BackgroundNeuroinflammation and systemic immune dysregulation are increasingly recognized as key contributors to secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). However, the temporal relationship between circulating cytokine responses and innate-like lymphocyte populations, particularly mucosal-associated invariant T (MAIT) cells, remains poorly characterized.MethodsIn this prospective observational study, peripheral blood cytokine profiles were longitudinally analyzed in 48 patients with aSAH on days 1, 5, and 9 after ictus and compared with healthy controls. Serum concentrations of IL-6, IL-7, IL-12p40, IL-12p70, IL-15, IL-17A, IL-18, IL-22, IP-10, and CXCL-9 were measured using multiplex immunoassay. Flow cytometric immunophenotyping was performed in a subgroup of 16 patients to evaluate MAIT cells, NK cells, γδ T cells, iNKT cells, and NKT-like cells. Associations between immune parameters and 3-month functional outcome were also assessed.ResultsPatients with aSAH demonstrated persistently elevated IL-6, IL-18, and IL-15 levels across all examined time points, while IL-7, IL-12p40, IP-10, and CXCL-9 showed delayed increases during the subacute phase. IL-6 and IL-15 concentrations were significantly higher in patients with unfavorable outcome, whereas IL-22 levels were increased in patients with favorable recovery. However, these associations were not independent of disease severity after adjustment for WFNS score and age. Flow cytometry revealed a persistent reduction in circulating MAIT-cell frequencies following aSAH, while other innate-like lymphocyte populations remained largely unchanged. DN MAIT-cell frequencies demonstrated significant negative correlations with circulating IL-18 levels across all examined time points.ConclusionaSAH is associated with sustained systemic inflammatory activation and selective alterations of MAIT-cell populations. Although several cytokines were associated with functional outcome in univariate analyses, these associations were attenuated after adjustment for WFNS score and age, suggesting that they primarily reflect disease severity rather than independent prognostic effects. The observed relationship between MAIT-cell dysregulation and IL-18–associated inflammation provides further evidence of altered innate-like immune responses following aSAH.

Background: Serum C–C motif chemokine ligand 18 (seCCL18) in systemic sclerosis (SSc) has been primarily associated with progressive interstitial lung disease (SSc-ILD) and mortality. However, its relationship with non-pulmonary organ involvement, disease activity, and long-term outcome has not been comprehensively evaluated. We therefore examined the clinical relevance of seCCL18 in a single-center SSc cohort. Methods: A total of 151 patients with SSc (83 diffuse cutaneous (dcSSc), 68 limited cutaneous SSc (lcSSc); median (IQR) disease duration: 9 (4;16) years) and 47 age- and sex-matched healthy controls (HCs) were enrolled. Serum CCL18 concentrations were measured by enzyme-linked immunosorbent assay. Elevated seCCL18 was defined as >130 ng/mL (mean + 2 SD of the healthy control group). Organ involvement and disease activity (EUSTAR Activity Index, EUSTAR-AI) were assessed at baseline, while survival was analysed longitudinally. Results: Patients with SSc had significantly higher seCCL18 levels than HCs (mean ± SD: 99.9 ± 43.2 vs. 75.0 ± 27.5 ng/mL, p < 0.01). Elevated seCCL18 was associated with SSc-ILD (81.1% vs. 60.5%, p = 0.022), reduced forced vital capacity (FVC < 70%: 16.2% vs. 3.5%, p = 0.006), and reduced diffusing capacity for carbon monoxide (DLCO < 70%: 80.6% vs. 54.4%, p = 0.005). Higher seCCL18 levels were observed in patients with myocardial disease (104.8 ± 41.8 vs. 83.8 ± 44.2 ng/mL, p = 0.008), left ventricular diastolic dysfunction (107.1 ± 40.5 vs. 84.5 ± 45.0 ng/mL, p < 0.001), and oesophageal involvement (110.7 ± 38.3 vs. 93.3 ± 43.1 ng/mL, p = 0.009). SeCCL18 levels above the cut-off were more frequently associated with tendon friction rubs (51.4% vs. 27.4%, p = 0.007), active disease (EUSTAR-AI ≥ 2.5: 73% vs. 44%, p = 0.002), and elevated inflammatory markers (CRP > 5 mg/L: 51.4% vs. 19.3%, p < 0.001; ESR > 28 mm/h: 37.8% vs. 18.4%, p = 0.015). During a median follow-up of 87 months, 22 patients (15%) died. Elevated baseline seCCL18 predicted poorer survival in univariate analysis (log-rank p = 0.013) and remained an independent predictor of mortality in multivariable Cox regression (HR 1.789; 95% CI 1.133–2.824; p = 0.013), together with declining DLCO and reduced six-minute walk test performance. Conclusions: Elevated seCCL18 may identify patients with systemic sclerosis who exhibit a more severe multisystem phenotype, including cardiopulmonary, gastrointestinal, and musculoskeletal involvement, increased inflammatory activity, and reduced long-term survival. These findings suggest that seCCL18 may have some clinical utility as a prognostic biomarker reflecting widespread disease involvement beyond the lungs, even in patients with long-standing disease; however, the lack of an established cut-off value requires further validation in prospective, multicentre studies.

