Immunological analysis of Blau syndrome, a unique autoinflammatory state Atika Dhar, Atsushi Kitani, Warren Strober Frontiers in Immunology, 2026 Autoinflammation typically arises from mutations affecting molecules such as inflammasome backbones that give rise to gain-of-function (GOF) pro-inflammatory activity requiring little or no normal ligand stimulation. This has been assumed to be the case in the auto-inflammation known as Blau syndrome wherein mutations usually present in the nucleotide oligomerization domain of the CARD15 gene encoding NOD2 result in widespread granulomatous inflammation, seemingly in the absence of NOD2 stimulation by its canonical ligand, muramyl dipeptide (MDP); moreover, despite such lack of ligand stimulation, NOD2 bearing a Blau mutation is thought to cause inflammation by initiating conventional downstream signaling that ultimately results in NF-κB activation. However, newer data concerning Blau syndrome pathogenesis suggest a more complex picture in which Blau CARD15 mutations cause inflammation by unconventional and/or loss of conventional signaling and which depend, at least in part, from a genetic defect which arises from loss-of-function pro-inflammatory activity. In this review, we present and analyze these newer data with the aim of defining a further pathway to the understanding and treatment of this disease.
Editorial: The role of nod-like receptor (NLR) family of proteins in inflammation Atika Dhar, Rishi Kumar Jaiswal, Hasan Zaki, Samithamby Jeyaseelan Frontiers in Immunology, 2026 Our knowledge on diverse functions of different NLR family proteins continues to evolve. This special issue makes a significant addition towards that goal. The research articles and reviews collected herein highlighted the function and significance of different NLR proteins in the context of infection and inflammation, with the NLRP3 inflammasome emerging as the central focus.Collectively, these studies expand our knowledge of the functions and biological roles of several NLRs and underscore their therapeutic potential in both human and animal diseases.Diffuse alveolar hemorrhage (DAH) is generally associated with autoimmune conditions such as Systemic Lupus Erythematosus (SLE) and small vessel vasculitis (SVV). The underlying mechanisms contributing to DAH, characterized by leakage of red blood cells from the alveolar capillaries, remain largely unknown. In an insightful study, Andrè-Jarrot et al., investigated the role of NLRP3 inflammasome in DAH by using a well-established pristane-induced DAH mouse model. The authors demonstrated that NLRP3 inflammasome activity is important for inducing neutrophil-extracellular trap (NET) following exposure to pristane, implicating NLRP3 in lung injury. Interestingly, while NLRP3 deficiency did not protect male mice, female mice exhibited reduced severity of pristane-induced DAH, accompanied by decreased neutrophil recruitment and NET formation in the lungs (4). The findings reveal a female sex-specific role of NLRP3 inflammasome in DAH pathogenesis and underscore a new avenue for future investigators.In a comprehensive review article, Liu et al., focused on the role of the NLRP3 inflammasome in atherosclerosis. Dysregulated NLRP3 inflammasome activation in arterial tissue has been previously linked to atherosclerosis development. This review article performed a systematic analysis of the existing literature on the use of Chinese herbal medicines (CHMs) in treating atherosclerosis by targeting the NLRP3 inflammasome and associated pathways. This review highlights the therapeutic benefits of the CHM, discussed their mechanism of action, and suggest the potential for safer and more targeted therapeutic strategies for using these compounds (5).In another in-depth review by Sun et al., have summarized the literature concerning the role NLRP3 inflammasome in the development of urogenital cancers, particularly bladder and renal cell carcinoma, prostate cancer, ovarian cancer, and uterine malignancies. The authors also discussed the therapeutic potential of targeting the NLRP3 inflammasome against different forms of cancer and provided an overview of specific NLRP3 inhibitors currently in preclinical or clinical development (6). This work serves as a valuable framework for future research exploring inflammasome-based therapies in urogenital cancers.In addition to human diseases, inflammasomes also plays critical roles in infectious diseases affecting animals. N. canium is the causative agent of Neosporosis, a disease