Mycobacterium marinum is a fish pathogen that has become a powerful and well-established model that has accelerated our understanding of the mechanisms of mycobacterial disease. M. marinum is a versatile surrogate for understanding the closely related human pathogen M. tuberculosis, which causes tuberculosis in humans. M. marinum has defined key mechanisms of pathogenesis, both shared with M. tuberculosis and unique to this species. In this review, we discuss the discovery of M. marinum as an occasional human pathogen, the shared aspects of pathogenesis with M. tuberculosis, and how M. marinum has been exploited as a model to define the molecular mechanisms of mycobacterial pathogenesis across several phases of infection.

The increasing use of tumor necrosis factor inhibitors (TNFi) in pediatric patients has raised concerns about their potential impact on the immune system and related adverse events. Infection-related adverse events (AEs) caused by TNFi have already raised widespread concerns in real-world settings. This study aims to comprehensively analyze and summarize the infection-related AEs associated with TNFi in pediatric patients. A retrospective pharmacovigilance study was conducted to identify cases of TNFi-related infections reported to the FDA Adverse Event Reporting System (FAERS) database between Q1 2004 and Q1 2023. TNFi reports were carefully reviewed to exclude confounding factors like other AEs, concomitant medications, and prescription indications. Proportionality analysis was conducted by comparing TNFi reports to the entire FAERS database to identify infection-related AEs significantly associated with TNFi use. Infection-related AEs accounted for 8.36% of all TNFi-related adverse event reports in the FAERS database. A total of 8050 cases of TNFi-associated infections were identified in the pediatric population, with 2.57% of reports resulting in fatalities. Infliximab and golimumab showed a stronger association with infection-related AEs compared to other TNFi. Notably, only adalimumab shows a lower risk of viral infections, while it exhibits an increased risk of bacterial and mycobacterial infections, similar to other TNFi.

This study identified a significant association between TNFi use and infection-related AEs in pediatric patients, providing the foothold for further research. However, due to its retrospective nature, further investigations are warranted to confirm these findings and identify potential risk factors in a controlled, prospective study setting.

• There is sufficient evidence to demonstrate the infection risk associated with TNFi in adult patients. • Pediatric patients, whose immune systems are still developing, are more vulnerable to certain infections.

• There is a significant association between TNFi use and infection-related adverse events in pediatric patients, and different TNFi have distinct infection profiles.

Gastrointestinal perforations have been reported in a small number of rheumatoid arthritis (RA) patients treated with Janus kinase (JAK) inhibitors in clinical trials. However, large-scale postmarketing data repositories are needed to further investigate this potentially rare but serious adverse event.

A retrospective, pharmacovigilance study of the FDA adverse event reporting system (July 2014 to September 2023) assessing the reporting of gastrointestinal perforations following JAK inhibitors compared to biological disease-modifying antirheumatic drugs (bDMARDs) in RA patients. The adjusted reporting odds ratio (adj.ROR) was calculated using a multivariable logistic regression model.

Of 399,983 RA patients included in the study, 76,446 were treated with JAK inhibitors (tofacitinib, n = 52,365; upadacitinib, n = 21,856; baricitinib, n = 2225) and 323,537 were treated with bDMARDs (TNF inhibitors, rituximab, and abatacept). Overall, 230 cases of gastrointestinal perforation following JAK inhibitors were identified, with a median time of 9 (IQR: 4-22) months from treatment initiation. Compared with bDMARDs, JAK inhibitors were associated with a higher-than-expected reporting of gastrointestinal perforations (adj.ROR = 1.98[1.69-2.31]). Increased reporting of gastrointestinal perforations was observed among recipients of JAK inhibitors or bDMARDs who used steroids or non-steroidal anti-inflammatory drugs concurrently (adj.ROR = 2.82 [2.41-3.31]). Perforations of both the upper and lower gastrointestinal tract were significantly over-reported (n = 51, adj.ROR = 1.55 [1.12-2.14], n = 143, adj.ROR = 1.78 [1.46-2.17], respectively). Furthermore, the safety signal was significant across all JAK inhibitors: tofacitinib (n = 125, adj.ROR = 1.52 [1.25-1.85]), upadacitinib (n = 84, adj.ROR = 2.73 [2.17-3.44]), and baricitinib (n = 21, adj.ROR = 5.38 [3.46-8.37]).

In this global pharmacovigilance study, all JAK inhibitors were associated with increased reporting of gastrointestinal perforations compared with bDMARDs in RA patients. Until more data on IBD patients emerge, careful surveillance and increased clinicians' awareness should also be advocated for this population.

The global tuberculosis (TB) pandemic continues despite living in the era of the greatest advances in human medicine. Severe TB in the form of meningitis and miliary TB kills and disables people around the world every day. It disproportionately affects the most vulnerable populations, especially children. Diagnosis and treatment are challenging, and most have poor outcomes, often never receiving treatment at all. Dedicated TB researchers continue to make improvements in the management of severe TB, but the long-term success will require a global commitment to improving health care for poor people around the world.

