Excellent response to anti-CD38 therapy with daratumumab in a patient with severe refractory CANOMAD.

BACKGROUND: Intravenous immunoglobulin (IVIG) and rituximab are considered the first-line and second-line treatments for Chronic Ataxic Neuropathy and Ophthalmoplegia with IgM-paraprotein, cold Agglutinins, and anti-Disialosyl antibodies (CANOMAD), with an overall clinical response around 50%. New anti-CD38 daratumumab, targeting long-lived plasma cells, has been reported as a promising therapy for treatment-refractory antibody-mediated disorders. We report the first case of a severe refractory CANOMAD, successfully treated with daratumumab. METHODS: A patient in their 70s with severe relapsing CANOMAD, refractory to IVIG, steroids, rituximab and ibrutinib developed severe tetraparesis and respiratory failure. Plasma exchange (PE) improved motor and ventilatory function; however, after 6 weeks, patient remained PE dependent. Intravenous daratumumab was initiated at 16 mg/kg weekly for 3 weeks, every 2 weeks for the second and third month, and monthly afterwards. RESULTS: After 3 weeks of starting daratumumab, PE was discontinued and, since then, the patient evolved to complete recovery. Antidisialosyl antibody titres decreased after PE and remained stable during daratumumab. Serum neurofilament light-chain levels were elevated in the exacerbation phase and normalised after daratumumab. The patient remains in clinical remission under monthly daratumumab, 12 months after initiation. CONCLUSIONS: The first patient with aggressive treatment-refractory CANOMAD treated with daratumumab provides proof-of-principle evidence that daratumumab may be an effective treatment in IgM-related neuropathies.

Clinical relevance of distinguishing autoimmune nodopathies from CIDP: longitudinal assessment in a large cohort.

BACKGROUND: The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP. METHODS: Serum IgG antibodies to neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) were detected with cell-based assays in patients diagnosed with CIDP. Clinical improvement was determined using the modified Rankin scale, need for alternative and/or additional treatments and assessment of the treating neurologist. RESULTS: We studied 401 patients diagnosed with CIDP and identified 21 patients with AN (10 anti-NF155, 6 anti-CNTN1, 4 anti-CASPR1 and 1 anti-NF155/anti-CASPR1 double positive). In patients with AN ataxia (68% vs 28%, p=0.001), cranial nerve involvement (34% vs 11%, p=0.012) and autonomic symptoms (47% vs 22%, p=0.025) were more frequently reported; patients with AN improved less often after intravenous immunoglobulin treatment (39% vs 80%, p=0.002) and required additional/alternative treatments more frequently (84% vs 34%, p<0.001), compared with patients with CIDP. Antibody titres decreased or became negative in patients improving on treatment. Treatment withdrawal was associated with a titre increase and clinical deterioration in four patients. CONCLUSIONS: Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies.

Autoimmune nodopathies, an emerging diagnostic category.

PURPOSE OF REVIEW: In the last decade, antibodies targeting cell adhesion molecules of the node of Ranvier were described in patients with autoimmune neuropathies. These nodal/paranodal antibodies associate with specific clinicopathological features that are different from classical chronic inflammatory demyelinating polyneuropathy (CIDP). In this review, we will summarize recent findings establishing autoimmune nodopathies (AN) as a new category of autoimmune neuropathies. RECENT FINDINGS: AN include anti-contactin 1, anti-contactin-associated protein 1, anti-neurofascin 155 and anti-pan-neurofascin antibody-mediated neuropathies. Their clinical spectrum includes acute, subacute or chronic onset sensory-motor neuropathies mimicking Guillain-Barré syndrome (GBS) and CIDP, although they differ in their response to standard therapy with intravenous immunoglobulin (IVIG). Neurophysiologically they overlap with acquired demyelinating neuropathies, but ultrastructural studies and animal models demonstrated antibody-mediated pathology restricted to the node of Ranvier. Anti-contactin1 and anti-pan-neurofascin also associate with nephrotic syndrome. Nodal/paranodal antibodies are predominantly of the immunoglobulin (IgG)4 subclass during the chronic phase of the disease, but complement-fixing IgG3 antibodies are detected during the early phase and associate with aggressive onset and IVIG response. Nodal/paranodal antibodies testing is key in the diagnosis of AN. SUMMARY: AN have emerged as a new diagnostic category pathologically different from acquired demyelinating neuropathies. Clinically they overlap with GBS and CIDP although they associate with specific clinical features that should lead to clinical suspicion. Nodal/paranodal antibodies are key effector mechanisms of disease and good diagnostic and disease-monitoring biomarkers in AN.

