An unusual pAIR: Anti-PKM2 antibody and occult pancreatic adenocarcinoma.

Purpose: To describe the clinical, laboratory and multimodal imaging findings in paraneoplastic autoimmune retinopathy (p-AIR) associated with anti-pyruvate kinase M2 antibody (anti-PKM2) and occult pancreatic adenocarcinoma. Observations: A 70 year old male with blurred vision, nyctalopia and concurrent difficulty with glucose control had retinal vascular attenuation and diffuse punctate pigment clumping in both eyes. Multimodal imaging demonstrated corresponding stippled hypofluorescence on fluorescein angiography, stippled hyperautofluorescence and a hyperautoflourescent macular ring with fundus autofluorescence, and focal hyperreflectivity at the level of the RPE-Bruch's membrane complex with diffuse loss of outer retinal layers on ocular coherence tomography. In addition, diffuse ganglion cell loss and severe visual field constriction were present. Genetic testing for retinitis pigmentosa was normal. Screening for anti-retinal antibodies was positive for only anti-PKM2. Systemic evaluation revealed previously undiagnosed adenocarcinoma of the pancreas. Conclusions and importance: Anti-PKM2 in the setting of autoimmune retinopathy may be associated with occult pancreatic cancer. The diagnosis of pAIR should be considered and systemic investigation for occult malignancy initiated even in the absence of more commonly associated anti-retinal antibodies.

Autoimmunity's enigmatic role: exploring the connection with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complicated, heterogeneous condition distinguished by post-exertional neuroimmune exhaustion and multisystem symptoms. Its complexity poses challenges for physicians, researchers and those inflicted by its presence. Due to conflicting evidence and limiting consensus, the association and contribution autoimmunity serves in the pathophysiology or aetiology of ME/CFS is yet to be confirmed. This systematic review synthesises the currently available data to clarify the role autoimmunity has in the pathogenesis of ME/CFS and explore the therapeutic limitations. METHODS: This systematic review was conducted in accordance with the PRISMA and Cochrane guidelines. Full-text articles containing the primary key terms "Autoimmunity/Autoimmune" and "ME/CFS" were included provided their suitability to the inclusion and exclusion criteria. RESULTS: Ten publications investigating the role of autoimmunity in ME/CFS were examined. One investigated the role of cytokine signalling; Three investigated the genetic nature of autoimmunity in ME/CFS patients; One examined the immune lineage of ME/CFS patients; Six investigated the presence and role of autoantibodies in ME/CFS patients. CONCLUSION: The findings generated from this systematic review highlight inconsistent and insufficient evidence to classify ME/CFS as an autoimmune disease. Additionally, it further emphasises the complexity of ME/CFS and highlights the challenges in distinguishing autoreactivity from deregulatory processes. Future research is urgently needed to advance the development of diagnostic and treatment strategies. PROSPERO REGISTRATION CODE: CRD42024533447.

Trends in endogenous insulin secretion capacity and anti-islet autoantibody titers in two childhood-onset slowly progressive insulin-dependent diabetes mellitus cases.

Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) is a subtype of type 1 diabetes. Although SPIDDM is not rare among Japanese children, there are few reports on endogenous insulin secretory capacity and anti-pancreatic islet autoantibodies in pediatric SPIDDM. We followed the trends in endogenous insulin secretory capacity and anti-pancreatic islet autoantibody titers in two pediatric SPIDDM cases over several years. Case 1 developed insulin deficiency eight months after diabetes diagnosis; as her insulinoma-associated antibody test result was positive, insulin therapy was initiated. Fourteen months after the diagnosis, she tested positive for glutamic acid decarboxylase autoantibodies (GADA) and was diagnosed with SPIDDM. Case 2 was mildly positive for GADA at the onset of diabetes, but became a high titer during the course of the disease. Fourteen months after the diagnosis of diabetes, he became mildly insulin deficient, and insulin therapy was initiated. However, his insulin secretory capacity was preserved for 60 mo after the onset. SPIDDM is generally indistinguishable from type 2 diabetes at diagnosis; therefore, repeated evaluation of the insulin secretory capacity and anti-islet autoantibodies facilitates early diagnosis and appropriate treatment, especially in nonobese children with type 2 diabetes.

Possible roles of neuropeptide/transmitter and autoantibody modulation in emotional problems and aggression.

