Revaccination of patients with systemic lupus erythematosus or rheumatoid arthritis without an initial COVID-19 vaccine response elicits seroconversion in half of the patients.

OBJECTIVES: To investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with rheumatic diseases (RD) who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion. METHODS: From a RD cohort vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralising antibodies, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. RESULTS: Forty-seven percent of cases had detectable neutralising antibodies after revaccination. However, antibody levels were significantly lower than in controls and blood donors. Revaccination induced an antibody class switch in cases with a decrease in IgM and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups. Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination. CONCLUSIONS: Forty-seven percent of initial non-responders seroconverted after two-dose revaccination but still had lower levels of SARS-CoV-2 antibodies compared with controls and blood donors. RD patients without a detectable serological response after the initial COVID-19 mRNA vaccine had a T-cell response similar to immunocompetent controls and blood donors.

[VEXAS gene variants explain previously unrecognized clinical syndrome].

This review aims to make clinicians aware of the newly described syndrome, VEXAS. VEXAS should become an obvious differential diagnosis in cases of unexplained inflammation, anemia, and rheumatological and/or hematological manifestations. Patients with VEXAS are typically male aged > 60, with inflammation, and macrocytic anaemia. On suspicion of cancer or infections patients have frequently been exposed to extensive diagnostic procedures and hospital admissions. In this review, we summarise the current knowledge of VEXAS regarding pathogenesis, symptoms, diagnosis, and treatment.

Low levels of the innate immune system proteins MASP-2 and MAp44 in patients with common variable immunodeficiency.

Patients with common variable immunodeficiency (CVID) display low antibody levels and associated symptoms, including an increased risk of infections. The causes of CVID are uncertain and likely heterogeneous. The complement system protects against pathogens and plays essential roles in homeostasis and development. The influence of the complement system in CVID is not established. We investigated CVID patients and healthy individuals for plasma levels of the complement proteins: MASP-1, MASP-2, MASP-3, MAp19 and MAp44. We also tested other patients with symptoms similar to the CVID patients. CVID patients had lower average MASP-2 and MAp44 levels than healthy individuals (P < 0.01); the MASP-2 level was 0.73-fold lower, and the MAp44 level was 0.87-fold lower. This was not observed in the other patient cohorts studied. Our findings in this exploratory study provide new insights into CVID and introduce a complement perspective for future investigations into the underlying mechanisms of the disease.

Patients with VEXAS diagnosed in a Danish tertiary rheumatology setting have highly elevated inflammatory markers, macrocytic anaemia and negative autoimmune biomarkers.

BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) is an autoinflammatory condition with overlapping features of rheumatology and haematology caused by somatic mutations in the UBA1 gene. Patients present with highly variable symptoms and their path towards diagnosis are often complicated and characterised by extensive examinations. It is, therefore, pivotal that clinicians become familiar with the clinical presentation of VEXAS to advance identification of patients with the disease. OBJECTIVES: We aimed to (1) characterise patients diagnosed with VEXAS in a tertiary rheumatology referral centre, (2) identify common rheumatological biomarkers that may distinguish VEXAS from other rheumatic diseases and (3) suggest which clinical findings should motivate genetic testing for VEXAS. METHODS: Patients were identified and diagnosed at the department of Rheumatology, Aarhus University Hospital (AUH), Denmark. Blood samples were examined for VEXAS-associated UBA1 variants by Sanger sequencing at the department of Clinical Immunology, AUH. Clinical and biochemical data were retrieved from the hospital electronic patient chart. RESULTS: Eleven male patients with clinical suspicion of VEXAS underwent sequencing. Five of these carried known VEXAS-associated variants. Median age at diagnosis was 84 (75-87) years. All patients had significantly elevated inflammatory markers with a median C-reactive protein (CRP) of 297 (196-386) mg/L and macrocytic anaemia. None of the patients presented common biomarkers for autoimmunity. CONCLUSION: Danish patients with VEXAS syndrome are men with persistent inflammation, constitutional symptoms and heterogeneous clinical presentations. Shared features for all patients in this study were highly elevated inflammatory markers, macrocytic anaemia and negative autoimmune biomarkers.

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome Manifesting as Lymphocytic Interstitial Pneumonia and Treatment-Resistant Bullous Pemphigoid.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare immune deficiency with a broad clinical presentation. IPEX syndrome causes dysfunctional regulatory T cells, increasing the risk of autoimmune diseases. In this case report, we describe a 7-year-old boy with lymphocytic interstitial pneumonia and bullous pemphigoid who was recently diagnosed with IPEX syndrome.

Pattern Recognition Molecules of the Lectin Pathway-Screening of Patients with Suspected Immunodeficiency.