High prevalence of paraspinal muscle involvement in adults with McArdle disease.

INTRODUCTION/AIMS: Very few studies analyzing the pattern of muscle involvement in magnetic resonance imaging (MRI) of patients with McArdle disease have been reported to date. We aimed to examine the pattern of muscle fat replacement in patients with McArdle disease. METHODS: We performed a retrospective study including all patients with genetically confirmed McArdle disease followed in our center from January 2010 to March 2021. Clinical data were collected from the medical record. Whole-body MRI was performed as part of the diagnostic evaluation. The distribution of muscle fat replacement and its severity were analyzed. RESULTS: Nine patients were included. Median age at onset was 7 y (range, 5-58) and median age at the time when MRI was performed was 57.3 y (range, 37.2-72.8). At physical examination, four patients had permanent weakness: in three the weakness was limited to paraspinal muscles, whereas in one the weakness involved the paraspinal and proximal upper limb muscles. Muscle MRI showed abnormalities in six of the seven studied patients. In all of them, fat replacement of paravertebral muscles was found. Other muscles frequently affected were the tongue in three, subscapularis in three, and long head of biceps femoris and semimembranosus in two. DISCUSSION: Our findings suggest that paraspinal muscle involvement is common in McArdle disease and support the need to include this disease in the differential diagnosis of the causes of paraspinal muscle weakness. Involvement of the tongue and subscapularis are also frequent in McArdle disease.

Antibodies to the Caspr1/contactin-1 complex in chronic inflammatory demyelinating polyradiculoneuropathy.

Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA.

Autoantibody screening in Guillain-Barré syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. METHODS: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. RESULTS: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. CONCLUSION: Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.

Effect of intermittent induced aeration on nitrogen removal and denitrifying-bacterial community structure in Cork and gravel vertical flow pilot-scale treatment wetlands.

In this work, we have evaluated the impact of intermittent induced aeration in total nitrogen (TN), ammonia (NH4-N) and nitrate-nitrogen (NO3-N) removal in four pilot-scale vertical flow constructed wetlands (VFCW) (two aerated two non-aerated) using cork by-product or gravel as the filter material and planted with Phragmites australis. Both aerated and non-aerated systems achieved high COD and BOD5 elimination rates (≥ 90%) at the end of the 5-month test period. However, the aerated systems presented maximal COD and BOD5 removal from the third month of operation onwards since air supply favored the oxidative bioprocesses occurring within the wetlands. Cork and gravel aerated VFCW also proved to be more efficient (p < 0.05) in NO3-N removal than the non-aerated systems and this upgraded performance was correlated with a significant higher relative abundance of the nirS gene. The aerated systems also showed a slightly improved NH4-N removal. Noticeably, cork VFCW showed higher TN removal mean values (∼35%) than gravel wetlands (27-28%) regardless aeration. Moreover, cork VFCW showed higher relative abundance of the nosZ gene. Our results demonstrated a better nitrogen elimination for the aerated cork pilot-scale VFCW, and this behavior was correlated with a higher abundance of both nirS and nosZ, two of the key functional genes involved in nitrogen metabolism.

Serum neurofilament light chain predicts long-term prognosis in Guillain-Barré syndrome patients.

OBJECTIVE: To study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barré syndrome (GBS). METHODS: We measured NfL in serum (98 samples) and cerebrospinal fluid (CSF) (24 samples) of patients with GBS prospectively included in the International GBS Outcome Study (IGOS) in Spain using single-molecule array (SiMoA) and compared them with 53 healthy controls (HCs). We performed multivariable regression to analyse the association between sNfL levels and functional outcome at 1 year. RESULTS: Patients with GBS had higher NfL levels than HC in serum (55.49 pg/mL vs 9.83 pg/mL, p<0.0001) and CSF (1308.5 pg/mL vs 440.24 pg/mL, p=0.034). Patients with preceding diarrhoea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90 pg/mL vs 47.86 pg/mL vs 38.02 pg/mL, p=0.016). sNfL levels correlated with Guillain-Barré Syndrome Disability Score and Inflammatory Rasch-built Overall Disability Scale (I-RODS) at every timepoint. Patients with pure motor variant and Miller Fisher syndrome showed higher sNfL levels than patients with sensorimotor GBS (162.18 pg/mL vs 95.50 pg/mL vs 38.02 pg/mL, p=0.025). Patients with acute motor axonal neuropathy cute motor axonal neuropathy had higher sNfL levels than other variants (190.55 pg/mL vs 46.79 pg/mL, p=0.013). sNfL returned to normal levels at 1 year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14 to 2.40, p=0.009) and lower I-RODS (ß -2.60, 95% CI -4.66 to -0.54, p=0.014) at 1 year. Cut-off points predicting clinically relevant outcomes at 1 year with high specificity were calculated: inability to walk independently (>319 pg/mL), inability to run (>248 pg/mL) and ability to run (<34 pg/mL). CONCLUSION: Baseline sNfL levels are increased in patients with GBS, are associated with disease severity and axonal variants and have an independent prognostic value in patients with GBS.

