes of unknown origin in the Almaty region spanning from April 1 to October 31, 2019. All sera samples obtained from patients with clinically suspected cases of acute WNV infection were retrospectively tested for WNV and tick-borne encephalitis virus by commercial immunoassays. Two cases were selected. Cases presentation We report two cases that occurred in August 2019 in a rural area near Tekeli city. Previously healthy 28- and 19-year-old husband and wife with febrile illness and neurological manifestations were hospitalized with the diagnosis of meningoencephalitis of unknown etiology and treated empirically. Retrospective serological analysis showed the presence of high titers of IgG against WNV on day 9 after onset of symptoms in cases. Conclusions This is the first report of aseptic meningitis with WNV infection in the background in Kazakhstan. The obtained data suggest circulation of WNV in the Almaty region and emphasize importance of laboratory testing for WNV in suspicious cases occurring in the region.

It is well documented that age-related impaired functioning of immunocompetent cells is associated with an increase in the rates of chronic inflammatory diseases. Recently, an ability of melatonin to modulate inflammatory processes by regulating leucocyte recruitment has been demonstrated. However, to date, no studies have attempted to determine the impact of melatonin on the expression of CD62L by lymphocytes. CD62L, also known as L-selectin, is required for the entry of lymphocytes into secondary lymphoid organs, sites of tumor growth and chronic inflammation through high endothelial venules. Here, we investigated the effect of melatonin at physiological concentrations on the expression of CD62L by T and NK cells in vivo and in vitro. We demonstrated that NK and CD3+ T cells obtained from the spleen of aged mice were characterized by decreased expression of CD62L compared to young mice. Melatonin administration up-regulated the levels of surface CD62L on NK and T cell populations in aged mice under non-inflammatory conditions and on CD8+ T cells in aged mice with chronic inflammation. Pre-incubation with melatonin prevented the reduction in CD62L expression by CD8+ T cells induced by the co-cultivation of peripheral blood mononuclear cells with human pancreatic adenocarcinoma cell line (MiaPaCa-2). The obtained results suggest that melatonin can modulate lymphocyte homing into lymph nodes and sites of chronic inflammation and, therefore, can stimulate immune responses in chronic inflammatory conditions associated with aging.

Regulatory T cells (Tregs) are a subset of T cells responsible for the regulation of immune responses, thereby maintaining immune homeostasis and providing immune tolerance to both self and non-self-antigens. An increasing number of studies revealed Treg numbers and functions in a variety of autoimmune diseases. Treg deficiency can cause the development of several autoimmune skin diseases including vitiligo, alopecia areata, pemphigoid and pemphigus, psoriasis, and systemic sclerosis. Many clinical trials have been performed for autoimmune conditions using polyclonal Tregs, but efficiency can be significantly improved using antigen-specific Tregs engineered using T cell receptor (TCR) or chimeric antigen receptor (CAR) constructs. In this review, we systematically reviewed altered frequencies, impaired functions, and phenotypic features of Tregs in autoimmune skin conditions. We also summarized new advances in TCR and CAR based antigen-specific Tregs tested both in animal models and in clinics. The advantages and limitations of each approach were carefully discussed emphasizing possible clinical relevance to patients with autoimmune skin diseases. Moreover, we have reviewed potential approaches for engineering antigen-specific Tregs, and strategies for overcoming possible hurdles in clinical applications. Thereby, antigen-specific Tregs can be infused using autologous adoptive cell transfer to restore Treg numbers and to provide local immune tolerance for autoimmune skin disorders.