Early delineation of host immune responses at the moment of Mycobacterium tuberculosis (Mtb) exposure and infection is critical to identify individuals at risk of progressing to active tuberculosis (TB). We performed single-cell transcriptional profiling of over 500,000 peripheral blood mononuclear cells from 57 HIV-negative close contacts of TB cases in Brazil, including 25 individuals who developed active disease within two years (progressors) and 32 matched controls who remained disease-free (non-progressors). Cells were stimulated separately with the MTB300 peptide pool or irradiated Mtb (gRV), enabling resolution of antigen-reactive states across adaptive (CD4⁺ T-cells expressing abundant cytokines including IFNG, TNF, and IL17F) and trained-innate lineages, such as NK cells (producing GM-CSF, IFNG, CCL3, CCL4) and monocytes (GM-CSF, IL12B, IL36G). Progressors exhibited early hyper-metabolic CD4⁺ T-cell programs and proliferative NK cell signatures, whereas non-progressors preferentially upregulated complement activation and CCL3/4-driven chemokine signaling in monocytes. Notably, among progressors, gene expression profiles within antigen-reactive CD4⁺ T-cells and monocytes predicted the timing of progression to active TB. Together, these findings reveal high frequencies and functional diversity of antigen-reactive cells in Mtb-exposed individuals and nominate tractable immune correlates for the rational design of next-generation TB vaccines.

The use of biological agents in various diseases in children has been increasing and the risk of tuberculosis (TB) increases with them. We aimed to investigate the role of biological agents in children diagnosed with TB in a moderate level of TB country where TB screening is mandatory before and during biological agent treatment.

This was a retrospective cohort study. All patients who were 0-18 years old and diagnosed with TB-related ICD-10 in the national health database system between 2018 and 2023 were included in the study. The number of patients, demographic characteristics, treatments used by the patients, underlying diseases, and organ involvement of TB were recorded. Children using and not using biological agents were compared.

A total of 4351 children were diagnosed with TB, and 1.9% of them were treated with biological agents. The age of diagnosis was older (p = 0.001), and both pulmonary and extrapulmonary involvement was more frequent in children using biological agents (p = 0.001). Pulmonary involvement was more frequent in rheumatological diseases (p = 0.001), and naproxen usage was higher in children with pulmonary involvement (p = 0.014). Naproxen was found to increase the risk of pulmonary TB in children using biological agents (OR:3.824, p = 0.033).

The low frequency of TB may be due to effective TB screening before and during the therapy. The age of diagnosis was older, pulmonary and extrapulmonary TB involvement was more common in children using biological agents, which may be related to the immunosuppressive effects. Children using biological agents who are also using naproxen should be closely followed up in terms of pulmonary TB.

Despite immune restoration after initiation of antiretroviral treatment (ART), the risk of tuberculosis (TB) persists in children with HIV (CHIV). We determined patterns of immune restoration of mycobacteria-specific T cells following ART in CHIV.

CD4 and CD8 T-cell activation and memory phenotype and functional profiles before and 6 months after ART were evaluated in peripheral blood mononuclear cells from CHIV enrolled in the PUSH study (NCT02063880) in Nairobi, Kenya. T-cell expression of cytokines and activation-induced markers were measured following stimulation of peripheral blood mononuclear cells with a pool of 300 peptides from TB (MTB300) or staphylococcal enterotoxin B.

Among 47 CHIV (median age, 1.5 years), staphylococcal enterotoxin B-induced Th1 cytokine+ and activation-induced marker+ CD4 cell frequencies increased significantly after 6 months of ART. Although MTB300-specific CD4 and CD8 cell frequency did not increase after ART, polyfunctional capacity of MTB300-specific CD4 cells expressing combinations of Th1 cytokines with CD40L increased significantly after ART. Baseline age, immune activation, and effector memory CD4 levels were associated with less restoration of MTB300-specific polyfunctional CD4 cells, whereas CD4 percentage and levels of naive CD4 cells following ART were associated with improved MTB300-specific polyfunctional capacity.

Despite increases in Th1 cytokine production, deficits in mycobacteria-specific CD4 cells persisted 6 months after ART, with higher deficits in older CHIV with more immunosuppression, higher immune activation, and lower proportion of naive CD4 cells. These findings may explain persistent TB risk during early ART among CHIV and identify those at highest risk.

FABP5 is upregulated in psoriasis. This study assessed the efficacy of the potent, selective, and orally active FABP5 inhibitor ART26.12 in preclinical psoriasis models. In vitro, reconstructed human epidermis was stimulated with cytokines (IL-17 + IL-22 + TNF at 3 ng/ml each) and treated with ART26.12 (1, 3, or 10 μM) or Jak1 inhibitor (10 μM) for 24 hours; after which, 64 psoriasis-related genes were measured. ART26.12 (3 and 10 μM) treatment reduced cytokines, chemokines, and markers of keratinocyte proliferation/differentiation and increased certain antimicrobial peptides. In vivo, ART26.12 (25 or 100 mg/kg twice a day) or BMS-986165 (TYK2 inhibitor; 10 mg/kg once a day) was given orally for 10 days in the imiquimod mouse model. Imiquimod increased psoriasis-like symptoms. ART26.12 (25 mg/kg twice a day) and BMS-986165 comparably reduced psoriasis-like symptoms by day 6 of imiquimod treatment. Histopathology showed that ART26.12 reduced symptom severity, for example, hyperkeratosis, parakeratosis, epidermal acanthosis, and inflammatory infiltrates. Proteomic analysis indicated that ART26.12 rescued the expression of FLG-2; promoted epidermal differentiation complex-associated proteins; and modulated peroxisome proliferator-activated receptor, NF-kB, and protein kinase C pathways likely downstream of lipid modulation. Lipidomic analysis showed widespread modulation, including ceramides and linoleic acid derivatives. These data suggest that ART26.12 may be a potential psoriasis treatment.

