RESUMO
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.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Evolução Clonal/imunologia , Suscetibilidade a Doenças , Imunoglobulina M/imunologia , Síndrome de Schnitzler/etiologia , Adulto , Alelos , Biomarcadores , Proteínas de Transporte/metabolismo , Evolução Clonal/genética , Suscetibilidade a Doenças/imunologia , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunoglobulina M/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Ligação Proteica/imunologia , Proteoma , Proteômica/métodos , Síndrome de Schnitzler/diagnóstico , Síndrome de Schnitzler/metabolismo , Recombinação V(D)JAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome de Schnitzler/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Biomarcadores , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Schnitzler/diagnóstico , Síndrome de Schnitzler/etiologia , Resultado do TratamentoAssuntos
Doenças Raras , Síndrome de Schnitzler , Antirreumáticos/uso terapêutico , Diagnóstico Diferencial , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Doenças Raras/etiologia , Síndrome de Schnitzler/diagnóstico , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/etiologiaRESUMO
Disease entities characterized by the presence of paraproteins have a variety of cutaneous manifestations. These manifestations may be classified in the following categories as a function of their mechanisms: * extracutaneous deposition of paraproteins, as in amyloidosis * intravascular paraprotein deposition, as in cryoglobulinemia * cutaneous lesions resulting from the biologic activity of paraprotein, as in patients with normolipemic xanthoma with monoclonal immunoglobulin anti-LDL activity * abnormal cytokine secretion, as in AESOP (adenopathy and extensive skin patch overlying a plasmacytoma) or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndromes * unknown mechanisms.