Torquetenovirus viral load is associated with anti-spike antibody response in SARS-CoV-2 mRNA BNT162b2 vaccinated kidney transplant patients.

INTRODUCTION: Kidney transplant patients (KT) are at high risk for severe COVID-19 and presented attenuated antibody responses to vaccination when compared to immunocompetent individuals. Torquetenovirus (TTV) has recently gained attention as a potential surrogate marker of the net state of immunosuppression. We evaluated the association between pre-vaccination TTV viral load and anti-spike total antibody response to SARS-CoV-2 vaccination in KT. MATERIAL AND METHODS: The 114 adult KT recipients enrolled in this prospective single-center cohort study received two doses of SARS-CoV-2 mRNA BNT162b2 vaccine. Serum samples were collected immediately before vaccination at the days when patients received both the first (T0) and the second dose (T1) and 16-45 days after the second dose (T2). Primary endpoint was the development of anti-spike total antibodies after vaccination. Demographic, clinical, and laboratorial parameters were compared between patients with and without detectable SARS-CoV-2 antibodies at T2. RESULTS: Ninety-nine patients (86.8%) were naïve for SARS-CoV-2 before vaccination. Fifty-six (56.6%) patients developed anti-spike total antibodies at T2. The use of mTOR inhibitors was associated with a favorable response (p = .005); conversely, mycophenolic acid (MPA) was associated with a negative response (p = .006). In a multivariable model, the presence of TTV at T0 ≥ 3.36 log10 cp/ml was associated with unfavorable vaccine response (OR: 5.40; 95% CI: 1.47-19.80; p = .011), after adjusting for age and eGFR at T0. CONCLUSIONS: Higher TTV viral loads before vaccination are associated with reduced anti-spike total antibody response in SARS-CoV-2 mRNA BNT162b2 vaccinated KT patients. The association between TTV viral load and vaccine response may be an added-value in the optimization of vaccination regimens in KT.

Prognostic value of kappa free light chains determination in first-ever multiple sclerosis relapse.

Given its highly variable clinical course, an unmet need for objective prognostic assessment in Multiple Sclerosis (MS) persists. In this work, we suggest that CSF kappa free light chains (KFLC) determination at first relapse may provide insight into future disease activity and disability worsening. We quantified KFLC by nephelometry in paired CSF/serum samples of 28 patients, collected within one month of first-ever MS relapse, and explored correlations with clinical data on disease activity, retrospectively registered across a median follow-up time of 79 months. We documented KFLC ratio (CSF-FKLC/Serum-KFLC) as an independent predictor of second relapse occurrence and disability worsening at follow-up, in this cohort.

Concomitant myeloproliferative and lymphoproliferative neoplasms, distinct progenitors: A case report and review of the literature.

Patients with a Philadelphia chromosome-negative myeloproliferative neoplasm may develop a lymphoproliferative disorder; however, the clinical and molecular determinants and the chronological onset of the two events remain unknown. We herein report the case of a 64-year-old man with concomitant diagnosis of high-risk essential thrombocythemia with evidence of a thrombotic event and high-count monoclonal B-cell lymphocytosis (high-count MBL). The patient harbored a JAK2V617F mutation and one of the most common genetic alterations found in chronic lymphocytic leukemia (CLL) (del 13q), which may represent a sign of disease progression. He was initiated on cytoreductive therapy with hydroxyurea 500 mg 3 times per week and hypocoagulation treatment, and is currently under regular surveillance of MBL without CLL criteria.

Concomitant presence of JAK2V617F mutation and BCR­ABL translocation in two patients: A new entity or a variant of myeloproliferative neoplasms (Case report).