I felt honored by the invitation to write this autobiography, although it was an arduous task to describe my journey through science: first bacterial adhesion, then cytokine function, and then immune responses in tuberculosis. Since only seven women had been authors of autobiographies for the Annual Review of Immunology, I felt I couldn't refuse to contribute to Volume 43 of the journal. Moreover, this was a good occasion to record my appreciation to all the lab members and collaborators for their contributions over the last 40 years, to remember the exciting times, and to reflect on the obstacles we faced. I often reflect on this line that is commonly attributed to Winston Churchill: Success is not final; failure is not fatal: It is the courage to continue that counts. What kept me going was a burning desire to know how things work and find enjoyment in the discovery. This passion to understand immune responses to infection remains with me to this day. I thank all those I have interacted with for the support and friendship they provided.

Interstitial lung disease (ILD) is a clinically relevant adverse event associated with biologic agent use. However, the current incidence of ILD remains unclear as large-scale risk assessments of biologic agents have not been conducted. The aim of this study was to clarify the association between biologic agent use and ILD development in clinical practice by detecting adverse event signals using a spontaneous adverse drug reaction database. The VigiBase database is used for spontaneous adverse event reporting. The analysis focused on nine biologics used to treat psoriasis, rheumatoid arthritis, and Crohn's disease. The safety of each biologic agent was evaluated using the information component signal detection method. There were 32,520,983 reports in VigiBase, of which 68,489 (0.21%) were for ILD. Signals were mainly detected for tumor necrosis factor-α inhibitors when the information component for ILD caused by biologic agents was calculated. Comorbidity analysis in patients who developed ILD and analysis of the time from the start of treatment with each drug to ILD onset showed differences for each biologic agent. ILD is a serious adverse effect of biologic agents, and there are several cases in which a causal relationship with ILD development cannot be ruled out. The occurrence of interstitial ILD should be noted when using biologics, particularly TNF-α inhibitors.

The risk of tuberculosis infection (TBI) and its progression to tuberculosis disease (TBD) among persons with immune-mediated inflammatory diseases (IMID) results from a complex interplay of patient and disease characteristics, immunosuppression level, and the epidemiological context. Brazilian recommendations are unclear about TBI screening and its preventive treatment (TPT) in persons with IMID.

To provide a comprehensive and evidence-based guideline for managing TBI in persons with IMID in Brazil.

This task force was constituded by 42 specialists with interest in IMID and TBD. A core leadership team (CLT) drafted fourteen clinical questions on the risk of tuberculosis and indications of TPT among persons with IMID who started, or are about to start immunosuppressive drugs. The CLT supervised the systematic reviews and formulated the recommendations. The experts voted using the Delphi Method.

Nine recommendations were established. More than 80% of panelists voted "agree" and "strongly agree" with all statements. In brief, all persons with IMID starting or about to start immunosuppressive treatment should undergo tuberculin skin testing (TST) or interferon-gamma release assays (IGRAs), a chest imaging test and investigation of contact with active pulmonary or laryngeal TBD. TPT is mandatory for those with any positive result after excluding TBD. Exceptions include individuals with a history of TBD or a past positive TBI infection test. IGRA is preferred only in persons BCG-vaccinated in the past 2 years. Those with inconclusive IGRA results can have the test repeated once, and TPT should be offered if it remains indeterminate. TST or IGRA should be repeated yearly, for three years, when the previous test was negative, when starting or changing to a different class of immunosuppressive drug. Overall, the included studies had a low quality of evidence and high risk of bias.

These guidelines are meant to improve the management of TBI in IMID. Health professionals must consider the epidemiological risk, host features, the social scenario, the characteristics of the disease, the access to health resources, and the development of an individualized plan for every patient.

Non-tuberculous mycobacteria (NTM) are widespread environmental pathogens that can lead to significant disease burden, particularly in immunocompromised individuals, but also in those with a normal immune system. The global incidence of NTM is increasing rapidly, with Mycobacterium avium complex (MAC) being one of the most common types. The immunopathogenesis of the MAC involves a complex interaction between the bacteria and the host immune system. MAC survives and replicates within macrophages by preventing the fusion of phagosomes and lysosomes. The mycobacteria can neutralize reactive oxygen and nitrogen species produced by the macrophages through their own enzymes. Additionally, MAC modulates cytokine production, allowing it to suppress or regulate the immune response. Diagnosing MAC infections can be challenging, and the effectiveness of available treatments may be limited due to MAC's unpredictable resistance to various antimycobacterial drugs in different regions. Treating MAC infection requires a collaborative approach involving different healthcare professionals and ensuring patient compliance. This review aims to shed light on the complexities of MAC infection treatment, discussing the challenges of MAC infection diagnosis, pharmacological considerations, such as drug regimens, drug monitoring, drug interactions, and the crucial role of a multidisciplinary healthcare team in achieving the best possible treatment outcomes for patients.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant health challenge. Clinical manifestations of TB exist across a spectrum with a majority of infected individuals remaining asymptomatic, commonly referred to as latent TB infection (LTBI). In vitro models have demonstrated that cells from individuals with LTBI can better control Mtb growth and form granuloma-like structures more quickly, compared to cells from uninfected (Mtb-naïve) individuals. These in vitro results agree with animal and clinical evidence that LTBI protects, to some degree, against reinfection. However, the mechanisms by which LTBI might offer protection against reinfection remain unclear, and quantifying the relative contributions of multiple control mechanisms is challenging using experimental methods alone. To complement in vitro models, we have developed an in silico agent-based model to help elucidate host responses that might contribute to protection against reinfection. Our simulations indicate that earlier contact between macrophages and CD4+ T cells leads to LTBI simulations having more activated CD4+ T cells and, in turn, more activated infected macrophages, all of which contribute to a decreased bacterial load early on. Our simulations also demonstrate that granuloma-like structures support this early macrophage activation in LTBI simulations. We find that differences between LTBI and Mtb-naïve simulations are driven by TNFα and IFNγ-associated mechanisms as well as macrophage phagocytosis and killing mechanisms. Together, our simulations show how important the timing of the first interactions between innate and adaptive immune cells is, how this impacts infection progression, and why cells from LTBI individuals might be faster to respond to reinfection.IMPORTANCETuberculosis (TB) remains a significant global health challenge, with millions of new infections and deaths annually. Despite extensive research, the mechanisms by which latent TB infection (LTBI) confers protection against reinfection remain unclear. In this study, we developed an in silico agent-based model to simulate early immune responses to Mycobacterium tuberculosis infection based on experimental in vitro infection of human donor cells. Our simulations reveal that early interactions between macrophages and CD4+ T cells, driven by TNFα and IFNγ, are critical for bacterial control and granuloma formation in LTBI. These findings offer new insights into the immune processes involved in TB, which could inform the development of targeted vaccines and host-directed therapies. By integrating experimental data with computational predictions, our research provides a robust framework for understanding TB immunity and guiding future interventions to mitigate the global TB burden.