Background In a previous study, we found a possible connection between pre-vaccination CD3+CD56+ T cells and seroresponse to influenza vaccination in immunosuppressed patients. Decreased circulating CD3+CD56+ T cells have been described in severe COVID-19, but their role in vaccination is unknown. This study evaluated the humoral immune response after SARS-CoV-2 vaccination in children with cancer following two doses of the BNT162b2 mRNA vaccine. We investigated the relationship between cellular immunity (including CD3+CD56+ T cells) and the post-vaccination antibody response.Methods A multicenter, prospective cohort study was completed by recruiting patients receiving chemotherapy and healthy controls, who received two doses of the BNT162b2 mRNA vaccine. Flow cytometric analysis of peripheral blood lymphocyte subpopulations was performed before vaccination; serum anti-SARS-CoV-2 IgG was measured before vaccination and 21-28 days after the second vaccination. We evaluated the relationship between various cellular parameters before vaccination and antibody response.Results Serological response was assessed in 20 oncology patients and 13 healthy controls. The seroconversion rate was 55% among oncology patients and 92.3% among healthy controls (p = 0.023). Geometric mean fold increase (GMFI) of the titers was 6.69 and 41.64 (p = 0.011), respectively. Flow cytometric analysis revealed a significantly higher seroconversion rate in patients with higher baseline CD3+CD56+ T cell (p = 0.044) and CD56+ NK (p = 0.038) cell counts. Based on GMFI, we found a positive association between a greater antibody response and higher baseline CD4+ (p = 0.007), CD4+CD3+CD56+ (p = 0.019), and CD4+ MAIT (p = 0.010) cell counts, as well as a higher CD4/CD8 ratio (p = 0.029).Conclusion Our study suggests that an adequate humoral immune response can be induced by the SARS-CoV-2 mRNA vaccine in pediatric oncology patients. We explored for the first time the possible association between pre-vaccination T lymphocyte subpopulations (CD3+CD56+, CD56+ NK, CD4+, CD4+CD3+CD56+ cells) and the antibody response to the COVID-19 vaccine. We have similar observations as previously reported with influenza vaccination, suggesting that CD3+CD56+ T cells may be involved in the immune response to SARS-CoV-2 vaccines. We highlight the connection between pre-vaccination CD4+ MAIT cell populations and the antibody response.