with major economic consequence for the dairy and beef industries. While cellular infection with N.canium has been associated with inflammasome activation and apoptosis, the pathogen-derived molecules involved in these processes remained unknown. To address this knowledge gap, Chen et. al., provided mechanistic insight into the role of the N. canium dense granule protein 7 (NcGRA7) in activation of the inflammasome and NF-kB pathway during infection via interaction with host cell prohibitins (7). This study enhances our understanding of pathogen strategies to establish infection and may guide for the development of novel therapeutic interventions.In another extensive review, Woolls et. al., discussed the multiple regulatory roles of atypical NLR family member NLRX1 in anti-viral immunity. Their work delves on the various complex interaction between NLRX1 and relevant molecular mediators of antiviral immunity such as MAVS, FAF1and FBXO6 and others. They comprehensively discussed various mechanisms by which NLRX1 regulates immune responses to both DNA and RNA viruses (8). Overall, this review provides a holistic overview of various roles of NLRX1 in anti-viral immunity and inflammation, while also pointing to the important gaps that need to be further investigated.Finally, in their case-report, Subhi Hnaihen et. al., present a case report describing a young patient with Blau syndrome who exhibited an unusual clinical symptom of renal failure. Blau syndrome is a rare genetic disorder resulting from mutations in the CARD15 (NOD2) gene, which is a member of the NLR family. The patients often show a characteristic triad of symptoms which is arthritis, skin rash and uveitis. The case presented by the authors, however, displayed a single symptom i.e. arthritis and was therefore misdiagnosed as having Juvenile Idiopathic arthritis (JIA). The authors therefore suggest a thorough assessment of family history, recognition of atypical treatment response and early genetic testing to facilitate faster diagnosis and management of Blau syndrome (9). In summary, these studies presented in this special issue significantly expand our knowledge on the roles of NLR family proteins in infection, inflammation, and cancer. The original research articles provide mechanistic insights into how NLRs regulate inflammatory pathways and disease pathogenesis, revealing novel therapeutic targets. The review articles offer comprehensive and accessible resources that integrate current knowledge of NLR functions, signaling mechanism, interacting partners, and therapeutic strategies. Altogether, this collection will enhance further interest in NLR signaling pathways and guide future research in immunology and inflammation.
Chronic social defeat stress-induced depression reduces BCG efficacy by promoting regulatory T-cell levels in mice Rohit Tyagi, Xi Chen, Atika Dhar, Bing Yang, Wei Zhou, Aikebaier Reheman, Yingying Lei, Gang Cao Animal Diseases, 2023 Despite the initial successes of the Bacillus Calmette-Guerin (BCG) vaccine in children, its efficacy against tuberculosis is highly variable. There is a lack of understanding about how mental conditions influence BCG vaccination. Here, we used the chronic social defeat stress (CSDS) model to explore the effects of depression on BCG vaccination efficacy. We observed higher lung and spleen bacterial loads and a lower organ index in depressed compared to BCG mice. Meanwhile, a relatively lower T cell protective efficacy was observed in both compared to control and BCG mice via a mycobacterium growth inhibition assay (MGIA). Cytokine expression of IL-12p40, IL-1β, IL-17, TNF-α and IFN-γ was reduced, whereas the expression of IL-10 and IL-5 was increased in the spleen of both compared to BCG mice. Moreover, the proportions of CD4+IFN-γ+, CD8+IFN-γ+ T lymphocytes and CD4+ effector/central memory T cells were reduced in the splenocytes of the depressed BCG mice. Depression promotes CD4+ regulatory T cells (Treg) and myeloid-derived suppressor cell (MDSC) generation in depressed mice, contributing to the reduced pro-inflammatory immune response upon BCG vaccination. This study provides insight into the decreased protective immunity by BCG vaccination attributable to depression in mice.
Role of Immunoglobulin A in COVID-19 and Influenza Infections Rohit Tyagi, Srijani Basu, Atika Dhar, Suman Gupta, Sneh Lata Gupta, Rishi K. Jaiswal Vaccines, 2023 Immunoglobulin A (IgA) is critical in the immune response against respiratory infections like COVID-19 and influenza [...]
