Omid Akbari

Rejection remains a major cause of allograft injury and loss in liver transplantation (LT). Mechanisms mediating clinical liver allograft rejection remain elusive, limiting the development of new immunosuppressive drugs and biomarker panels for monitoring rejection for decades. Herein, multiomic data and systems immunology were combined to define the “rejectome” of T-cell–mediated rejection (TCMR) in 98 pediatric LT recipients. Spatial proteomics of liver biopsies revealed enrichment of HLADR ^high and PD1T-cell and B-cell subtypes in TCMR. Two peripheral PD1+ T-cell subsets shared expression profiles with T cells within the alloimmune microenvironment. Plasma proteomics and predictive modeling identified a tissue-correlative panel of 11 biomarkers linked to immune function and liver metabolism that differentiates TCMR from no-rejection and proteomic profiles in other liver diseases. These data highlight multi-tissue proteomics features of the alloimmune microenvironment during clinical TCMR and suggest that a clinical plasma proteomic “liquid biopsy” can be developed to manage TCMR in LT.

Pemphigus encompasses autoimmune blistering diseases driven by autoantibodies to desmosomal proteins. Disruption of keratinocyte adhesion produces acantholysis and epidermal fragility. Anti-CD20 B-cell depletion and IgG lowering strategies have transformed care, but many patients relapse, some variants respond incompletely, and durable drug-independent tolerance remains uncommon across variants. These gaps highlight that pemphigus is not a simple linear B-cell disorder, but an autoantibody disease sustained by a network linking the innate immunity, the adaptive lymphocytes, and the stromal niches. In this review, we focus on pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome, and IgA pemphigus as representative variants within this network. We place these entities within a conceptual type 1, type 2, and type 3 immunity framework and summarize how central and peripheral B-cell tolerance can fail. We further consider current and emerging therapies as partial interventions within this network and outline next-generation strategies that modulate innate circuits, rewire survival pathways, restore antigen-specific regulation, and shift the adaptive autoimmune response toward a more tolerogenic state. Framing pemphigus in this way may help move the field from empiric immunosuppression toward precise immune engineering with the goal of durable immune reset and long-term drug-independent remission.

Allergic asthma is characterized by type 2 inflammation and overnight worsening of symptoms, yet dynamic fluxes in cellular metabolic profiles driving time-of-day variation remain poorly defined. Group 2 innate lymphoid cells (ILC2s) are central mediators of airway hyperreactivity. We identify melatonin as a previously unrecognized regulator of ILC2 metabolism and function. In murine models of allergic airway inflammation, melatonin reduced eosinophilia, type 2 cytokine production, and airway hyperreactivity without altering ILC2 abundance. Mechanistically, melatonin acted independently of canonical melatonin receptors and instead reprogrammed ILC2 metabolism toward pentose phosphate pathway activity, enhancing NADPH generation and NRF2-dependent glutathione accumulation. Metabolic profiling, loss-of-function approaches, and pharmacologic activation studies demonstrated that NRF2 is both necessary and sufficient to restrain ILC2 effector function. Importantly, primary human ILC2s exhibited conserved NRF2 activation, glutathione accumulation, and reduced type 2 cytokine production in response to melatonin, underscoring clinical relevance. Together, these findings identify the melatonin-NRF2-glutathione axis as a metabolic checkpoint regulating innate type 2 immunity and suggest that therapeutic targeting of redox metabolism may represent a strategy for modulating airway inflammation in allergic asthma.

Group 2 innate lymphoid cells (ILC2s) are tissue-resident immune cells that play a central role in type 2 immunity. Beyond cytokine signaling, they integrate inputs from lipids, nutrients, neuroendocrine mediators, and local metabolic cues, establishing cellular metabolism as a key regulator of their function. Immunometabolism provides a framework to understand how ILC2s adapt to diverse tissue environments such as the lung, adipose tissue, gut, skin, and brain, each defined by distinct nutrient availability, oxygen tension, and inflammatory conditions. Unlike many immune cells that primarily rely on glycolysis, ILC2s dynamically balance glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) depending on activation state and tissue context. Lipids not only serve as energy substrates but also regulate membrane organization, lipid raft–dependent signaling, and the generation of bioactive mediators, including eicosanoids, oxysterols, and sphingolipids. Emerging evidence linking cholesterol biosynthesis, steroid metabolism, and sphingolipid signaling to ILC2 function underscores the importance of lipid-dependent immune regulation. Dysregulation of these pathways contributes to chronic inflammatory diseases such as asthma, metabolic disorders, and fibrosis. Targeting metabolic pathways and checkpoints may therefore offer new strategies to modulate ILC2-driven pathology. This review summarizes current insights into metabolic programs governing ILC2 activation, survival, and plasticity and highlights emerging therapeutic opportunities.

