Negative impact of Interleukin-9 on synovial regulatory T cells in rheumatoid arthritis.

In Rheumatoid Arthritis (RA), regulatory T cells (Tregs) have been found to be enriched in the synovial fluid. Despite their accumulation, they are unable to suppress synovial inflammation. Recently, we showed the synovial enrichment of interleukin-9 (IL-9) producing helper T cells and its positive correlation with disease activity. Therefore, we investigated the impact of IL-9 on synovial Tregs in RA. Here, we confirmed high synovial Tregs in RA patients, however these cells were functionally impaired in terms of suppressive cytokine production (IL-10 and TGF-ß). Abrogating IL-9/ IL-9 receptor interaction could restore the suppressive cytokine production of synovial Tregs and reduce the synovial inflammatory T cells producing IFN-γ, TNF-α, IL-17. However, blocking these inflammatory cytokines failed to show any effect on IL-9 producing T cells, highlighting IL-9's hierarchy in the inflammatory network. Thus, we propose that blocking IL-9 might dampen synovial inflammation by restoring Tregs function and inhibiting inflammatory T cells.

Interleukin-9 rescues class switching of Memory B cells derived from Common variable immunodeficiency patients.

Impaired class switch memory (CSM) B cell formation is the hallmark of common variable immunodeficiency (CVID). Various T cell abnormalities have been observed in CVID patients indicating inadequate T-cell help to B cells. A major setback in understanding its pathogenesis is due to diverse clinical presentation. Therefore, we performed extensive immunological investigation in a cohort of CVID patients with similar clinical findings in order to unravel the T cell dysfunction and its influence on the defective humoral immune response. All recruited CVID patients exhibited B cells in the normal range, but reduced CSM B cells. However, patients showed reduced T cell proliferation, reduced level of serum Interleukin-9 (IL-9) and frequency of IL-9 expressing CD4 (Th-9) cells. IL-9 supplementation along with CD40 engagement was effective in inducing in vitro CSM B cells formation in CVID patients. Thus, IL-9 supplementation has the potential to restore impaired CSM B cell formation in CVID.

Mechanistic insight of interleukin-9 induced osteoclastogenesis.

Interleukin (IL)-9 is an emerging player in the pathogenesis of various chronic inflammatory diseases including bone disorders like rheumatoid arthritis (RA) and psoriatic arthritis. Recently, IL-9 was shown to enhance the osteoclast formation and their function in RA. However, the mechanisms by which IL-9 influences osteoclastogenesis are not known. Therefore, in this study we aimed to unravel the direct and indirect ways by which IL-9 can influence osteoclast formation. We used mouse bone marrow precursor cells for checking the effect of IL-9 on osteoclast differentiation and its function. Next, IL-9 induced signalling pathway were checked in the process of osteoclastogenesis. T cells play an important role in enhancing osteoclastogenesis in inflammatory conditions. We used splenic T cells to understand the impact of IL-9 on the functions of T effector (Teff) and regulatory T (Treg) cells. Furthermore, the effect of IL-9 mediated modulation of the T cell response on osteoclasts was checked using a coculture model of T cells with osteoclast precursors. We showed that IL-9 enhanced osteoclast formation and its function. We found that IL-9 activates STAT3, P38 MAPK, ERK1/2, NFκB and we hypothesize that it mediates the effect on osteoclastogenesis by accelerating mitochondrial biogenesis. Additionally, IL-9 was observed to facilitate the functions of pro-osteoclastogenic IL-17 producing T cells, but inhibits the function of anti-osteoclastogenic Treg cells. Our observations suggest that IL-9 can influence osteoclastogenesis directly by modulating the signalling cascade in the precursor cells; indirectly by enhancing IL-17 producing T cells and by reducing the functions of Treg cells.

Activated TLR2/4-positive T cells boost cell exhaustion during lepromatous leprosy infection via PD-1 upregulation.