TNFα has long stood as a hallmark feature of both inflammatory bowel disease and arthritis with its therapeutic potential demonstrated in neutralizing monoclonal antibody treatments such as Infliximab. Due to the high global burden of latent Mycobacterium tuberculosis (TB) infections, prior to receiving anti-TNF therapy, patients testing positive for latent TB are given prophylactic treatment with anti-tuberculoid medications including the first described TB-selective antibiotic, Isoniazid. While this is common clinical practice to prevent the emergence of TB, little is known about whether Isoniazid modifies intestinal inflammation alone. The aim of this study, therefore, was to determine whether Isoniazid presents a novel TB-independent therapeutic option for the treatment of Crohn's disease (CD)-like ileitis and uncover new mechanisms predisposing the host to intestinal inflammation.

The transgenic TNFΔARE mouse model of Crohn's-like terminal ileitis was used. The impact of Isoniazid administration (10 mg/kg/day dose in drinking water) on disease development was monitored between 8 and 12 weeks of age using a variety of behavioral and serological assays. Behavioral and motor functions were assessed using the LABORAS automated monitoring system while systemic and local tissue inflammation were determined at experimental termination using multiplex cytokine analysis. Whole-mount tissue immunofluorescence and fluorescent in situ hybridization were used to qualify changes within the host as well as the microbial compartment of the ileum and associated mesentery. Proposed cellular mechanisms of altered cytokine decay were performed on isolated primary splenocytes in vitro using selective pharmacological agents.

Compared to age-matched wild-type littermates, TNFΔARE mice display prominent progressive sickness behaviors from 8 through 12 weeks of age indicated by reduced movement, climbing, and rearing. Prophylactic administration of Isoniazid (10 mg/kg/day) is effectively able to protect TNFΔARE mice from this loss of function during the same period. Analysis revealed that Isoniazid was able to significantly reduce both systemic and intestinal inflammation compared to untreated vehicle controls impacting the epithelial colonization of known pathobiont segmented filamentous bacteria (SFB). Reduction in terminal ileal inflammation was also associated to the diminished formation of precursor-tertiary lymphoid organs within the associated ileal mesentery which were found to be associated with endospores derived SFB itself. Finally, we reveal that due to their genetic manipulation, TNFΔARE mice display accelerated posttranscriptional decay of IL-22 mRNA resulting in diminished IL-22 protein production and associated downstream antimicrobial peptide production.

Isoniazid protects against the development of intestinal and systemic inflammation in the TNFΔARE model of terminal ileitis by limiting the expansion of mucosal SFB and progression of the associated microbial-driven inflammation. This work highlights a possible mycobacterial-independent function of Isoniazid in limiting CD pathophysiology through limiting the mucosal establishment of pathobionts such as SFB and the association of such microbe-derived endospores linked to the formation of ectopic tertiary lymphoid organs seen commonly in patients.

Rheumatology patients on biological disease-modifying anti-rheumatic drugs (bDMARDs) have been proposed to be at a higher risk of infections. Our review summarizes the current evidence behind this theory as well as explores which factors predispose patients to various infections, which agents are more likely to cause infections, and which infections are common in these patients. We also aim to explore updated guidelines on infection prevention in patients on bDMARDs.

Acute lung injury is a devastating complication when occurring in immunocompromised patients. The incidence appears to be increasing as more patients survive for longer in this susceptible state. Being aware of potential causes of acute lung injury may lead to earlier recognition and diagnosis. Infection is a common cause of acute lung injury and needs to be considered in the diagnostic algorithm. Management involves use of supportive ventilatory strategies and potentially pharmacologic therapies.

