Potential clinical implications of molecular mimicry-induced autoimmunity.

BACKGROUND: Molecular mimicry is hypothesized to be a mechanism by which autoimmune diseases are triggered. It refers to sequence or structural homology between foreign antigens and self-antigens, which can activate cross-reactive lymphocytes that attack host tissues. Elucidating the role of molecular mimicry in human autoimmunity could have important clinical implications. OBJECTIVE: To review evidence for the role of molecular mimicry in major autoimmune diseases and discuss potential clinical implications. METHODS: Comprehensive literature review of clinical trials, observational studies, animal models, and immunology studies on molecular mimicry in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, lupus, Guillain-Barre syndrome, autoimmune myocarditis, and primary biliary cirrhosis published from 2000-2023. RESULTS: Substantial indirect evidence supports molecular mimicry as a contributor to loss of self-tolerance in several autoimmune conditions. Proposed microbial triggers include Epstein-Barr virus, coxsackievirus, Campylobacter jejuni, and bacterial commensals. Key mechanisms involve cross-reactive T cells and autoantibodies induced by epitope homology between microbial and self-antigens. Perpetuation of autoimmunity involves epitope spreading, inflammatory mediators, and genetic factors. CONCLUSIONS: Molecular mimicry plausibly explains initial stages of autoimmune pathogenesis induced by infection or microbiota disturbances. Understanding mimicry antigens and pathways could enable improved prediction, monitoring, and antigen-specific immunotherapy for autoimmune disorders. However, definitive proof of causation in humans remains limited. Further research should focus on establishing clinical evidence and utility.

Robust memory humoral immune response to SARS-CoV-2 in the tonsils of adults and children.

Background: Adaptive humoral immunity against SARS-CoV-2 has mainly been evaluated in peripheral blood. Human secondary lymphoid tissues (such as tonsils) contain large numbers of plasma cells that secrete immunoglobulins at mucosal sites. Yet, the role of mucosal memory immunity induced by vaccines or natural infection against SARS-CoV-2 and its variants is not fully understood. Methods: Tonsillar mononuclear cells (TMNCs) from adults (n=10) and children (n=11) were isolated and stimulated using positive SARS-CoV-2 nasal swabs. We used endpoint enzyme-linked immunosorbent assays (ELISAs) for the measurement of anti-S1, -RBD, and -N IgG antibody levels and a pseudovirus microneutralization assay to assess neutralizing antibodies (nAbs) in paired serum and supernatants from stimulated TMNCs. Results: Strong systemic humoral response in previously SARS-CoV-2 infected and vaccinated adults and children was observed in accordance with the reported history of the participants. Interestingly, we found a significant increase in anti-RBD IgG (305 and 834 folds) and anti-S1 IgG (475 and 443 folds) in the stimulated TMNCs from adults and children, respectively, compared to unstimulated cells. Consistently, the stimulated TMNCs secreted higher levels of nAbs against the ancestral Wuhan strain and the Omicron BA.1 variant compared to unstimulated cells by several folds. This increase was seen in all participants including children with no known history of infection, suggesting that these participants might have been previously exposed to SARS-CoV-2 and that not all asymptomatic cases necessarily could be detected by serum antibodies. Furthermore, nAb levels against both strains were significantly correlated in adults (r=0.8788; p = 0.0008) and children (r = 0.7521; p = 0.0076), and they strongly correlated with S1 and RBD-specific IgG antibodies. Conclusion: Our results provide evidence for persistent mucosal humoral memory in tonsils from previously infected and/or vaccinated adults and children against recent and old variants upon re-exposure. They also highlight the importance of targeting mucosal sites with vaccines to help control infection at the primary sites and prevent potential breakthrough infections.

Polymorphisms in the Drug Transporter Gene ABCB1 Are Associated with Drug Response in Saudi Epileptic Pediatric Patients.