Uvod. Rickettsia typhi svrstava se u skupinu pjegavih tifusa i uzrokuje endemski tifus. Slučajevi endemskog tifusa i seropozitivnosti na R. typhi zabilježeni su u susjednoj Kini i Rusiji. Međutim, o endemskom tifusu u Kazahstanu se malo zna. Svrha ove studije bila je procijeniti prevalenciju IgG protutijela na R. typhi u populaciji južne regije Kazahstana. Metode. U istraživanje je uključeno ukupno 253 osoba (142 žena, 111 muškaraca) u dobi od 1 do 71 godine. Detekcija serumskih IgG protutijela na R. typhi provedena je imunoenzimskim ELISA testom. Rezultati. Ukupna seropozitivnost na R. typhi iznosila je 34,4%. Najveća seroprevalencija od 91,8% zabilježena je u regiji Turkestan. Najniža seropozitivnost od 6,1% otkrivena je u selu Lepsinsk, regija Almaty. Seroprevalencija se nije značajno razlikovala prema spolu. Seropozitivnost kod odraslih pojedinaca nije bila značajno povezana s dobi, ali pozitivni rezultati nisu otkriveni u dobnoj skupini djece mlađe od 14 godina. Zaključak. Dobiveni rezultati potvrđuju aktivnu cirkulaciju R. typhij u regijama Turkestan i Almaty u Kazahstanu. Podaci ukazuju na hitnu potrebu za daljnjim istraživanjima čiji je cilj procijeniti klinički učinak R. typhi u južnoj regiji Kazahstana., Background. Rickettsia typhi belongs to the typhus group of rickettsiae and causes endemic typhus. Cases of endemic typhus and seropositivity to R. typhi have been reported in the neighbouring China and Russia. However, little is known of the endemic typhus in Kazakhstan. The purpose of this study was to evaluate the prevalence of IgG antibodies to R. typhi in the population of southern region of Kazakhstan. Methods. A total of 253 individuals (142 women, 111 men) aged from 1 to 71 years were recruited into the study. Detection of serum IgG antibodies against R. typhi was performed by enzyme-linked immunosorbent assay (ELISA). Results. The overall R. typhi seropositivity has reached 34.4%. The highest seroprevalence of 91.8% was recorded in the Turkestan Region. The lowest seropositivity of 6.1% was detected in the village Lepsinsk, Almaty Region. The seroprevalence did not differ significantly between genders. Seropositivity in adult individuals was not significantly associated with age, but positive results were not detected in the age group of children under 14 years. Conclusion. The obtained results confirm active circulation of R. typhi in the Turkestan and Almaty Regions of Kazakhstan. The data indicate an urgent need for further studies aimed to evaluate the clinical impact caused by R. typhi in the southern region of Kazakhstan.

Regulatory T cells (Tregs) play a major role in tumor escape from immunosurveillance by suppressing effector cells. The number of Tregs is increased in tumor sites and peripheral blood of breast cancer patients. However, the data regarding phenotypic and functional heterogeneity of Treg subpopulations in breast cancer are limited. The present study aimed to investigate the number and suppressive potential of Tregs that possess natural naive-(N nTregs), effector/memory-like (EM nTregs), and Tr1-like phenotypes in breast cancer patients and healthy women. The study included 10 HW and 17 primary breast cancer patients. Numbers of CD4+CD25+FoxP3+CD45RA+ N nTregs, CD4+CD25+FoxP3+CD45RA− EM nTregs, and CD4+IL-4−IL-10+ Tr1 subsets and the expression of CTLA-4, CD39, GITR, LAP, and IL-35 by these Treg subsets were measured in freshly obtained peripheral blood by flow cytometry. Herein, we demonstrate that the percentages of N nTregs, EM nTregs, CD25+ and FoxP3+ Tr1 cells are elevated in the peripheral blood of breast cancer patients, but do not correlate with cancer stages. Nevertheless, the frequency of CD25+ Tr1 cells was associated with nodal involvement, while the number of EM nTregs correlated with clinical outcome. The expression of CTLA-4 and IL-35 by all assessed Treg subsets was increased throughout all tumor stages (I–III). Collectively, the current study shows phenotypic alterations in suppressive receptors of Treg subsets, suggesting that breast cancer patients have increased activity of N nTregs, EM nTregs and Tr1 cells; and EM nTregs and CD25+ Tr1 cells represent prospective markers for assessing disease prognosis.

Regulatory T cells (Treg), both natural and induced, play an important role in maintaining immune homeostasis. Alterations in the number and functions of Tregs are involved in tumor growth. One of the possible regulatory mechanisms of Treg functional activity involves interaction with major component of extracellular matrix hyaluronan. It has been demonstrated that high molecular weight hyaluronan promotes Treg function via increased expression of FoxP3 and production of IL-10. Moreover, previous research has shown highly enhanced suppressor function of hyaluronan-binding CD4+CD25+ Tregs in mice. Breast cancer is characterized by upregulated production of tumor-associated hyaluronan, therefore we investigated hyaluronan-binding subset of Tregs obtained from peripheral blood of breast cancer patients. As a result, we showed that the majority of peripheral blood Tregs were able to adhere to immobilized hyaluronan, and these cells exerted superior suppressor activity, suggesting a key role in regulatory functions of these cells. The percentage of CD4+FoxP3+ Treg cells binding hyaluronan, as well as CD39+ hyaluronan-binding Tregs were significantly increased in breast cancer patients compared to healthy donors. Enhanced number of the activated Treg cells might play an important role in the suppression of antitumor immunity.