Atypical Presentation of Stenotrophomonas maltophilia Stomatitis Post COVID-19 in an Immunocompetent Adolescent.

Stenotrophomonas maltophilia (S. maltophilia) is a rare, multi-drug-resistant opportunistic bacteria that typically causes serious infections in immunocompromised and hospitalized patients, often leading to fatal pneumonia or bacteremia. We present the case of a healthy 15-year-old immunocompetent female who developed severe oral ulcers due to S. maltophilia following a recent COVID-19 infection. To our knowledge, this is the first reported case of S. maltophilia manifesting in this manner after COVID-19. Scrapes from the oral lesions were collected and cultured, confirming the infection.The CBC and immunoglobulin reports revealed mildly elevated IgA and platelet levels, with no evidence of immunodeficiency.The patient was treated with trimethoprim/sulfamethoxazole (TMP-SMX) based on culture sensitivity, and she responded well to treatment. She was referred to an infectious disease specialist for further monitoring. COVID-19 has recently been implicated in many unusual presentations, associations, and syndromes. One of the most supported theories about COVID-19 is its association with a transient immunodeficient state or a generalized state of immune system dysregulation that can compromise both innate and adaptive immunity. This case supports that theory, as no other apparent etiology for such an otherwise opportunistic infection was identified. The recognition of such atypical infections in previously healthy individuals, particularly post COVID-19, highlights the importance of sharpening clinical vigilance and considering opportunistic pathogens in differential diagnoses. Further research is warranted to explore the potential link between COVID-19 and the susceptibility to rare opportunistic infections, which may guide future clinical practices.

Inborn errors of immunity and somatic variant phenocopies disrupting human JAK-STAT signaling.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling cascade is an evolutionarily conserved signal transduction pathway that regulates many vital cellular processes, including immune function and hematopoiesis. Human genetic variants that disrupt JAK-STAT signaling are being found to cause a rapidly increasing number of diseases, including both germline-encoded inborn errors of immunity (IEI) and acquired somatic variants causing a 'phenocopy' of the IEI. Multiple genetic mechanisms are responsible for this growing group of JAK-STAT diseases including loss-of-function (LOF), gain-of-function (GOF), and dominant negative (DN) effects. In this review, we discuss the clinical presentation and pathogenesis of all currently described JAK/STAT defects, as well as providing an overview of the guiding principles to consider in diagnosing and treating these conditions.

Immune-Mediated Inflammatory Diseases and Cancer - a dangerous liaison.

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.

Revisiting double-negative T cells in autoimmune lymphoproliferative immunodeficiencies: a case series.

BACKGROUND: Elevated level of double-negative T (DNT) cells is a historical hallmark of autoimmune lymphoproliferative syndrome (ALPS) diagnosis. However, the peripheral blood level of DNT cells might also be compromised in autoimmune lymphoproliferative immunodeficiencies (ALPID) other than ALPS, inattention to which would increase the delay in diagnosis of the underlying genetic defect and hinder disease-specific treatment. MATERIALS AND METHODS: This cross-sectional study recruited patients suffering from ALPID (exclusion of ALPS) with established genetic diagnosis. Following thorough history taking, immunophenotyping for lymphocyte subsets was performed using BD FACS CaliburTM flowcytometry. RESULTS: Fifteen non-ALPS ALPID patients (60% male and 40% female) at a median (interquartile range: IQR) age of 14.0 (7.6-21.8) years were enrolled. Parental consanguinity and family history of immunodeficiency were present in 8 (53.3%) patients. The median (IQR) age at first presentation, clinical and molecular diagnosis were 18 (4-36) months, 8.0 (4.0-17.0) years, and 9.5 (5.0-20.9) years, respectively. Molecular defects were observed in these genes: LRBA (3, 20%), CTLA-4 (2, 13.3%), BACH2 (2, 13.3%), AIRE (2, 13.3%), and FOXP3, IL2Rß, DEF6, RASGRP1, PIK3CD, and PIK3R1 each in one patient (6.7%). The most common manifestations were infections (14, 93.3%), autoimmunity (12, 80%), and lymphoproliferation (10, 66.7%). The median (IQR) count of white blood cells (WBCs) and lymphocytes were 7160 (3690-12,600) and 3266 (2257-5370) cells/mm3, respectively. The median (IQR) absolute counts of CD3+ T lymphocytes and DNTs were 2085 (1487-4222) and 18 (11-36) cells/mm3, respectively. Low lymphocytes and low CD3+ T cells were observed in 3 (20%) patients compared to normal age ranges. Only one patient with FOXP3 mutation had DNT cells higher than the normal range for age. CONCLUSIONS: Most non-ALPS ALPID patients manifested normal DNT cell count. For a small subgroup of patients with high DNT cells, defects in other IEI genes may explain the phenotype and should be included in the diagnostic genetic panel.