Biosimilar medicines for psoriasis. Positioning of the Mexican Academy of Dermatology.

The development and marketing of biosimilars opens a new scenario in the treatment of many pathologies, including psoriasis. This article reflects the position of the Mexican Academy of Dermatology (AMD) on the use of biosimilar medicines for the treatment of psoriasis in Mexico. In summary, the AMD estates that there is sufficient evidence to accept comparability of pharmacokinetics and pharmacodynamics of some biosimilar medicines to adalimumab, infliximab and etanercept; this evidence does not sufficiently support interchangeability or indication extrapolation. It is essential to establish a close pharmacovigilance not only to guarantee compliance with the Cofepris rules in Mexico, but also to facilitate the effective monitoring of the adverse effects of biosimilar medicines. Although the goal of biotechnological drugs is to achieve substantial savings for patients and public institutions, no economic criteria should prevail over rigorous scientific criteria that guarantee maximum therapeutic efficacy and optimum safety for patients.

El desarrollo y comercialización de biocomparables abre un nuevo escenario en el tratamiento de muchas patologías, entre ellas la psoriasis. El presente artículo recoge la postura de la Academia Mexicana de Dermatología (AMD) respecto al uso de medicamentos biocomparables para el tratamiento de la psoriasis en México. En resumen, la AMD establece que existe suficiente evidencia para aceptar la comparabilidad farmacocinética y farmacodinámica entre algunos medicamentos biocomparables al adalimumab, el infliximab y el etanercept; esta evidencia no sustenta suficientemente su intercambiabilidad ni la extrapolación de indicaciones; es fundamental establecer una farmacovigilancia estrecha no solo para garantizar el cumplimiento de las reglas de la Comisión Federal para la Protección contra Riesgos Sanitarios en México, sino para facilitar un seguimiento efectivo de los efectos adversos de los medicamentos biocomparables. Si bien la meta de los medicamentos biotecnológicos es lograr un ahorro sustancial para los pacientes y las instituciones públicas, los criterios económicos no deben anteponerse a criterios científicos rigurosos que garanticen la máxima eficacia terapéutica y la óptima seguridad para los pacientes.

Expert recommendations for biological treatment in patients with psoriasis.

In recent years, the introduction of a series of biological drugs for the treatment of psoriasis has considerably increased the therapeutic armamentarium of doctors, and thus a strongly positive impact on the control of this condition has been achieved. With the purpose to provide the best recommendations for the use of these biological agents in patients with psoriasis, the Mexican group of psoriasis experts, PSOMEX, has developed recommendations in order to improve the understanding and therapeutic positioning of this type of medications.

En los últimos años, la introducción de diversos medicamentos biológicos para el tratamiento de la psoriasis ha aumentado considerablemente el arsenal terapéutico del médico, con lo cual se ha logrado un fuerte impacto positivo en el control de la enfermedad. Con el fin de proveer de las mejores recomendaciones para el uso de estos biológicos en los pacientes afectados de psoriasis, el grupo mexicano de expertos en psoriasis PSOMEX ha formulado recomendaciones para mejorar la comprensión y el posicionamiento terapéutico de este tipo de medicamentos.

Autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy.