Children’s SARS-CoV-2 Infection and Their Vaccination Sneh Lata Gupta, Rohit Tyagi, Atika Dhar, Neelam Oswal, Ankita Khandelwal, Rishi Kumar Jaiswal Vaccines, 2023 SARS-CoV-2, a novel coronavirus, causes respiratory tract infections and other complications in affected individuals, and has resulted in numerous deaths worldwide. The unprecedented pace of its transmission worldwide, and the resultant heavy burden on healthcare systems everywhere, prompted efforts to have effective therapeutic strategies and vaccination candidates available to the global population. While aged and immunocompromised individuals form a high-risk group for COVID-19 and have severe disease outcome, the rate of infections among children has also increased with the emergence of the Omicron variant. In addition, recent reports of threatening SARS-CoV-2-associated complications in children have brought to the forefront an urgent necessity for vaccination. In this article, we discuss the current scenario of SARS-CoV-2 infections in children with a special focus on the differences in their immune system response as compared to adults. Further, we describe the various available COVID-19 vaccines, including the recent bivalent vaccines for children, in detail, intending to increase willingness for their acceptance.
Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function Liming Mao, Atika Dhar, Guangxun Meng, Ivan Fuss, Kim Montgomery-Recht, Zhiqiong Yang, Qiuyun Xu, Atsushi Kitani, Warren Strober Frontiers in Immunology, 2022 The studies described here provide an analysis of the pathogenesis of Blau syndrome and thereby the function of NOD2 as seen through the lens of its dysfunction resulting from Blau-associated NOD2 mutations in its nucleotide-binding domain (NBD). As such, this analysis also sheds light on the role of NOD2 risk polymorphisms in the LRR domain occurring in Crohn’s disease. The main finding was that Blau NOD2 mutations precipitate a loss of canonical NOD2 signaling via RIPK2 and that this loss has two consequences: first, it results in defective NOD2 ligand (MDP)-mediated NF-κB activation and second, it disrupts NOD2-mediated cross-regulation whereby NOD2 downregulates concomitant innate (TLR) responses. Strong evidence is also presented favoring the view that NOD2-mediated cross-regulation is under mechanistic control by IRF4 and that failure to up-regulate this factor because of faulty NOD2 signaling is the proximal cause of defective cross-regulation and the latter’s effect on Blau syndrome inflammation. Overall, these studies highlight the role of NOD2 as a regulatory factor and thus provide additional insight into its function in inflammatory disease. Mutations in the nucleotide binding domain of the CARD15 (NOD2) gene underlie the granulomatous inflammation characterizing Blau syndrome (BS). In studies probing the mechanism of this inflammation we show here that NOD2 plasmids expressing various Blau mutations in HEK293 cells result in reduced NOD2 activation of RIPK2 and correspondingly reduced NOD2 activation of NF-κB. These in vitro studies of NOD2 signaling were accompanied by in vivo studies showing that BS-NOD2 also exhibit defects in cross-regulation of innate responses underlying inflammation. Thus, whereas over-expressed intact NOD2 suppresses TNBS-colitis, over-expressed BS-NOD2 does not; in addition, whereas administration of NOD2 ligand (muramyl dipeptide, MDP) suppresses DSS-colitis in Wild Type (WT) mice it fails to do so in homozygous or heterozygous mice bearing a NOD2 Blau mutation. Similarly, mice bearing a Blau mutation exhibit enhanced anti-collagen antibody-induced arthritis. The basis of such cross-regulatory failure was revealed in studies showing that MDP-stimulated cells bearing BS-NOD2 exhibit a reduced capacity to signal via RIPK2 as well as a reduced capacity to up-regulate IRF4, a factor shown previously to mediate NOD2 suppression of NF-κB activation. Indeed, TLR-stimulated cells bearing a Blau mutation exhibited enhanced in vitro cytokine responses that are quieted by lentivirus transduction of IRF4. In addition, enhanced anti-collagen-induced joint inflammation in mice bearing a Blau mutation was accompanied by reduced IRF4 expression in inflamed joint tissue and IRF4 expression was reduced in MDP-stimulated cells from BS patients. Thus, inflammation characterizing Blau syndrome are caused, at least in part, by faulty canonical signaling and reduce IRF4-mediated cross-regulation.