The theoretical foundations of understanding psychiatric disorders are undergoing changes. Explaining behaviour and neuroendocrine cell communication leaning towards immunology represents a different approach compared to previous models for understanding complex central nervous system processes. One such approach is the study of immunoglobulins or autoantibodies, and their effect on peptide hormones in the neuro-endocrine system. In the present review, we provide an overview of the literature on neuropeptide/transmitter and autoantibody modulation in psychiatric disorders featuring emotional problems and aggression, including associated illness behaviour. Finally, we discuss the role of psycho-immunology as a growing field in the understanding of psychiatric disorders, and that modulation and regulation by IgG autoAbs represent a relatively new subcategory in psycho-immunology, where studies are currently being conducted.

How underappreciated autoinflammatory (innate immunity) mechanisms dominate disparate autoimmune disorders.

Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate "horror autotoxicus". The 20th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term 'auto inflammation' and terminology such as "horror autoinflammaticus" to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation.

Canine idiopathic generalized tremor syndrome, immune-mediated?

Idiopathic generalized tremor syndrome is a disorder characterized by an acute onset of full-body tremors, sometimes accompanied by vestibulo-cerebellar signs, that is responsive to treatment with corticosteroids. Although considered to have an overall good outcome, relapsing and persistent mild clinical signs have been described. So far, little is known about the etiopathology of this syndrome, but it is believed to have an immune-mediated origin. In human medicine, description of numerous autoantibodies involved in certain non-infectious neurologic disorders has revolutionized understanding of their pathophysiology, diagnosis and treatment. In this multicenter retrospective study, we aimed to describe the clinical signs, course, and outcome of dogs with idiopathic generalized tremor syndrome and correlate potential findings with the presence or absence of autoantibodies associated with autoimmune cerebellar syndromes in humans. Information regarding signalment, history, clinical signs, laboratory findings, diagnostic imaging and testing for regional infectious diseases was gathered and the remaining serum and CSF samples were then analyzed for neural antibodies against targets associated with autoimmune encephalitic diseases of humans. Thirty-three dogs were included, and screening for neural antibodies was performed in 30 of those dogs. The analysis showed an increased titer of mGluR1 antibodies in two dogs, GFAP and later in the course of disease mGluR1 antibodies in one dog and an increase in unspecific autoantibodies which could not be further classified in two dogs. Dogs with detectable neural autoantibodies always had cerebrospinal fluid abnormalities in the form of a pleocytosis, with or without increased protein concentration, and tended to present with hyperthermia, potentially indicating a more severe clinical form of idiopathic generalized tremor syndrome in these cases. In conclusion, idiopathic generalized tremor syndrome is proposed to be an immune-mediated disorder potentially mediated by neural autoantibodies in a subgroup of dogs.

Highly sensitive reporter cell line for detection of interferon types I-III and their neutralization by antibodies.

Interferons (IFNs) are a critical component of innate immune defenses and limit viral disease severity. To advance studies on IFNs and their neutralization by pathogenic autoantibodies, we generated a Renilla luciferase-based reporter cell line capable of detecting the activities of IFN-Is, IFN-II, and IFN-IIIs. The reporter cell line exhibits a 125- to 2000-fold higher sensitivity to IFNs than a commonly used alternative biological reporter system and allows for a rapid and simple live-cell workflow for detecting low titer amounts of neutralizing anti-IFN antibodies.

Emerging Biomarkers for the Early Detection of Autoimmune Encephalitis: A Narrative Review.

Autoimmune encephalitis (AE) is a rare yet critical neurological disorder characterized by inflammation of the brain, typically triggered by an abnormal immune response. The early detection and diagnosis of AE are crucial for effective treatment and improved patient outcomes. However, the diagnostic process is often complicated by the diverse clinical presentations of AE, which can mimic other neurological and psychiatric conditions. Currently, diagnosis relies on a combination of clinical evaluation, neuroimaging, cerebrospinal fluid analysis, and the detection of specific autoantibodies. Despite advances in these areas, challenges remain, particularly in cases where patients are seronegative or present with nonspecific symptoms. This narrative review provides a comprehensive overview of emerging biomarkers for the early detection of AE, highlighting their potential to enhance diagnostic accuracy and speed. We explore a variety of biomarkers, including novel autoantibodies, inflammatory markers, cytokines, and neuronal damage indicators, and discuss their clinical implications. This review emphasizes the need for biomarkers that are not only sensitive and specific but also accessible and rapid to facilitate earlier diagnosis and treatment. By synthesizing current research, this review aims to contribute to the ongoing efforts to refine the diagnostic approach to AE, ultimately improving outcomes for patients affected by this challenging condition.

Nodular Scleroderma: Characterization of a Distinct Clinical Phenotype.