PURPOSE OF REVIEW: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous disorder that includes diverse clinical presentations and immunopathological mechanisms. Antibodies targeting proteins of the node of Ranvier are present in a subset of CIDP patients. These autoantibodies are pathogenic and associate with specific clinical phenotypes and therapeutic peculiarities. This review summarizes the novel insights that the discovery of novel autoantibodies has brought to the understanding of CIDP. RECENT FINDINGS: Several reports have confirmed the association of the antineurofascin 155 (NF155) antibodies with tremor, ataxia and poor response to IVIG, and with novel pathological features in CIDP patients. The association of nephrotic syndrome with anticontactin 1 (CNTN1) and antinodal neurofascin antibodies has also been described. Also, complement-fixing IgG3 antibodies targeting paranodal proteins have been associated with acute-onset CIDP. Importantly, detection of these autoantibodies has helped selecting CIDP patients for rituximab treatment. Finally, anti-CNTN1 and anti-NF155 antibodies have proven to be the first pathogenic autoantibodies described in CIDP. SUMMARY: The discovery of autoantibodies against nodal and paranodal proteins has proven useful in clinical practice, has uncovered novel pathophysiological mechanisms, clinical phenotypes, therapeutic response and prognosis within the CIDP disease spectrum and has boosted the search for other clinically relevant autoantibodies.

Patient Navigation to Enhance Access to Care for Underserved Patients with a Suspicion or Diagnosis of Cancer.

BACKGROUND: Interventions aimed at improving access to timely cancer care for patients in low- and middle-income countries (LMIC) are urgently needed. We aimed to evaluate a patient navigation (PN) program to reduce referral time to cancer centers for underserved patients with a suspicion or diagnosis of cancer at a public general hospital in Mexico City. MATERIALS AND METHODS: From January 2016 to March 2017, consecutive patients aged >18 years with a suspicion or diagnosis of cancer seen at Ajusco Medio General Hospital in Mexico City who required referral to a specialized center for diagnosis or treatment were enrolled. A patient navigator assisted patients with scheduling, completing paperwork, obtaining results in a timely manner, transportation, and addressing other barriers to care. The primary outcome was the proportion of patients who obtained a specialized consultation at a cancer center within the first 3 months after enrollment. RESULTS: Seventy patients (median age 54, range 19-85) participated in this study. Ninety-six percent (n = 67) identified >1 barrier to cancer care access. The most commonly reported barriers to health care access were financial burden (n = 50) and fear (n = 37). Median time to referral was 7 days (range 0-49), and time to specialist appointment was 27 days (range 1-97). Ninety-one percent of patients successfully obtained appointments at cancer centers in <3 months. CONCLUSION: Implementing PN in LMIC is feasible, and may lead to shortened referral times for specialized cancer care by helping overcome barriers to health care access among underserved patients. IMPLICATIONS FOR PRACTICE: A patient navigation program for patients with suspicion or diagnosis of cancer in a second-level hospital was feasible and acceptable. It reduced patient-reported barriers, and referral time to specialized appointments and treatment initiation were within international recommended limits. Patient navigation may improve access to care for underserved patients in developing countries.

Glans penis necrosis caused by calcific uremic arteriolopathy.

Calcific uremic arteriolopathy (CUA) or calciphylaxis is a syndrome characterized by calcification of vessels located in the dermis and adipose tissue. It commonly occurs in patients with diabetes mellitus, hypertension, and end-stage renal disease. Clinical presentation generally begins with severe pain, followed by the presence of liveloid or purpuric plaques. Later the formation necrotic ulcers occur. This condition is associated with a poor prognosis, with a high rate of mortality within months of the diagnosis. Penile involvement is an uncommon but severe manifestation. We present an 81-year-old man with a history of diabetes mellitus, hypertension, and end-stage renal disease with a one-month evolution of painful necrotic ulcers on his glans penis. He was diagnosed with CUA. Owing to infection complicated by sepsis; penectomy was performed. Unfortunately, the patient died of myocardial infarction during his hospitalization.

Pfeiffer Syndrome Type 3 and Prune Belly Anomaly in a Female: Case Report and Review.

Background: Pfeiffer syndrome (PS) is an autosomal dominant entity characterized by craniosynostosis, broad thumbs, and preaxially deviated great toes. It is classified in three types depending on the severity. Type 1: Mild to moderate severity, Type 2: Severe presentation with cloverleaf skull, and Type 3: Severe craniosynostosis with prominent ocular proptosis. Association of Pfeiffer syndrome (PS) types 2 and 3 with "prune belly" anomaly has been reported in two non-related patients, one PS type 2 and one PS type 3. Case Report: we report the second case of PS type 3 in a female neonate with "prune belly" anomaly and prenatal exposure to Parvovirus B19. Conclusions: We suggest that the "prune belly" anomaly and others abdominal wall defects as omphalocele and scar-type defects may be included as a feature in PS type 2 and 3.