Myeloproliferative neoplasms (MPNs) are classically divided into BCR RhoGEF and GTPase activating protein (BCR)-ABL proto­oncogene 1 non­receptor tyrosine kinase (ABL) positive chronic myeloid leukemia (CML) and BCR­ABL negative MPNs, including essential thrombocythemia (ET). One of the major diagnostic criteria for ET is the absence of the philadelphia chromosome, thus when present it is almost indicative of CML. ET and CML are considered to be mutually exclusive; however, there are rare situations in which patients with ET present positive BCR­ABL without the features of CML. Although from the literature review, the frequency of JAK2V617F mutation and BCR­ABL translocation coexistence in MPNs is low, it may be higher than expected. The current study reported cases of two patients with an initial diagnosis of ET in the presence of JAK2V617F mutation and BCR­ABL translocation by fluorescent in situ hybridization. Both patients presented with a heterozygous BCR­ABL translocation, and absence of p190 and p210 transcripts, seemingly a der(9) in the background of an ET JAK2V617F mutation.

Atypical haematological presentation in a case of polycythaemia vera with a new variant mutation detected in exon 12: c.1605G>T (p.Met535Ile).

One of the major genetic insights into the pathogenesis of polycythaemia vera included the identification of the somatic point gain-of-function mutations in Janus kinase 2 gene-first JAK2V617F on exon 14, present in 95%-97% of the cases, and later on exon 12. In the literature, we can find some reported studies where different exon 12 mutations are identified. Unlike patients with JAK2V617F mutation in exon 14, the mutation at exon 12 is not usually associated with an increase in the three haematopoietic series (erythrocytosis, leucocytosis and thrombocytosis). It appears to be associated with a distinct syndrome, mostly characterised by isolated and more marked erythrocytosis, independently of the mutational variant. We report here the case of a patient who is JAK2exon 12 positive, presenting a novel mutation-c.1605G>T (p.Met535Ile)-associated with c.1612C>T (p.His538Tyr) mutation previously described, evidencing an atypical clinical phenotype.

Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus.

Several lines of evidence implicate the Cytotoxic T Lymphocyte Antigen 4 (CTLA4) gene in susceptibility to autoimmune disease. We have examined the association of systemic lupus erythematosus (SLE) with polymorhisms within the CTLA4 gene that were previously proposed to regulate CTLA-4 function: a single nucleotide polymorphism (SNP) in position +49 of exon 1 and a dinucleotide repeat in the 3' untranslated region (3'UTR). The 3'UTR repeat showed a significant association with SLE, with one allele conferring susceptibility and another conferring protection to the disease. The associated alleles do not support previous suggestions of an allele size-dependent effect of the 3' UTR polymorphism in autoimmunity development and instead suggest that it is in linkage disequilibrium with a true causative locus. No association of the exon 1 SNP with SLE was found in our population. Given the conflicting results obtained in different studies on the association of SLE with this polymorphism, we performed a meta-analysis including seven previously published studies and the present one. Significantly increased and decreased risks for SLE were found for carriers of the G allele and the A allele, respectively. The functional characterization of disease-associated CTLA4 gene variants is now required to elucidate their role in the pathogenesis of SLE and other autoimmune diseases.

Heritable factors shape natural human IgM reactivity to Ro60/SS-A and may predispose for SLE-associated IgG anti-Ro and anti-La autoantibody production.

Systemic lupus erythematosus (SLE) is characterized by various IgG autoreactivities, among which anti-Ro/SS-A is particularly pathology-associated and early detectable. SLE also shows significant familial aggregation, but genetic factors are not well understood and remain controversial for disease-associated IgG. Here we report that IgM anti-Ro showed a uniquely high degree of heritability in a study of SLE-affected families. Unlike IgM anti-La or anti-dsDNA, IgM anti-Ro was also significantly correlated to IgG anti-Ro among SLE patients, as well as to IgG anti-La and anti-dsDNA. We conclude that largely genetically determined, thus natural IgM anti-Ro-bearing precursor B-cells, may be an important factor for class switching and determinant spreading in early phases of SLE pathogenesis. Furthermore, we found unexpected sex differences in isotype/specificity correlations among SLE-unaffected relatives and control subjects, which could help understand the strong gender bias associated with SLE. We propose that the study of such correlation structures may reveal characteristic spreading pathways relevant for human SLE.