A single center experience on PI3K/AKT/MTOR signaling defects: Towards pathogenicity assessment for four novel defects.

BACKGROUND: Phosphoinositide 3 kinases (PI3K) are lipid kinases expressed in lymphocytes/myeloid cells. PI3K/AKT/mTOR signaling defects present with recurrent infections, autoimmunity, lymphoproliferation, and agammaglobulinemia. OBJECTIVE: To characterize the PI3K/AKT/mTOR pathway defects and perform pathway analyses to assess novel variant pathogenicity. METHODS: We included 12 patients (heterozygous PIK3CD (n = 9) and PIK3R1 (n = 1) (activated PI3K delta syndrome (APDS) with gain-of-function mutations) and homozygous PIK3R1 variant (n = 2)), performed clinical/laboratory/genetic evaluation, and flow cytometric PI3K/AKT/mTOR pathway analyses. RESULTS: Median age at onset of complaints was 17.5 months (3 months to 12 years) and at diagnosis was 15.7 years (2.5-37) in APDS. Median diagnostic delay was 12.9 years (1.6-27). Recurrent respiratory tract infections (90%), lymphoproliferation (70%), autoimmune/inflammatory findings (60%), and allergy (40%) were common in APDS. Recurrent viral infections were present in 4/10 and malignancy (non-Hodgkin lymphoma and testicular yolk sac tumor) was present in 2/10 in APDS. Low CD4+ T cells(5/8) with increased CD4+ effector memory (8/8) and CD4+ TEMRA cells (6/8) were present in the given number of APDS patients. We diagnosed tubulointerstitial nephritis, Langerhans cell histiocytosis, and late-onset congenital adrenal hyperplasia in APDS. Allergic findings, lymphoproliferation/malignancy, and high IgM were present in the APDS but not in PIK3R1 deficiency. Low IgM/IgG/CD19+ B cell counts were characteristic in patients with PIK3R1 homozygous loss-of function mutations. CONCLUSION: Differential diagnosis with combined immunodeficiency and diseases of immune dysregulation make molecular genetic analysis crucial for diagnosing mTOR pathway defects. It is easy to differentiate APDS and homozygous PIK3R1 defects with specific laboratory features. Additionally, mTOR pathway functional analysis is a definitive diagnostic and pathogenicity assessment tool for novel APDS mutations.

Delineating the Clinical and Immunologic Characteristics: A Comparative Study of Inborn Errors of Immunity in Adult versus Pediatric Diagnosed.

INTRODUCTION: Inborn errors of immunity (IEIs) are rare genetic disorders primarily identified in children due to their significant effects on immune system functionality. However, an increasing number of IEI cases are being diagnosed in adults, attributed to delayed presentation or advancements in diagnostic capabilities. This study explores the clinical and immunologic distinctions between IEIs diagnosed in adulthood versus childhood, shedding light on their differential presentations, the impact of diagnostic delays, and treatment outcomes. METHODS: This study focused on 122 adult patients with IEI above 17 years old, diagnosed in adulthood or childhood. We collected comprehensive data on demographics, clinical presentations, genetic mutations, and therapeutic interventions. RESULTS: The study revealed that 72.9% of participants were diagnosed in adulthood, facing a median diagnostic delay of 96 months. Diagnostic delays were longer in adults (132 months vs. 24 months) than in children. The most common clinical manifestations at onset were recurrent infections (46.7%) and autoimmunity (18%). Predominantly antibody deficiency was the most frequently diagnosed immunodeficiency (54.9%), followed by immunodysregulation at a rate of 26.2%. A higher incidence of immune thrombocytopenia or other complications, such as hepatomegaly and enteropathy, was observed in adult-diagnosed patients with IEI. Malignancies were more prevalent in patients with adult-onset IEI compared to those with childhood-onset (18.1% vs. 5.2%). Overall, 15 different malignancies were recorded in 13 patients (10.6%), including lymphomas and cancers of the stomach, thymus, skin, breast, and colon. CONCLUSIONS: The findings highlight a considerable diagnostic delay in recognizing IEI, especially in adults, and illustrate distinct differences in disease manifestation and progression between adult-onset and delayed-diagnosis groups.