Prenatal inflammation remodels lung immunity and function by programming ILC2 hyperactivation.

Here, we examine how prenatal inflammation shapes tissue function and immunity in the lung by reprogramming tissue-resident immune cells from early development. Maternal, but not fetal, type I interferon-mediated inflammation provokes expansion and hyperactivation of group 2 innate lymphoid cells (ILC2s) seeding the developing lung. Hyperactivated ILC2s produce increased IL-5 and IL-13 and are associated with acute Th2 bias, decreased Tregs, and persistent lung eosinophilia into adulthood. ILC2 hyperactivation is recapitulated by adoptive transfer of fetal liver precursors following prenatal inflammation, indicative of developmental programming at the fetal progenitor level. Reprogrammed ILC2 hyperactivation and subsequent lung immune remodeling, including persistent eosinophilia, is concomitant with worsened histopathology and increased airway dysfunction equivalent to papain exposure, indicating increased asthma susceptibility in offspring. Our data elucidate a mechanism by which early-life inflammation results in increased asthma susceptibility in the presence of hyperactivated ILC2s that drive persistent changes to lung immunity during perinatal development.

Membrane Proteome-Wide Screening of Autoantibodies in CIDP Using Human Cell Microarray Technology.

BACKGROUND AND OBJECTIVES: Autoantibody discovery in complex autoimmune diseases is challenging. Diverse successful antigen identification strategies are available, but, so far, have often been unsuccessful, especially in the discovery of protein antigens in which conformational and post-translational modification are critical. Our study assesses the utility of a human membrane and secreted protein microarray technology to detect autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A cell microarray consisting of human embryonic kidney-293 cells expressing >5,000 human proteins was used. First, a validation step was performed with 4 serum samples from patients with autoimmune nodopathy (AN) to assess the ability of this technology to detect circulating known autoantibodies. The ability of the cell microarray technology to discover novel IgG autoantibodies was assessed incubating the array with 8 CIDP serum samples. Identified autoantibodies were subsequently validated using cell-based assays (CBAs), ELISA, and/or tissue immunohistochemistry and analyzed in a cohort of CIDP and AN (n = 96) and control (n = 100) samples. RESULTS: Serum anti-contactin-1 and anti-neurofascin-155 were detected by the human cell microarray technology. Nine potentially relevant antigens were found in patients with CIDP without other detectable antibodies; confirmation was possible in six of them: ephrin type-A receptor 7 (EPHA7); potassium-transporting ATPase alpha chain 1 and subunit beta (ATP4A/4B); leukemia-inhibitory factor (LIF); and interferon lambda 1, 2, and 3 (IFNL1, IFNL2, IFNL3). Anti-ATP4A/4B and anti-EPHA7 antibodies were detected in patients and controls and considered unrelated to CIDP. Both anti-LIF and anti-IFNL antibodies were found in the same 2 patients and were not detected in any control. Both patients showed the same staining pattern against myelinating fibers of peripheral nerve tissue and of myelinating neuron-Schwann cell cocultures. Clinically relevant correlations could not be established for anti-LIF and anti-IFNL3 antibodies. DISCUSSION: Our work demonstrates the utility of human cell microarray technology to detect known and discover unknown autoantibodies in human serum samples. Despite potential CIDP-associated autoantibodies (anti-LIF and anti-IFNL3) being identified, their clinical and pathogenic relevance needs to be elucidated in bigger cohorts.

Prenatal inflammation reprograms hyperactive ILC2s that promote allergic lung inflammation and airway dysfunction.

Allergic asthma is a chronic respiratory disease that initiates in early life, but causal mechanisms are poorly understood. Here we examined how prenatal inflammation shapes allergic asthma susceptibility by reprogramming lung immunity from early development. Induction of Type I interferon-mediated inflammation during development provoked expansion and hyperactivation of group 2 innate lymphoid cells (ILC2s) seeding the developing lung. Hyperactivated ILC2s produced increased IL-5 and IL-13, and were associated with acute Th2 bias, eosinophilia, and decreased Tregs in the lung. The hyperactive ILC2 phenotype was recapitulated by adoptive transfer of a fetal liver precursor following exposure to prenatal inflammation, indicative of developmental programming. Programming of ILC2 function and subsequent lung immune remodeling by prenatal inflammation led to airway dysfunction at baseline and in response to papain, indicating increased asthma susceptibility. Our data provide a link by which developmental programming of progenitors by early-life inflammation drives lung immune remodeling and asthma susceptibility through hyperactivation of lung-resident ILC2s. One Sentence Summary: Prenatal inflammation programs asthma susceptibility by inducing the production of hyperactivated ILC2s in the developing lung.