A role for cell-autocrine interleukin-2 in regulatory T-cell homeostasis Amanpreet Singh Chawla, Jasneet Kaur Khalsa, Atika Dhar, Suman Gupta, Danish Umar, Gopalakrishnan Aneeshkumar Arimbasseri, Vineeta Bal, Anna George, Satyajit Rath Immunology, 2020 SummaryActivated T‐cells make both interleukin‐2 (IL2) and its high‐affinity receptor component CD25. Regulatory CD4 T‐cells (Treg cells) do not make IL2, and the IL2‐CD25 circuit is considered a paracrine circuit crucial in their generation and maintenance. Yet, all T‐cells are capable of making IL2 at some stage during differentiation, making a cell‐intrinsic autocrine circuit additionally possible. When we re‐visited experiments with mixed bone marrow chimeras using a wide range of ratios of wild‐type (WT) and IL2−/− genotype progenitors, we found that, as expected, thymic Treg cells were almost equivalent between WT and IL2−/− genotypes at ratios with WT prominence. However, at WT‐limiting ratios, the IL2−/− genotype showed lower thymic Treg frequencies, indicating a role for cell‐intrinsic autocrine IL2 in thymic Treg generation under IL2‐limiting conditions. Further, peripheral IL2−/− naive CD4 T‐cells showed poor conversion to inducible Tregs (pTregs) both in vivo and in vitro, again indicating a significant role for cell‐intrinsic autocrine IL2 in their generation. Peripherally, the IL2−/− genotype was less prominent at all WT:IL2−/− ratios among both thymic Tregs (tTregs) and pTregs, adoptively transferred IL2−/− Tregs showed poorer survival than WT Tregs did, and RNA‐seq analysis of WT and IL2−/− Tregs showed interesting differences in the T‐cell receptor and transforming growth factor‐beta‐bone morphogenetic protein‐JNK pathways between them, suggesting a non‐titrating role for cell‐intrinsic autocrine IL2 in Treg programming. These data indicate that cell‐intrinsic autocrine IL2 plays significant roles in Treg generation and maintenance.
Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation Atika Dhar, Meenakshi Chawla, Somdeb Chattopadhyay, Neelam Oswal, Danish Umar, Suman Gupta, Vineeta Bal, Satyajit Rath, Anna George, G. Aneeshkumar Arimbasseri, Soumen Basak Scientific Reports, 2019 The immunological roles of the nuclear factor-kappaB (NF-κB) pathway are mediated via the canonical components in immune responses and via non-canonical components in immune organogenesis and homeostasis, although the two components are capable of crosstalk. Regulatory CD4 T cells (Tregs) are homeostatically functional and represent an interesting potential meeting point of these two NF-κB components. We show that mice deficient in the non-canonical NF-κB component geneNfkb2(p100) had normal thymic development and suppressive function of Tregs. However, they had enhanced frequencies of peripheral ‘effector-phenotype’ Tregs (eTregs). In bi-parental chimeras of wild-type (WT) andNfkb2−/− mice, theNfkb2−/− genotype was over-represented in Tregs, with a further increase in the relative prominence of eTregs. Consistent with distinct properties of eTregs, theNfkb2−/− genotype was more prominent in Tregs in extra-lymphoid tissues such as liver in the bi-parental chimeras. TheNfkb2−/− Tregs also displayed greater survival, activation and proliferationin vivo. TheseNfkb2−/− Tregs showed higher nuclear NF-κB activity mainly comprising of RelB-containing dimers, in contrast to the prominence of cRel- and RelA-containing dimers in WT Tregs. Since p100 is an inhibitor of RelB activation as well as a participant as cleaved p52 in RelB nuclear activity, we tested bi-parental chimeras of WT andRelb−/− mice, and found normal frequencies ofRelb−/− Tregs and eTregs in these chimeric mice. Our findings confirm and extend recent data, and indicate that p100 normally restrains RelB-mediated Treg activation, and in the absence of p100, p50-RelB dimers can contribute to Treg activation.
