Evidence of B Cell Clonality and Investigation Into Properties of the IgM in Patients With Schnitzler Syndrome

Abstract

The Schnitzler Syndrome (SchS) is an acquired, autoinflammatory condition successfully treated with IL-1 inhibition. The two main defining features of this late-onset condition are neutrophilic urticarial dermatoses (NUD) and the presence of an IgM monoclonal component. While the former aspect has been extensively studied in this disease setting, the enigmatic paraproteinaemia and its potential consequential effects within SchS, has not previously been thoroughly addressed. Previous studies analyzing clonal B cell repertoires have largely focused on autoimmune disorders such as Systemic Lupus Erythematous (SLE) and hematological malignancies such as Chronic Lymphocytic Leukaemia (CLL), where B-cell clonality is central to disease pathology. The present study uses next-generation sequencing to provide detailed insight into aspects of B cell VDJ recombination and properties of the resulting immunoglobulin chains. An overview of IgH regional dynamics in 10 SchS patients, with a particular focus on CDR3 sequences and VDJ gene usage is reported, highlighting the presence of specific B cell expansions. Protein microarray detected a substantial proportion of autoreactive IgM to nuclear target proteins, though a single universal target was not identified. Together, these genetic and functional findings impart new understanding into this rare disorder.

Schnitzler syndrome and Schnitzler-like syndromes

“…It could be postulated that IgM binds to DPP10 leading to aberrant activation of NLRP3. [ 48 ] These findings are interesting yet to be replicated in independent cohorts of patients.…”

“…However, little to none is known regarding the role of these paraproteins in pathogenesis. Pathak et al [ 48 ] investigated the B cell clonality in ten patients with Schnitzler syndrome. By analyzing the variable, diversity, and junctional segment composition of the immunoglobulin heavy chain and sequencing the complementarity determining region 3, the authors found evidence of clonality of individual patients but failed to demonstrate shared B cell clonality between these patients.…”

Genetics of somatic auto-inflammatory disorders

“…However, testing of 30 SchS patient for the p.L265P variant using ASO-PCR technique, which has a detection sensitivity down to 1% of the mutant allele, found that only 9/30 patients carried the p.L265P mutation (43). This finding suggests that somatic MYD88 mutations might have a role in the pathogenesis of SchS but this is unlikely to be a universal mechanism.…”

“…This study found that only 1 out of 6 patients carried pathogenic variants associated with CHIP. The affected patient was found to have 3 mutations: one in DNMT3-A (c.2645G>A p.Arg882His) and two mutations in TET-2 (c.4585C>T p.Gln1529; p.Gln1699*), all with a significant VAF (0.407, 0.388 and 0.402 respectively) (43). These mutations were also associated with allelic skewing, which was determined by testing for X chromosome inactivation.…”

“…It is therefore not surprising that low grade somatic mutations in NLRP3 were purported to play a role in the pathogenesis of SchS. However, across two studies with a total of 32 patients, no evidence of either somatic or germline pathogenic NLRP3 variants was found (43,46). Furthermore, 21 patients who were tested for 32 additional genes typically associated with SAID, were found not to carry any significant mutations (46).…”