IntroductionNatural autoantibodies (nAAbs) contribute to immune homeostasis and may be altered in patients with autoimmune diseases. While anti-heat shock protein (Hsp) antibodies have been previously described in juvenile idiopathic arthritis (JIA), their relationship with disease severity and treatment effects during remission remains unclear. This study aimed to measure the serum levels of IgM and IgG nAbs against heat shock protein (Hsp) 60 and Hsp70 in children with JIA in remission (mean age: 7.41 years, range:1.27-14.54 years) and to explore their associations with disease subtype, severity, and treatment.MethodsSerum samples from 47 children with JIA in remission and 22 apparently healthy controls (HC) were analyzed. Patient groups were stratified according to the treatment regimen (methotrexate monotherapy versus methotrexate plus adalimumab) and disease subtype and severity. Anti-Hsp60 and anti-Hsp70 IgM and IgG antibodies were measured using an in-house indirect ELISA.ResultsNo significant differences in anti-Hsp60 or anti-Hsp70 nAAb levels were observed between patients with JIA and apparently healthy controls or between treatment groups. However, severity-based analyses revealed significantly lower anti-Hsp60 and anti-Hsp70 IgM levels in patients with polyarticular JIA than in those with milder oligoarticular forms and in apparently healthy controls. No significant differences were observed in the anti-Hsp60 or anti-Hsp70 IgG levels.ConclusionReduced levels of natural IgM autoantibodies against Hsp60 and Hsp70 are associated with more severe JIA phenotypes during remission, supporting the potential immunoregulatory and protective roles of natural IgM autoantibodies in JIA.

Natural autoantibodies (nAAbs) recognize self-antigens and are an important component of the immune system, having evolved from invertebrates to vertebrates, and are viewed as stable byproducts of immune function and essential players in health and disease. Initially characterized by their conserved nature and multi-reactivity, primarily as IgM isotypes, nAAbs are now recognized for their adaptability in response to infections and vaccinations, bridging innate and adaptive immunity. The nAAbs and the cellular elements, such as γδ T, iNKT, and MAIT cells, of the natural immune system perform a primary defense network with moderate antigen-specificity. This comprehensive literature review was conducted to analyze the role of natural autoantibodies (nAAbs) in health and disease. The review focused on research published over the past 40 years, emphasizing studies related to infectious diseases, vaccinations, and autoimmune disorders. Recent studies suggest that nAAbs engage in complex interactions in autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and type 1 diabetes. Their roles in immunological processes, such as maternal tolerance during pregnancy, further underscore their complexity. Emerging evidence indicates that nAAbs and the cellular elements of the natural immune system may contribute to both disease pathogenesis and protective mechanisms, highlighting their dual nature. Continued research on nAAbs is vital for improving our understanding of immune responses and developing therapeutic strategies for autoimmune disorders and infectious diseases.

BACKGROUND:Annual flu vaccination is recommended for children with rheumatic diseases. We investigated the cellular and humoral immune response and safety in pediatric patients that received inactivated influenza vaccines. METHODS:This is a comparative study of in 41 children with juvenile idiopathic arthritis (JIA) receiving influenza vaccination while being treated with methotrexate (MTX) or biological therapy. The influenza vaccination was administered as a single dose of trivalent influenza vaccine (TIV). Serological tests to monitor seroconversion and seroprotection were performed at baseline and at 4 as well as 12 weeks after vaccination. RESULTS:In all of the 41 children with JIA and the 22 healthy children seroconversion and seroprotection were observed for Influenza A. For Influenza B, no adequate seroconversion rates were not detected in any of the groups studied. No significant differences were observed in lymphocyte subpopulations when analysing time points and groups simultaneously. There were no relapses or cases of influenza infection after the vaccination. Our findings do not suggest non-specific immune activation following vaccination based on the distribution and quantity of the lymphocyte subsets that were investigated. CONCLUSION:The present study demonstrates adequate seroprotection rates against influenza A in immunosuppressed children with JIA. The trivalent vaccine had good immunogenicity and was safe to use in both JIA treatment groups.