PURPOSE: To compare plasma concentrations of all lectin pathway (LP) pattern recognition molecules (PRMs) in patients referred for laboratory evaluation due to recurrent infections with healthy individuals. METHODS: Patients were divided into categories according to referral: recurrent airway infections (RAI), recurrent abscesses, common variable immunodeficiency (CVID), lung transplantation candidates (LTX), and 'other causes'. LP PRMs (mannose-binding lectin (MBL), collectin liver 1 (CL-L1), H-ficolin, L-ficolin, M-ficolin) and C-reactive protein (CRP) were determined in 332 patients and 150 healthy blood donors using time-resolved immunofluorometric assays. RESULTS: None of the LP PRMs was found in lower concentration in the patient categories; however, several PRMs were detected in higher concentrations. M-ficolin was found in higher concentrations in all patient categories. Patients suffering from RAI had higher concentrations of CL-L1 and H-ficolin. Patients suffering from abscesses exhibited higher concentrations of MBL and CL-L1, whereas LTX had higher concentrations of MBL. Patients with other causes of referral had higher concentrations of MBL and CL-L1. Prevalence of combined deficiencies of PRMs in patient categories and controls did not differ. CRP was used as a marker of ongoing inflammation and was significantly higher among all patient categories. Furthermore, CRP was found to correlate with both M-ficolin and L-ficolin. CONCLUSION: The results suggest that neither single nor combined deficiencies of LP PRMs are more frequent among patients referred for an immunological evaluation than in healthy individuals. Future studies are needed and should focus on deficiencies of LP PRMs combined with deficiencies in other parts of the immune system.

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy.

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections and defined by reduced levels of IgG, IgA, and/or IgM, insufficient response to polysaccharide vaccination, and an abnormal B-cell immunophenotype with a significantly reduced fraction of isotype-switched memory B cells. In addition to this infectious phenotype, at least one third of the patients experience autoimmune, autoinflammatory, granulomatous, and/or malignant complications. The very heterogeneous presentation strongly suggests a collection of different disease entities with somewhat different pathogeneses and most likely diverse genetic etiologies. Major progress has been made during recent years with the advent and introduction of next-generation sequencing, initially for research purposes, but more recently in clinical practice. In the present study, we performed whole exome sequencing on 20 CVID patients with autoimmunity, autoinflammation, and/or malignancy from the Danish CVID cohort with the aim to identify gene variants with a certain, possible, or potential disease-causing role in CVID. Through bioinformatics analyses, we identified variants with possible/probable disease-causing potential in nine of the patients. Of these, three patients had four variants in three different genes classified as likely pathogenic (NFKB1, TNFAIP3, and TTC37), whereas in six patients, we identified seven variants of possible pathogenic potential classified as variants of unknown significance (STAT3, IL17F, IRAK4, DDX41, NLRC3, TNFRSF1A, and PLCG2). In the remaining 11 patients, we did not identify possible genetic causes. Genetic findings were correlated to clinical disease presentation, clinical immunological phenotype, and disease complications. We suggest that the variants identified in the present work should lay the ground for future studies to functionally validate their disease-causing potential and to investigate at the mechanistic and molecular level their precise role in CVID pathogenesis. Overall, we believe that the present work contributes important new insights into the genetic basis of CVID and particular in the subset of CVID patients with a complex phenotype involving not only infection, but also autoimmunity, autoinflammation, and malignancy.

Endotoxemia is associated with altered innate and adaptive immune responses in untreated HIV-1 infected individuals.

BACKGROUND: Microbial translocation may contribute to the immunopathogenesis in HIV infection. We investigated if microbial translocation and inflammation were associated with innate and adaptive immune responses in adults with HIV. METHODOLOGY/PRINCIPAL FINDINGS: This was an observational cohort study. Sera from HIV-infected and HIV-uninfected individuals were analyzed for microbial translocation (soluble CD14, lipopolysaccharides [LPS], endotoxin core antibody, and anti-α-galactosyl antibodies) and inflammatory markers (high sensitivity C-reactive protein, IL-6, IL-1 receptor antagonist, soluble tumor necrosis factor receptor II, and IL-10) with enzyme-linked immunosorbent assays. Peripheral blood mononuclear cells (PBMC) from HIV-infected persons and healthy controls (primed with single-stranded HIV-1-derived RNA) were stimulated with LPS, and cytokine production was measured. Finally, HIV-infected patients were immunized with Prevnar 7vPnC±CpG 7909 followed by Pneumo Novum PPV-23. Effects of microbial translocation and inflammation on immunization were analyzed in a predictive regression model. We included 96 HIV-infected individuals, 76 on highly active antiretroviral therapy (HAART), 20 HAART-naive, and 50 healthy controls. Microbial translocation and inflammatory markers were higher among HIV-infected persons than controls. Cytokine levels following LPS stimulation were increased in PBMCs from HAART-naive compared to HAART-treated HIV-infected persons. Further, RNA-priming of PBMCs from controls acted synergistically with LPS to augment cytokine responses. Finally, high serum LPS levels predicted poor vaccine responses among HAART-naive, but not among HAART-treated HIV-infected individuals. CONCLUSIONS/SIGNIFICANCE: LPS acts synergistically with HIV RNA to stimulate innate immune responses in vitro and increasing serum LPS levels seem to predict poor antibody responses after vaccination among HAART-naive HIV-infected persons. Thus, our results suggest that microbial translocation may be associated with innate and adaptive immune dysfunction in untreated HIV infection.