Tuberculosis (TB) is the leading cause of death in the world from an infectious disease. Its etiologic agent, the Mycobacterium tuberculosis (Mtb), is a slow-growing bacterium that has coexisted in humans for thousands of years. According to the World Health Organization, 10.6 million new cases of TB and over 1 million deaths were reported in 2022. It is widely recognized that patients affected by chronic autoimmune arthritis such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) have an increased incidence rate of TB disease compared to the general population. As conceivable, the risk is associated with age ≥65 years and is higher in endemic regions, but immunosuppressive therapy plays a pivotal role. Several systematic reviews have analysed the impact of anti-TNF-α agents on the risk of TB in patients with chronic autoimmune arthritis, as well as for other biologic disease-modifying immunosuppressive anti-rheumatic drugs (bDMARDs) such as rituximab, abatacept, tocilizumab, ustekinumab, and secukinumab. However, the data are less robust compared to those available with TNF-α inhibitors. Conversely, data on anti-IL23 agents and JAK inhibitors (JAK-i), which have been more recently introduced for the treatment of RA and PsA/AS, are limited. TB screening and preventive therapy are recommended in Mtb-infected patients undergoing bDMARDs and targeted synthetic (ts)DMARDs. In this review, we evaluate the current evidence from randomized clinical trials, long-term extension studies, and real-life studies regarding the risk of TB in patients with RA, PsA, and AS treated with bDMARDs and tsDMARDs. According to the current evidence, TNF-α inhibitors carry the greatest risk of TB progression among bDMARDs and tsDMARDs, such as JAK inhibitors and anti-IL-6R agents. The management of TB screening and the updated preventive therapy are reported.

Use of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with preexisting tuberculosis (TB), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection can have serious consequences. Although various society guidelines recommend routine screening for these infections before initiating certain b/tsDMARDs, adherence to these recommendations varies widely. This quality improvement initiative evaluated local compliance with screening and assessed whether an automated computerized decision support system in the form of a best practice advisory (BPA) in the electronic health record could improve patient screening.

Established patients with autoimmune rheumatic disease (ARD) aged 18 years or older with at least one visit to our rheumatology practice between October 1, 2017, and March 3, 2022, were included. When prescribing a new b/tsDMARD, clinicians were alerted via a BPA that showed the most recent results for TB, HBV, and HCV. Screening proportions for TB, HBV, and HCV before BPA initiation were compared with those of eligible patients after the BPA implementation.

A total of 711 patients pre-BPA and 257 patients post-BPA implementation were included in the study. The BPA implementation was associated with statistically significant improvement in screening for TB from 66% to 82% (P ≤ 0.001), HCV from 60% to 79% (P ≤ 0.001), hepatitis B core antibody 32% to 51% (P ≤ 0.001), and hepatitis B surface antigen from 51% to 70% (P ≤ 0.001).

Implementation of a BPA can improve infectious disease screening for patients with ARD who are started on b/tsDMARDs and has potential to improve patient safety.

We aimed to investigate the frequency and clinical characteristics of tuberculosis in pediatric patients receiving both anti-TNF-alpha and other biological agents.

The data of 270 patients who used biological agents due to rheumatologic diseases and inflammatory bowel disease (IBD) and were followed between January 2021 and October 2023 were retrospectively collected from their files.

Of the patients, 138(51.1%) were female, 132(48.9%) were male. The mean age at diagnosis was 107 months (min 8-max 215 months). Patients were most commonly followed for juvenile idiopathic arthritis (JIA) (191 patients, 70.7%), followed by other autoinflammatory diseases (49 patients) and IBD (26 patients, 9.6%). Treatments included adalimumab (97 patients, 35.9%), etanercept (85 patients, 31.5%), canakinumab (33 patients, 12.2%), tocilizumab (31 patients, 11.5%), infliximab (16 patients, 5.9%), anakinra (5 patients, 1.9%), tofacitinib (2 patients, 0.7%), and rituximab (1 patient, 0.4%). During follow-up, latent tuberculosis infection (LTBI) developed in 5 (1.9%) patients. Three of these patients had JIA (using adalimumab, etanercept and tocilizumab), one had Familial Mediterranean Fever (using canakinumab), and one had IBD (using adalimumab). The mean duration of biological agent treatment until LTBI development was 14.6 months (min 6-max 29 months). Tuberculosis disease was diagnosed in two patients. Both were patients followed up due to IBD. One of the patients was diagnosed with miliary tuberculosis after infliximab treatment, while the other was followed for tuberculosis lymphadenitis after adalimumab treatment. Quadruple anti-tuberculosis therapy was initiated for the patients.

The use of biological agents has revolutionized the course of chronic inflammatory diseases in childhood. However, in these patients, monitoring for tuberculosis risk is crucial.

Tumor necrosis factor inhibitors (TNFi) are known to increase the risk of tuberculosis (TB) reactivation, though cases involving Mycobacterium bovis are rarely reported.

We describe a case of disseminated TB with M. bovis in a 78-year-old woman with a negative Interferon-Gamma-Release Assay (IGRA), taking adalimumab due to rheumatoid polyarthritis, which resulted in a fatal outcome. The atypical clinical and histopathological features were initially interpreted as sarcoidosis. The case occurred in Switzerland, an officially bovine tuberculosis-free country. The whole genome sequence of the patient's cultured M. bovis isolate was identified as belonging to the animal lineage La1.2, the main genotype in continental Europe, but showed significant genetic distance from previously sequenced Swiss cattle strains. In a literature review, four cases of bovine tuberculosis reactivation under TNFi treatment were identified, with pulmonal, oral and intestinal manifestations. Similar to our patient, two cases presented a negative IGRA before TNFi initiation, which later converted to positive upon symptomatic presentation of M. bovis infection.