Antiphospholipid antibody (aPL)-induced activation of the mTOR (mammalian target of rapamycin) signaling pathway in endothelial cells plays a role in the pathogenesis of vascular lesions in antiphospholipid syndrome (APS). However, there are no data on whether this mechanism also contributes to the development of skin ulcers commonly observed in APS. We investigated the activation of mTOR in skin specimens from aPL-positive and aPL-negative patients with leg ulcers. Patients with leg ulcers who had primary or secondary APS or no detectable aPLs were included in the study. Biopsies were taken from the ulcer edges and the adjacent non-ulcerated skin areas. Activation of mTORC1 (mTOR Complex1) and mTORC2 (mTOR Complex2) in endothelial cells was determined by immunohistochemical analysis of phosphorylated ribosomal S6 protein (pS6RP) and phosphorylated protein kinase B (pAKT), respectively. In all aPL-positive patients, regardless of whether they had primary or secondary APS, we found a positive immunohistochemical reaction to pS6RP (mTORC1 activation) in the endothelial cells of the ulcer samples. On the other hand, pS6RP could not be detected in samples from aPL-negative chronic venous ulcers. Furthermore, pS6RP was not present in samples taken from the unaffected skin adjacent to the ulcers in aPL-positive patients. The pAKT reaction (mTORC2) was negative in both aPL-positive and aPL-negative patients, both in the ulcers and in the periulcer skin. Activation of the mTOR pathway may contribute to ulcer development in APS. The mTORC1 may be a target for therapeutic modification in APS-associated skin ulcers.

Purpose:Despite the worldwide decrease in the incidence of serious pneumococcal infections following the introduction of the 13-valent pneumococcal conjugate vaccines (PCV13), invasive infections still occur. This study aimed to investigate the immunological function of children with severe parapneumonic effusion (PPE) both during their hospitalization and after full recovery. Methods:This was a prospective, single-center study. Children with PPE were admitted to our clinic between 1 January 2011 and 30 June 2023, and participated in the study. Due to the severity of the effusion, all PPE cases required thoracic drainage and some children also underwent fibrinolysis and/or video-assisted thoracoscopic surgery. Demographic and clinical data and laboratory results were collected at admission. Extended immunological testing was performed at the time of clinical admission and again 6-8 weeks after discharge. Results:A total of 66 episodes of PPE were identified. During hospitalization, one patient was diagnosed with human immunodeficiency virus infection and another with immunoglobulin A deficiency. Extended immunological evaluation was performed during follow-up in 49 patients. Within this cohort, seven patients were diagnosed with mannose-binding lectin deficiency and three with specific antibody deficiency. In total, immune dysfunction was confirmed in 12 patients. When comparing the immunocompromised and non-immunocompromised groups, the duration of hospitalization was longer in the immunocompromised group, with no other differences observed. Conclusion:Although the incidence of severe PPE has declined since the introduction of PCV13, immunological evaluation remains essential for identifying underlying immunodeficiencies. Despite vaccination, screening patients with PPE for immune dysfunction is crucial. Early diagnosis and timely treatment can help prevent organ damage and reduce long-term morbidity.

Aneurysmal subarachnoid hemorrhage (aSAH) is a serious condition complicated by delayed cerebral ischemia (DCI), where inflammation plays a key role. Although altered gut permeability is noted in other conditions, its significance in aSAH remains unclear. Fatty acid-binding protein (FABP-I), lipopolysaccharide-binding protein (LBP), and soluble CD-14 (sCD-14) are established markers of barrier dysfunction. This study investigates gut permeability marker changes in early and late aSAH phases. The study included 177 aSAH patients and 100 controls. Serum samples were collected on days 1 (D1) and 9 (D9) after ictus. FABP-I, LBP, and sCD-14 levels were measured via ELISA, and clinical data were recorded. Outcomes were assessed using the 90-day modified Rankin scale (mRS 0-3 = favorable outcome). Serum FABP-I was significantly lower in aSAH patients (p < 0.05), while LBP and sCD-14 were higher (p < 0.001) compared to controls. FABP-I did not differ between outcome groups, but LBP and sCD-14 were significantly elevated in unfavorable outcomes (p < 0.001). These markers differed in patients without in-hospital infection, with higher levels noted in DCI patients during the later phase (p < 0.05). In aSAH patients without infection, differences in LBP and sCD-14 levels between outcome groups suggest potential endotoxin release from microbial systems, contributing to neuroinflammation and influencing outcomes.