Allergic asthma is promoted by type 2 inflammation involving cytokines such as IL-4, IL-5, and IL-13, with group 2 innate lymphoid cells (ILC2s) playing a key pathogenic role. Here, we identify T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) as a negative regulator of ILC2 function. Tim-3 expression is upregulated in activated pulmonary ILC2s, and engagement with Tim-3 agonists inhibits ILC2 activation, proliferation, and type 2 cytokine production via the Nemo Like Kinase (NLK) signaling pathway and suppression of mitochondrial metabolism. In vivo, Tim-3 agonists alleviate airway hyperreactivity (AHR) and inflammation in both IL-33- and Alternaria alternata-induced AHR models, while ILC2-specific Tim-3 deletion exacerbates AHR. These results are confirmed in human ILC2s and humanized mice, supporting the translational relevance. Our findings establish Tim-3 as an inhibitory checkpoint for ILC2s and suggest its potential as a therapeutic target in allergic asthma and other ILC2-mediated diseases.

Autoimmune and immune-mediated alopecias demonstrate how a site-specific failure of immune privilege can produce reversible or irreversible hair loss. In alopecia areata (AA), cytotoxic injury is concentrated at the anagen bulb but preserves the stem cell pool, permitting regrowth following immune suppression. Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) feature a spectrum of chronic interface dermatitis that destroys the stem cell niche, leading to permanent fibrosis. These entities overlap in bulge-targeted inflammation and histopathology but diverge in clinical distribution and demographic risk. Discoid lupus erythematosus (DLE) of the scalp reflects immune-complex–driven complement injury to the upper follicle, whereas central centrifugal cicatricial alopecia (CCCA) represents a fibroblast-dominant process associated with chronic stress and is sustained by stromal remodeling. Here, we frame these entities as four follicular immune network archetypes defined by the axial locus of immune privilege collapse, effector programs, loss of tolerogenic programs, stromal trajectories, and dermoscopic correlates. Using a Network Engineering for Site-Specific Tolerance (NEST) framework, we situate these archetypes within a three-tier taxonomy comprising intrinsic follicular privilege, local tolerogenic repertoires, and stromal checkpoint circuits. Specifically, AA localizes to the anagen bulb, DLE spans the upper follicle and interfollicular epidermis, LPP/FFA targets the bulge stem cell niche, and CCCA converges on the upper follicle–interfollicular epidermis unit. Within their respective niches, AA and DLE exhibit comparatively resolved clonotypic effector modules dominated by pathogenic T cells or B cells, whereas LPP/FFA and CCCA are framed as polyclonal networks in which the failure of tolerogenic programs or stress signaling pathways constitutes the dominant archetypal engine.

Group 2 innate lymphoid cells (ILC2s) play a pivotal role in the initiation and propagation of allergic airways disease. These cells, first discovered 15 years ago, respond to a range of stimuli in a non‐antigen‐dependent manner. ILC2s produce copious amounts of cytokines including IL‐5 and IL‐13, which are critical in the pathogenesis of allergic asthma. While allergic airways diseases have long been considered T‐helper 2 cell‐driven diseases, ILC2s are capable of inducing allergic‐type pathologies in mice even in the absence of the adaptive immune system. The role of ILC2s in driving the pathology of allergic airways disease remains an expanding field of knowledge that may unlock novel therapeutic approaches in the management of asthma, a disease that affects up to 300 million people worldwide. In this review, we survey current knowledge of ILC2 immunobiology and present an overview of ILC2 phenotyping, concurrent with insights into ILC2 plasticity, and an exploration of the roles of costimulatory molecules, neuroendocrine signals, and diet‐derived nutrients in modulating ILC2 activity.