This case highlights the diagnostic challenges of TB in immunosuppressed patients, the limited sensitivity of IGRA, and the importance of considering TB reactivation even in regions declared free of bovine tuberculosis. Detailed patient histories, including potential exposure to unpasteurized dairy products, are essential for guiding preventive TB treatment before TNFi initiation.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder that represents a significant public health challenge worldwide. This multifactorial condition results from complex interactions among genetic, environmental, immune, and microbial factors. Some beneficial microbes, known as probiotics, have been identified as promising therapeutic agents for inflammatory conditions, such as IBD. In this review, we explore the potential of probiotics as a therapeutic strategy for managing IBD. Probiotics have shown promise due to their ability to modulate the gut microbiota, regulate histamine levels, and enhance vitamin D metabolism, thereby promoting a tolerant immune profile and reducing inflammation. While the exact mechanisms underlying these benefits remain incompletely understood, probiotics represent a novel and emerging approach for alleviating the exacerbated inflammation characteristic of this disorder.

Background/Objectives: The nuclear factor (NF)-kB essential modulator (NEMO) has a crucial role in the NFκB pathway. Hypomorphic IKBKG pathogenic variants cause ectodermal dysplasia with immunodeficiency (EDA-ID) in affected males. However, heterozygous amorphic IKBKG variants could be responsible for Incontinentia Pigmenti (IP) in female carriers. Typically, IP patients do not exhibit immunodeficiency, although hypomorphic variants might lead to immunodeficiency in female IP patients. Here, we report the case of an IKBKG female carrier, with no IP but an unexpected picture of immunodeficiency. She had a positive family history for the same genetic condition. Methods: We performed immunological, molecular, and functional analysis to evaluate NEMO contribution. Results: The patient was healthy until the age of 25 when severe asthma and Hashimoto thyroiditis occurred. She had HLAB27-positive ankylosing spondylitis, non-tubercular mycobacteriosis, and pulmonary aspergillosis infections. We found CD19+ B cell lymphopenia and T cell subset alterations. Sanger sequencing revealed a heterozygous IKBKG variant at position +1 of the 5' UTR of the gene which disrupted the normal pre-mRNA splicing. We observed a decreased NEMO protein expression, a reduced level of mRNA, and a defective NF-κB pathway. Conclusions: These findings suggest a possible correlation between the partial loss of NEMO function and the immunodeficiency observed in this patient. This case could expand our understanding of NEMO deficiency in female carriers.

Exposure to pulmonary tuberculosis (PTB) culminates in heterogeneous outcomes, including variation in Mtb antigen-specific interferon-gamma (IFN-γ) T-cell responses. IFN-γ-independent cytokines, including tumor necrosis factor (TNF) and interleukin (IL-2), offer potential diagnostic improvements and insights into pathogenesis. We hypothesized that ESAT6/CFP10 TNF and IL-2 responses improve Mtb infection detection among exposed household contacts (HHCs) and are associated with index case Mtb aerosolization (i.e., cough aerosol culture positive for Mtb growth, CAC+) and HIV co-infection. We enrolled individuals with PTB and their HHCs in a longitudinal study in Nairobi, Kenya. We measured TNF and IL-2 in HHCs from QuantiFERON-TB Plus TB1 tube supernatants. An additional 9.2% (25) HHCs beyond the 58.6% (129) with an IFN-γ response demonstrated an antigen-specific increase in IL-2 and TNF. HHCs of CAC + participants were more likely to have positive IL-2 (84.6% vs. 53.8%, p = 0.02) and IFN-γ (88.0% vs. 54.9%, p = 0.01), but not TNF responses, compared to CAC-negative individuals. While HIV co-infection in the index was negatively associated with IFN-γ responses in HHCs (35.7% vs. 62.3%, p = 0.03), IL-2 and TNF responses did not differ. Antigen-specific ESAT6/CFP10 IL-2 and TNF may increase rates of Mtb infection detection and provide insights into Mtb transmission and pathogenesis.

The pathogenesis of inflammatory bowel disease (IBD) involves the dysregulation of multiple inflammatory pathways. The understanding of these mechanisms allows their selective targeting for therapeutic purposes. The discovery of Tumor Necrosis Factor-alpha's (TNF-α) role in mucosal inflammation ushered an exciting new era of drug development which now comprises agents targeting multiple pro-inflammatory signaling pathways, integrins, and leukocyte trafficking regulators.

This review provides an overview of the main molecular players of IBD, their translation into therapeutic targets and the successful development of the advanced agents modulating them. We combine basic science with clinical trials data to present a critical review of both the successful and failed drug development programs. A PubMed literature search was conducted to delve into the available literature and clinical trials.

The treatment landscape for IBD has rapidly expanded, particularly with the development of biologics targeting TNF-α, integrins, and S1P modulators, as well as newer agents such as IL-12/IL-23 inhibitors and JAK inhibitors, offering robust efficacy and safety profiles. However, challenges persist in understanding and effectively treating difficult-to-treat IBD, highlighting the need for continued research to uncover novel therapeutic targets and optimize patient outcomes.