Stress as a possible trigger in anti-N-methyl-á´ -aspartate receptor encephalitis: a case series.

Anti-N-methyl-ᴅ-aspartate receptor (NMDAR) encephalitis is a rare disease with a range of neurological and psychiatric presentations. Antibodies against NMDAR receptor are purported to be pathologic, and the two known potential immunological triggers are tumors and viral infection. In half of the cases, the trigger is not known. We present two cases where stress seemed to have triggered encephalitis. These cases illustrate the possible role of stress in leading to immune dysregulation, which can lead to encephalitis. We review the role of stress in anti-NMDAR encephalitis and possible mechanisms by which stress can trigger an immune dysregulation.

Longitudinal Baboon (Papio anubis) Neutrophil to Lymphocyte Ratio (NLR), and Correlations with Monthly Sedation Rate and Within-Group Sedation Order.

Neutrophil to lymphocyte ratio (NLR) is a simple marker of stress and inflammation, but there is limited research regarding NLR in nonhuman primates (NHPs), with studies showing associations with longevity, certain medical conditions, and stressful circumstances. Here, we examined baboon NLR longitudinally, and as a function of health parameters. We also examined whether NLR was affected by sedation rate, as well as the order of sedation within a group, given that sedation events during clinical and research practices can induce stress in NHPs. While older adult and geriatric baboon NLR did not differ longitudinally, juvenile and young adult NLR tended to increase, primarily driven by increases in females. Additionally, baboons sedated later within a group showed significantly higher NLRs than those sedated earlier in the process. However, baboons with higher sedation rates per month showed lower NLRs. These data indicate that NLR may be dysregulated in different ways as a function of different types of stress, with sedation order (i.e., acute stress) causing pathological increases in NLR, and sedation rate over time (i.e., chronic stress) causing decreases. Importantly, we propose that NLR, a routinely obtained veterinary measure, has potential utility as a welfare indicator of stress resulting from clinical and research practices, as well as a measure that can inform behavioral management practices and interventions.

Pathological mechanisms and crosstalk among various cell death pathways in cardiac involvement of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prevalent autoimmune disease primarily characterized by the involvement of multiple systems and organs. Cardiovascular disease is the primary cause of mortality in patients with SLE, though the mechanisms underlying the increased cardiovascular risk in SLE patients remain unclear. Recent studies indicate that abnormal activation of programmed cell death (PCD) signaling and the crosstalk among various forms of cell death are critical in the immunopathogenesis of SLE. Furthermore, apoptosis, necroptosis, pyroptosis, NETosis, and ferroptosis are recognized as key cellular processes in the pathogenesis of SLE and are closely linked to cardiac involvement. This review uniquely explores the intricate crosstalk between apoptosis, necroptosis, and other cell death pathways, discussing their roles and interactions in the pathogenesis of cardiac involvement in SLE. Investigating the interplay between PCD signaling and cardiac involvement in SLE in understanding the disease's underlying mechanisms and offers opportunities for new therapeutic interventions. The integration of precision medicine and innovative strategies targeting these complex pathways holds promise for enhancing the treatment prospects of SLE with cardiac involvement.

The lung in inborn errors of immunity.

The lungs are integral to immune defense, and inborn errors of immunity (IEI) often manifest as lung disease. Lung complications of IEI can involve the airways, alveolar spaces, interstitium, vasculature, and pleura. Accurate identification of these lung disease patterns requires a thorough clinical history, physical examination, and high-resolution computed tomography (HRCT), as lung imaging patterns guide further respiratory and immunological evaluations. Respiratory assessment may also include pulmonary function tests, bronchoscopy with bronchoalveolar lavage, and, in some cases, lung biopsy. Additionally, molecular diagnosis of underlying immune defects, typically through comprehensive clinical phenotyping, functional immune studies, and genetic testing, is crucial for informing patient management and guiding targeted therapies. Importantly, given the complexity of IEI, a multidisciplinary approach is necessary. Furthermore, ongoing research is required to refine therapies and improve outcomes for lung complications.

Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development.

Endometriosis: A Comprehensive Exploration of Inflammatory Mechanisms and Fertility Implications.

Endometriosis is a prevalent gynecological disorder characterized by the ectopic growth of endometrial-like tissue outside the uterus. This condition poses significant challenges due to its chronic nature, debilitating symptoms such as pelvic pain and infertility, and substantial impact on quality of life. Central to the pathogenesis of endometriosis are inflammatory mechanisms that perpetuate tissue proliferation, adhesion formation, and immune dysregulation within the pelvic cavity. Inflammation plays a pivotal role in the development and progression of endometriosis, influencing the severity of symptoms and complications associated with the disease. Dysregulated immune responses contribute to the persistence of ectopic endometrial implants, exacerbating pelvic pain and other symptoms experienced by affected individuals. Moreover, the inflammatory milieu created by endometriotic lesions disrupts normal ovarian function, impairs follicular development, and compromises reproductive outcomes, thereby posing challenges to fertility. This review comprehensively explores the inflammatory mechanisms underlying endometriosis and their implications for fertility. Synthesizing current research and clinical insights elucidates the intricate interplay between inflammation, disease progression, and reproductive health outcomes. Understanding these complex interactions is essential for developing targeted diagnostic strategies and optimizing therapeutic approaches tailored to alleviate symptoms and improve fertility outcomes in individuals with endometriosis. Ultimately, this review aims to enhance the understanding of endometriosis pathophysiology, inform clinical practice, and stimulate further research to advance personalized care and management strategies for this challenging condition.

Cognitive functions in a 29-year-old male with post-COVID syndrome and long-term psoriasis - a case study.

Post-acute COVID syndrome (PACS), or long COVID, is a newly defined condition emerging as a widespread post-pandemic diagnosis with prevalent neuro-psychiatric symptoms and possible neuroinflammation-associated pathogenetic mechanisms.

Immune checkpoint blockade lowers the threshold of naïve T-cell priming to drug-associated antigens in a dose-dependent fashion.

A growing body of clinical and experimental evidence indicates that immune checkpoint blockade enhances patient susceptibility to hypersensitivity reactions to co-administered medications. In this study, we utilized an in vitro T-cell priming assay to demonstrate one of the mechanistic hypotheses on how this occurs; through lowering of the threshold in patients to elicit aberrant T-cell responses. We outline the dependency of de novo T-cell priming responses to drug-associated antigens on dose at initial exposure. Findings support the aforementioned hypothesis and offer an experimental representation of fundamental parameters at play in hypersensitivity reactions to low molecular weight compounds.

A rare cause of immune dysregulation, prolidase deficiency: a case report and review of the literature.

We report a pediatric patient with prolidase deficiency, caused by a mutation in the PEPD gene, which encodes the enzyme prolidase D, with a lupus-like clinic and marked dysmorphic features along with pulmonary, neurological, skeletal, and immune system involvement. In addition to being the first known case in the literature where Friedrich's ataxia and prolidase deficiency were observed together, we aimed to highlight that this diagnosis should be considered in patients with autoimmunity and additional systemic findings such as treatment-resistant skin lesions, intellectual disability, and pulmonary manifestations. Furthermore, we sought to compare this case with others documented in the literature.

Familial autoimmunity and risk of developing immune thrombocytopenia and Evans syndrome.

BACKGROUND: Immune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune-related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity. PROCEDURE: We assessed family history in two ways: via patient report for ITP and ES and by population-based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB. RESULTS: Chart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19-2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63-1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy. CONCLUSIONS: The findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.

PLCG2 variants in cherubism.

