Genetics of Neonatal Autoimmune and Autoinflammatory Diseases

Abstract

Genetic predisposition has been widely studied in autoimmune and autoinflammatory diseases and has been found to play a significant role in pathogenesis, although the environment, including dietary habits, chemicals and hygienic conditions have been postulated to influence expression of these diseases as well. The autoimmune diseases most prevalent in the newborn include neonatal lupus and neonatal antiphospholipid antibody syndrome. The diseases are characterised by maternal antibodies to SS‐A (Ro) and SS‐B (La). The genetics underlying these diseases have been found to involve both HLA and non‐HLA associations. The neonatal autoinflammatory diseases include the cryopyrin‐associated periodic syndromes (CAPS), of which familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal onset multisystem inflammatory diseases (NOMID) are the three distinct phenotypes resulting from mutations in the CIAS 1 gene (NLRP3 gene). The gene mutation in CAPS are gain‐of‐function mutation of the NLRP3 gene coding for cryopyrin, resulting in dysfunctional inflammasomes. A defect in the inflammasome leads to overproduction of interleukin‐1, resulting in inflammatory symptoms seen in CAPS. Understanding the genetics responsible for neonatal lupus, neonatal antiphospholipid antibody syndrome and CAPS may drive future research into an elucidation of complex pathophysiologic mechanisms of these diseases and perhaps ultimately lead to better treatment modalities.

Key Concepts:

  • Diseases that involve immune dysfunction in the neonate include neonatal autoimmune and autoinflammatory conditions, along with the more well‐defined immunodeficiency syndromes.

  • The genetics of neonatal autoimmunity and neonatal autoinflammatory syndromes are very different.

  • In addition to a genetic component, the pathogenesis of these two groups of diseases may also involve an epigenetic and environmental component.

  • The presence of a common genetic defect may result in different clinical phenotypes, as illustrated by the three CAPS syndromes.

  • Treatment of these diseases is dependent on an increased knowledge of the pathogenesis of these diseases.

  • Genetic counselling is an important component of the management of these diseases.

Keywords: autoimmune disease; autoinflammatory disease; neonatal lupus; neonatal antiphospholipid syndrome; Cryopyrin‐associated periodic syndromes (CAPS); familial cold autoinflammatory syndrome (FCAS); Muckle–Wells syndrome (MWS); neonatal onset multisystem inflammatory disease (NOMID); NLRP3; CIAS 1

Figure 1.

Spectrum of cryopyrin‐associated periodic syndromes.

Figure 2.

Structure of the NLRP3 gene.

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Further Reading

Chang C (2013) The pathogenesis of neonatal autoimmune and autoinflammatory diseases: a comprehensive review. Journal of Autoimmunity 41: 100–110.

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Bachove, Inessa, and Chang, Christopher(Sep 2014) Genetics of Neonatal Autoimmune and Autoinflammatory Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025735]