Nodular scleroderma is a rare variant of systemic sclerosis (SSc) characterized by fleshy, indurated nodules commonly distributed over the upper and lower extremities and in the trunk. Most scientific publications of the nodular and keloid variants of scleroderma use the terms interchangeably. However, nodular scleroderma has been recently differentiated from keloid forms. Although few cases of isolated local involvement have been reported, nodular scleroderma more commonly presents in conjunction with other manifestations of SSc. We performed a review of all cases of nodular scleroderma reported in the literature to characterize their clinical features. This review indicated that Nodular Scleroderma is usually associated with a Diffuse SSc phenotype and develops during the early progressive skin involvement. Patients with the Nodular Scleroderma phenotype display antinuclear antibodies with speckled or nucleolar patterns, a low frequency of positive SSc-specific antibodies, and typical SSc multiorgan involvement. However, a very low frequency of pulmonary hypertension was found in these patients. Although immunosuppressive or antifibrotic treatment may improve skin thickening and organ involvement, the characteristic nodules are refractory to treatment with these agents. This is the first review, to our knowledge, characterizing the nodular phenotype in patients with SSc.

Inflammatory myopathies in 2024: Better classify them to better treat them.

The discovery, over the last forty years or so, of specific myositis auto-antibodies (easily dosed in routine nowadays) and the fine clinically and pathologically phenotypic descriptions of affected patients have made it possible to review the classification of inflammatory myopathies. The arrival of "omic" techniques has also led to the discovery of different pathophysiological mechanisms among these different subgroups of myositis. Naturally, therapeutic approaches specifically targeting the representative abnormal pathways of each subgroup are being evaluated. This modern approach to myositis, which is clinical, pathophysiological, and therapeutic in the making, is presented in this review article.

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Immunological Features Underpinning Controversial Entities.

Pediatric acute-onset neuropsychiatric syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), represent an overlapping group of disorders which is characterized by acute-onset obsessive compulsive disorders, eating restriction, tics, cognitive and behavioral deterioration which typically follows a relapsing-remitting course but some patients have a primary or secondary persistent progress. This condition is likely caused by heterogeneous inflammatory mechanisms (autoantibodies, complement activation, pro-inflammatory cytokine production) involving the basal ganglia as evidenced by imaging studies (patients vs. controls), sleep studies that found movements and/or atonia during REM sleep, and neurological soft signs that go along with basal ganglia dysfunction. The condition causes significant psychiatric and behavioral symptoms, caregiver burden and sleep abnormalities. Autoantibodies resulting from molecular mimicry of infectious agents (namely group A Streptococcus) and neuronal autoantigens that map to the basal ganglia play also a subtle role. This narrative review aims to describe the key immunological features documented thus far and that likely play a role in the pathogenesis and clinical manifestations of this disorder.

Advances in Juvenile Dermatomyositis: Pathophysiology, Diagnosis, Treatment and Interstitial Lung Diseases-A Narrative Review.

Juvenile idiopathic inflammatory myopathy (JIIM) is a rare systemic autoimmune disease characterized by skeletal muscle weakness with or without a skin rash. Juvenile dermatomyositis (JDM) is the most common subtype of JIIM, accounting for 80% of JIIM. Recent studies identified several myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs). Each MSA or MAA is associated with distinct clinical features and outcomes, although there are several differences in the prevalence of MSA/MAA and autoantibody-phenotype relationships between age and ethnic groups. Histopathological studies have revealed critical roles of type I interferons and vasculopathy in the development of JDM. Serological classification mostly corresponds to clinicopathological classification. Novel therapeutic agents, such as biologics and Janus kinase inhibitors (JAKi), have been developed; however, to date, there is a lack of high-level evidence. As advances in treatment have reduced the mortality rate of JIIM, recent studies have focused on medium- and long-term outcomes. However, rapidly progressive interstitial lung disease (RP-ILD) remains a major cause of death in anti-melanoma differentiation gene 5 autoantibody-positive JDM. Early diagnosis and intervention using a multi-drug regimen is critical for the treatment of RP-ILD. Rituximab and JAKi may reduce mortality in patients with JDM-associated RP-ILD refractory to conventional therapy.

Extracellular vesicle autoantibodies.

Autoantibodies are immunoglobulin proteins produced by autoreactive B cells responding to self-antigens. Extracellular vesicles (EVs) are membranous structures released by almost all types of cells and extensively distributed in various biological fluids. Studies have indicated that EVs loaded with self-antigens not only play important roles in antigen presentation and autoantibody production but can also form functional immune complexes with autoantibodies (termed EV autoantibodies). While numerous papers have summarized the production and function of pathogenic autoantibodies in diseases, especially autoimmune diseases, reviews on EV autoantibodies are rare. In this review, we outline the existing knowledge about EVs, autoantibodies, and EV antigens, highlighting the formation of EV autoantibodies and their functions in autoimmune diseases and cancers. In conclusion, EV autoantibodies may be involved in the occurrence of disease(s) and also serve as potential non-invasive markers that could help in the diagnosis and/or prognosis of disease. Additional studies designed to define in more detail the molecular characteristics of EV autoantibodies and their contribution to disease are recommended.