Functionally significant metabolic differences between B and T lymphocyte lineages Jasneet Kaur Khalsa, Amanpreet Singh Chawla, Savit B. Prabhu, Mukti Vats, Atika Dhar, Gagan Dev, Nabanita Das, Sandip Mukherjee, Shalini Tanwar, Hridesh Banerjee, Jeannine Marie Durdik, Vineeta Bal, Anna George, Satyajit Rath, Gopalakrishnan Aneeshkumar Arimbasseri Immunology, 2019
Immunological analysis of Blau syndrome, a unique autoinflammatory state A Dhar, A Kitani, W Strober Frontiers in Immunology 17, 1793228 , 2026 2026
NOD2-Related Multisystem Inflammatory Disorders and Recent Advances D Wu, T Matsuda, D Xie, M Shen, A Dhar, JM Davis III, B Shen, N Kambe, ... Current rheumatology reports 28 (1), 5 , 2026 2026
The role of nod-like receptor (NLR) family of proteins in inflammation A Dhar, RK Jaiswal, H Zaki, S Jeyaseelan Frontiers in immunology 17, 1793019 , 2026 2026
Nanotechnology-based theranostic and prophylactic approaches against SARS-CoV-2 A Dhar, SL Gupta, P Saini, K Sinha, A Khandelwal, R Tyagi, A Singh, ... Immunologic Research 72 (1), 14-33 , 2024 2024 Citations: 8
Chronic social defeat stress-induced depression reduces BCG efficacy by promoting regulatory T-cell levels in mice R Tyagi, X Chen, A Dhar, B Yang, W Zhou, A Reheman, Y Lei, G Cao Animal Diseases 3 (1), 40 , 2023 2023 Citations: 3
Role of immunoglobulin A in COVID-19 and influenza infections R Tyagi, S Basu, A Dhar, S Gupta, SL Gupta, RK Jaiswal Vaccines 11 (11), 1647 , 2023 2023 Citations: 10
Children’s SARS-CoV-2 infection and their vaccination SL Gupta, R Tyagi, A Dhar, N Oswal, A Khandelwal, RK Jaiswal Vaccines 11 (2), 418 , 2023 2023 Citations: 10
Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function L Mao, A Dhar, G Meng, I Fuss, K Montgomery-Recht, Z Yang, Q Xu, ... Frontiers in immunology 13, 988862 , 2022 2022 Citations: 34
A role for cell‐autocrine interleukin‐2 in regulatory T‐cell homeostasis AS Chawla, JK Khalsa, A Dhar, S Gupta, D Umar, GA Arimbasseri, V Bal, ... Immunology 160 (3), 295-309 , 2020 2020 Citations: 21
A role for cell-autocrine interleukin-2 in regulatory T-cell homeostasis A George, S Rath, V Bal, GA Arimbasseri, D Umar, S Gupta, A Dhar, ... John Wiley & Sons Ltd. , 2020 2020
Functionally significant metabolic differences between B and T lymphocyte lineages JK Khalsa, AS Chawla, SB Prabhu, M Vats, A Dhar, G Dev, N Das, ... Immunology 158 (2), 104-120 , 2019 2019 Citations: 29
Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation A Dhar, M Chawla, S Chattopadhyay, N Oswal, D Umar, S Gupta, V Bal, ... Scientific Reports 9 (1), 13867 , 2019 2019 Citations: 19
Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation S Basak, A Dhar, M Chawla, S Chattopadhyay, N Oswal, D Umar, S Gupta, ... Springer Nature Limited , 2019 2019
A TNF‐p100 pathway subverts noncanonical NF‐κB signaling in inflamed secondary lymphoid organs T Mukherjee, B Chatterjee, A Dhar, SS Bais, M Chawla, P Roy, A George, ... The EMBO Journal 36 (23), 3501-3516 , 2017 2017 Citations: 34
SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease SA Mustfa, M Singh, A Suhail, G Mohapatra, S Verma, D Chakravorty, ... Open biology 7 (6) , 2017 2017 Citations: 57