Background: Human papillomavirus type 16 (HPV16) positive cancers have a tumor environment that induces antigen-presenting cells to increase IL-23 expression. Unclear is if HPV16 E6/E7 oncoproteins expressed in these cancers play a role in upregulating interleukin (IL)-23 in the tumor microenvironment (TME), and how this cytokine impacts the antitumor cytotoxic T-cell response in HPV16+ cancer. Methods: CD8 T-cells targeting HPV16+ cancer cells were isolated from C57BL/6 mice bearing HPV16+ C3.43 tumors that were therapeutically vaccinated against HPV16 E6/E7 and incubated with IL-23. These T-cells were then co-incubated with HPV16+ target cells in a cytotoxicity assay to assess their cytolytic capacity. Additionally, carboxyfluorescein succinimidyl ester (CFSE) labeled T-cells were used to track the effect of IL-23 on their proliferation. The effect of IL-23 neutralization on vaccine-induced antitumor immunity during tumor progression was studied in vivo to assess its potential as either a standalone treatment or combined with a vaccine targeting HPV16 E6/E7. HPV16− tumors were engineered to express E6/E7 to find out if these oncoproteins upregulate IL-23. To understand how HPV oncoproteins in the TME affect transcriptional regulation of IL-23 producing cells, we used single-cell Assay for Transposase-Accessible Chromatin (ATAC)+RNA sequencing. Results: Inside macrophages residing in the HPV+ TME, transcription factor enrichment and linkage analysis identified KLF2 as a potential regulator of Il23a. Overexpression of KLF2 in macrophages upregulates IL-23 production. CD8 T-cells that recognize HPV16+ cells incubated with IL-23 are inhibited in both their killing and proliferative capacities. IL-23 neutralization increased the presence of HPV-specific cytotoxic CD8 T-cells inside the HPV16+TME in an IL-17 independent manner. Combination of IL-23 neutralization followed by HPV16 E6/E7 vaccination increases survival by amplifying the anti-tumor immune response. Conclusion: This study finds that the presence of HPV oncoproteins in tumor cells increases KLF2 expression in tumor-associated macrophages in vivo. It also shows that KLF2 upregulates IL-23 production in M2 macrophages, resulting in increased IL-23 levels in the TME. In addition, it is shown that elevated levels of IL-23 suppress the antitumor immune response and that IL-23 neutralization synergizes with therapeutic vaccination against HPV oncoproteins.

CD48 is a cell surface protein belonging to the signaling lymphocyte activation molecule family and is known to regulate immune cell function. Although asthma has traditionally been associated with adaptive immune responses, recent evidence highlights a central role for group 2 innate lymphoid cells (ILC2s) in orchestrating type 2 inflammation, independent of adaptive immunity. Here, we investigated the immunomodulatory function of CD48 on ILC2s and its contribution to the development of airway inflammation and airway hyperreactivity (AHR). Using an ILC2-dependent induced murine model of asthma, we employed both CD48 knockout mice and blocking antibodies to dissect the role of CD48 in vivo. We found that CD48 is expressed on lung-resident ILC2s and that its absence significantly impairs ILC2 activation, reduces eosinophilic infiltration, and alleviates AHR. Adoptive transfer experiments further confirmed that these effects are ILC2 intrinsic. Transcriptomic profiling of CD48-deficient ILC2s revealed downregulation of key effector genes and enrichment of pathways involving PI3K and PKCβ. Pharmacologic modulation of PKCβ altered ILC2 cytokine production in a CD48-dependent manner, establishing a mechanistic link between CD48 signaling and ILC2 function. Moreover, human ILC2s isolated from peripheral blood and cultured under activating conditions upregulated CD48, and blockade of CD48 suppressed ILC2 cytokine production. In a humanized mouse model, CD48 inhibition likewise reduced airway inflammation, mirroring findings in murine systems. These results identify CD48 as a critical regulator of ILC2-driven AHR and suggest that targeting CD48 or its downstream signaling pathways may offer novel therapeutic opportunities for the treatment of asthma.

Group 2 innate lymphoid cells (ILC2s) play a crucial role in inducing type 2 inflammation in the lungs in response to allergens. Our study investigated the regulatory mechanism of IL-10 production by ILC2s and its impact on airway hyperreactivity (AHR), focusing on the role of ICOS. We found that inhibiting ICOS in pulmonary ILC2s significantly enhanced IL-10 production. The absence of ICOS reprogrammed ILC2 steroid metabolism, leading to increased cholesterol and cortisol biosynthesis and subsequent glucocorticoid receptor (GR) activation. This reprogramming regulated MAF and NFIL3 activation, promoting IL-10 production. Notably, in vivo GR inhibition or ILC2-specific GR deficiency exacerbated AHR development in multiple mouse models. We extended these findings to human ILC2s, demonstrating concordant results between murine models and human cells. Our results indicate that ICOS negatively regulates IL-10 production in ILC2s by controlling cholesterol and cortisol biosynthesis. This mechanism provides new insights into the complex interplay between ILC2s, ICOS, and glucocorticoid signaling in the context of allergic airway inflammation.