Perceptions of the complete eradication of vaccine-preventable diseases such as measles, mumps, and rubella (MMR) may foster complacency and compromise vaccination efforts. Decreased measles vaccination rates during the COVID-19 pandemic have heightened the risk of outbreaks, even in adequately vaccinated populations. To address this, we have aligned with ECDC recommendations, leveraging previous cross-border sero-epidemiological assessments between Pécs, Hungary, and Osijek, Croatia, to identify latent risk groups and uncover potential parallels between our nations. Testing 2680 Hungarian and 1764 Croatian serum samples for anti-MMR IgG via ELISAs revealed anti-measles seropositivity ratios below expectations in Croatian cohorts aged ~20–30 (75.7%), ~30–40 (77.5%) and ~40–50 years (73.3%). Similarly, Hungarian samples also showed suboptimal seropositivity ratios in the ~30–40 (80.9%) and ~40–50 (87.3%) age groups. Considering mumps- and rubella-associated seropositivity trends, in both examined populations, individuals aged ~30–50 years exhibited the highest vulnerability. Additionally, we noted congruent seropositivity trends across both countries, despite distinct immunization and epidemiological contexts. Therefore, we propose expanding research to encompass the intricate dynamics of vaccination, including waning long-term immunity. This understanding could facilitate targeted interventions and bolster public awareness. Our findings underscore persistent challenges in attaining robust immunity against measles despite vaccination endeavors.

Natural autoantibodies (natAAbs) react with evolutionarily conserved antigens but they do not lead to pathological tissue destruction, contrary to pathological autoantibodies (pathAAbs). NatAAbs usually belong to the IgM isotype, and their network, also known as the “immunological homunculus”, is thought to play a role in immunological tolerance. NatAAbs are produced by B1 cells found mostly on the serosa surfaces or the spleen. The exact relation between natAAbs and pathAAbs is still not completely understood. The recombinant human proteoglycan (PG) aggrecan G1 domain (rhG1)-induced arthritis (GIA) is an excellent mouse model for rheumatoid arthritis because it represents most of the clinical, immunological and laboratory parameters of the corresponding human pathology. Recently, we studied the role of the spleen in GIA, and found that a splenectomy modified the development of autoimmunity. To further characterize the possible role of the nAAb levels in tolerance and autoimmunity, in the present study, we set out to measure the nat- and pathAAb levels in GIA. We analyzed the natAAb levels in the serum against cartilage PG aggrecan, Hsp60 and Hsp70, and the mitochondrial citrate synthase (CS) antigens in healthy control and arthritic mice. Furthermore, we studied whether the splenectomy influenced the production of nat- and pathAAbs in mice with GIA. Our results show that the natAAb levels against PG aggrecan, Hsp60, Hsp70 and CS showed age-related variations in healthy BALB/c mice. The induction of autoimmune arthritis did not change the levels of the measured natAAbs significantly. Splenectomy, on the other hand, clearly decreased the levels of all the measured natAAbs. Interestingly, the levels of the pathAAbs showed the opposite change: they were higher in the splenectomized group than in the control arthritic mice. Based on these results, we conclude that the spleen plays a role in setting the balance between nat- and pathAAbs in autoimmune arthritis.