The most important stage in activating an appropriate immune response during an infection is pathogen detection. Pattern recognition receptors (PRRs) are innate sensors used for pathogen detection that mould and link the innate and adaptive immune responses by the host. Toll Like receptors (TLRs) specifically TLR2 and TLR4, are PRRs, which have gained prominence due to their exceptional capacity to recognize unique molecular patterns from invading pathogens. They also play a critical role in maintaining the balance between Th1 and Th2 responses, which are necessary for the host's survival. Leprosy is a spectral disease with a wide range of immunological manifestations in the host. Cells of both the innate and adaptive branches play crucial roles in this polarized immune state. Here, we have analysed the proportional expression patterns of TLR2 and TLR4 on the surface of CD3+, CD4+, CD8+, CD19+ and CD161+ lymphocytes and CD14+ monocytes in different groups of leprosy patients. Further, these TLRs positive cells were correlated with the surface markers of cell exhaustion such as Programmed Death-1 (PD-1) and its ligand (PD-L1), which indicated their role in immunosuppression. Additionally, blocking the interaction of PD-1 with PD-L1 in lymphocytes demonstrated visible improvement in their immune activation status through release of pro-inflammatory cytokines (IFN-γ and TNF-α).

Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism.

Mycobacterium tuberculosis (M. tb) gene Rv1515c encodes a conserved hypothetical protein exclusively present within organisms of MTB complex and absent in non-pathogenic mycobacteria. In silico analysis revealed that Rv1515c contain S-adenosylmethionine binding site and methyltransferase domain. The DNA binding and DNA methyltransferase activity of Rv1515c was confirmed in vitro. Knock-in of Rv1515c in a model mycobacteria M. smegmatis (M. s_Rv1515c) resulted in remarkable physiological and morphological changes and conferred the recombinant strain with an ability to adapt to various stress conditions, including resistance to TB drugs. M. s_Rv1515c was phagocytosed at a greater rate and displayed extended intra-macrophage survival in vitro. Recombinant M. s_Rv1515c contributed to enhanced virulence by suppressing the host defense mechanisms including RNS and ROS production, and apoptotic clearance. M. s_Rv1515c, while suppressing the phagolysosomal maturation, modulated pro-inflammatory cytokine production and also inhibited antigen presentation by downregulating the expression of MHC-I/MHC-II and co-stimulatory signals CD80 and CD86. Mice infected with M. s_Rv1515c produced more Treg cells than vector control (M. s_Vc) and exhibited reduced effector T cell responses, along-with reduced expression of macrophage activation markers in the chronic phase of infection. M. s_Rv1515c was able to survive in the major organs of mice up to 7 weeks post-infection. These results indicate a crucial role of Rv1515c in M. tb pathogenesis.

Jurkat T Cells are Immunophenotypically Distinct from T-Cell Acute Lymphoblastic Leukemia Cells Due to High-Level Surface Expression of CD5.

Human leukemic T cells show decreased surface CD5 (sCD5) and increased cytoplasmic CD5 (cCD5). When we examined their expressions in the Jurkat T cells, it showed increased sCD5 and decreased cCD5, which is in sharp contrast with the pattern of CD5 expression observed for human leukemic T cells. Furthermore, this opposite pattern was due to the absence of an exonal switch between E1A and E1B. This study suggests that Jurkat cell does not retain all characteristics of T-ALL cells; thus, we should carefully interpret the data obtained using Jurkat T cell as a model cell line of T-ALL.

Interferon-gamma and perforin-positive T cells in acquired aplastic anemia: implication in therapeutic response.

Acquired aplastic anemia (aAA) is an autoimmune disease, characterized by infiltration of T lymphocytes in the bone marrow with destruction of hematopoietic stem cells by the effector cells. Interferon-gamma (IFN-γ) and perforin are important mediators of cell destruction. In this flow cytometry-based study, we have investigated the percentage of intracellular IFN-γ+ and perforin+ CD5+ T cells in peripheral blood of newly diagnosed aAA patients before and after immunosuppressive therapy (IST). Patients were categorized as per standard disease severity and response to IST. The median percentage of IFN-γ+ and perforin+ CD5+ T cells was higher in untreated patients compared to healthy controls. The percentage of these cells was also increased in untreated severe and very severe aplastic anemia when compared with non-severe aplastic anemia patients. In patients before and after IST the median percentage of T cells producing IFN-γ and perforin was elevated in non-responders as compared to partial plus complete responders. The higher percentage of IFN-γ+ and perforin+ CD5+ T cells may be useful as an early diagnostic marker for aberrant activation of immune system and predict poor response to IST in aAA patients, who will benefit from alternative therapy.