Epilepsy is one of the most common chronic neurodisorders in the pediatric age group. Despite the availability of over 20 anti-seizure medications (ASMs) on the market, drug-resistant epilepsy still affects one-third of individuals. Consequently, this research aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of the ATP-binding cassette subfamily B member 1 (ABCB1) gene in epileptic pediatric patients and their response to ASMs. This multicentric, cross-sectional study was conducted among Saudi children with epilepsy in Jeddah, Saudi Arabia. The polymorphism variants of ABCB1 rs1128503 at exon 12, rs2032582 at exon 21, and rs1045642 at exon 26 were genotyped using the Sanger sequencing technique. The study included 85 children with epilepsy: 43 patients demonstrated a good response to ASMs, while 42 patients exhibited a poor response. The results revealed that good responders were significantly more likely to have the TT genotypes at rs1045642 and rs2032582 SNPs compared to poor responders. Additionally, haplotype analysis showed that the T-G-C haplotype at rs1128503, rs2032582, and rs1045642 was only present in poor responders. In conclusion, this study represents the first pharmacogenetic investigation of the ABCB1 gene in Saudi epileptic pediatric patients and demonstrates a significant association between rs1045642 and rs2032582 variants and patient responsiveness. Despite the small sample size, the results underscore the importance of personalized treatment for epileptic patients.

Impact of GSTT1 and GSTM1 Polymorphisms in the Susceptibility to Philadelphia Negative Chronic Myeloid Leukaemia.

BACKGROUND: Our research aimed to clarify the role of genetic polymorphisms in GST (T1 and M1) in the development of Ph-ve CML. MATERIALS AND METHODS: We report on a case-control study with 126 participants, divided into 26 patients with Ph-ve CML (57.7% male, 42.3% female) and 100 healthy volunteers (51% male, 49% female) with no medical history of cancer as a control population. All Ph-ve CML patients were diagnosed according to standard hematologic and cytogenetic criteria based on CBC, confirmed by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) to determine the presence or absence of the BCRABL gene, followed by bone marrow (BM) examination. RESULTS: Of the 26 studied cases, 50% had the GSTT1 null genotype against 21% of the control group, a statistically significant difference (CI= 1.519 - 9.317; p-value= 0.004). The GSTM1 null genotype was detected in 23.1% of cases and 35% of controls, a difference not statistically significant (OR= 0.557; CI= 0.205-1.515; p-value= 0.252). The distribution of GSTT1 and GSTM1 polymorphisms was also examined according to gender, age and ethnic grouping; these findings revealed no statistically significant differences. CONCLUSION: Our study reveals a strong correlation between GSTT1 polymorphism and Ph-ve CML, whereas the data for GSTM1 polymorphisms indicates no role in the initial development of the disease. More studies are required to further clarify these and other genes' roles in disease development.

TLR8 is highly conserved among the Saudi population and its mutations have no effect on the severity of COVID-19 symptoms.

Coronavirus 2019 (COVID-19) is an infection caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The innate system is the first line of defense against pathogens and diverse infectious agents. It has been suggested to play a key role in the development of the cytokine storm and promoting other severe forms of chronic inflammation. Toll-like receptors (TLRs) are crucial for the innate immune response to pathogens. TLR8 is expressed on myeloid cells and phagocytes, where it acts as an endosomal sensor of RNA degradation. The present study aimed to investigate whether the severity of COVID-19 symptoms could be associated with certain genetic variations of TLR8. We collected blood samples from 45 participants who had moderate to severe respiratory symptoms and a positive COVID-19 PCR test result within 3-5 days of sample collection. Genomic DNA was extracted from the blood samples, then exon 2 of the TLR8 gene was amplified with polymerase chain reaction (PCR), and PCR products were utilized for sequencing. DNA sequencing showed an average of 99.63% sequence homology in TLR8 across all samples. Base-pair homology analysis revealed variations in TLR8 at two positions: X:12937804 (rs5744080) and X:12937513 (rs2159377). The results revealed that these two mutations had no detrimental effect on symptoms in the target population. Our results show that specific SNPs did not affect the final receptor function of TLR8. This finding also indicates that the innate immune response, once activated, does not depend on the innate immune receptor's level of affinity for identifying their respective glycoprotein structures on the SARS-CoV-2 virus.

