Genetic and Molecular Investigation of the Schnitzler Syndrome

The Schnitzler Syndrome (SchS) is a rare, autoinflammatory condition with an unknown pathological mechanism, but treatment with IL-1 inhibition provides remarkable efficacy. Exhibiting two main defining features: (1) an urticarial rash and (2) an IgM gammopathy, this IL-1 mediated disease phenotypically bears stark resemblance to NLRP3-associated inflammatory disease. The latter monogenic entity is known to show gain-of-function and pathological mutations in the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. Furthermore, 20% of SchS patients go on to develop overt lymphoproliferative diseases, namely Waldenström's Macroglobulinaemia (WM). This condition presents with a specific mutation in the Myeloid Differentiation Primary Response (MYD88) gene in over 90% of patients. Against the backdrop of these imperative findings, the work presented in this thesis therefore examines the role of these immunological constituents in SchS, via the assessment of mutations in NLRP3 and MYD88 alongside a panel of genes frequently mutated in haematological malignancies. Identification of a causative gene would not only improve molecular diagnosis, but allows for potential unearthing of genotype-phenotype correlations. Since the identification of this condition in 1972, the features and consequences of the IgM gammopathy has remained elusive. In a bid to delineate the latter, examination of the heavy chain of the immunoglobulin repertoire would therefore indicate aspects of the adaptive immune response integral to formation of the monoclonal component. A biased repertoire would therefore indicate the existence of a clonal B-cell population. Additionally, isolation of SchS-IgM and interrogation of a protein array comprising of over 15,700 human proteins further indicates whether this element causes pathological effects. Exploration of the genetic and molecular components did not expose a common mechanism through which SchS manifests, ruling out the notion that NLRP3, MYD88 and other associated genes are universally causative of this enigmatic disease. Assessment of the IgH repertoire indicated that SchS patients show evidence of expanded B-cell populations, and together with protein array analysis demonstrating the preference of IgM binding to nuclear antigens, this study supports the theory that SchS is a clonal disorder. The breadth and depth of these findings broadens the currently limited scientific knowledge pertaining to SchS, forming the basis upon which further investigations can commence.