Increased Expression of NOTCH-1 and T Helper Cell Transcription Factors in Patients with Acquired Aplastic Anemia.

Background: Acquired aplastic anemia is an autoimmune disease in which auto-aggressive T cells destroy hematopoietic progenitors. T-cell differentiation is controlled by transcription factors that interact with NOTCH-1, which influences the respective T-cell lineages. Notch signaling also regulates the BM microenvironment. The present study aimed to assess the gene expressions of NOTCH-1 and T helper cell transcription factors in the acquired aplastic anemia patients. Methods: Using quantitative real-time PCR, we studied the mRNA expression level for NOTCH-1, its ligands (DLL-1 and JAG-1), and T helper cell transcription factors (T-BET, GATA-3, and ROR-γt) in both PB and BM of aAA patients and healthy controls. Further, patients of aplastic anemia were stratified by their disease severity as per the standard criteria. Results: The mRNA expression level of NOTCH-1, T-BET, GATA-3, and ROR-γT genes increased in aAA patients compared to healthy controls. There was no significant difference in the mRNA expression of Notch ligands between patients and controls. The mRNA expression level of the above-mentioned genes was found to be higher in SAA and VSAA than NSAA patients. In addition, NOTCH-1 and T helper cell-specific transcription factors enhanced in aAA. We also observed a significant correlation between the genes and hematological parameters in patients. Conclusion: The interaction between NOTCH-1, T-BET, GATA-3, and ROR-γT might lead to the activation, proliferation, and polarization of T helper cells and subsequent BM destruction. The mRNA expression levels of genes varied with disease severity, which may contribute to pathogenesis of aAA.

Interleukin-9 Facilitates Osteoclastogenesis in Rheumatoid Arthritis.

In rheumatoid arthritis (RA), inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis leading to articular destruction. Recent studies have demonstrated enhanced levels of interleukin-9 (IL-9) in the serum and synovial fluid of patients with RA. In RA, strong correlation has been observed between tissue inflammation and IL-9 expression in synovial tissue. Therefore, we investigated whether IL-9 influences osteoclastogenesis in patients with RA. We conducted the study in active RA patients. For inducing osteoclast differentiation, mononuclear cells were stimulated with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage-colony-stimulating factor (M-CSF) in the presence or absence of recombinant (r) IL-9. IL-9 stimulation significantly enhanced M-CSF/sRANKL-mediated osteoclast formation and function. Transcriptome analysis revealed differential gene expression induced with IL-9 stimulation in the process of osteoclast differentiation. IL-9 mainly modulates the expression of genes, which are involved in the metabolic pathway. Moreover, we observed that IL-9 modulates the expression of matrix metalloproteinases (MMPs), which are critical players in bone degradation. Our results indicate that IL-9 has the potential to influence the structural damage in the RA by promoting osteoclastogenesis and modulating the expression of MMPs. Thus, blocking IL-9 pathways might be an attractive immunotherapeutic target for preventing bone degradation in RA.

Inhibiting OX40 Restores Regulatory T-Cell Function and Suppresses Inflammation in Pulmonary Sarcoidosis.