Dynamics of COVID-19 Lockdown on Blood Indices and Its Impact on Individuals' Immunological Health Status: A Cohort Study in Madinah, Saudi Arabia.

OBJECTIVE: The complete blood count (CBC) is an essential blood test that has been used for decades to assess individuals' overall health status. This study aimed to investigate the contributions of lockdown conditions to individuals' overall health status using blood indices as biological markers. During lockdown, people are limited to confined spaces, have access to limited nutritional supply options, experience increased stress, and are exposed to other environmental factors. METHODS: Our study's target population included all outpatients who were severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative and requested CBC assessments as part of their routine health checks. A total of 2414 CBC results were included, covering a period from February 2019 to December 2020. The average of different blood indices during the COVID-19 lockdown was compared to the 10-month period preceding the lockdown. RESULTS: The average counts of RBCs, hemoglobin, and hematocrit showed a significant increase during the lockdown period, which lasted from May 2020 to September 2020. Reductions were observed for the RBC distribution width, total white blood cell count, platelets, and platelet distribution width. CONCLUSION: Our findings suggested that the overall health status of individuals improved during the lockdown period in the short term, but health status might be adversely affected under these conditions of a longer period. Both RDW and PDW could be used as indicators for the overall health status when assessed against other blood indices.

The detection of SARS-CoV-2 in outpatient clinics and public facilities during the COVID-19 pandemic.

The transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can occur through an airborne route, in addition to contaminated surfaces and objects. In hospitals, it has been confirmed by several studies that SARS-CoV-2 can contaminate surfaces and medical equipment especially in hospitals dedicated to coronavirus disease 2019 (COVID-19) patients. The aim of this study was to detect the contamination of hands, objects, and surfaces in isolation rooms and also in outpatients' clinics in hospitals and polyclinics. Environmental contamination of public high-touch surfaces in public facilities was also investigated during an active COVID-19 pandemic. Random swabs were also taken from public shops, pharmacies, bakeries, groceries, banknotes, and automated teller machines (ATMs). Samples were analyzed for SARS-CoV-2 positivity using real-time polymerase chain reaction. In the COVID-19 regional reference hospital, only 3 out of 20 samples were positive for SARS-CoV-2 RNA. Hand swabs from SARS-CoV-2-positive patients in isolation rooms were occasionally positive for viral RNA. In outpatients' clinics, door handles were the most contaminated surfaces. Dental chairs, sinks, keyboards, ophthalmoscopes, and laboratory equipment were also contaminated. Although no positive swabs were found in shops and public facilities, random ATM swabs returned a positive result for SARS-CoV-2. Although there is no longer a focus on COVID-19 wards and isolation hospitals, more attention is required to decontaminate frequently touched surfaces in health-care facilities used by patients not diagnosed with COVID-19. Additionally, high-touch public surfaces such as ATMs require further disinfection procedures to limit the transmission of the infection.

Promyelocytic leukemia zinc finger triggers ATP-binding cassette subfamily E member 1-mediated growth inhibition in breast cancer cells.

The promyelocytic leukemia zinc finger (PLZF) protein is a transcription factor that is involved in a number of biological processes, including those regulating cellular growth; however, little is known regarding how it achieves its inhibitory effect in different cell and tissue types. It has previously been demonstrated that PLZF expression levels become diminished during the oncogenic transformation of certain tissue types and thus, may serve as a hallmark for tumor aggressiveness. To examine this in breast cancer, survival curves from available oncology databases were analyzed and demonstrated that PLZF expression was positively associated with increased survival in patients with breast cancer. The mRNA and protein levels of PLZF were also revealed to be associated with the tumorigenicity of four breast cancer cell lines. Since ATP-binding cassette subfamily E member 1 (ABCE1), also known as RNase L inhibitor, has been determined to be a target gene of PLZF, the present study also investigated whether the tumor suppressive effect of PLZF was associated with ABCE1 expression. PLZF was revealed to downregulate the expression of ABCE1 in vitro, which relieved the inhibitory effect of ABCE1 on the ribonuclease L enzyme. Finally, it was concluded that PLZF expression caused an ABCE1-mediated increase in cellular cytotoxicity, as demonstrated by a reduction in the proliferation rate of breast cancer cell lines. The results of the present study are important for understanding how PLZF exerts its final inhibitory actions in breast cancer cells, and potentially in other solid tumors, through the modulation of immunological pathways.

MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile.

The Middle East respiratory syndrome coronavirus (MERS-CoV) has been recognized as a highly pathogenic virus to humans that infects the respiratory tract and is associated with high morbidity and mortality. Studies in animal models suggest that MERS-CoV infection induces a strong inflammatory response, which may be related to the severity of disease. Data showing the cytokine profiles in humans during the acute phase of MERS-CoV infection are limited. In this study, we have analyzed the profile of cytokine responses in plasma samples from patients with confirmed MERS-CoV infections (n = 7) compared to healthy controls (n = 13). The cytokine profiles, including T helper (Th) 1, Th2 and Th17 responses, were analyzed using cytometric bead array (CBA). A prominent pro-inflammatory Th1 and Th17 response was clearly seen in patients with MERS-CoV infection, with markedly increased concentrations of IFN-γ, TNF-α, IL-15 and IL-17 compared to controls. IL-12 expression levels showed no difference between patients with MERS-CoV infection and the healthy controls despite the significantly increased levels of IFN-α2 and IFN-γ (P < .01). No changes were observed in the levels of IL-2, IL-4, IL-5, IL-13, and TGF-α (P > .05). Our results demonstrate a marked pro-inflammatory cytokine response during the acute phase of MERS-CoV infection in humans.

A Comprehensive In Silico Analysis on the Structural and Functional Impact of SNPs in the Congenital Heart Defects Associated with NKX2-5 Gene-A Molecular Dynamic Simulation Approach.

Congenital heart defects (CHD) presented as structural defects in the heart and blood vessels during birth contribute an important cause of childhood morbidity and mortality worldwide. Many Single nucletotide polymorphisms (SNPs) in different genes have been associated with various types of congenital heart defects. NKX 2-5 gene is one among them, which encodes a homeobox-containing transcription factor that plays a crucial role during the initial phases of heart formation and development. Mutations in this gene could cause different types of congenital heart defects, including Atrial septal defect (ASD), Atrial ventricular block (AVB), Tetralogy of fallot and ventricular septal defect. This highlights the importance of studying the impact of different SNPs found within this gene that might cause structural and functional modification of its encoded protein. In this study, we retrieved SNPs from the database (dbSNP), followed by identification of potentially deleterious Non-synonymous single nucleotide polymorphisms (nsSNPs) and prediction of their effect on proteins by computational screening using SIFT and Polyphen. Furthermore, we have carried out molecular dynamic simulation (MDS) in order to uncover the SNPs that would cause the most structural damage to the protein altering its biological function. The most important SNP that was found using our approach was rs137852685 R161P, which was predicted to cause the most damage to the structural features of the protein. Mapping nsSNPs in genes such as NKX 2-5 would provide valuable information about individuals carrying these polymorphisms, where such variations could be used as diagnostic markers.

The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PLZF.

To date, the activities of protein kinases have formed the core of our understanding of cell signal transduction. Comprehension of the extent of protein acetylation has raised expectations that this alternate post-transcriptional modification will be shown to rival phosphorylation in its importance in mediating cellular responses. However, limited instances have been identified. Here we show that signalling from Toll-like or TNF-α receptors triggers the calcium/calmodulin-dependent protein kinase (CaMK2) to activate histone acetyltransferase-1 (HAT1), which then acetylates the transcriptional regulator PLZF. Acetylation of PLZF promotes the assembly of a repressor complex incorporating HDAC3 and the NF-κB p50 subunit that limits the NF-κB response. Accordingly, diminishing the activity of CaMK2, the expression levels of PLZF or HAT1, or mutating key residues that are covalently modified in PLZF and HAT1, curtails control of the production of inflammatory cytokines. These results identify a central role for acetylation in controlling the inflammatory NF-κB transcriptional programme.