Insulin Autoimmune Syndrome (Hirata's Disease) Caused by Methimazole in a 47-Year-Old Man.

Insulin autoimmune syndrome (IAS), or Hirata's disease, is a rare disease characterized by episodes of hypoglycemia with elevated levels of insulin secondary to high concentrations of insulin autoantibodies. The use of methimazole is a risk factor for the development of Hirata's disease. We report a case of a 47-year-old man being treated for thyroid storm initially with methimazole and other agents. Medical management was stopped, as the patient was refractory to treatment. Ultimately, the patient underwent plasmapheresis and thyroidectomy. While the patient was initially noted to have hyperglycemia during his hospital stay, requiring a regular insulin drip, he subsequently developed hypoglycemia even after cessation of insulin therapy. Lab work was positive for insulin autoantibodies, and the patient was diagnosed with IAS. IAS should be considered in patients with hypoglycemia who have been exposed to specific agents.

Effect of Spermidine on Endothelial Function in Systemic Lupus Erythematosus Mice.

Endothelial dysfunction is common in Systemic Lupus Erythematosus (SLE), even in the absence of cardiovascular disease. Evidence suggests that impaired mitophagy contributes to SLE. Mitochondrial dysfunction is also associated with impaired endothelial function. Spermidine, a natural polyamine, stimulates mitophagy by the PINK1-parkin pathway and counters age-associated endothelial dysfunction. However, the effect of spermidine on mitophagy and vascular function in SLE has not been explored. To address this gap, 9-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned to spermidine treatment (lpr_Spermidine and MpJ_Spermidine) for 8 weeks or as control (lpr_Control and MpJ_Control). lpr_Control mice exhibited impaired endothelial function (e.g., decreased relaxation to acetylcholine), increased markers of inflammation, and lower protein content of parkin, a mitophagy marker, in the thoracic aorta. Spermidine treatment prevented endothelial dysfunction in MRL-lpr mice. Furthermore, aortas from lpr_Spermidine mice had lower levels of inflammatory markers and higher levels of parkin. Lupus phenotypes were not affected by spermidine. Collectively, these results demonstrate the beneficial effects of spermidine treatment on endothelial function, inflammation, and mitophagy in SLE mice. These results support future studies of the beneficial effects of spermidine on endothelial dysfunction and cardiovascular disease risk in SLE.

Clinical Characteristics of Distinct Subgroups of Patients with Primary Sjögren's Syndrome Classified by Serological Profiles: A Comparison Study.

Sjögren's syndrome (SS) is an autoimmune disease characterized by heterogeneous clinical presentation and the presence of various autoantibodies. This study aimed to determine the differences in clinical findings according to antibody positivity in patients with primary Sjögren syndrome (pSS) in the Turkish population. A retrospective study was conducted and 402 patients (378 women and 24 men) with pSS were analyzed. The patients were categorized into three subgroups based on serological tests. These were (1) quadruple seropositivity (positive for anti-Sjögren's syndrome-related antigen A antibodies (anti-SSA; anti-Ro) and anti-Sjögren's syndrome-related antigen B antibodies (anti-SSB; anti-La), rheumatoid factor (RF), and antinuclear antibody (ANA); (2) double seropositivity (positive for ANA and anti-SSA/Ro antibodies); and (3) quadruple seronegativity (negative for ANA, RF, anti-SSA/Ro and anti-SSB/La antibodies). The number of quadruple-seropositive patients was 72 (18.6%), double-seropositive 174 (43.2%), and quadruple-seronegative was 85 (21.1%). The age at diagnosis of quadruple-seropositive pSS was 42.4 ± 10.8, which was significantly younger than that of patients with double-seropositive and quadruple-seronegative pSS (p = 0.021, p = 0.112). In terms of organ involvement, salivary gland enlargement, arthralgia, arthritis, Raynaud's phenomenon, lymphadenopathy, cutaneous vasculitis, interstitial lung disease, neurological involvement, autoimmune thyroiditis, renal interstitial disease, anemia, leukopenia, hypergammaglobulinemia, and hypocomplementemia were more common in quadruple-seropositive patients with pSS than in quadruple-seronegative patients (p < 0.0001). The results of this study confirmed the strong impact of immunological markers on the pSS phenotype at the time of diagnosis. Immunological patterns play a central role in the phenotypic expression of the disease, even during the initial diagnostic phase, and can guide physicians in designing personalized treatment plans for patients with pSS.