BACKGROUND: Pulmonary sarcoidosis (PS) is a noncaseating granulomatous disease of unknown origin. Despite conflicting reports, it is considered that the regulatory T (Treg) cells are functionally impaired in PS, but the underlying mechanisms remain unclear. OX40, a pivotal costimulatory molecule, is essential for T-cell functions and memory development, but its impact on Treg cells is ambiguous. RESEARCH QUESTION: Does the OX40 pathway influence the suppressive functions of Treg cells in PS? STUDY DESIGN AND METHODS: Fifty treatment-naïve patients with PS and 30 healthy control participants were recruited for this study. Polychromatic flow cytometry-based immunologic assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time polymerase chain reaction analysis, small interfering RNA, and pharmacologic inhibitors, the impact of OX40 on Treg cell function was investigated. RESULTS: We observed enrichment of Th-9 cells perhaps for the first time along with Th-1, Th-17, and Treg cells in patients' BAL fluid (BALF) compared with peripheral blood. However, Treg cells were observed to be functionally defective at the pathological site. We observed higher expression of OX40 on both T effector (CD4+Foxp3-) and Treg (CD4+Foxp3+) cells obtained from the BALF of patients with PS. However, OX40 exerted contrasting impact on these T-cell subsets, enhancing effector T-cell functions (interferon γ, tumor necrosis factor α) while inhibiting Treg cell function (IL-10, transforming growth factor ß). OX40 silencing or blocking on Treg cells resulted in restoration of their impaired functions. INTERPRETATION: We propose that inhibiting the OX40 pathway may constitute a therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in patients with PS.

Mycobacterium smegmatis Bacteria Expressing Mycobacterium tuberculosis-Specific Rv1954A Induce Macrophage Activation and Modulate the Immune Response.

Mycobacterium tuberculosis (M. tb), the intracellular pathogen causing tuberculosis, has developed mechanisms that endow infectivity and allow it to modulate host immune response for its survival. Genomic and proteomic analyses of non-pathogenic and pathogenic mycobacteria showed presence of genes and proteins that are specific to M. tb. In silico studies predicted that M.tb Rv1954A is a hypothetical secretory protein that exhibits intrinsically disordered regions and possess B cell/T cell epitopes. Treatment of macrophages with Rv1954A led to TLR4-mediated activation with concomitant increase in secretion of pro-inflammatory cytokines, IL-12 and TNF-α. In vitro studies showed that rRv1954A protein or Rv1954A knock-in M. smegmatis (Ms_Rv1954A) activates macrophages by enhancing the expression of CD80 and CD86. An upregulation in the expression of CD40 and MHC I/II was noted in the presence of Rv1954A, pointing to its role in enhancing the association of APCs with T cells and in the modulation of antigen presentation, respectively. Ms_Rv1954A showed increased infectivity, induction of ROS and RNS, and apoptosis in RAW264.7 macrophage cells. Rv1954A imparted protection against oxidative and nitrosative stress, thereby enhancing the survival of Ms_Rv1954A inside macrophages. Mice immunized with Ms_Rv1954A showed that splenomegaly and primed splenocytes restimulated with Rv1954A elicited a Th1 response. Infection of Ms_Rv1954A in mice through intratracheal instillation leads to enhanced infiltration of lymphocytes in the lungs without formation of granuloma. While Rv1954A is immunogenic, it did not cause adverse pathology. Purified Rv1954A or Rv1954A knock-in M. smegmatis (Ms_Rv1954A) elicited a nearly two-fold higher titer of IgG response in mice, and PTB patients possess a higher IgG titer against Rv1954A, also pointing to its utility as a diagnostic marker for TB. The observed modulation of innate and adaptive immunity renders Rv1954A a vital protein in the pathophysiology of this pathogen.

Successful reconstitution of leukocyte adhesion defect after umbilical cord blood stem cell transplant.

Leukocyte adhesion deficiencies (LADs) are a type of primary immunodeficiencies characterized by delayed detachment of the umbilical cord, impaired wound healing, leukocytosis, and recurrent infections. The disease is caused by genetic defects affecting different steps in the process of leukocyte adhesion cascade such as rolling, integrin activation, and adhesion of leukocytes, resulting in the impairment of leukocyte trafficking. Till date, three types of LAD have been documented: type I, II and III. Type I LAD is caused by congenital defect in the ß2 integrin receptor complex CD11/CD18 on the cell surface of leukocytes, which results in impaired leukocytes connection to endothelial cells and migration. Type II LAD is caused by defect in the fucose metabolism resulting in the absence of fucosylated selectin ligands on neutrophils and impaired rolling phase of the leukocyte adhesion cascade. Type III LAD is caused by mutations in the kindlin-3 gene resulting in defective integrin activation. In this article, we present a review of literature for type I LAD, and successful treatment of patient using umbilical cord blood stem cell transplantation.