Mycobacterium tuberculosis causes human tuberculosis (TB). As mycobacteria are protected by a thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, the antigenicity of most adjuvantic lipids is unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activated human T cells bearing a unique αβ T cell receptor (αβTCR). This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA-Seq using newly established CD1b-TMM tetramers revealed that TMM-specific T cells were present as CD4+ effector memory T cells in the periphery of uninfected donors but expressed IFN-γ, TNF, and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells were detected in cord blood and PBMCs of donors without bacillus Calmette-Guérin vaccination but were expanded in patients with active TB. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively charged CDR3α, and long CDR3β regions. These results indicate that humans have a commonly shared and preformed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.

Mycobacterium tuberculosis (M.tb) is a bacterial pathogen that has evolved in humans, and its interactions with the host are complex and best studied in humans. Myriad immune pathways are involved in infection control, granuloma formation, and progression to tuberculosis (TB) disease. Inflammatory cells, such as macrophages, neutrophils, conventional and unconventional T cells, B cells, NK cells, and innate lymphoid cells, interact via cytokines, cell-cell communication, and eicosanoid signaling to contain or eliminate infection but can alternatively mediate pathological changes required for pathogen transmission. Clinical manifestations include pulmonary and extrapulmonary TB, as well as post-TB lung disease. Risk factors for TB progression, in turn, largely relate to immune status and, apart from traditional chemotherapy, interventions primarily target immune mechanisms, highlighting the critical role of immunopathology in TB. Maintaining a balance between effector mechanisms to achieve protective immunity and avoid detrimental inflammation is central to the immunopathogenesis of TB. Many research gaps remain and deserve prioritization to improve our understanding of human TB immunopathogenesis.

Granulomas, organized aggregates of immune cells which form in response to Mycobacterium tuberculosis (Mtb), are characteristic but not exclusive of tuberculosis (TB). Despite existing investigations on TB granulomas, the determinants that differentiate host-protective granulomas from granulomas that contribute to TB pathogenesis are often disputed. Thus, the goal of this narrative review is to help clarify the existing literature on such determinants. We adopt the a priori view that TB granulomas are host-protective organelles and discuss the molecular and cellular determinants that induce protective granulomas and those that promote their failure. While reports about protective TB granulomas and their failure may initially seem contradictory, it is increasingly recognized that either deficiencies or excesses of the molecular and cellular components in TB granuloma formation may be detrimental to the host. More specifically, insufficient or excessive expression/representation of the following components have been reported to skew granulomas toward the less protective phenotype: (i) epithelioid macrophages; (ii) type 1 adaptive immune response; (iii) type 2 adaptive immune response; (iv) tumor necrosis factor; (v) interleukin-12; (vi) interleukin-17; (vii) matrix metalloproteinases; (viii) hypoxia in the TB granulomas; (ix) hypoxia inducible factor-1 alpha; (x) aerobic glycolysis; (xi) indoleamine 2,3-dioxygenase activity; (xii) heme oxygenase-1 activity; (xiii) immune checkpoint; (xiv) leukotriene A4 hydrolase activity; (xv) nuclear-factor-kappa B; and (xvi) transforming growth factor-beta. Rather, more precise and timely coordinated immune responses appear essential for eradication or containment of Mtb infection. Since there are several animal models of infection with Mtb, other species within the Mtb complex, and the surrogate Mycobacterium marinum - whether natural (cattle, elephants) or experimental (zebrafish, mouse, guinea pig, rabbit, mini pig, goat, non-human primate) infections - we also compared the TB granulomatous response and other pathologic lung lesions in various animals infected with one of these mycobacteria with that of human pulmonary TB. Identifying components that dictate the formation of host-protective granulomas and the circumstances that result in their failure can enhance our understanding of the macrocosm of human TB and facilitate the development of novel remedies - whether they be direct therapeutics or indirect interventions - to efficiently eliminate Mtb infection and prevent its pathologic sequelae.

Tuberculosis (TB) risk associated with tumor necrosis factor-alpha (TNF-α) antagonist therapy in patients with autoimmune diseases is a significant concern. This study aims to evaluate the risk of TB disease associated with TNF-α antagonist therapy.

An extensive search of PubMed/MEDLINE, EMBASE, and the Cochrane CENTRAL databases was conducted to identify randomized controlled trials (RCTs) assessing TB disease risk in patients receiving TNF-α antagonist therapy available until November 1, 2024. The pooled statistic used was the weighted odds ratio (OR) and a corresponding 95 % confidence interval (CI). Statistical analysis was performed using Comprehensive Meta-Analysis software, version 3.0 (Biostat Inc., Englewood, NJ, USA).

Fifty-six RCTs, totaling 22,212 adult patients, met the specified eligibility criteria. Pooled analysis revealed an increased risk of TB disease associated with TNF-α antagonist therapy (OR 1.52, 95 % CI 1.03-2.26, p = 0.03). Subgroup analyses indicated a higher risk in patients with rheumatoid arthritis (RA) (OR 2.25, 95 % CI 1.13-4.45, p = 0.02), while no significant associations were found in patients with ankylosing spondylitis (AS) or psoriasis (Ps). Analyses by specific TNF-α antagonist drugs did not yield significant associations with risk of TB disease.

Our study highlights an increased risk of TB disease associated with TNF-α antagonist therapy, particularly in patients with RA. However, the absence of significant associations in AS or Ps patients suggests disease-specific variations in risk of TB disease. Further research is needed to elucidate the long-term safety profile of TNF-α antagonist drugs and their associations with risk of TB disease in different patient populations.