Mediation of transitional B cell maturation in the absence of functional Bruton’s tyrosine kinase S Tanwar, A Dhar, V Varanasi, T Mukherjee, R Boppana, S Basak, V Bal, ... Scientific Reports 7 (1), 46029 , 2017 2017 Citations: 12
MOST CITED SCHOLAR PUBLICATIONS
SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease SA Mustfa, M Singh, A Suhail, G Mohapatra, S Verma, D Chakravorty, ... Open biology 7 (6) , 2017 2017 Citations: 57
Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function L Mao, A Dhar, G Meng, I Fuss, K Montgomery-Recht, Z Yang, Q Xu, ... Frontiers in immunology 13, 988862 , 2022 2022 Citations: 34
A TNF‐p100 pathway subverts noncanonical NF‐κB signaling in inflamed secondary lymphoid organs T Mukherjee, B Chatterjee, A Dhar, SS Bais, M Chawla, P Roy, A George, ... The EMBO Journal 36 (23), 3501-3516 , 2017 2017 Citations: 34
Functionally significant metabolic differences between B and T lymphocyte lineages JK Khalsa, AS Chawla, SB Prabhu, M Vats, A Dhar, G Dev, N Das, ... Immunology 158 (2), 104-120 , 2019 2019 Citations: 29
A role for cell‐autocrine interleukin‐2 in regulatory T‐cell homeostasis AS Chawla, JK Khalsa, A Dhar, S Gupta, D Umar, GA Arimbasseri, V Bal, ... Immunology 160 (3), 295-309 , 2020 2020 Citations: 21
Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation A Dhar, M Chawla, S Chattopadhyay, N Oswal, D Umar, S Gupta, V Bal, ... Scientific Reports 9 (1), 13867 , 2019 2019 Citations: 19
Mediation of transitional B cell maturation in the absence of functional Bruton’s tyrosine kinase S Tanwar, A Dhar, V Varanasi, T Mukherjee, R Boppana, S Basak, V Bal, ... Scientific Reports 7 (1), 46029 , 2017 2017 Citations: 12
Role of immunoglobulin A in COVID-19 and influenza infections R Tyagi, S Basu, A Dhar, S Gupta, SL Gupta, RK Jaiswal Vaccines 11 (11), 1647 , 2023 2023 Citations: 10
Children’s SARS-CoV-2 infection and their vaccination SL Gupta, R Tyagi, A Dhar, N Oswal, A Khandelwal, RK Jaiswal Vaccines 11 (2), 418 , 2023 2023 Citations: 10
Nanotechnology-based theranostic and prophylactic approaches against SARS-CoV-2 A Dhar, SL Gupta, P Saini, K Sinha, A Khandelwal, R Tyagi, A Singh, ... Immunologic Research 72 (1), 14-33 , 2024 2024 Citations: 8
Chronic social defeat stress-induced depression reduces BCG efficacy by promoting regulatory T-cell levels in mice R Tyagi, X Chen, A Dhar, B Yang, W Zhou, A Reheman, Y Lei, G Cao Animal Diseases 3 (1), 40 , 2023 2023 Citations: 3
Immunological analysis of Blau syndrome, a unique autoinflammatory state A Dhar, A Kitani, W Strober Frontiers in Immunology 17, 1793228 , 2026 2026
NOD2-Related Multisystem Inflammatory Disorders and Recent Advances D Wu, T Matsuda, D Xie, M Shen, A Dhar, JM Davis III, B Shen, N Kambe, ... Current rheumatology reports 28 (1), 5 , 2026 2026
The role of nod-like receptor (NLR) family of proteins in inflammation A Dhar, RK Jaiswal, H Zaki, S Jeyaseelan Frontiers in immunology 17, 1793019 , 2026 2026
A role for cell-autocrine interleukin-2 in regulatory T-cell homeostasis A George, S Rath, V Bal, GA Arimbasseri, D Umar, S Gupta, A Dhar, ... John Wiley & Sons Ltd. , 2020 2020
Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation S Basak, A Dhar, M Chawla, S Chattopadhyay, N Oswal, D Umar, S Gupta, ... Springer Nature Limited , 2019 2019