Old age-associated enrichment of peripheral T regulatory cells and altered redox status in pulmonary tuberculosis patients.

Aging influences the susceptibility and prognosis to various infectious diseases including tuberculosis (TB). Despite the impairment of T-cell function and immunity in older individuals, the mechanism for the higher incidence of TB in the elderly remains largely unknown. Here, we evaluated the age-associated immune alterations, particularly in effector and Treg responses in pulmonary TB patients. We also evaluated the impact of redox status and its modulation with N-acetyl-cysteine (NAC) in elderly TB. Higher frequency of Treg cells and reduced IFN-γ positive T cells were observed among older TB patients. The elevated number of Treg cells correlated tightly with bacillary load (i.e. disease severity); which declined significantly in response to successful anti-tubercular treatment. We could rescue Myobacterium tuberculosis-specific effector T cell (Th1) responses through various in vitro approaches, for example, Treg cell depletion and co-culture experiments, blocking experiments using antibodies against IL-10, TGF-ß, and programmed death-1 (PD-1) as well as NAC supplementation. We report old age-associated enrichment of Treg cells and suppression of M. tuberculosis-specific effector T (Th1) cell immune responses. Monitoring these immune imbalances in older patients may assist in immune potentiation through selectively targeting Treg cells and/or optimizing redox status by NAC supplementation.

Improved Mycobacterium tuberculosis clearance after the restoration of IFN-γ+ TNF-α+ CD4+ T cells: Impact of PD-1 inhibition in active tuberculosis patients.

Prolonged therapy, drug toxicity, noncompliance, immune suppression, and alarming emergence of drug resistance necessitate the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN-γ, but polyfunctional response including TNF-α, which is essential for protective granuloma formation. Here, we investigated the impact of PD-1 inhibition in facilitating protective polyfunctional T cells (PFTs), bacillary clearance, and disease resolution. We have observed PD-1 inhibition preferentially rescued the suppressed PFTs in active tuberculosis patients. In addition, polyfunctional cytokine milieu favored apoptosis of infected MDMs over necrosis with markedly reduced bacillary growth (≪CFU) in our in vitro monocyte-derived macrophages (MDMs) infection model. Furthermore, the animal study revealed a significant decline in the bacterial burden in the lungs and spleen of infected mice after in vivo administration of α-PD-1 along with antitubercular treatment. Our findings suggest that rescuing polyfunctional immune response by PD-1 inhibition works synergistically with antituberculosis chemotherapy to confer improved control over bacillary growth and dissemination. In summary, our data strongly indicate the therapeutic potential of α-PD-1 as adjunct immunotherapy that can rejuvenate suppressed host immunity and enhance the efficacy of candidate therapeutic vaccine(s).

Predicting the artificial immunity induced by RUTI® vaccine against tuberculosis using universal immune system simulator (UISS).