Antibodies against the flotillin-1/2 complex in patients with multiple sclerosis.

Multiple sclerosis is a tissue-specific autoimmune disease of the central nervous system in which the antigen(s) remains elusive. Antibodies targeting the flotillin-1/2 complex have been described in 1-2% of the patients in a recent study. Other candidate antigens as anoctamin-2 or neurofascin-155 have been previously described in multiple sclerosis patients, although their clinical relevance remains uncertain. Our study aims to analyse the frequency and clinical relevance of antibodies against neurofascin-155, anoctamin-2 and flotillin-1/2 complex in multiple sclerosis. Serum (n = 252) and CSF (n = 50) samples from 282 multiple sclerosis patients were included in the study. The control group was composed of 260 serum samples (71 healthy donors and 189 with other neuroinflammatory disorders). Anti-flotillin-1/2, anti-anoctamin-2 and anti-neurofascin-155 antibodies were tested by cell-based assays using transfected cells. We identified six multiple sclerosis patients with antibodies against the flotillin-1/2 complex (2.1%) and one multiple sclerosis patient with antibodies against anoctamin-2 (0.35%). All multiple sclerosis patients were negative for anti-neurofascin-155 antibodies. Three of the anti-flotillin-1/2 positive patients showed anti-flotillin-1/2 positivity in other serum samples extracted at different moments of their disease. Immunoglobulin G subclasses of anti-flotillin-1/2 antibodies were predominantly one and three. We confirm that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis. Further studies are needed to understand the clinical and pathological relevance of anti-flotillin-1/2 autoantibodies in multiple sclerosis.

mRNA COVID-19 Vaccination Does Not Exacerbate Symptoms or Trigger Neural Antibody Responses in Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: In people with multiple sclerosis (pwMS), concern for potential disease exacerbation or triggering of other autoimmune disorders contributes to vaccine hesitancy. We assessed the humoral and T-cell responses to SARS-CoV-2 after mRNA vaccination, changes in disease activity, and development of antibodies against central or peripheral nervous system antigens. METHODS: This was a prospective 1-year longitudinal observational study of pwMS and a control group of patients with other inflammatory neurologic disorders (OIND) who received an mRNA vaccine. Blood samples were obtained before the first dose (T1), 1 month after the first dose (T2), 1 month after the second dose (T3), and 6 (T4), 9 (T5), and 12 (T6) months after the first dose. Patients were assessed for the immune-specific response, annualized relapse rate (ARR), and antibodies to onconeuronal, neural surface, glial, ganglioside, and nodo-paranodal antigens. RESULTS: Among 454 patients studied, 390 had MS (22 adolescents) and 64 OIND; the mean (SD) age was 44 (14) years; 315 (69%) were female; and 392 (87%) were on disease-modifying therapies. Antibodies to the receptor-binding domain were detected in 367 (86%) patients at T3 and 276 (83%) at T4. After a third dose, only 13 (22%) of 60 seronegative patients seroconverted, and 255 (92%) remained seropositive at T6. Cellular responses were present in 381 (93%) patients at T3 and in 235 (91%) patients at T6 including all those receiving anti-CD20 therapies and in 79% of patients receiving fingolimod. At T3 (429 patients) or T6 (395 patients), none of the patients had developed CNS autoantibodies. Seven patients had neural antibodies that were already present before immunization (3 adult patients with MS had MOG-IgG, 2 with MG and 1 with MS had neuronal cell surface antibodies [unknown antigen], and 1 with MS had myelin antibody reactivity [unknown antigen]. Similarly, no antibodies against PNS antigens were identified at T3 (427 patients). ARR was lower in MS and not significantly different in patients with OIND. Although 182 (40%) patients developed SARS-CoV-2 infection, no cases of severe COVID-19 or serious adverse events occurred. DISCUSSION: In this study, mRNA COVID-19 vaccination was safe and did not exacerbate the autoimmune disease nor triggered neural autoantibodies or immune-mediated neurologic disorders. The outcome of patients who developed SARS-CoV-2 infection was favorable.