Exposure to pulmonary tuberculosis (PTB) culminates in heterogeneous outcomes, including variation in Mtb antigen-specific interferon-gamma (IFN-γ) T-cell responses. IFN-γ-independent cytokines, including tumor necrosis factor (TNF) and interleukin (IL-2), offer potential diagnostic improvements and insights into pathogenesis. We hypothesized that ESAT6/CFP10 TNF and IL-2 responses improve Mtb infection detection among exposed household contacts (HHCs) and are associated with index case Mtb aerosolization (i.e., cough aerosol culture positive for Mtb growth, CAC+]) and HIV co-infection. We enrolled individuals with PTB and their HHCs in a longitudinal study in Nairobi, Kenya. We measured TNF and IL-2 in HHCs from QuantiFERON-TB Plus TB1 tube supernatants. An additional 9.2% (25) HHCs beyond the 58.6% (129) with an IFN-γ response demonstrated an antigen-specific increase in IL-2 and TNF. HHCs of CAC + participants were more likely to have positive IL-2 (84.6% vs. 53.8%, p = 0.02) and IFN-γ (88.0% vs. 54.9%, p = 0.01), but not TNF responses, compared to CAC-negative individuals. While HIV co-infection in the index was negatively associated with IFN-γ responses in HHCs (35.7% vs. 62.3%, p = 0.03), IL-2 and TNF responses did not differ. Antigen-specific ESAT6/CFP10 IL-2 and TNF may increase rates of Mtb infection detection and provide insights into Mtb transmission and pathogenesis.

Crystal structure of the secretory chorismate mutase protein of Mycobacterium tuberculosis (MtbCM) reveals presence of a proline rich region on its surface that serve as a recognition site for protein-protein interaction. This study shows that MtbCM upregulates IL-10 which favors M. tuberculosis by affecting PKCε-MKP-1-p38 MAPK signaling. MtbCM translocates to the Golgi-network where it interacts with AKAP9 via its SH3-binding domain to inhibit AKAP9-PKCε interaction and reducing PKCε phosphorylation. In the absence of phosphorylated PKCε, IRAK3 fails to stabilize MKP-1 resulting in higher p38 MAPK activation and IL-10 production. M. smegmatis expressing MtbCM survived better in infected mice. Mutation in SH3-binding domain ablated MtbCM-AKAP9 interaction resulting in IL-10 production and decreased bacterial survival. This study highlights the importance of SH3-binding domain in host-pathogen interaction and a role of MtbCM in modulation of cytokine response and mycobacterial virulence in addition to its role in shikimate pathway.

Alimentary tract inflammation in inflammatory bowel disease (IBD) is treated by systemically administered drugs that alter fundamental host immune responses. Biologics that target tumor necrosis factor (TNF) are first-line biologics in IBD, used widely for their effectiveness, steroid-sparing quality, and lower cost. While they enable a significant proportion of patients to achieve clinical remission, they carry an increased risk of infection and poor serological responses to vaccination. Conversely, our understanding of adaptive T cell responses in anti-TNF-treated IBD patients remains limited. The introduction of COVID-19 vaccines has prompted research that both challenges and refines our view on immunomodulatory therapy and its potential implications for immunity and protection. Here, we review these emergent findings, evaluate how they shape our understanding of vaccine-induced T cell responses in the context of anti-TNF therapy in IBD, and provide a perspective highlighting the need for a holistic evaluation of both cellular and humoral immunity in this population.

A 26-year-old female presented with a 3-month history of dry cough, unintentional weight loss, night sweats and fatigue. Her background history was significant for ulcerative colitis, managed with Adalimumab for almost 2 years. Clinical examination was unremarkable, apart from some mild pallor. Abnormal chest x-ray findings prompted a computerised tomography (CT) thorax which demonstrated multifocal peri-bronchial consolidation. The differential diagnosis was multifocal organising pneumonia and tuberculosis (TB). Extensive investigations, including invasive bronchial imaging and biopsy, ultimately ruled out TB. This paper reports a case of Adalimumab-induced organising pneumonia and discusses its clinical implications.

This article explores the pulmonary complications associated with inflammatory bowel disease (IBD). It presents a detailed case study of a 22-year-old male with Crohn's disease exhibiting pulmonary symptoms. The review delves into the spectrum of pulmonary involvement in IBD, covering clinical presentations, diagnostic challenges, underlying pathophysiology, and management strategies. It highlights the significance of these extraintestinal manifestations on patient outcomes and quality of life. The article underscores the need for heightened clinical awareness and a systematic approach to diagnosis and management, integrating the expertise of multiple specialists. The review identifies gaps in current research, suggesting avenues for future investigation to enhance the understanding and treatment of these complex manifestations.

A previously healthy man developed pulmonary symptoms 2 weeks after starting treatment with a tumour necrosis factor (TNF) inhibitor. A negative interferon-gamma release assay (IGRA) test was obtained prior to TNF inhibitor exposure, without consideration of the fact that the patient was already immunosuppressed and had a previous positive IGRA test 17 months earlier. The patient was treated for pneumonia twice but did not achieve remission. His physical health progressively deteriorated over the following months. Malignancy was suspected but not found. Eight months after the onset of symptoms, Mycobacterium tuberculosis was found in samples from mediastinal lymph nodes, and the patient was diagnosed with multidrug-resistant tuberculosis (MDR-TB).This case illustrates the diagnostic challenge of TB, the need to raise awareness of the increased risk of TB in patients treated with TNF inhibitors and the need to increase knowledge regarding the effect of immunosuppressive agents on IGRA tests.

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.