BACKGROUND: Tuberculosis (TB) represents a worldwide cause of mortality (it infects one third of the world's population) affecting mostly developing countries, including India, and recently also developed ones due to the increased mobility of the world population and the evolution of different new bacterial strains capable to provoke multi-drug resistance phenomena. Currently, antitubercular drugs are unable to eradicate subpopulations of Mycobacterium tuberculosis (MTB) bacilli and therapeutic vaccinations have been postulated to overcome some of the critical issues related to the increase of drug-resistant forms and the difficult clinical and public health management of tuberculosis patients. The Horizon 2020 EC funded project "In Silico Trial for Tuberculosis Vaccine Development" (STriTuVaD) to support the identification of new therapeutic interventions against tuberculosis through novel in silico modelling of human immune responses to disease and vaccines, thereby drastically reduce the cost of clinical trials in this critical sector of public healthcare. RESULTS: We present the application of the Universal Immune System Simulator (UISS) computational modeling infrastructure as a disease model for TB. The model is capable to simulate the main features and dynamics of the immune system activities i.e., the artificial immunity induced by RUTI® vaccine, a polyantigenic liposomal therapeutic vaccine made of fragments of Mycobacterium tuberculosis cells (FCMtb). Based on the available data coming from phase II Clinical Trial in subjects with latent tuberculosis infection treated with RUTI® and isoniazid, we generated simulation scenarios through validated data in order to tune UISS accordingly to STriTuVaD objectives. The first case simulates the establishment of MTB latent chronic infection with some typical granuloma formation; the second scenario deals with a reactivation phase during latent chronic infection; the third represents the latent chronic disease infection scenario during RUTI® vaccine administration. CONCLUSIONS: The application of this computational modeling strategy helpfully contributes to simulate those mechanisms involved in the early stages and in the progression of tuberculosis infection and to predict how specific therapeutical strategies will act in this scenario. In view of these results, UISS owns the capacity to open the door for a prompt integration of in silico methods within the pipeline of clinical trials, supporting and guiding the testing of treatments in patients affected by tuberculosis.

Prophylactic interferon-γ and interleukin-17 facilitate parasite clearance in experimental visceral leishmaniasis.

BACKGROUND AND OBJECTIVE: The synergy of interleukin (IL)-17 along with other pro-inflammatory cytokines is well known in various autoimmune and infectious diseases. A longitudinal study in the Sudanese population showed an association of IL-17 with the protection of kala-azar outbreak. The protective role of IL-17 is also known in terms of expansion of IL-17-producing cells in vaccine-induced immunity. However, the prophylactic role of IL-17 in visceral leishmaniasis has still not been validated. In the present study, we evaluated the prophylactic efficacy of IL-17A and interferon (IFN)-γ in Leishmania donovani-challenged Balb/c mice. MATERIALS AND METHODS: Two doses of recombinant IL (rIL)-17A and/or IFN-γ were administered intraperitoneally after/at 1 week interval and then the mice were challenged with amastigote form of L. donovani. At 45 days of postchallenge, mice were sacrificed and evaluated for change in the body and organ weight, parasitic load in visceral organs, and fold change in gene expression of cytokines. RESULTS: We observed that the prophylactic use of rIL-17A and IFN-γ alone or in combination significantly inhibited the parasitic load in visceral organs. Furthermore, pro-inflammatory cytokine gene expression increased up to 2-4-folds in mice treated with recombinant cytokines. CONCLUSION: Our results suggest that prophylactic use of recombinant IFN-γ and IL-17A inhibits parasitic growth in visceral organs of L. donovani-challenged experimental mice model, especially through upregulation of pro-inflammatory cytokines' gene expression.

An Update on Interleukin-9: From Its Cellular Source and Signal Transduction to Its Role in Immunopathogenesis.

Interleukin-9 (IL-9) is a pleiotropic cytokine and was primarily studied in the context of T helper 2 (TH2)-associated immuno-pathological conditions such as asthma and parasitic infections. There was a paradigm shift in the biology of IL-9 after the recent discovery of TH9 cells, a new subtype of TH cells which secrete IL-9 in copious amounts. This has resulted in renewed interest in this cytokine, which was neglected since discovery because it was considered it to be just another TH2 cytokine. Recent studies have shown that it has multiple cellular sources and is critically involved in the immune-pathogenesis of inflammatory diseases and in guarding immune tolerance. In this review, we will discuss its discovery, gene organization, cellular sources, and signaling pathways. Especially, we will give an update on the recent development regarding its relevance in the immune pathogenesis of human diseases.

Hematopoietic stem cell transplantation in children with Griscelli Syndrome type 2: Experience and outcomes.