Background: Accelerated inflammatory atherosclerosis, as well as increased cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Natural autoantibodies (nAAbs) have been implicated in both arthritides and atherosclerosis. The possible effects of anti-TNF therapy on these nAAbs are largely unknown. Objectives: Therefore we assessed the effects of one-year anti-TNF therapy on nAAbs in association with several other biomarkers. Methods: Altogether 53 patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV) in all patients. Among nAAbs, anti-citrate synthase (CS) and anti-topoisomerase fragment 4 (TOPO-F4) IgM and IgG, as well as anti-Heat shock protein 60 (Hsp60) IgG levels were determined by in-house ELISA. All assessments were performed at baseline and 6 and 12 months after treatment initiation. Simple Pearson's correlation, uni- and multivariable regression, RM-ANOVA and two-way ANOVA analyses were performed. Results: One-year anti-TNF therapy transiently improved FMD and maintained ccIMT and PWV in RA and AS. TNF inhibition significantly increased anti-CS IgM and IgG, anti-TOPO-F4 IgG after 12 months versus baseline (p<0.005). There was no change in anti-hsp60 levels overtime. In various correlation analysis, anti-CS and anti-TOPO-F4 variably correlated with disease activity, rheumatoid factor, ACPA, FMD and PWV (p<0.005). Anti-TOPO-F4 IgG also correlated with anti-Hsp60 IgG (p<0.005). RM-ANOVA and two-way ANOVA confirmed that changes in anti-CS and anti-TOPO-F4 levels overtime variably correlated with changes of CRP, disease activity, FMD, ccIMT and PWV overtime (p<0.005). Conclusion: TNF inhibition improved or stabilized vascular pathophysiology in RA and AS. Biologic therapy also increased anti-CS and anti-TOPO-F4 levels. The production of nAAbs was variably associated with, among other parameters, CRP, disease activity and vascular pathophysiology suggesting that nAAbs might form a link between arthritis and atherosclerosis. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Zoltán Szekanecz Abbvie, Roche, Pfizer, MSD, Richter, Lilly, Novartis, Abbvie, Roche, Pfizer, MSD, Richter, Lilly, Novartis, Pfizer, Diana Simon: None declared, Dorottya Kacsándi: None declared, Anita Pusztai: None declared, Boglárka Soós: None declared, Edit Végh: None declared, György Kerekes: None declared, Monika Bodoki: None declared, Szilvia Szamosi: None declared, Gabriella Szücs: None declared, Peter Nemeth: None declared, Timea Berki: None declared.

Background and Objectives Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. Methods This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABA(B)R-AIE, who had been seizure-free for >= 3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. Results We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABA(B)R-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABA(B)R. Discussion Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely utilized to investigate plasticity mechanisms and functional reorganization in multiple sclerosis (MS). Among many resting state (RS) networks, a significant role is played by the salience network (SN, ventral attention network). Previous reports have demonstrated the involvement of osteopontin (OPN) in the pathogenesis of MS, which acts as a proinflammatory cytokine ultimately leading to neurodegeneration. Concentration of serum OPN was related to MRI findings 10.22±2.84 years later in 44 patients with MS. Local and interhemispheric correlations (LCOR, IHC), ROI-to-ROI and seed-based connectivity analyses were performed using serum OPN levels as independent variable along with age and gender as nuisance variables. We found significant associations between OPN levels and local correlation in right and left clusters encompassing the central opercular- and insular cortices (p-FDR = 0.0018 and p-FDR = 0.0205, respectively). Moreover, a significant association was identified between OPN concentration and interhemispheric correlation between central opercular- and insular cortices (p-FDR = 0.00015). Significant positive associations were found between OPN concentration and functional connectivity (FC) within the SN (FC strength between the anterior insula ventral division and 3 other insular regions, F(2,13) = 7.84, p-FDR = 0.0117). Seed-based connectivity analysis using the seven nodes of the SN resulted in several positive and inverse associations with OPN level. Serum OPN level may predict FC alterations within the SN in 10 years.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.

The function of natural autoantibodies (nAAbs) in maintaining immunological tolerance has been comprehensively explained; however, their function in pregnant patients dealing with autoimmune diseases has not been thoroughly investigated. As Hashimoto’s thyroiditis (HT) is the predominant organ-specific autoimmune condition of women of childbearing age, this study’s objective was to evaluate IgM and IgG nAAbs targeting mitochondrial citrate synthase (CS) and heat shock proteins (Hsp60 and Hsp70) in women diagnosed with HT who were pregnant (HTP). Serum samples collected from HTP and healthy pregnant (HP) women in the first and third trimesters were tested using in-house-developed enzyme-linked immunosorbent assays (ELISAs). Our findings indicate the stability of nAAbs against CS and Hsps throughout the pregnancies of both healthy women and those with HT. However, during both trimesters, HTP patients displayed elevated levels of IgM isotype nAAbs against Hsp60 and Hsp70 compared to HP women, suggesting a regulatory role of IgM nAAbs during the pregnancies of patients with HT. Nonetheless, levels of IgG isotype nAAbs against Hsps were lower solely in the third trimester among HTP patients, resulting in a higher IgM/IgG ratio, which indicates their importance in alterations of the nAAb network during pregnancy in patients with HT.