BACKGROUND: Cherubism is most commonly caused by rare heterozygous gain-of-function (GOF) missense variants in SH3BP2, which appear to signal through phospholipase C gamma 2 (PLCG2) to cause excessive osteoclast activity leading to expansile lesions in facial bones in childhood. GOF variants in PLCG2 lead to autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation (autoinflammatory PLAID, or PLAID-GOF), characterized by variably penetrant autoinflammatory, autoimmune, infectious, and atopic manifestations. Cherubism has not been reported in PLAID to date. OBJECTIVE: We determined whether GOF PLCG2 variants may be associated with cherubism. METHODS: Clinical, laboratory, and genomic data from 2 patients with cherubism and other clinical symptoms observed in patients with PLCG2 variants were reviewed. Primary B-cell receptor-induced calcium flux was assessed by flow cytometry. RESULTS: Two patients with lesions consistent with cherubism but no SH3BP2 variants were found to have rare PLCG2 variants previously shown to be GOF in vitro, leading to increased primary B-cell receptor-induced calcium flux in one patient's B cells. Variable humoral defects, autoinflammatory rash, and other clinical and laboratory findings consistent with PLAID were observed as well. CONCLUSION: GOF PLCG2 variants likely represent a novel genetic driver of cherubism and should be assessed in SH3BP2-negative cases. Expansile bony lesions expand the phenotypic landscape of autoinflammatory PLAID, and bone imaging should be considered in PLAID patients.

Primary Progressive Multiple Sclerosis-A Key to Understanding and Managing Disease Progression.

Primary progressive multiple sclerosis (PPMS), the least frequent type of multiple sclerosis (MS), is characterized by a specific course and clinical symptoms, and it is associated with a poor prognosis. It requires extensive differential diagnosis and often a long-term follow-up before its correct recognition. Despite recent progress in research into and treatment for progressive MS, the diagnosis and management of this type of disease still poses a challenge. Considering the modern concept of progression "smoldering" throughout all the stages of disease, a thorough exploration of PPMS may provide a better insight into mechanisms of progression in MS, with potential clinical implications. The goal of this study was to review the current evidence from investigations of PPMS, including its background, clinical characteristics, potential biomarkers and therapeutic opportunities. Processes underlying CNS damage in PPMS are discussed, including chronic immune-mediated inflammation, neurodegeneration, and remyelination failure. A review of potential clinical, biochemical and radiological biomarkers is presented, which is useful in monitoring and predicting the progression of PPMS. Therapeutic options for PPMS are summarized, with approved therapies, ongoing clinical trials and future directions of investigations. The clinical implications of findings from PPMS research would be associated with reliable assessments of disease outcomes, improvements in individualized therapeutic approaches and, hopefully, novel therapeutic targets, relevant for the management of progression.

Nef defect attenuates HIV viremia and immune dysregulation in the bone marrow-liver-thymus-spleen (BLTS) humanized mouse model.

In vitro studies have shown that deletion of nef and deleterious mutation in the Nef dimerization interface attenuates HIV replication and associated pathogenesis. Humanized rodents with human immune cells and lymphoid tissues are robust in vivo models for investigating the interactions between HIV and the human immune system. Here, we demonstrate that nef deletion impairs HIV replication and HIV-induced immune dysregulation in the blood and human secondary lymphoid tissue (human spleen) in bone marrow-liver-thymus-spleen (BLTS) humanized mice. Furthermore, we also show that nef defects (via deleterious mutations in the dimerization interface) impair HIV replication and HIV-induced immune dysregulation in the blood and human spleen in BLTS-humanized mice. We demonstrate that the reduced replication of nef-deleted and nef-defective HIV is associated with robust antiviral innate immune response, and T helper 1 response. Our results support the proposition that Nef may be a therapeutic target for adjuvants in HIV cure strategies.

Murine Models of Familial Cytokine Storm Syndromes.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disease caused by mutations in effectors and regulators of cytotoxicity in cytotoxic T cells (CTL) and natural killer (NK) cells. The complexity of the immune system means that in vivo models are needed to efficiently study diseases like HLH. Mice with defects in the genes known to cause primary HLH (pHLH) are available. However, these mice only develop the characteristic features of HLH after the induction of an immune response (typically through infection with lymphocytic choriomeningitis virus). Nevertheless, murine models have been invaluable for understanding the mechanisms that lead to HLH. For example, the cytotoxic machinery (e.g., the transport of cytotoxic vesicles and the release of granzymes and perforin after membrane fusion) was first characterized in the mouse. Experiments in murine models of pHLH have emphasized the importance of cytotoxic cells, antigen-presenting cells (APC), and cytokines in hyperinflammatory positive feedback loops (e.g., cytokine storms). This knowledge has facilitated the development of treatments for human HLH, some of which are now being tested in the clinic.