Griscelli syndrome is a rare autosomal recessive inherited disorder characterized by hypopigmentation, silver colored hair, and associated immunological deficiency, which proves fatal in the absence of timely intervention. Our patients diagnosed with Griscelli syndrome-2 presented with fever, hepatosplenomegaly, and deranged hematological and biochemical parameters. Both cases underwent detailed investigations comprising of hair mount microscopic examination, degranulation assay, and mutational studies. Our cases showed defective degranulation activity by NK cells and gene mutation analysis revealed RAB27A mutation that causes defect of cytotoxic granule exocytosis from natural killer (NK) and T-cells, manifesting clinically as hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplantation in one of the patients resulted in stable chimerism; however, the second case relapsed within a month after SCT. Stem cell transplantation is the only curative therapeutic option for GS2; thus, improvement in posttransplantation management may reduce mortality and posttransplant complications. Hence, any child who presents with partial albinism and clinical features suggestive of HLH, a peripheral blood, hair shaft mount examination along with basic immunological NK and T-cell cytotoxicity assay by flow cytometry will help clinch the diagnosis early. It can subsequently be confirmed by molecular study. Timely therapeutic intervention can prevent relapses and severe infection and improve outcome in these cases.

Emerging Concepts of Adaptive Immunity in Leprosy.

Leprosy is a chronic intracellular infection caused by the acid-fast bacillus, Mycobacterium leprae. The disease chiefly affects the skin, peripheral nerves, mucosa of the upper respiratory tract, and the eyes. The damage to peripheral nerves results in sensory and motor impairment with characteristic deformities and disability. Presently, the disease remains concentrated in resource-poor countries in tropical and warm temperate regions with the largest number of cases reported from India. Even though innate immunity influences the clinical manifestation of the disease, it is the components of adaptive immune system which seem to tightly correlate with the characteristic spectrum of leprosy. M. leprae-specific T cell anergy with bacillary dissemination is the defining feature of lepromatous leprosy (LL) patients in contrast to tuberculoid leprosy (TT) patients, which is characterized by strong Th1-type cell response with localized lesions. Generation of Th1/Th2-like effector cells, however, cannot wholly explain the polarized state of immunity in leprosy. A comprehensive understanding of the role of various regulatory T cells, such as Treg and natural killer T cells, in deciding the polarized state of T cell immunity is crucial. Interaction of these T cell subsets with effector T cells like Th1 (IFN-γ dominant), Th2 (interluekin-4 dominant), and Th17 (IL-17+) cells through various regulatory cytokines and molecules (programmed death-1/programmed death ligand-1) may constitute key events in dictating the state of immune polarization, thus controlling the clinical manifestation. Studying these important components of the adaptive immune system in leprosy patients is essential for better understanding of immune function, correlate(s) the immunity and mechanism(s) of its containment.

Inhibiting HLA-G restores IFN-γ and TNF-α producing T cell in pleural Tuberculosis.

Human Leukocyte Antigen-G (HLA-G), a non-classical, class Ib molecule, has been shown to mediate immunoregulatory functions by inducing apoptosis, inhibits cytotoxicity and differentiation by modulating cytokine secretion. Due to its immune-suppressive function, it facilitates tolerance in feto-maternal interface and transplantation. In contrary, it favours immune evasion of microbes and tumors by inhibiting immune and inflammatory responses. In Tuberculosis (TB), we previously reported differential expression of HLA-G and its receptor Ig-like transcript -2 (ILT-2) in disseminated vs. localized Tuberculosis. The present study explores the impact of HLA-G inhibition on the function of T cells and monocytes, in TB Pleural Effusion (PE), a localized form of TB. Blocking of HLA-G resulted in significant increase in IFN-γ and TNF-α production by CD3+ T cells. Additionally, we observed that HLA-G influences the apoptosis and cytotoxic effect of T cells from TB- PE patients. Next, we checked the impact of interaction between HLA-G and ILT-4 receptor in monocytes derived from TB-PE patients upon blocking and observed significant increase in IFN-γ production. The present study reveals for the first time HLA-G mediated suppression of Th1 cytokines, especially, IFN-γ and TNF-α in TB-PE patients.